Development and preliminary evaluation of a novel physician-report tool for assessing barriers to providing care to autistic patients.

BACKGROUND: Individuals on the autism spectrum face significant disparities in health and physicians often report difficulties in providing care to autistic patients. In order to improve the quality of care autistic individuals receive, it is important to identify the barriers that physicians experience in providing care so that these may be addressed. This paper reports the initial development and preliminary evaluation of a physician-report 'Barriers to Providing Healthcare' measurement tool. METHOD: An established taxonomy of healthcare barriers for autistic individuals informed the initial draft of a 22-item measurement tool. This measurement tool was distributed to physicians working in various healthcare specialties and settings. Exploratory factor analysis (EFA) was conducted to determine the construct validity of the tool; discriminant validity between, and internal consistency of, the resultant factors were assessed. Multiple regressions were used to explore variables potentially associated with barriers endorsed by physicians. RESULTS: A total of 203 physicians were included in the analyses. The EFA resulted in a 17-item tool with three distinct factors which explained 37.6% of the variance: 1) Patient-related barriers (Cronbach's α = 0.83; e.g., the patient's reactivity to the healthcare environment); 2) Healthcare provider (HCP)/family-related barriers (Cronbach's α = 0.81; e.g., a lack of providers willing to work with autistic patients); and 3) System-related barriers (Cronbach's α = 0.84; e.g., there is a lack of support for patients and families). Discriminant validity between the factors was adequate (r < .8). The barriers that were most frequently endorsed as occurring 'often' or 'very often' included a lack of support for patients and families (endorsed by 79.9% of physicians); communication difficulties (73.4%); and a lack of coordination between services (69.9%). The regression analyses identified no significant associated variables. CONCLUSION: A preliminary version of a novel physician-report tool to assess barriers to providing care to autistic patients has been developed although further validation work is required. The use of this tool will help physicians to identify issues specific to different medical specialities and healthcare settings. This information may help identify the supports physicians require to recognise and implement the required accommodations. Future research which elucidates barriers to healthcare provision for autistic patients is required to support systemic change in healthcare so as to improve care experiences and health outcomes for people on the autism spectrum.

Cerebrofacial arteriovenous metameric syndrome (CAMS): a spectrum disorder of craniofacial vascular malformations.

Cerebrofacial arteriovenous metameric syndrome (CAMS) is a recent classification of vascular malformations that encompasses a spectrum of phenotypic expression involving arteriovenous malformations (AVMs) of the cerebral, orbital, and facial region. Recognizing the embryologic basis of CAMS is important for diagnosing other AVMs along the same metameric level. Visual loss is the most common presentation prompting ophthalmologic evaluation followed by neuroimaging. We present two pediatric patients with ipsilateral optic nerve and chiasmal AVMs without cutaneous manifestations, characteristic of CAMS 2. The diagnosis of cerebral AVMs was made by magnetic resonance imaging of the brain and confirmed with cerebral angiography. High-resolution flat-panel computed tomography was performed in one patient and was useful to demonstrate the intraneural invasion of the optic nerve by the AVM.

Phase I study of low-dose metronomic temozolomide for recurrent malignant gliomas.

BACKGROUND: The treatment goal for recurrent malignant gliomas centers on disease stabilization while minimizing therapy-related side effects. Metronomic dosing of cytotoxic chemotherapy has emerged as a promising option to achieve this objective. METHODS: This phase I study was performed using metronomic temozolomide (mTMZ) at 25 or 50 mg/m2/day continuously in 42-day cycles. Correlative studies were incorporated using arterial spin labeling MRI to assess tumor blood flow, analysis of matrix metalloproteinase-2 (MMP-2) and MMP-9 activities in the cerebrospinal fluid (CSF) as surrogates for tumor angiogenesis and invasion, as well as determination of CSF soluble interleukin-2 receptor alpha (sIL-2Rα) levels as a marker of immune modulation. RESULTS: Nine subjects were enrolled and toxicity consisted of primarily grade 1 or 2 hematological and gastrointestinal side effects; only one patient had a grade 3 elevated liver enzyme level that was reversible. Tumor blood flow was variable across subjects and time, with two experiencing a transient increase before a decrease to below baseline level while one exhibited a gradual drop in blood flow over time. MMP-2 activity correlated with overall survival but not with progression free survival, while MMP-9 activity did not correlate with either outcome parameters. Baseline CSF sIL-2Rα level was inversely correlated with time from initial diagnosis to first progression, suggesting that subjects with higher sIL-2Rα may have more aggressive disease. But they lived longer when treated with mTMZ, probably due to drug-related changes in T-cell constituency. CONCLUSIONS: mTMZ possesses efficacy against recurrent malignant gliomas by altering blood flow, slowing invasion and modulating antitumor immune function.

