Low-dose daily folic acid (400 µg) supplementation does not affect regulation of folate transporters found present throughout the terminal ileum and colon of humans: a randomized clinical trial.

BACKGROUND: Folic acid supplementation during the periconceptional period reduces the risk of neural tube defects in infants, but concern over chronic folic acid exposure remains. An improved understanding of folate absorption may clarify potential risks. Folate transporters have been characterized in the small intestine, but less so in the colon of healthy, free-living humans. The impact of folic acid fortification or supplementation on regulation of these transporters along the intestinal tract is unknown. OBJECTIVE: The objective was to characterize expression of folate transporters/receptor (FT/R) and folate hydrolase, glutamate carboxypeptidase II (GCPII), from the terminal ileum and throughout the colon of adults and assess the impact of supplemental folic acid. METHODS: In this 16-wk open-labeled randomized clinical trial, adults consumed a low folic acid-containing diet, a folate-free multivitamin, and either a 400 µg folic acid supplement or no folic acid supplement. Dietary intakes and blood were assessed at baseline, 8 wk, and 16 wk (time of colonoscopy). Messenger RNA (mRNA) expression and protein expression of FT/R and GCPII were assessed in the terminal ileum, cecum, and ascending and descending colon. RESULTS: Among 24 randomly assigned subjects, no differences in dietary folate intake or blood folate were observed at baseline. Mean ± SD red blood cell folate at 16 wk was 1765 ± 426 and 911 ± 242 nmol/L in the 400 and 0 µg folic acid group, respectively (P < 0.0001). Reduced folate carrier, proton-coupled folate transporter, and folate-receptor alpha expression were detected in the terminal ileum and colon, as were efflux transporters of breast cancer resistance protein and multidrug resistance protein-3. Other than a higher mRNA expression of FR-alpha and GCPII in the 400 µg supplement group in the ascending colon, no treatment differences were observed (P < 0.02). CONCLUSIONS: Folate transporters are present throughout the terminal ileum and colon; there is little evidence that a low dose of folic acid supplementation affects colonic absorption. This trial was registered at clinicaltrials.gov as NCT03421483.

Ethical Dilemmas, Moral Distress, and the Risk of Moral Injury: Experiences of Residents and Fellows During the COVID-19 Pandemic in the United States.

The ongoing COVID-19 pandemic has brought numerous ethical dilemmas to the forefront of clinical care, including for resident and fellow physician trainees. In this paper, the authors draw on their own experiences providing frontline COVID-19 clinical care in New York City in their respective roles as an internal medicine resident and later a pulmonary and critical care fellow, and as an associate program director for a pulmonary and critical care fellowship, along with published literature on trainees' experiences in the pandemic, to describe common ethical dilemmas confronted by residents and fellows during the pandemic. These dilemmas are related to personal health risk, resource allocation, health care inequities, and media relations. The authors use a framework of microethics to underscore how these dilemmas are highly contextualized within trainees' institutions, their specific roles, and the patient populations to which they provide care. They argue that frequent ethical dilemmas, compounded by the intense physical and emotional stress of medical training and the pandemic itself, increase the potential for trainees to experience moral distress. Recurrent moral distress may, in turn, put trainees at risk for moral injury with consequences for their mental health and overall well-being. It is imperative to gain a clear understanding of this issue, not only for those trainees who have experienced or are at risk for experiencing personal consequences but also because it may help identify ways to better support the well-being of providers and the care of patients going forward.

Open-label, add-on trial of cetirizine for neuromyelitis optica.

OBJECTIVE: This pilot study preliminarily examined the efficacy and tolerability of cetirizine as an add-on to standard therapy for neuromyelitis optica (NMO). METHODS: Eligible participants met the Wingerchuk 2006 diagnostic criteria or had a single typical episode along with positive NMO immunoglobulin G. After baseline clinical and laboratory assessments, participants began treatment with cetirizine 10 mg orally daily, in addition to their usual disease-modifying therapy for NMO, and continued for 1 year. The primary end point was the annualized relapse rate (ARR) while on the same disease-modifying therapy before starting cetirizine compared with after taking cetirizine. Additional end points included disability (Expanded Disability Status Scale [EDSS]), relapse severity, tolerability, especially with respect to drowsiness measured by the Epworth Sleepiness Scale (ESS), and laboratory parameters. RESULTS: The ARR before cetirizine was 0.4 ± 0.80 and after cetirizine was 0.1 ± 0.24 (p = 0.047). There was no statistically significant difference in the EDSS (mean 3.9 ± 2.18 before the start of the study and 3.2 ± 2.31 at the conclusion of the study, p = 0.500). The ESS remained fairly consistent throughout the study (mean 6.5 ± 5.33 at baseline and 6.9 ± 4.50 at month 12, p = 0.740). Laboratory studies were unrevealing. CONCLUSIONS: In this pilot study, cetirizine was well tolerated, and the prespecified primary efficacy end point was satisfied. However, the open-label design and the small sample size of this pilot study preclude definitive conclusions. Further research is needed. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with NMO, the addition of cetirizine to standard therapy is safe, well tolerated, and reduces relapses.

