Disparities in Genetic Testing for Neurologic Disorders.

BACKGROUND AND OBJECTIVES: Genetic testing is now the standard of care for many neurologic conditions. Health care disparities are unfortunately widespread in the US health care system, but disparities in the utilization of genetic testing for neurologic conditions have not been studied. We tested the hypothesis that access to and results of genetic testing vary according to race, ethnicity, sex, socioeconomic status, and insurance status for adults with neurologic conditions. METHODS: We analyzed retrospective data from patients who underwent genetic evaluation and testing through our institution's neurogenetics program. We tested for differences between demographic groups in 3 steps of a genetic evaluation pathway: (1) attending a neurogenetic evaluation, (2) completing genetic testing, and (3) receiving a diagnostic result. We compared patients on this genetic evaluation pathway with the population of all neurology outpatients at our institution, using univariate and multivariable logistic regression analyses. RESULTS: Between 2015 and 2022, a total of 128,440 patients were seen in our outpatient neurology clinics and 2,540 patients underwent genetic evaluation. Black patients were less than half as likely as White patients to be evaluated (odds ratio [OR] 0.49, p < 0.001), and this disparity was similar after controlling for other demographic factors in multivariable analysis. Patients from the least wealthy quartile of zip codes were also less likely to be evaluated (OR 0.67, p < 0.001). Among patients who underwent evaluation, there were no disparities in the likelihood of completing genetic testing, nor in the likelihood of a diagnostic result after adjusting for age. Analyses restricted to specific indications for genetic testing supported these findings. DISCUSSION: We observed unequal utilization of our clinical neurogenetics program for patients from marginalized and minoritized demographic groups, especially Black patients. Among patients who do undergo evaluation, all groups benefit similarly from genetic testing when it is indicated. Understanding and removing barriers to accessing genetic testing will be essential to health care equity and optimal care for all patients with neurologic disorders.

The Importance of Offering Exome or Genome Sequencing in Adult Neuromuscular Clinics.

Advances in gene-specific therapeutics for patients with neuromuscular disorders (NMDs) have brought increased attention to the importance of genetic diagnosis. Genetic testing practices vary among adult neuromuscular clinics, with multi-gene panel testing currently being the most common approach; follow-up testing using broad-based methods, such as exome or genome sequencing, is less consistently offered. Here, we use five case examples to illustrate the unique ability of broad-based testing to improve diagnostic yield, resulting in identification of SORD-neuropathy, HADHB-related disease, ATXN2-ALS, MECP2 related progressive gait decline and spasticity, and DNMT1-related cerebellar ataxia, deafness, narcolepsy, and hereditary sensory neuropathy type 1E. We describe in each case the technological advantages that enabled identification of the causal gene, and the resultant clinical and personal implications for the patient, demonstrating the importance of offering exome or genome sequencing to adults with NMDs.

Assembly, stability, and dynamics of the infant gut microbiome are linked to bacterial strains and functions in mother's milk.

The establishment of the gut microbiome in early life is critical for healthy infant development. Although human milk is recommended as the sole source of nutrition for the human infant, little is known about how variation in milk composition, and especially the milk microbiome, shapes the microbial communities in the infant gut. Here, we quantified the similarity between the maternal milk and the infant gut microbiome using 507 metagenomic samples collected from 195 mother-infant pairs at one, three, and six months postpartum. We found that the microbial taxonomic overlap between milk and the infant gut was driven by bifidobacteria, in particular by B. longum. Infant stool samples dominated by B. longum also showed higher temporal stability compared to samples dominated by other species. We identified two instances of strain sharing between maternal milk and the infant gut, one involving a commensal (B. longum) and one a pathobiont (K. pneumoniae). In addition, strain sharing between unrelated infants was higher among infants born at the same hospital compared to infants born in different hospitals, suggesting a potential role of the hospital environment in shaping the infant gut microbiome composition. The infant gut microbiome at one month compared to six months of age was enriched in metabolic pathways associated with de-novo molecule biosynthesis, suggesting that early colonisers might be more versatile and metabolically independent compared to later colonizers. Lastly, we found a significant overlap in antimicrobial resistance genes carriage between the mother's milk and their infant's gut microbiome. Taken together, our results suggest that the human milk microbiome has an important role in the assembly, composition, and stability of the infant gut microbiome.

