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Prenatal identification by magnetic resonance imaging (MRI) of callosal anomalies, particularly with accompanying intracranial abnormalities, poses a challenge for accurate prognostication and fetal counseling as outcome can vary widely depending on underlying etiology. In female patients, Aicardi syndrome is an important consideration, and prompt postnatal ophthalmologic assessment to identify ocular stigmata of Aicardi syndrome can aid with anticipatory guidance and greater vigilance for seizures. We present a case of a female with fetal and postnatal MRI findings of agenesis of corpus callosum and type 2b interhemispheric cysts, characteristically found in Aicardi syndrome, but was found to have oral-facial-digital syndrome type 1 (OFD1). We also present 3 other companion cases with pre- and postnatal imaging of patients with Aicardi syndrome. These cases highlight the importance of widening the differential diagnosis to also include OFD1 for female patients with callosal anomalies.

Transthyretin (TTR) dissociation is the rate limiting step for both aggregation and subunit exchange. Kinetic stabilisers, small molecules that bind to the native tetrameric structure of TTR, slow TTR dissociation and inhibit aggregation. One such stabiliser is the non-steroidal anti-inflammatory drug (NSAID), diflunisal, which has been repurposed to treat TTR polyneuropathy. Previously, we compared the efficacy of diflunisal, tafamidis, tolcapone, and AG10 as kinetic stabilisers for transthyretin. However, we could not meaningfully compare diflunisal because we were unsure of its plasma concentration after long-term oral dosing. Herein, we report the diflunisal plasma concentrations measured by extraction, reversed phase HPLC separation, and fluorescence detection after long-term 250 mg BID oral dosing in two groups: a placebo-controlled diflunisal clinical trial group and an open-label Japanese polyneuropathy treatment cohort. The measured mean diflunisal plasma concentration from both groups was 282.2 μM ± 143.7 μM (mean ± standard deviation). Thus, quantification of TTR kinetic stabilisation using subunit exchange was carried out at 100, 200, 300, and 400 μM diflunisal concentrations, all observed in patients after 250 mg BID oral dosing. A 250 μM diflunisal plasma concentration reduced the wild-type TTR dissociation rate in plasma by 95%, which is sufficient to stop transthyretin aggregation, consistent with the clinical efficacy of diflunisal for ameliorating transthyretin polyneuropathy.

Background Social determinants of health have a significant impact on health outcomes. However, the complexity and interaction of multiple factors influencing glycemic control remain understudied. Purpose This study examined associations of socioeconomic position (income, education, and occupation), environmental (physical activity facilities, neighborhood social cohesion, neighborhood problem, and violence), behavioral (physical activity, nutrition, and smoking), and psychological factors (depressive symptoms, stress, and discrimination) with glycemic control (hemoglobin A1c [A1c]) using the World Health Organization Social Determinants of Health framework in African American adults with type 2 diabetes. Methods A secondary data analysis was conducted using a longitudinal cohort of 1,240 African American adults with type 2 diabetes who participated in the community-based Jackson Heart Study. Socioeconomic position, environmental, behavioral, and psychological factors were measured using validated instruments in the Jackson Heart Study. Longitudinal structural equation modeling was used with glycemic control (A1c) collected over time (Exams 1–3) as the study outcome. Results Our study presents the complex interplay of socioeconomic determinants of health and glycemic control over time. Higher socioeconomic position (higher income, higher level of education, and professional occupation) was directly associated with improvement in glycemic control over time. An association of socioeconomic position on glycemic control mediated through health behavior factors was also observed. Conclusions In this analysis, socioeconomic position components were determinants of glycemic control in African American adults with type 2 diabetes. Future studies aimed at reducing health disparities and achieving equality of outcomes in this population will benefit from embedding socioeconomic position components into their design.

Animals sense sounds through hierarchical neural pathways that ultimately reach higher-order cortices to extract complex acoustic features, such as vocalizations. Elucidating how spectrotemporal integration varies along the hierarchy from primary to higher-order auditory cortices is a crucial step in understanding this elaborate sensory computation. Here we used two-photon calcium imaging and two-tone stimuli with various frequency-timing combinations to compare spectrotemporal integration between primary (A1) and secondary (A2) auditory cortices in mice. Individual neurons showed mixed supralinear and sublinear integration in a frequency-timing combination-specific manner, and we found unique integration patterns in these two areas. Temporally asymmetric spectrotemporal integration in A1 neurons suggested their roles in discriminating frequency-modulated sweep directions. In contrast, temporally symmetric and coincidence-preferring integration in A2 neurons made them ideal spectral integrators of concurrent multifrequency sounds. Moreover, the ensemble neural activity in A2 was sensitive to two-tone timings, and coincident two-tones evoked distinct ensemble activity patterns from the linear sum of component tones. Together, these results demonstrate distinct roles of A1 and A2 in encoding complex acoustic features, potentially suggesting parallel rather than sequential information extraction between these regions.

SUMMARYPharmacological activation of the activating transcription factor 6 (ATF6) arm of the Unfolded Protein Response (UPR) has proven useful for ameliorating proteostasis deficiencies in a variety of etiologically diverse diseases. Previous high-throughput screening efforts identified the small molecule AA147 as a potent and selective ATF6 activating compound that operates through a mechanism involving metabolic activation of its 2-amino-p-cresol substructure affording a quinone methide, which then covalently modifies a subset of ER protein disulfide isomerases (PDIs). Intriguingly, another compound identified in this screen, AA132, also contains a 2-amino-p-cresol moiety; however, this compound showed less transcriptional selectivity, instead globally activating all three arms of the UPR. Here, we show that AA132 activates global UPR signaling through a mechanism analogous to that of AA147, involving metabolic activation and covalent PDI modification. Chemoproteomic-enabled analyses show that AA132 covalently modifies PDIs to a greater extent than AA147. Paradoxically, activated AA132 reacts slower with PDIs, indicating it is less reactive than activated AA147. This suggests that the higher labeling of PDIs observed with activated AA132 can be attributed to its lower reactivity, which allows this activated compound to persist longer in the cellular environment prior to quenching by endogenous nucleophiles. Collectively, these results suggest that AA132 globally activates the UPR through increased engagement of ER PDIs. Consistent with this, reducing the cellular concentration of AA132 decreases PDI modifications and allows for selective ATF6 activation. Our results highlight the relationship between metabolically activatable-electrophile stability, ER proteome reactivity, and the transcriptional response observed with the enaminone chemotype of ER proteostasis regulators, enabling continued development of next-generation ATF6 activating compounds.