A Systematic Review of Severe Neurological Manifestations in Pediatric Patients with Coexisting SARS-CoV-2 Infection.

SARS-CoV-2 infection in children produces mild respiratory symptoms or no symptoms at all in most cases. Some pediatric patients develop a severe complication associated with high mortality, the multisystem inflammatory syndrome in children (MIS-C). In both scenarios, there are reports of neurological manifestations. This article aims to review the cases of pediatric patients with severe neurological issues and a coexisting positive SARS-CoV-2 test. A literature search was performed between March 2020 and May 2021. The results included the data from 41 studies, with 159 children with severe neurological manifestations, within an age range from 24 h to 17 years. The neurological disorders included 38 cases with stroke, 32 with encephalitis, 22 with encephalopathy, and 10 with Guillain-Barre syndrome. Sixty-five out of 159 cases with severe neurological manifestations were diagnosed with MIS-C. Direct neuroinvasion and the exaggerated immune response in some patients seem to be the most critical factors triggering these manifestations. Further research in the ongoing pandemic is needed to elucidate the precise mechanism.

A conserved serine residue is required for the phosphatidate phosphatase activity but not the transcriptional coactivator functions of lipin-1 and lipin-2.

Mammalian lipins (lipin-1, lipin-2, and lipin-3) are Mg2+-dependent phosphatidate phosphatase (PAP) enzymes, which catalyze a key reaction in glycerolipid biosynthesis. Lipin-1 also functions as a transcriptional coactivator in conjunction with members of the peroxisome proliferator-activated receptor family. An S734L mutation in LPIN2 causes Majeed syndrome, a human inflammatory disorder characterized by recurrent osteomyelitis, fever, dyserythropoietic anemia, and cutaneous inflammation. Here we demonstrate that mutation of the equivalent serine in mouse lipin-1 and lipin-2 to leucine or aspartate abolishes PAP activity but does not impair lipin association with microsomal membranes, the major site of glycerolipid synthesis. We also determined that lipin-2 has transcriptional coactivator activity for peroxisome proliferator-activated receptor-response elements similar to lipin-1 and that this activity is not affected by mutating the conserved serine. Therefore, our results indicate that the symptoms of the Majeed syndrome result from a loss of lipin-2 PAP activity. To characterize sites of lipin-2 action, we detected lipin-2 expression by in situ hybridization on whole mouse sections and by quantitative PCR of tissues relevant to Majeed syndrome. Lipin-2 was most prominently expressed in liver, where levels were much higher than lipin-1, and also in kidney, lung, gastrointestinal tract, and specific regions of the brain. Lipin-2 was also expressed in circulating red blood cells and sites of lymphopoiesis (bone marrow, thymus, and spleen). These results raise the possibility that the loss of lipin-2 PAP activity in erythrocytes and lymphocytes may contribute to the anemia and inflammation phenotypes observed in Majeed syndrome patients.

Prehabilitation for patient positioning: pelvic exercises assist in minimizing inter-fraction sacral slope variability during radiation therapy.

Reproducible patient positioning is essential for precision in radiation therapy (RT) delivery. We tested the hypothesis that a structured daily pre-treatment stretching regimen is both feasible and effective for minimizing variability in positioning, as measured by sacral slope angles (SSA). Eight female subjects undergoing pelvic radiotherapy performed a structured daily hip exercise regimen (extension and external rotation) immediately prior to both simulation imaging and daily treatment, throughout their RT course. This exercising cohort was compared to a retrospective review of 20 subjects (17 women and 3 men) undergoing RT, who had usual care. SSA measurements from daily pre-treatment imaging were compared to SSA measurements from the simulation CT. The average variation in SSA among the intervention subjects was 0.91° (± 0.58°), with a range among subjects of 0.57°-1.27°. The average variation for the control subjects was 2.27° (± 1.43°), ranging 1.22°-5.09°. The difference between the two groups was statistically significant (p = 0.0001). There was a statistically significant SSA variation between groups at each week of treatment. There was no significant variation among the intervention subjects between week 1 and later weeks, whereas subjects in the control group demonstrated significant SSA variation between week 1 and later weeks. We demonstrated a significant decrease in the variability of SSA by implementing a simple pre-treatment exercise program, while control subjects exhibited increasing variation in SSA over the course of treatment. We conclude that there is a potential benefit of prehabilitation during pelvic RT; however, a larger randomized control trial is required to confirm the findings.Clinical Trial: This research project was approved by the University of Massachusetts Medical School IRB (IRB ID H00012353) on January 21, 2017. The study is listed on ClinicalTrials.gov, provided by the U.S. National Library of Medicine, found with identifier NCT03242538.