Remimazolam: A Retrospective Study of Initial Safety and Recovery Data in Diverse Procedural Sedation.

PURPOSE: The new ultra-short-acting benzodiazepine, remimazolam, offers a pharmacokinetic and pharmacodynamic advantage over commonly used procedural sedation medication. This retrospective study explored the real-world utilization of remimazolam during procedural sedation to support the development of a nurse sedation protocol. The primary outcome was to identify associations between recovery time, adverse reactions, and dose-response in expanded patient populations. METHODS: This study reviewed charts of 292 adult patients from 3 hospitals within one institution who received remimazolam during procedural sedation between June 1, 2021 and December 31, 2021. Data were analyzed using logistic and linear regression. FINDINGS: The median time to alert in patients receiving remimazolam alone was 12 minutes (interquartile range 10, 17) and increased when additional sedation medications were utilized. Receiving additional sedative medication significantly increased the odds of hypoxia (OR 2.77, 95% CI 1.30-5.91, P = 0.008) after adjusting for body mass index (BMI), American Society of Anesthesiologists physical status (ASA-PS), and total remimazolam dose. There was a 25% increase in odds of experiencing hypoxia for every 5 kg/m2 increase in BMI (95% CI 1.01-1.54, P = 0.037). IMPLICATIONS: Remimazolam presents as a promising option for nurse procedural sedation, offering minimal impact on hemodynamics and respirations, quick recovery, and no residual sedative effects.

Genetic testing in adults with neurologic disorders: indications, approach, and clinical impacts.

The role of genetic testing in neurologic clinical practice has increased dramatically in recent years, driven by research on genetic causes of neurologic disease and increased availability of genetic sequencing technology. Genetic testing is now indicated for adults with a wide range of common neurologic conditions. The potential clinical impacts of a genetic diagnosis are also rapidly expanding, with a growing list of gene-specific treatments and clinical trials, in addition to important implications for prognosis, surveillance, family planning, and diagnostic closure. The goals of this review are to provide practical guidance for clinicians about the role of genetics in their practice and to provide the neuroscience research community with a broad survey of current progress in this field. We aim to answer three questions for the neurologist in practice: Which of my patients need genetic testing? What testing should I order? And how will genetic testing help my patient? We focus on common neurologic disorders and presentations to the neurology clinic. For each condition, we review the most current guidelines and evidence regarding indications for genetic testing, expected diagnostic yield, and recommended testing approach. We also focus on clinical impacts of genetic diagnoses, highlighting a number of gene-specific therapies recently approved for clinical use, and a rapidly expanding landscape of gene-specific clinical trials, many using novel nucleotide-based therapeutic modalities like antisense oligonucleotides and gene transfer. We anticipate that more widespread use of genetic testing will help advance therapeutic development and improve the care, and outcomes, of patients with neurologic conditions.

Xeroform Gauze Bolster: A Cost-Effective Alternative to Synthetic Skin Grafts.

This case presentation describes and justifies the use of petrolatum gauze that is impregnated with 3% bismuth tribromophenate (Xeroform) as a low-cost and effective alternative for synthetic skin grafts. Herein, we discuss clinical trials that demonstrate the benefits of utilizing Xeroform for second-intention healing as well as photographs of a case in which the authors used this method and followed a patient's wound-healing process over time.

Importance of human milk for infants in the clinical setting: Updates and mechanistic links.

INTRODUCTION: Human milk (HM) is the optimal source of nutrition for infants and has been implicated in multiple aspects of infant health. Although much of the existing literature has focused on the individual components that drive its nutrition content, examining HM as a biological system is needed for meaningful advancement of the field. Investigation of the nonnutritive bioactive components of HM and the maternal, infant, and environmental factors which affect these bioactives is important to better understand the importance of HM provision to infants. This information may inform care of clinical populations or infants who are critically ill, hospitalized, or who have chronic diseases and may benefit most from receiving HM. METHODS: In this narrative review, we reviewed literature examining maternal and infant influences on HM composition with a focus on studies published in the last 10 years that were applicable to clinical populations. RESULTS: We found multiple studies examining HM components implicated in infant immune and gut health and neurodevelopment. Additional work is needed to understand how donor milk and formula may be used in situations of inadequate maternal HM. Furthermore, a better understanding of how maternal factors such as maternal genetics and metabolic health influence milk composition is needed. CONCLUSION: In this review, we affirm the importance of HM for all infants, especially clinical populations. An understanding of how HM composition is modulated by maternal and environmental factors is important to progress the field forward with respect to mechanistic links between HM biology and infant health outcomes.