The prophylactic use of amiodarone to reduce the incidence of postoperative arrhythmias is effective for patients undergoing general cardiac surgeries; however, no data exists for the use of prophylactic amiodarone to prevent postoperative arrhythmias after CF-LVAD. This single-center, retrospective analysis compared patients with CF-LVADs placed between April 2014 and June 2020 who received prophylactic postoperative amiodarone to those who did not. Based on institution practice at the respective times, patients with a CF-LVAD placed between April 2014 and June 2018 were included in the group receiving postoperative amiodarone arrhythmia prophylaxis and patients with a CF-LVAD placed July 2018 to June 2020 were included in the group not receiving arrhythmia prophylaxis. The primary outcome was the incidence of first occurring atrial or ventricular arrhythmia from CF-LVAD placement to 21 days or hospital discharge. Sixty patients received amiodarone for arrhythmia prophylaxis and 27 patients did not receive prophylaxis. The primary outcome occurred in 40% of the prophylaxis group and 66.7% in the no prophylaxis group (RR, 0.60; 95% CI, 0.40-0.90; p = 0.038). In patients receiving CF-LVADs, the use of prophylactic amiodarone was associated with a reduction in the incidence of postoperative arrhythmias, which was driven primarily by a reduction in postoperative atrial arrhythmias, without significantly increasing the rate of amiodarone-related adverse events.

Prenatal tobacco smoke exposure (TSE) and preterm birth are associated with abnormal brain and neurodevelopmental outcomes in infants. Studies that can disentangle indirect mediating effects from direct effects of prenatal TSE on sensitive early brain MRI biomarkers in very preterm infants are needed.We sought to determine whether prenatal TSE in preterm infants posed any direct effects on MRI-determined global brain abnormality score and secondary measures of brain abnormalities after removing any indirect mediating effects of preterm birth on neurostructural outcomes.We examined brain MRI findings collected at 39-44 weeks postmenstrual age from a prospective cohort of 395 infants born very preterm (≤32 weeks of gestational age). The primary outcome was global brain abnormality score and secondary outcomes were: global efficiency of structural connectome, diffuse white matter abnormality volume, total brain tissue volume, total gray and white matter volume, and cerebellar volume. Maternal reports of smoking during pregnancy were obtained. We performed multivariable linear regression analyses to examine the association between prenatal TSE and our MRI outcomes, controlling for prospectively collected confounders. We performed a mediation analysis to estimate the direct effects of prenatal TSE on brain abnormalities and any indirect effects through preterm birth.In total, 12.6% of infants had prenatal TSE. Compared to nonexposed infants, infants with prenatal TSE had a higher median(range) global brain abnormality score of 7(0, 41) vs. 5(0, 34) (p=.001); findings remained significant (p.001) after controlling for antenatal confounders. Global efficiency (p.001), diffuse white matter volume (p=.037), and total brain tissue volume (p=.047), were significantly different between TSE groups in multivariable analyses. On mediation analysis, preterm birth mediated between 0 and 29% of the indirect effect of prenatal TSE on several measures of brain abnormality outcomes. Thus, prenatal TSE had a direct adverse effect between 71% and 100% on brain injury or abnormal development.We identified multiple adverse effects of prenatal TSE on sensitive and objective measures of neonatal brain injury/abnormal development; most appear to be a direct effect of prenatal TSE on fetal brain development. Results underscore the significant adverse neurostructural effects of prenatal TSE to tobacco smoke pollutants.

SummaryAutophagy activation has the potential to ameliorate neurodegenerative disease phenotypes, including protein aggregation, lipid level perturbations and axonal trafficking defects. We performed a high content imaging-based screen assessing 940,000 small molecules to identify those that accelerate lipid droplet clearance. Hits were validated in diverse cell lines and by counter-screening. Of the 77 validated structurally diverse hits, 24 increase autophagy flux. Herein, we highlight CCT020312 as a mammalian target of rapamycin (mTOR) inhibitor-independent autophagy activator, which should function without suppressing the immune response. CCT020312 dose-dependently reduces cytotoxic axonal mutant prion protein aggregate levels within endosomes of primary murine hippocampal neurons and normalizes axonal trafficking deficiencies. Moreover, CCT020312 robustly clears phosphorylated insoluble tau, while reducing tau-mediated neuronal stress vulnerability in patient-derived neuronal models. CCT020312 also restores lysosomal function in neurons differentiated from sporadic Alzheimer’s patients fibroblasts bearing epigenetic marks of aging. Taken together, we describe a promising strategy to uncover novel pharmacological agents that normalize cellular neurodegenerative disease pathology.

Deletion of 17p13.3 has varying degrees of severity on brain development based on precise location and size of the deletion. The most severe phenotype is Miller-Dieker syndrome (MDS) which is characterized by lissencephaly, dysmorphic facial features, growth failure, developmental disability, and often early death. Haploinsufficiency of PAFAH1B1 is responsible for the characteristic lissencephaly in MDS. The precise role of YWHAE haploinsufficiency in MDS is unclear. Case reports are beginning to elucidate the phenotypes of individuals with 17p13.3 deletions that have deletion of YWHAE but do not include deletion of PAFAH1B1. Through our clinical genetics practice, we identified four individuals with 17p13.3 deletion that include YWHAE but not PAFAH1B1. These patients have a similar phenotype of dysmorphic facial features, developmental delay, and leukoencephalopathy. In a review of the literature, we identified 19 patients with 17p13.3 microdeletion sparing PAFAH1B1 but deleting YWHAE. Haploinsufficiency of YWHAE is associated with brain abnormalities including cystic changes. These individuals have high frequency of epilepsy, intellectual disability, and dysmorphic facial features including prominent forehead, epicanthal folds, and broad nasal root. We conclude that deletion of 17p13.3 excluding PAFAH1B1 but including YWHAE is associated with a consistent phenotype and should be considered a distinct condition from MDS.