Objective and subjective measures of dalfampridine efficacy in clinical practice.

BACKGROUND: Multiple sclerosis affects mobility in over 80% of patients. Dalfampridine is the only approved treatment for walking impairment in multiple sclerosis. We assessed dalfampridine utilization in our practice and investigated response using timed 25 foot walk (T25FW) improvement and a patient-reported ambulation inventory. METHODS: Chart review identified patients with multiple sclerosis for whom dalfampridine was prescribed. T25FW data were extracted from medical records. Participants completed a dalfampridine-specific version of the multiple sclerosis walking scale (dMSWS-12) to assess the qualitative impact of dalfampridine on ambulation. We evaluated two responder categories: liberally defined as any improvement in T25FW; and over 20% T25FW improvement. RESULTS: The dMSWS-12 questionnaire was completed by 39 patients. Eighteen patients (46%) did not show any T25FW improvement. Of the 21 patients (54%) with T25FW improvement, four patients (11%) showed improvement greater than 20%. Analysis of dMSWS-12 scores showed a median score of 40 (range 12-60). Eleven patients (28%) showed no improvement (dMSWS-12 score ≤36). In contrast to objective T25FW improvement (54%), 28 patients (72%) reported improvement in walking ability (dMSWS-12 score ≥37). CONCLUSION: Our results suggest that T25FW alone might not be sufficient for response characterization and that adding patient-reported measures may further elucidate the therapeutic response.

Synchronization and variability imbalance underlie cognitive impairment in primary-progressive multiple sclerosis.

We aimed to investigate functional connectivity and variability across multiple frequency bands in brain networks underlying cognitive deficits in primary-progressive multiple sclerosis (PP-MS) and to explore how they are affected by the presence of cortical lesions (CLs). We analyzed functional connectivity and variability (measured as the standard deviation of BOLD signal amplitude) in resting state networks (RSNs) associated with cognitive deficits in different frequency bands in 25 PP-MS patients (12 M, mean age 50.9 ± 10.5 years) and 20 healthy subjects (9 M, mean age 51.0 ± 9.8 years). We confirmed the presence of a widespread cognitive deterioration in PP-MS patients, with main involvement of visuo-spatial and executive domains. Cognitively impaired patients showed increased variability, reduced synchronicity between networks involved in the control of cognitive macro-domains and hyper-synchronicity limited to the connections between networks functionally more segregated. CL volume was higher in patients with cognitive impairment and was correlated with functional connectivity and variability. We demonstrate, for the first time, that a functional reorganization characterized by hypo-synchronicity of functionally-related/hyper-synchronicity of functionally-segregated large scale networks and an abnormal pattern of neural activity underlie cognitive dysfunction in PP-MS, and that CLs possibly play a role in variability and functional connectivity abnormalities.

Retinal degeneration in primary-progressive multiple sclerosis: A role for cortical lesions?

BACKGROUND: Retinal atrophy in multiple sclerosis (MS) is secondary to optic nerve focal inflammation and to injury of the posterior visual pathway. OBJECTIVES: To investigate the contribution of cortical lesions (CLs) to retinal pathology in primary-progressive multiple sclerosis (PPMS). METHODS: We performed a cross-sectional evaluation of 25 patients and 20 controls, relating magnetic resonance imaging (MRI) metrics of visual pathway integrity with parameters derived from spectral-domain optical coherence tomography (peripapillary retinal nerve fiber layer (RNFL) thickness, ganglion cell + inner plexiform layer (GCIPL) thickness, and macular volume (MV)). RESULTS: Mean RNFL, GCIPL thickness, and MV were significantly reduced in patients compared to controls. MV and GCIPL thickness were significantly correlated with visual acuity. RNFL thinning was associated with thalamus and visual cortex volume (respectively, p = 0.01 and p < 0.05). In addition to thalamic volume, GCIPL thinning was associated with CLs and intracortical lesion number and volume, leucocortical lesion volume (all p ⩽ 0.05) while MV decrease was associated with CLs volume ( p = 0.05) and intracortical lesion number and volume ( p < 0.05). CONCLUSION: Our results suggest that RNFL thinning and GCIPL thinning/MV decrease may be explained by alternative mechanisms including retrograde trans-synaptic degeneration and/or a common pathophysiologic process affecting both the brain with CLs and the retina with neuronal loss.