Preimplantation Genetic Testing for Adult-Onset Neurodegenerative Disease: Considerations for Access, Utilization, and Counseling.

Preimplantation genetic testing for monogenic conditions (PGT-M), formerly called preimplantation genetic diagnosis, is a specialized assisted reproduction technique that aims to reduce the risk of a pregnancy inheriting a monogenic condition. Despite calls to increase awareness and prepare neurologists for discussing PGT-M with patients and their families, no guidelines currently exist. When introducing PGT-M to those who may be interested in using it, there are major factors for discussion, including (1) genetic considerations (e.g., requirement for a confirmed genetic diagnosis; timing of genetic test results); (2) practical considerations (e.g., access to PGT-M and genetic services); (3) technical considerations (e.g., factors that can affect the success rate of PGT-M); and (4) psychosocial and ethical considerations (e.g., predictive testing for asymptomatic family members; family dynamics and values). Here, our team of neurologists and specialized genetic counselors discusses the current state of genetic characterization in adult-onset neurodegenerative conditions and highlights the major factors that should be considered when discussing PGT-M with families.

Human Cytomegalovirus in breast milk is associated with milk composition, the infant gut microbiome, and infant growth.

Human cytomegalovirus (CMV) is a highly prevalent herpesvirus that is often transmitted to the neonate via breast milk. Postnatal CMV transmission can have negative health consequences for preterm and immunocompromised infants, but any effects on healthy term infants are thought to be benign. Furthermore, the impact of CMV on the composition of the hundreds of bioactive factors in human milk has not been tested. Here, we utilize a cohort of exclusively breastfeeding full term mother-infant pairs to test for differences in the milk transcriptome and metabolome associated with CMV, and the impact of CMV in breast milk on the infant gut microbiome and infant growth. We find upregulation of the indoleamine 2,3- dioxygenase (IDO) tryptophan-to-kynurenine metabolic pathway in CMV+ milk samples, and that CMV+ milk is associated with decreased Bifidobacterium in the infant gut. Our data indicate a complex relationship between milk CMV, milk kynurenine, and infant growth; with kynurenine positively correlated, and CMV viral load negatively correlated, with infant weight-for-length at 1 month of age. These results suggest CMV transmission, CMV-related changes in milk composition, or both may be modulators of full term infant development.

Mercury accumulation, biomagnification, and relationships to δ13C, δ15N and δ34S of fishes and marine mammals in a coastal Arctic marine food web.

Combining mercury and stable isotope data sets of consumers facilitates the quantification of whether contaminant variation in predators is due to diet, habitat use and/or environmental factors. We investigated inter-species variation in total Hg (THg) concentrations, trophic magnification slope between δ15N and THg, and relationships of THg with δ13C and δ34S in 15 fish and four marine mammal species (249 individuals in total) in coastal Arctic waters. Median THg concentration in muscle varied between species ranging from 0.08 ± 0.04 µg g-1 dw in capelin to 3.10 ± 0.80 µg g-1 dw in beluga whales. Both δ15N (r2 = 0.26) and δ34S (r2 = 0.19) best explained variation in log-THg across consumers. Higher THg concentrations occurred in higher trophic level species that consumed more pelagic-associated prey than consumers that rely on the benthic microbial-based food web. Our study illustrates the importance of using a multi-isotopic approach that includes δ34S when investigating trophic Hg dynamics in coastal marine systems.

Exploring Racial and Ethnic Differences in Parent-Reported Strengths in Children with Autism Spectrum Disorder.