BACKGROUND AND PURPOSE: Dandy-Walker malformation, vermian hypoplasia, and Blake pouch remnant represent a continuum of anomalies and are common reasons for referral for fetal MR imaging. This study aimed to determine biometric measurements that quantitatively delineate these 3 posterior fossa phenotypes. MATERIALS AND METHODS: Our single-center institutional review board approved a retrospective analysis of all fetal MRIs for posterior fossa malformations, including Dandy-Walker malformation, vermian hypoplasia, and Blake pouch remnant. Measurements included the anterior-to-posterior pons, craniocaudal and anterior-to-posterior vermis, lateral ventricle size, and tegmentovermian and posterior fossa angles. Measurements were compared with normal biometry and also between each subgroup. RESULTS: Thirty-three fetuses met the criteria and were included in the study. Seven were designated as having Dandy-Walker malformation; 16, vermian hypoplasia; and 10, Blake pouch remnant. No significant group interactions with adjusted mean gestational age for tegmentovermian and posterior fossa angles were observed. The tegmentovermian angle was significantly higher in Dandy-Walker malformation (109.5° [SD, 20.2°]) compared with vermian hypoplasia (52.13° [SD, 18.8°]) and Blake pouch remnant (32.1° [SD, 17.9°]), regardless of gestational age. Lateral ventricle sizes were significantly higher in Dandy-Walker malformation at a mean of ≥23.1 weeks’ gestational age compared with vermian hypoplasia and Blake pouch remnant. The anterior-to-posterior and craniocaudal vermes were significantly smaller in Dandy-Walker malformation compared with vermian hypoplasia and Blake pouch remnant at mean of ≥23.1 weeks’ gestational age. CONCLUSIONS: Dandy-Walker malformation can be described in relation to vermian hypoplasia and Blake pouch remnant by an increased tegmentovermian angle; however, other potential qualifying biometric measurements are more helpful at ≥23.1 weeks’ gestational age. Because they fall along the same spectrum of abnormalities, the difficulty in distinguishing these entities from one another makes precise morphologic and biometric descriptions important.

Fetal MRI and neonatal MRI of the central nervous system (CNS) are complementary tools that can help to accurately counsel and direct the management of children with anomalies of the central nervous system. Postnatal MRI can add to fetal MRI by allowing for monitoring of changes in the severity of disease, better delineation of a suspected prenatal anomaly, evaluation for secondary pathologies related to the primary diagnosis, and surgical management direction. In this review we discuss the roles of fetal and neonatal MRI in the diagnosis and treatment of congenital anomalies of the CNS through a series of case examples and how both are important in patient management.

Tolerance to cannabinoids could limit their therapeutic potential. Male mice expressing a desensitization-resistant form (S426A/S430A) of the type-1 cannabinoid receptor (CB1R) show delayed tolerance to delta-9-tetrahydrocannabinol (∆9-THC) but not CP55,940. With more women than men using medical cannabis for pain relief, it is essential to understand sex differences in cannabinoid antinociception, hypothermia, and resultant tolerance. Our objective was to determine whether female mice rely on the same molecular mechanisms for tolerance to the antinociceptive and/or hypothermic effects of cannabinoids that we have previously reported in males. We determined whether the S426A/S430A mutation differentially disrupts antinociceptive and/or hypothermic tolerance to CP55,940 and/or Δ9-THC in male and female S426A/S430A mutant and wild-type littermates. The S426A/S430A mutation conferred an enhanced antinociceptive response for ∆9-THC and CP55,940 in both male and female mice. While the S426A/S430A mutation conferred partial resistance to ∆9-THC tolerance in male mice, disruption of CB1R desensitization had no effect on tolerance to ∆9-THC in female mice. The mutation did not alter tolerance to the hypothermic effects of ∆9-THC or CP55,940 in either sex. Interestingly, female mice were markedly less sensitive to the antinociceptive effects of 30 mg/kg ∆9-THC and 0.3 mg/kg CP55,940 compared with male mice. Our results suggest that disruption of the GRK/βarrestin2 pathway of desensitization alters tolerance to Δ9-THC but not CP55,940 in male but not female mice. As tolerance to Δ9-THC appears to develop differently in males and females, sex should be considered when assessing the therapeutic potential and dependence liability of cannabinoids.

As the safety and efficacy of fetal magnetic resonance imaging (MRI) at 3 tesla (T) continues to evolve, understanding its potential benefits and limitations is becoming increasingly important. We aim to compare the image quality of fetal MRI between 1.5 T and 3 T in routine clinical practice. Fetal MRIs performed at 3 T between Jan. 1, 2019, and Dec. 31, 2019, at our institution were retrospectively reviewed by four fellowship-trained subspecialty radiologists. Imaging quality by system, sequence and artifacts were compared with matched controls at 1.5 T and rated using a modified Likert scale. Thirty-three fetal MRIs at 3 T were reviewed, and a control group of studies for the same clinical indication and equivalent gestational age were selected for comparison. Two of the four radiologists preferred 3-T image quality of the brain with slight agreement among the four reviewers (k=0.19, P=0.01). Three of the four radiologists had no preference for 1.5 T vs. 3 T in the majority of cases in evaluating the chest and abdomen. In the overall assessment, 3 T was preferred in less than half of cases by all four radiologists (k=0.07, P=0.26). In the evaluation of standing wave, moire fringe and magnetic susceptibility artifacts, 3 T was not preferred in the majority of studies by all four radiologists. Total exam time was significantly longer in the 3-T fetal MRIs (75.0±15.1 min) compared to the 1.5-T fetal MRIs (55.5±13.3 min, P