Phase-Sensitive Inversion-Recovery MRI Improves Longitudinal Cortical Lesion Detection in Progressive MS.

Previous studies comparing phase sensitive inversion recovery (PSIR) to double inversion recovery (DIR) have demonstrated that use of PSIR improves cross-sectional in vivo detection of cortical lesions (CL) in multiple sclerosis. We studied the utility of PSIR in detection/characterization of accrual of CL over time in a 1-year longitudinal study in primary progressive multiple sclerosis (PPMS) compared to DIR. PSIR and DIR images were acquired with 3T magnetic resonance imaging (MRI) in 25 patients with PPMS and 19 healthy controls at baseline, and after 1 year in 20 patients with PPMS. CL were classified as intracortical, leucocortical or juxtacortical. Lesion counts and volumes were calculated for both time points from both sequences and compared. Correlations with measures of physical and cognitive disability were determined as well as new CL counts and volumes. Compared to DIR, PSIR led to detection of a higher number of CL involving a larger proportion of patients with PPMS both cross-sectionally (p = 0.006, 88%) and longitudinally (p = 0.007, 95%), and led to the reclassification of a third of CL seen on DIR at each time point. Interestingly, PSIR was more sensitive to new CL accumulation over time compared to DIR. PSIR is a promising technique to monitor cortical damage and disease progression in patients with PPMS over a short-term follow-up.

Relationship between timed 25-foot walk and diffusion tensor imaging in multiple sclerosis.

OBJECTIVE/BACKGROUND: The majority of multiple sclerosis patients experience impaired walking ability, which impacts quality of life. Timed 25-foot walk is commonly used to gauge gait impairment but results can be broadly variable. Objective biological markers that correlate closely with patients' disability are needed. Diffusion tensor imaging, quantifying fiber tract integrity, might provide such information. In this project we analyzed relationships between timed 25-foot walk, conventional and diffusion tensor imaging magnetic resonance imaging markers. DESIGN/METHODS: A cohort of gait impaired multiple sclerosis patients underwent brain and cervical spinal cord magnetic resonance imaging. Diffusion tensor imaging mean diffusivity and fractional anisotropy were measured on the brain corticospinal tracts and spinal restricted field of vision at C2/3. We analyzed relationships between baseline timed 25-foot walk, conventional and diffusion tensor imaging magnetic resonance imaging markers. RESULTS: Multivariate linear regression analysis showed a statistically significant association between several magnetic resonance imaging and diffusion tensor imaging metrics and timed 25-foot walk: brain mean diffusivity corticospinal tracts (p = 0.004), brain corticospinal tracts axial and radial diffusivity (P = 0.004 and 0.02), grey matter volume (p = 0.05), white matter volume (p = 0.03) and normalized brain volume (P = 0.01). The linear regression model containing mean diffusivity corticospinal tracts and controlled for gait assistance was the best fit model (p = 0.004). CONCLUSIONS: Our results suggest an association between diffusion tensor imaging metrics and gait impairment, evidenced by brain mean diffusivity corticospinal tracts and timed 25-foot walk.

Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) and Alberta Infant Motor Scale (AIMS): Validity and Responsiveness.

BACKGROUND: Although preliminary studies have established a good psychometric foundation for the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) for a broad population of youth with disabilities, additional validation is warranted for young children. OBJECTIVE: The study objective was to (1) examine concurrent validity, (2) evaluate the ability to identify motor delay, and (3) assess responsiveness of the PEDI-CAT Mobility domain and the Alberta Infant Motor Scale (AIMS). METHODS: Fifty-three infants and young children (<18 months of age) admitted to a pediatric postacute care hospital and referred for a physical therapist examination were included. The PEDI-CAT Mobility domain and the AIMS were completed during the initial physical therapist examination, at 3-month intervals, and at discharge. A Spearman rank correlation coefficient was used to examine concurrent validity. A chi-square analysis of age percentile scores was used to examine the identification of motor delay. Mean score differences from initial assessment to final assessment were analyzed to evaluate responsiveness. RESULTS: A statistically significant, fair association (rs=.313) was found for the 2 assessments. There was no significant difference in motor delay identification between tests; however, the AIMS had a higher percentage of infants with scores at or below the fifth percentile. Participants showed significant changes from initial testing to final testing on the PEDI-CAT Mobility domain and the AIMS. LIMITATIONS: This study included only young patients (<18 months of age) in a pediatric postacute hospital; therefore, the generalizability is limited to this population. CONCLUSIONS: The PEDI-CAT Mobility domain is a valid measure for young children admitted to postacute care and is responsive to changes in motor skills. However, further item and standardization development is needed before the PEDI-CAT is used confidently to identify motor delay in children <18 months of age.