BACKGROUND: Several studies have demonstrated racial/ethnic differences in parental concerns in children with autism spectrum disorder (ASD). However, no studies have investigated racial/ethnic differences in parent-reported strengths. The purpose of this study was to explore racial/ethnic differences in parent-reported strengths in children with ASD. DESIGN AND METHODS: This was a retrospective cross-sectional study investigating the relationship between parent-reported strengths and race/ethnicity at the time of an ASD diagnosis. Parent-reported strengths were qualitatively clustered into themes, and theme frequencies were quantitatively examined for relationships to race/ethnicity. RESULTS: Parents of Caucasian children reported a mean of 5.00 (SD = 2.17) total strengths compared to 3.75 (SD = 2.32) among Hispanic/Latinx children, 3.36 (SD = 1.43) among Asian/PI children, and 3.91 (SD = 2.05) among children from other races/ethnicities. Bivariate linear regression analyses indicated that Asian/PI, Hispanic, and other child race/ethnicity, compared to Caucasian child race/ethnicity, were associated with significantly fewer parent-reported total strengths. Asian/PI and Hispanic child race/ethnicity were associated with significantly fewer personality strengths, while maternal education was associated with a greater number of personality strengths. CONCLUSION: This study found racial and ethnic differences in parent-reported strengths in children with ASD. Further, higher levels of maternal education influenced total, personality, and behavioral strengths. Receipt of a greater number of child services was also associated with a greater number of behavioral strengths.

Potential mechanism for hyperhomocysteinemia in Greyhound dogs.

BACKGROUND: Greyhounds have been reported to have hyperhomocysteinemia (HHC), but the underlying mechanisms and clinical implications are unclear. HYPOTHESIS: Our primary aim was to assess serum concentrations of homocysteine (HCy) and related analytes in Greyhounds and to identify a likely metabolic pathway for HHC. A secondary aim was to determine whether HHC is associated with evidence of oxidative stress. ANIMALS: Healthy pet Greyhounds (n = 31) and non-sighthound control dogs (n = 15). METHODS: Analysis of serum HCy, cobalamin, folate, and methionine, and plasma cysteine, glutathione, and total 8-isoprostane concentrations. RESULTS: Homocysteine concentrations were higher in Greyhounds (median, 25.0 µmol/L) compared to controls (13.9 µmol/L; P < .0001). Cobalamin concentrations were lower in Greyhounds (median, 416 ng/L) compared to controls (644 ng/L; P = .004) and were inversely correlated with HCy (r = -0.40, P = .004). Serum concentrations of folate, which is regenerated when HCy is converted to methionine, also were inversely correlated with HCy (r = -0.47, P = .002). Serum methionine concentrations were more than 4-fold lower in Greyhounds (median, 3.2 µmol/L) compared to controls (median, 15.0 µmol/L), but this difference was not significant (P = .3). Plasma cysteine, glutathione, and 8-isoprostane concentrations did not differ significantly between groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Our findings suggest a primary defect in conversion of HCy to methionine in Greyhounds, with related impaired folate generation. Ineffective cycling by methionine synthase could lead to secondary cobalamin depletion. Notably, low serum folate and cobalamin concentrations can be observed in Greyhounds without signs of intestinal disease.

Primary prevention interventions for adults at-risk of obesity: An international scoping review.

The number of adults experiencing obesity continues to rise. A significant amount of research has addressed primary prevention interventions within pediatric populations to minimize the onset of obesity. However, research efforts within adult populations have commonly emphasized secondary and tertiary prevention for obesity. Therefore, this scoping review aimed to characterize and identify gaps in primary prevention interventions targeting adult populations at risk for obesity. A scoping review was conducted via PubMed, CINAHL, Cochrane, and PscyINFO. A total of 7216 papers were retrieved. Sixteen articles were included in the review. Seven of the studies included only females in the interventions. Only two studies occurred within the United States. Three studies included multi-modal interventions. Interventions were delivered by dieticians in four studies and nurses in three studies. Fifteen of the studies proved to be effective overall for improving weight-related outcomes. The following themes were revealed through this review: (1) participants were usually female and homogenous; (2) studies frequently occurred outside of the United States; (3) studies most often explored unimodal interventions; (4) dieticians and nurses were the most common intervention providers; and (5) favorable outcomes for reducing weight were demonstrated across studies. This scoping review reveals that primary prevention interventions have the potential to minimize obesity onset in at-risk adult populations. However, evaluation of current interventions shows multiple gaps in population target, intervention origin, intervention type, and provider type.

Effects of a mobile health nutrition intervention on dietary intake in children who have autism spectrum disorder.