Early life stress (ELS) is associated with increased morbidity and mortality across the lifecourse. Studies observing a relationship between ELS and stress physiology (cortisol), may help explain the connection to poor health outcomes, but have been limited by cortisol measures used.We examined the association between ELS measured by a Risky Family (RF) environment questionnaire, and adult diurnal cortisol profile inclusive of multiple cortisol measures.RF and cortisol were collected from Coronary Artery Risk Development in Young Adults Study participants at follow-up (Year 15). Complete case (n = 672) data were included in multi-variable regression analyses with log transformed cortisol measures (outcomes) including wake-up cortisol, cortisol awakening response [CAR], AUC and five other cortisol diurnal curve measures.Participants were age 39.9 + /- 3.7 years and 51.6% Black. For every 1 unit increase in RF, there was a 1.4% greater wake-up cortisol and flatter CAR after adjustment for age, sex, income, and smoking (B=0.014, p = 0.023; B=-0.014, p = 0.028, respectively). Each unit increase in caregiver warmth/affection was associated with a 6.9% higher (steeper) CAR (B=0.069, p = 0.03). Results remained significant after adjusting for other covariates except social support in adulthood. An interaction between child abuse and caregiver warmth was nearly significant (p = 0.068), such that for those with exposure to the greatest caregiver warmth and lowest child abuse, CAR was steepest CONCLUSIONS: We demonstrate that ELS is associated with altered cortisol regulation in adulthood. However, further research is needed to assess how healthy relationships throughout the life course may modulate cortisol regulation in adulthood.

ObjectiveLiver herniation is a known risk factor for increased severity in CDH and is associated with clinically significant pulmonary hypoplasia and pulmonary hypertension. Better studies are needed to understand the growth of the herniated liver compared to the liver that remains in the abdomen and how this liver growth then affects lung development. Serial hi-resolution fetal MRI enables characterization of liver growth throughout gestation and examination of macroscopic features that may regulate liver growth. Here, we hypothesized that the nature of liver herniation affects liver growth and, in turn, affects lung growth.MethodsClinical data were retrospectively collected from consecutive cases of prenatally diagnosed isolated left-sided or right-sided CDH from June 2006 to August 2021. Only those cases with MRI lung volumetry for both mid-gestation and late-gestation time points were recruited for analysis. Cases with fetal chromosomal abnormalities and other major structural abnormalities were excluded. Fractional liver volume and liver growth was indexed to estimated fetal weight and compared to lung growth.ResultsData was collected from 28 fetuses with a left liver-down CDH (LLD), 37 left liver-up CDH (LLU) and 9 right liver-up CDH (RLU). Overall, RLU fetuses had greater overall and fractional (intra-thoracic vs. intra-abdominal) liver growth when compared to LLD and LLU fetuses. Additionally, intra-thoracic liver growth was consistently slower than intra-abdominal liver growth for either right- or left-sided CDH. When the liver was not herniated, a positive correlation was seen between liver growth and lung growth. However, when the liver was herniated above the diaphragm, this positive correlation was lost.ConclusionRight-sided CDH fetuses exhibit greater liver growth compared to left-sided CDH. Liver herniation disrupts the normal positive correlation between liver and lung growth that is seen when the liver is entirely within the abdomen.

Despite newer guideline-recommended antidiabetic agents demonstrating a reduction of disease burden and improved health outcomes, high drug cost and restrictive insurance coverage limit public access. To address this issue, many manufacturers offer free medication through manufacturer patient assistance programs.This study aimed to determine the impact of pharmacist intervention using manufacturer patient assistance programs in individuals who are uninsured or enrolled in Medicare Part D prescription drug plan and to evaluate the impact of pharmacist utilization in meeting diabetic quality measures set forth by accountable care organizations (ACOs).This single-center, retrospective cohort study evaluated 171 participants enrolled into a manufacturer patient assistance program owing to pharmacist intervention compared with 171 participants receiving usual care. The primary outcome was the change in glycosylated hemoglobin (A1c) between groups. Secondary outcomes included the impact of pharmacist management on change in weight, change in blood pressure, and the number of participants meeting ACO quality measures.The average change in A1c in the intervention group was -2.5% compared with an average A1c reduction of -1.3% in the control group (95% CI -2.11 to -1.67, P0.001). The average change in weight of the intervention group was -4.01 kg, whereas the control group had an average weight reduction of -1.4 kg from baseline (95% CI -3.95 to -1.61, P0.05). The body mass index (BMI) of the intervention group was a value of 1.4 kg/mParticipants who were enrolled in a manufacturer patient assistance program by a pharmacist and were followed for diabetes care management experienced greater A1c lowering and weight loss than participants receiving usual care.

Meroanencephaly occurs when there is an incomplete open median calvarial defect. This condition, which is in the spectrum of anencephaly, results in ectopic brain without skin covering and a normal foramen magnum. We present a rare case of a female fetus with meroanencephaly referred to our institution at 24 weeks and imaged with both prenatal ultrasound and MRI, demonstrating an open neural tube defect in the high parietal area and lack of visualization of the supratentorial ventricular system. Postnatal the child survived and went on to require antibiotic therapy and closure of the defect without cerebral spinal fluid diversion but demonstrates severe permanent neurologic deficits.

Blake pouch remnant, also known as Blake pouch cyst or persistent Blake pouch, is a posterior fossa embryologic anomaly that is often seen in isolation with most affected patients being asymptomatic. However, even in isolation, Blake pouch remnant can result in obstructive hydrocephalus requiring early neurosurgical intervention making it an important diagnosis for the fetal radiologist to consider. We present a rare case of a patient with prenatally diagnosed “inferior vermian hypoplasia” on fetal MRI that went on to develop progressive obstructive hydrocephalus in infancy secondary to what was determined to be a Blake pouch remnant.

Over the last decade fetal surgery to repair open spinal dysraphisms has become an acceptable and in some cases desirable alternative to the traditional method of postnatal closure. Fetal MRI is an essential part of the workup in these patients, not only to select the appropriate candidates for fetal surgery but also to guide prenatal counseling and perinatal management. In this article we review current surgical techniques for prenatal repair, relevant imaging findings in the era of fetal surgery, and expected imaging findings of the brain and spine in the fetal and postnatal periods.