Treatment Toxicity: Radiation.

Intentional and unintentional radiation exposures have a powerful impact on normal tissue function and can induce short-term and long-term injury to all cell systems. Radiation effects can lead to lifetime-defining health issues for a patient and can produce complications to all organ systems. Providers need to understand acute and late effects of radiation treatment and how the fingerprints of therapy can have an impact on health care in later life. This article reviews current knowledge concerning normal tissue tolerance with therapy.

Positioning of port films for radiation: variability is present.

PURPOSE: Pelvic radiation treatment demands precision and consistency in patient setup for efficacy of therapy and to limit radiation dosage to normal tissue. Despite the use of immobilization devices and positioning techniques, there is still concern for variation in daily setup. The purpose of this retrospective study was to determine the presence and degree of variation in sacral slope in 20 subjects receiving radiation therapy for pelvic malignancies. METHODS: Each of the 20 subjects received between 20 and 25 fractions of external beam radiation treatment to the pelvis. The sacral slope was measured on each of the daily port films taken prior to treatment and compared to the sacral slope angle measured on the initial treatment planning simulation digitally reconstructed radiographic imaging. RESULTS: Compared to this initial imaging, the average sacral slope variation across all 20 subjects was 2.27° (± 1.43°), and the average variation among patients ranged from 1.22° to 5.09°. Variation in sacral slope across all 20 subjects from one treatment day to the next was 2.05° (± 1.47°), and ranged from 0.97° to 3.21°. CONCLUSIONS: This study demonstrates that despite the rigorous use of immobilization devices, there still exists day-to-day variation in sacral slope angle between treatment days and compared to initial baseline imaging off which the treatment plan is developed. There is an on-going study at our institution with an attempt to reduce this variation by offering exercises prior to radiation.

Effects of juvenile exposure to predator odor on adolescent and adult anxiety and pain nociception.

Clinical researchers have tracked patients with early life trauma and noted generalized anxiety disorder, unipolar depression, and risk-taking behaviors developing in late adolescence and into early adulthood. Animal models provide an opportunity to investigate the neural and developmental processes that underlie the relationship between early stress and later abnormal behavior. The present model used repeated exposure to 2,3,5-trimethyl-3-thiazoline (TMT), a component of fox feces, as an unconditioned fear-eliciting stimulus in order to induce stress in juvenile rats aged postnatal day (PND) 23 through 27. After further physical maturation characteristic of the adolescent stage (PND 42), animals were tested using an elevated plus maze (EPM) for anxiety and plantar test (Hargreaves method) for pain to assess any lingering effects of the juvenile stress. To assess how an additional stress later in life affects anxiety and pain nociception, PND 43 rats were exposed to inescapable shock (0.8mA) and again tested on EPM and plantar test. A final testing period was conducted in the adult (PND 63) rats to assess resulting changes in adult behaviors. TMT-exposed rats were significantly more anxious in adolescence than controls, but this difference disappeared after exposure to the secondary stressor. In adulthood, but not in adolescence, TMT-exposed rats demonstrated lower pain sensitivity than controls. These results suggest that early life stress can play a significant role in later anxiety and pain nociception, and offer insight into the development and manifestation of anxiety- and trauma-related disorders.

Regulation of lipin-1 gene expression by glucocorticoids during adipogenesis.

Lipin-1 deficiency in the mouse causes generalized lipodystrophy, characterized by impaired adipose tissue development and insulin resistance. Lipin-1 expression in differentiating preadipocytes is required for normal expression of adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma and CCAAT enhancer binding protein alpha, and for the synthesis of triacylglycerol. The requirement of lipin-1 for adipocyte differentiation can be explained, in part, by its activity as the sole adipocyte phosphatidic acid phosphatase-1 enzyme, which converts phosphatidate to diacylglycerol, the immediate precursor of triacylglycerol. Here we identify glucocorticoids as the stimulus for the induction of lipin-1 expression in differentiating adipocytes, and characterize a glucocorticoid response element (GRE) in the Lpin1 promoter. The Lpin1 GRE binds to the glucocorticoid receptor and leads to transcriptional activation in adipocytes and hepatocytes, as demonstrated by reporter gene transcription, electrophoretic mobility shift, and chromatin immunoprecipitation assays. This represents the first gene regulatory element identified to directly influence lipin-1 expression levels, and may modulate lipin-1 mRNA levels in adipose tissue and liver in conditions associated with increased local glucocorticoid concentrations in vivo, such as obesity and fasting.