Background: Children who have Autism Spectrum Disorder (ASD) show preferences for processed foods, such as salty and sugary snacks (SSS) and sugar-sweetened beverages (SSB), while healthier foods, such as fruits and vegetables (FV), are consumed less. Innovative tools are needed that can efficiently disseminate evidence-based interventions and engage autistic children to improve their diet. Aim: The aim of this 3-month randomized trial was to test the initial efficacy of a mobile health (mHealth) nutrition intervention on changing consumption of targeted healthy (FV) and less healthy foods/beverages (SSS, SSB) in children who have ASD, ages 6-10, who were picky eaters. Methods: Thirty-eight parent-child dyads were randomly assigned to either an intervention (technology) group or a wait list control (education) group. The intervention included behavioral skills training, a high level of personalization for dietary goals, and involved parents as "agents of change." Parents in the education group received general nutrition education and the dietary goals but did not receive skills training. Children's intake was assessed at baseline and at 3 months using 24-hour dietary recalls. Results: While there were no significant group-by-time interactions (P > 0.25) for any of the primary outcomes, we found a significant main effect of time for FV intake (P = 0.04) indicating that both groups consumed more FV at 3 months (2.58 ± 0.30 servings/day) than at baseline (2.17 ± 0.28 servings/day; P = 0.03). Children in the intervention group who consumed few FV at baseline and showed high engagement with the technology increased their FV intake by 1.5 servings/day (P < 0.01). Children's taste/smell sensitivity significantly predicted their FV intake (P = 0.0446); for each unit of lower taste/smell sensitivity (indicating greater sensory processing abnormalities), FV intake increased by 0.13 ± 0.1 servings/day. Discussion: This mHealth intervention did not yield significant between-group differences for changing consumption of targeted foods/beverages. Only children who consumed few FV at baseline and highly engaged with the technology increased their FV intake at 3 months. Future research should test additional strategies to expand the intervention's impact on a wider range of foods while also reaching a broader group of children who have ASD. This trial was registered at clinicaltrials.gov as NCT03424811.Clinical Trial Registration: This study was registered at clinicaltrials.gov as NCT03424811.

Human milk variation is shaped by maternal genetics and impacts the infant gut microbiome.

Human milk is a complex mix of nutritional and bioactive components that provide complete nutrition for the infant. However, we lack a systematic knowledge of the factors shaping milk composition and how milk variation influences infant health. Here, we used multi-omic profiling to characterize interactions between maternal genetics, milk gene expression, milk composition, and the infant fecal microbiome in 242 exclusively breastfeeding mother-infant pairs. We identified 487 genetic loci associated with milk gene expression unique to the lactating mammary gland, including loci that impacted breast cancer risk and human milk oligosaccharide concentration. Integrative analyses uncovered connections between milk gene expression and infant gut microbiome, including an association between the expression of inflammation-related genes with IL-6 concentration in milk and the abundance of Bifidobacteria in the infant gut. Our results show how an improved understanding of the genetics and genomics of human milk connects lactation biology with maternal and infant health.

Narrative Theater to Examine and Mitigate Anti-Black Racism Within Occupational Therapy.

Theater has long-standing roots in social justice and holds promise for reducing racist attitudes and behaviors. Objectives of this study were to (a) collect and theatrically portray narratives from Black occupational therapy students and practitioners to a national audience and (b) examine the impact of the theatrical performance on anti-Black racism among attendees. The Identity Development Evolution and Sharing (IDEAS) model guided translation of narratives into a filmed performance. Paired t-test of pre/post administration of the Acceptance and Action Questionnaire-Stigma (AAQ-S) measured changes in stigma beliefs. Qualitative thematic analysis of an open-ended post-survey question elucidated experiences of the performance. The performance engendered significant decreases in stigma; qualitative data elucidated potential mechanisms of change. This study provides insight into experiences of anti-Black racism within occupational therapy and offers a promising means for occupational therapists to engage in anti-Black racism.

Rapid brain MRI protocols result in comparable differential diagnoses versus a full brain protocol in most canine and feline cases.