Mainstem bronchial atresia (MBA) is a rare and fatal entity with no survivors reported to date. We describe a neonate born at 36 weeks gestational age (GA) with right MBA who underwent successful slide tracheobronchoplasty at 32 days of life. It is theorized that during fetal life a transient fistulous connection developed, allowing right lung decompression and left lung development.

A lay patient navigator model involving a culturally tailored intervention to improve palliative care outcomes for Hispanics with advanced cancer was tested across 3 urban and 5 rural cancer centers in Colorado. Five home visits were delivered over 3 months to 112 patients assigned to the randomized controlled trial's intervention arm. Grounded in core Hispanic values, visits addressed palliative care domains (advance care planning, pain/symptom management, and hospice utilization). To describe the content of patient navigator visits with patients/family caregivers, research team members analyzed 4 patient navigators' field notes comprising 499 visits to 112 patients. Based on previous work, codes were established a priori to identify ways patient navigators help patients/family caregivers. Key words and comments from field notes were classified into themes using ATLAS.ti and additional codes established. Nine common themes and exemplars describing the lay patient navigator role are described: activation/empowerment, advocacy, awareness, access, building rapport, providing support, exploring barriers, symptom screening, and the patient experience. Patient navigators used advocacy, activation, education, and motivational interviewing to address patient/family concerns and reduce barriers to quality palliative care in urban and rural settings. Adapting and implementing this model across cultures has potential to improve palliative care access to underserved populations.

An unexplained $>4\,\sigma$ discrepancy persists between "beam" and "bottle" measurements of the neutron lifetime. A new model proposed that conversions of neutrons $n$ into mirror neutrons $n'$, part of a dark mirror sector, can increase the apparent neutron lifetime by $1\%$ via a small mass splitting $\Delta{m}$ between $n$ and $n'$ inside the 4.6 T magnetic field of the National Institute of Standards and Technology Beam Lifetime experiment. A search for neutron conversions in a 6.6 T magnetic field was performed at the Spallation Neutron Source which excludes this explanation for the neutron lifetime discrepancy.

Background: Prior studies demonstrate a higher prevalence of pulmonary hypertension (PH) and more severe hemodynamics in patients with higher body mass index (BMI). However, this association was only described in post-capillary PH. To better understand the relationship between pre-capillary PH and BMI, we compared various PH parameters stratified by BMI class. Methods: Data from right heart catheterization (RHC), 6-minute walk (6MW), and functional class (FC) were collected from the University of Michigan Pulmonary Hypertension Patient Registry from 2016-2020 at baseline and 3-month follow-up. Group 1 pulmonary arterial hypertension (PAH) patients were grouped into 4 BMI weight classes: under/normal weight (BMI < 25), overweight (25 < BMI < 30), obesity class 1 (30 < BMI < 35), obesity class 2/3 (BMI > 35). Results: Among 175 PAH patients, obese patients exhibited higher right atrial and pulmonary capillary wedge pressures. There were no major differences in mean pulmonary artery (PA) pressures, pulmonary vascular resistance (PVR), cardiac index Fick, 6MW distance walked, or peak Borg Dyspnea score among BMI groups. Despite having similar mean PA pressure and PVR (major determinants of functional capacity in PAH), patients in higher weight classes had higher dyspnea symptom burden by WHO FC. Specifically, a greater prevalence of normal/overweight patients were in FC 1 while more obese patients were in FC 3. Conclusions: Overall, in patients with PAH, higher BMI classes presented with worse FC for dyspnea, higher RA and PCW pressures, with similar PA pressures and 6MW results. Our data suggests that BMI may be an important factor that influences PAH symptoms. The impact of BMI in PAH outcomes is yet to be determined. It is possible that patients with higher BMI may exhibit more frequent comorbid conditions contributing to multifactorial symptoms of dyspnea; further study is warranted.

Understanding computational principles in hierarchically organized sensory systems requires functional parcellation of brain structures and their precise targeting for manipulations. Although brain atlases are widely used to infer area locations in the mouse neocortex, it has been unclear whether stereotaxic coordinates based on standardized brain morphology accurately represent functional domains in individual animals. Here, we used intrinsic signal imaging to evaluate the accuracy of area delineation in the atlas by mapping functionally-identified auditory cortices onto bregma-based stereotaxic coordinates. We found that auditory cortices in the brain atlas correlated poorly with the true complexity of functional area boundaries. Inter-animal variability in functional area locations predicted surprisingly high error rates in stereotaxic targeting with atlas coordinates. This variability was not simply attributed to brain sizes or suture irregularities but instead reflected differences in cortical geography across animals. Our data thus indicate that functional mapping in individual animals is essential for dissecting cortical area-specific roles with high precision.

Background There is a growing awareness surrounding gender diversity and the critical need for more robust research and evidence to guide gender-affirming healthcare, including gender-affirming hormone therapy (GAHT). Research priorities are often determined by clinicians and researchers; we lack data about the transgender and gender diverse (TGD) community's priorities for research. Objective To determine the research priorities of adult TGD patients who receive care at a multidisciplinary gender-affirming clinical program at a tertiary academic medical center. Design/Methods IRB-approved electronic surveys were sent to 719 patients who sought care from the program in the last year. Participants were asked to rank research topics within six domains based on the importance of the topic to their care: 1) care access/utilization within the program, 2) GAHT impacts on the body, 3) GAHT concerns/potential adverse effects, 4) gender-affirming surgeries, 5) mental health, and 6) navigating healthcare/work/school, with 6-7 choices in each category, including a free text option to fill out their own research priority. Results 135 individuals consented and responded to the survey (19% response rate). Almost half were aged 18-29 years (45%), and several were aged 50 years or older (16%). Nearly all identified as white (92%). Participants were able to check more than one response for these demographics: feminine gender identity (55%; inclusive of female, transgender female, and/or transfeminine); masculine gender identity (37%; inclusive of male, transgender male, and/or transmasculine), nonbinary (25%), and/or something else (25%). The top two research priorities (by % respondents ranking the topic as most important) within each of the six domains were: 1) care access/utilization within the program: have insurance coverage for gender-affirming care (66%), have gender-affirming surgery (33%); 2) GAHT impacts on the body: overall feminizing/masculinizing effects (81%), mental health/mood (69%); 3) GAHT concerns/potential adverse effects: heart health (54%), blood clots/stroke (47%); 4) gender-affirming surgeries: common complications (57%), post-op sexual function/pleasure (51%); 5) mental health: GAHT (59%) and surgeries (46%) impact on suicide risk; and 6) navigating healthcare/work/school: barriers to accessing care (61%), training community providers (58%). Fertility was ranked as the least important research priority. Research on the discontinuation of gender-affirming interventions and regret in getting gender-affirming surgery were also ranked as low priorities. Conclusions TGD adults receiving care at a tertiary academic medical center ranked GAHT's effects on overall feminization/masculinization, mental health/suicide risk, common surgery complications, and cardiovascular health as top research priorities. They also indicated a desire for more research on barriers to accessing care, especially insurance coverage and provider education. Compared to other topics, fertility was ranked as the least important research priority. The TGD community's research priorities should be used to inform TGD health funding and researcher priorities to ensure that research evidence leads to improvements in patient-centered gender-affirming care. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Magnetic resonance imaging offers unrivaled visualization of the fetal brain, forming the basis for establishing age-specific morphologic milestones. However, gauging age-appropriate neural development remains a difficult task due to the constantly changing appearance of the fetal brain, variable image quality, and frequent motion artifacts. Here we present an end-to-end, attention-guided deep learning model that predicts gestational age with R2 score of 0.945, mean absolute error of 6.7 days, and concordance correlation coefficient of 0.970. The convolutional neural network was trained on a heterogeneous dataset of 741 developmentally normal fetal brain images ranging from 19 to 39 weeks in gestational age. We also demonstrate model performance and generalizability using independent datasets from four academic institutions across the U.S. and Turkey with R2 scores of 0.81–0.90 after minimal fine-tuning. The proposed regression algorithm provides an automated machine-enabled tool with the potential to better characterize in utero neurodevelopment and guide real-time gestational age estimation after the first trimester.

Background: Access to and quality of care for Substance Use Disorders (SUDs) remain a major public health issue. Stigma associated with SUDs contributes to the gap between the number of patients who need treatment and the much smaller fraction that receive it. Healthcare professional students are future care providers; an opportunity exists to characterize their collective perspectives on patients with SUDs and how that informs the care they provide. Methods: Healthcare professional students participated in online, semi-structured focus group (FGs) between March and April 2021. The FGs were conducted until thematic saturation was achieved. All verbatim transcripts were analyzed applying Thematic Analysis using Dedoose® qualitative software. Inductive codes were grouped into categories based on similarities that facilitated the emergence of themes. Results: Thematic Analysis revealed one theme (1) Decreasing stigma among healthcare professionals by viewing substance use disorder as a disease; and two sub-themes: Subtheme 1a: Relating with the patients, “It could be me…”; Subtheme 1b: Interactions with patients, “We just don’t know exactly how to counsel these patients…” These themes describe how future healthcare professionals might perceive and approach patients with SUDs and highlight the importance of SUD training in the curriculum. Conclusion: Medical and pharmacy students are uniquely positioned to apply critical thinking from their didactic training to their real-world clinical experiences, and their collective perspectives inform gaps in training and opportunities to develop best practices for SUD care. An opportunity exists to leverage these findings in order to train future healthcare professionals to ensure access to and quality of SUD care.

The COVID-19 restrictions have impacted people’s lifestyles in all spheres (social, psychological, political, economic, and others). This study explored which factors affected the level of anxiety during the time of the first wave of COVID-19 and subsequent quarantine in a substantial proportion of 23 countries, included in this study. The data was collected from May to August 2020 (5 June 2020). The sample included 15,375 participants from 23 countries: (seven from Europe: Belarus, Bulgaria, Croatia, Hungary, Italy, Romania, Russia; 11 from West, South and Southeast Asia: Armenia, India, Indonesia, Iran, Iraq, Jordan, Malaysia, Pakistan, Saudi Arabia, Thailand, Turkey; two African: Nigeria and Tanzania; and three from North, South, and Central America: Brazil, Canada, United States). Level of anxiety was measured by means of the 7-item Generalized Anxiety Disorder Scale (GAD-7) and the 20-item first part of The State-Trait Anxiety Inventory (STAI)—State Anxiety Inventory (SAI). Respondents were also asked about their personal experiences with COVID-19, attitudes toward measures introduced by governments, changes in attitudes toward migrants during a pandemic, family income, isolation conditions, etc. The factor analysis revealed that four factors explained 45.08% of variance in increase of anxiety, and these components were interpreted as follows: (1) personal awareness of the threat of COVID-19, (2) personal reaction toward officially undertaken measures and attitudes to foreigners, (3) personal trust in official sources, (4) personal experience with COVID-19. Three out of four factors demonstrated strong associations with both scales of anxiety: high level of anxiety was significantly correlated with high level of personal awareness of the threat of COVID-19, low level of personal reaction toward officially undertaken measures and attitudes to foreigners, and high level of presence of personal experience with COVID-19. Our study revealed significant main effects of sex, country, and all four factors on the level of anxiety. It was demonstrated that countries with higher levels of anxiety assessed the real danger of a pandemic as higher, and had more personal experience with COVID-19. Respondents who trusted the government demonstrated lower levels of anxiety. Finally, foreigners were perceived as the cause of epidemic spread.