Evaluation of brain disease in veterinary patients uses a wide variety of MRI sequences. A shortened protocol that maintains consistency of interpretation would reduce radiologist reporting time, patient anesthetic time, and client cost. The aims of this retrospective, methods comparison, observer agreement study were to evaluate whether abbreviated MRI protocols alter differential diagnoses and recommendations compared to our institution's standard protocol; evaluate interobserver agreement on standard brain MRIs; and assess whether differential diagnoses change after postcontrast images. Normal and pathologic canine and feline brain MRIs were retrieved from hospital archives. Three protocols were created from each: a 5-sequence noncontrast enhanced Fast Brain Protocol 1 (FBP1); a 6-sequence contrast-enhanced Fast Brain Protocol 2 (FBP2); and an 11-sequence standard brain protocol (SBP). Three blinded veterinary radiologists interpreted FBP images for 98 cases (1 reader/case) and SBP images for 20 cases (3 readers/case). A fourth observer compared these interpretations to the original MRI reports (OMR). Overall agreement between FBPs and OMR was good (k = 0.75) and comparable to interobserver agreement for multiple reviews of SBP cases. Postcontrast images substantially altered conclusions in 17/97 cases (17.5%), as well as improved interobserver agreement compared to noncontrast studies. The conclusions reached with shortened brain protocols were comparable to those of a full brain study. The findings supported the use of a 6-sequence brain MRI protocol (sagittal T2-weighted [T2w] TSE; transverse T2w turbo spin echo fluid-attenuated inversion recovery, T2*-weighted gradient recalled echo, T1-weighted spin echo, and diffusion weighted imaging/apparent diffusion coefficient; and postcontrast transverse T1-weighted spin echo) for dogs and cats with suspected intracranial disease.

Screening for Early Emerging Mental Experiences (SEE ME): A Model to Improve Early Detection of Psychosis in Integrated Primary Care.

Early intervention in serious mental health conditions relies on the accurate identification of adolescents and young adults at high risk or with very recent onset of psychosis. Current early detection strategies have had limited success, identifying only a fraction of these individuals within the recommended 3- to 6-month window. Broader public health strategies such as population screening are hampered by low base rates and poor self-report screen specificity. Screening for Early Emerging Mental Experiences (SEE ME) is a three-stage "SCREEN-TRIAGE-ENGAGE" model for the early detection of psychosis in integrated primary care adolescent and young adult patients during the period of peak onset. It builds on the KNOW THE SIGNS-FIND THE WORDS-MAKE THE CONNECTION framework outlined on psychosisscreening.org and developed with input from community collaborators. Systematic screening aims to expand the reach of early detection and reduce reliance on provider knowledge. Triage and engagement by trained mental health clinicians aims to improve the specificity of screen responses, enhance engagement in appropriate care, and reduce provider burden. Leveraging the low stigma of primary care, its reach to non-help-seeking adolescents and young adults, and the mental health training of clinicians within integrated care practices, SEE ME has potential to improve the benefit/risk ratio of early detection of psychosis by improving both the sensitivity and specificity of screening and clinical response. We review the rationale and design of this promising model.

The Influence of Geographical Origin, Age, Sex, and Animal Husbandry on the Spontaneous Histopathology of Laboratory Cynomolgus Macaques (Macaca Fascicularis): A Contemporary Global and Multisite Review of Historical Control Data.

To investigate the influence of geographical origin, age, and sex on toxicologically relevant spontaneous histopathology findings in cynomolgus macaques (Macaca fascicularis), we performed a comparative analysis of historical control data (HCD) from 13 test sites that included 3351 animals (1645 females and 1706 males) sourced from Mauritius, China, Vietnam, and Cambodia, aged from 2 to 9.5 years, and from 446 toxicology studies evaluated between 2016 and 2021. The most common findings were mononuclear infiltrates in the kidney, liver, brain, and lung, which showed highest incidences in Mauritian macaques, and heart, salivary glands, and gastrointestinal tract (GIT), which showed highest incidences of mononuclear infiltrates in mainland Asian macaques. Developmental and degenerative findings were more common in Mauritian macaques, while lymphoid hyperplasia and lung pigment showed higher incidences in Asian macaques. Various sex and age-related differences were also present. Despite origin-related differences, the similarities in the nature and distribution of background lesions indicate that macaques from all geographical regions are suitable for toxicity testing and show comparable lesion spectrum. However, in a toxicity study, it is strongly recommended to use animals from a single geographical origin and to follow published guidelines when using HCD to evaluate and interpretate commonly diagnosed spontaneous lesions.