Turnover of staff is an ongoing concern in the state-federal vocational rehabilitation (VR) system. To better understand employee turnover intent, a multiple regression analysis was conducted using professional identity and organizational factors (e.g., pay, work tenure) as predictor variables. An internet-based survey solicited counselor perceptions regarding professional identity, turnover intent, and job satisfaction. Respondents ( n = 351) described their level of satisfaction relevant to several workplace conditions (co-workers, job in general, work assignments, pay, promotion, and supervision), and their current level of professional identity. The outcome variable representing current or future turnover intent was whether participants were actively looking for a new position or planning to look for a new position in the next 5 years. Results indicated that a little over one third of current counselors would look for a new position in the coming year, with half of current counselors seeking a new position within 5 years. Findings suggest that turnover in state-federal VR settings exceeds the national average of 19%. Purposeful pre-hire considerations, goodness of fit, motivation factors (i.e., opportunities for promotion), and hygiene factors (i.e., caseload size, supervision, and pay) identified in this study should be elements of a state-federal VR agency’s plan to mitigate turnover intent.

Introduction: Fibromuscular dysplasia (FMD) is a non-inflammatory vasculopathy associated with arterial stenosis, aneurysm, dissection, and tortuosity. We investigated racial differences in clinical manifestations and events of multifocal FMD. Methods: Demographics, medical history, presenting signs and symptoms, and major vascular events were queried from the US Registry for FMD and stratified into White or Black based on self-identified race. Results: Of the 1897 female patients (pts) with multifocal FMD and race reported from 14 sites as of 12/23/2020, there were 1697 (89.5 %) White, 123 (6.5 %) Black, 52 (2.7%) Hispanic, and 25 (1.3%) pts of other races. Given a small number of pts in other groups, analysis was only performed between White and Black pts. Age at diagnosis and at first sign/symptom was similar between the two groups. Black pts were more likely to have a history of hypertension (p=0.009), stroke (p=0.002), and subarachnoid hemorrhage (p Conclusion: We noted a low number of Black patients enrolled in the US Registry for FMD at FMD specialty centers. There were differences in clinical manifestations, events, and pattern of vascular involvement among Black and White patients enrolled in US Registry, the mechanisms for which require additional study.

Introduction: Anticoagulation (AC) with warfarin or direct oral anticoagulants (DOAC) is the core of VTE treatment. Due to lower risk of VTE recurrence, American College of Chest Physicians (ACCP) recommends three months AC in patients with provoked VTE and without other indication for long-term AC. We aimed to assess how closely “real world” practice followed guideline recommendations. Hypothesis: We hypothesize most patients taking warfarin or DOAC for provoked VTE receive no more than three months AC. Patients who get prolonged AC are more likely to be taking DOAC than warfarin. Methods: We identified patients who initiated warfarin or DOAC from a six center AC clinic registry between 2008-20. Provoked VTE was defined as VTE after a transient risk factor: surgery, lower extremity cast/immobilization, childbirth, or OCPs. AC duration was categorized as 120 days. Appropriate treatment window was defined as 80-120 days to adjust for variability in clinic scheduling. Median AC length for DOAC vs. warfarin was compared with a two-sample test. Prevalence of extended AC was compared using chi-square test. Variables increasing risk of extended AC were analyzed with logistic regression, adjusted for baseline demographic and clinical characteristics. Results: At six centers, we identified 488 patients with provoked VTE on warfarin and 302 on DOAC. Average AC length was 137 days for warfarin and 180 days for DOAC (p120 days of AC (p120 days AC include recurrent VTE (OR 2.11; CI 1.34,3.32), prior MI (OR 4.09; CI 1.37,12.2), and DOAC use (OR 2.34; CI 1.69, 3.23) (Figure 1). Conclusions: In this multi-center analysis, most patients receive AC longer than guideline-recommended. DOAC use, recurrent VTE, and prior MI are associated with prolonged AC. Understanding the relationship between prior MI and AC duration in provoked VTE warrants future investigation.

Dandy-Walker continuum, which includes Dandy-Walker malformation, vermian hypoplasia, and Blake pouch cyst, is among the most commonly diagnosed posterior fossa malformation by fetal magnetic resonance imaging (MRI). The objective of our retrospective study was to evaluate fetal and postnatal MRI scan and clinical outcomes. Seventy-two patients were identified; 40 patients had postnatal imaging and follow-up (7 Dandy-Walker malformation, 26 vermian hypoplasia, and 7 Blake pouch cyst). Although all patients with Dandy-Walker malformation required ventriculoperitoneal shunts and 66% were intubated at birth, none required tracheostomy tube and 2 of 5 surviving children had no neurologic deficits. Vermian hypoplasia was strongly associated with genetic conditions and cardiac malformations; odds of not ambulating normally were 12 times greater if a syndrome or injury was present. Echocardiogram and genetic screening are recommended with vermian hypoplasia. There is a risk for epilepsy in both Dandy-Walker malformation and vermian hypoplasia. Blake pouch cyst can be complicated by hydrocephalus, but outcome is favorable.

This study explores marital satisfaction, division of child tasks, and satisfaction with the division of childcare outcomes among low-income Caucasian and Mexican American (MA) couples with young c...

OBJECTIVE Interventions are needed to improve mental health (ie, depression, anxiety) and palliative care (ie, symptoms, goals of care, and advance care planning) outcomes in Latino/as with advanced cancer. METHODS An interprofessional study team used the ecological validity model and a participatory approach to adapt an evidence-based counseling intervention for Latino/as and integrate the counseling intervention with an evidence-based patient navigator intervention. Next, a small pilot study was conducted to understand and improve the feasibility of the integrated puente para cuidar intervention. RESULTS Adaptations were made to language, literacy, and content of the counseling intervention, and video vignettes of the counseling case studies were produced on the recommendation of Latino/a stakeholders. Bicultural, bilingual patient navigators were used as "cultural brokers" between Latino/a patients and the counselor. The pilot study of puente para cuidar demonstrated feasibility based on participant perception of helpfulness and acceptability and nearing goal visit completion rates. CONCLUSIONS A culturally adapted intervention to address mental health and palliative care needs in Latino/as with advanced cancer was developed from prior evidenced-based interventions using a cultural adaptation model and a participatory approach. The intervention is ready for effectiveness testing.

PURPOSE: Patient navigation (PN) is an increasingly recognized element of high-quality, patient-centered cancer care, yet PN in many cancer programs is absent or limited, often because of concerns of extra cost without tangible financial benefits. METHODS: Five real-world examples of PN programs are used to demonstrate that in the pure fee-for-service and the alternative payment model worlds of reimbursement, strong cases can be made to support the benefits of PN. RESULTS: In three large programs, PN resulted in increased patient retention and increased physician loyalty within the cancer programs, leading to increased revenue. In addition, in two programs, PN was associated with a reduction in unnecessary resource utilization, such as emergency department visits and hospitalizations. PN also reduces burdens on oncology providers, potentially reducing burnout, errors, and costly staff turnover. CONCLUSION: PN has resulted in improved patient outcomes and patient satisfaction and has important financial benefits for cancer programs in the fee-for-service and the alternative payment model worlds, lending support for more robust staffing of PN programs.

Ventriculomegaly is the term used to describe abnormal enlargement of ventricles in the brain. Neuroimaging, whether it is by ultrasound, computed tomography, or magnetic resonance imaging, is the key to its identification and can help to diagnose its cause and guide management in many cases. The implementation of the imaging modalities and potential differential considerations varies from the fetus, infant, and pediatric patient. Here we discuss how the imaging modalities can be used in these patient populations and review some of the differential considerations.

Purpose The purpose of the study is to examine MRI findings of the brain and spine on prenatal and postnatal MRI following intrauterine repair of open spinal dysraphism (OSD) by open hysterotomy and fetoscopic approaches. Materials and methods This study is a single-center HIPAA-compliant and IRB-approved retrospective analysis of fetal MRIs with open spinal dysraphism from January 2011 through December 2018 that underwent subsequent prenatal repair of OSD. Results Sixty-two patients met inclusion criteria: 47 underwent open repair, and 15 underwent fetoscopic repair, with an average gestational age of 22.6 ± 1.4 weeks at initial MRI. On postnatal MRI, spinal cord syrinx was seen in 34% (16/47) of patients undergoing open versus 33.3% (5/15) undergoing fetoscopic repair (P = 0.96). Postnatally, there was no significant difference in hindbrain herniation between the open versus fetoscopic repair groups (P = 0.28). Lateral ventricular size was significantly larger in the open (20.9 ± 6.7 mm) versus the fetoscopic repair (16.1 ± 4.9 mm) group (P = 0.01). Conclusion Though lateral ventricular size in the open repair group was larger than the fetoscopic repair group, this can likely be explained by initial selection criteria used for fetoscopic repair. Other postoperative imaging parameters on postnatal MRI were not significantly different between the two groups.

Fetal Magnetic Resonance Imaging (MRI) is increasingly used in prenatal evaluations. Identify common brain malformations on fetal MRI and evaluate perinatal course. Fetal consultations from 10/2016 to 12/2017 reviewed. Hundred consultations were requested; 94 were completed. Findings included: posterior fossa malformations (19%), agenesis/dysgenesis of corpus callosum (15%), congenital aqueductal stenosis (CAS) (14%), ventriculomegaly (11%), isolated cortical malformations (8.5%), and holoprosencephaly (6%). Posterior fossa malformations were more likely to be associated with genetic conditions and cardiac malformations. Patients with CAS all required intensive care unit admission. Overall, few patients with congenital brain malformations required feeding or respiratory support at discharge. None had seizures as neonates except two with early epileptic encephalopathy syndromes. Even though long term neurological prognosis is poor for many conditions including high lifetime risk of epilepsy, most are discharged with no feeding or respiratory support. Seizures are rarely seen in the neonatal period.

Many neonates with hypoxic ischemic encephalopathy and seizures do not respond to the first line antiepileptic drug, phenobarbital. Little is known about what factors are associated with its failure.To examine factors associated with failure of phenobarbital therapy in neonates with hypoxic ischemic encephalopathy and seizures.A single-center retrospective review of 50 term (35 weeks) neonates with hypoxic ischemic encephalopathy and seizures treated with phenobarbital as the first-line antiepileptic. Neonates were classified into either responders (n = 30) or nonresponders (n = 20). Nonresponse was defined as continued seizures after maximum dosing of phenobarbital or an additional antiepileptic. Subjects with acceptable magnetic resonance imaging (MRI) scans obtained within 2 weeks of birth were included in the study and rated using an MRI injury scoring system. Charts were reviewed for demographic, clinical, and laboratory variables. Resuscitation and seizure scores were also calculated. Electroencephalographic (EEG) background activity was reviewed in 2 different time epochs (12-24 hours and 24-36 hours of life) and graded as per ACNS guidelines.There were no significant group differences in demographic, clinical, and laboratory variables except nonresponders, who had higher mean seizure score (In the presence of above factors, one can anticipate that additional antiepileptic medication may be needed. These data also support that larger studies should be done to look prospectively at using alternative agents first line in patients with severe injury.

Objective The accuracy of structural magnetic resonance imaging (MRI) to predict later cerebral palsy (CP) in newborns with perinatal brain injury is variable. Diffusion tensor imaging (DTI) and task-based functional MRI (fMRI) show promise as predictive tools. We hypothesized that infants who later developed CP would have reduced structural and functional connectivity as compared with those without CP. Study Design We performed DTI and fMRI using a passive motor task at 40 to 48 weeks' postmenstrual age in 12 infants with perinatal brain injury. CP was diagnosed at age 2 using a standardized examination. Results Five infants had CP at 2 years of age, and seven did not have CP. Tract-based spatial statistics showed a widespread reduction of fractional anisotropy (FA) in almost all white matter tracts in the CP group. Using the median FA value in the corticospinal tracts as a cutoff, FA was 100% sensitive and 86% specific to predict CP compared with a sensitivity of 60 to 80% and a specificity of 71% for structural MRI. During fMRI, the CP group had reduced functional connectivity from the right supplemental motor area as compared with the non-CP group. Conclusion DTI and fMRI obtained soon after birth are potential biomarkers to predict CP in newborns with perinatal brain injury.