Diagnostic uncertainty during the transition to secondary progressive multiple sclerosis.

Secondary progressive multiple sclerosis (MS) is typically defined as deterioration independent of relapses for ≥ 6 months following an initial relapsing-remitting course; however, this definition is not always easily applied in clinical practice and the declaration of the change in clinical phenotype is often delayed. To identify the length of time required to re-classify relapsing-remitting MS (RRMS) patients whom have clinically transitioned to secondary progressive MS (SPMS) in clinical practice. We reviewed 123 patients with long-term follow-up and identified a sub-group whom transitioned from RRMS to SPMS, then characterized this transition period. There were 14/20 patients who transitioned during the follow-up period that had visits with uncertainty related to the clinical phenotype characterized by possible, but not definitive progression. The mean duration of this period of uncertainty was 2.9 ± 0.8 years. A period of diagnostic uncertainty regarding the transition from RRMS to SPMS existed in many of our patients. Potential reasons included the subtle nature of early progressive disease and caution in applying a progressive label, in light of the lack of evidence-based treatments as well as third-party payer concerns. Delay in definitive identification of an SPMS phenotype has a variety of implications related to patient care and research.

Evaluating merger and intersection of equivalence classes with one member in common.

Sidman (1994) noted that the existence of a member that is common to more than one class may produce either class merger (union) or class intersection. A multiple-selection, matching-to-sample test was developed to examine the conditions under which these outcomes occur. Test trials each required three conditional discriminations involving selection or rejection of comparison stimuli under control of samples representing two categories. Test results obtained from an initial group of typical adults using familiar stimuli (DOG and BIRD, pictures of dogs and birds and relevant printed breed names (e.g., DALMATIAN, RETRIEVER) showed the conditional stimulus control best described as intersection. For example, the word DALMATIAN provided the context for selecting the dalmatian but not the retriever picture. However, these results may have depended on the participants' verbal history as English speakers. Would conditional-discrimination training with overlapping sets of laboratory-generated stimuli also result in intersection? Naïve typical adults were assigned to one of three different training conditions. Like the participants tested with familiar stimuli, these participants demonstrated highly reliable test outcomes best described as showing class intersection, regardless of training condition. These findings begin to elucidate the necessary and sufficient conditions for establishing complex category-like classes of stimuli.

Effectiveness of intensive residential treatment (IRT) for severe, refractory obsessive-compulsive disorder.

OBJECTIVE: The aim of this study was to determine the effectiveness of an innovative Intensive Residential Treatment (IRT) program for severe refractory Obsessive-Compulsive Disorder (OCD). No formalized OCD IRT outcome studies have been completed to date in North America. METHOD: Subjects admitted to the Massachusetts General Hospital/McLean OCD Institute (OCDI) between February 1997 and June 2003 comprised the intent-to-treat sample. Measures of OCD severity, depression severity and psychosocial well-being were determined at admission, interim and discharge points, and were subsequently compared via t-tests using a last-observation-carried-forward approach. Initial OCD severity subgroups and treatment length subgroups were created and analyzed. Correlations and stepwise linear regressions were conducted to determine treatment length predictors. RESULTS: The sample of 403 individuals (58.7% male) had an average 66 day treatment length. Mean YBOCS scores decreased by 30.1%, from 26.6 (SD 6.1) at admission to 18.6 (SD 7.2) at discharge, reflecting a clinically meaningful improvement (p<0.001). Psychosocial functioning, depression severity scores and self-report global functioning ratings also indicated significant improvement. Subgroups with longer treatment lengths tended to have earlier ages of OCD onset and increased OCD severity scores at admission. CONCLUSION: IRT deserves recognition as a therapeutic approach for severe, refractory OCD. In the largest study to date for IRT significant improvements of OCD severity, depression severity and quality of life were determined. IRT should be considered prior to more invasive approaches for severe refractory OCD.

Excellent outcome in infants and small children with thrombophilias undergoing kidney transplantation.

One of the most common causes of early graft failure in children undergoing renal transplantation is vascular thrombosis. Numerous risk factors for graft thrombosis have been previously described. Children with various types of thrombophilias such as protein C, protein S and factor V Leiden deficiencies are at an increased risk for vascular thrombosis. Infants and small children with these disorders undergoing renal transplantation have not been well documented in the literature. We reviewed our experience in the diagnosis, peri-operative management and follow up of these patients at our institution. A retrospective analysis of all children undergoing renal transplantation at our institution, using data obtained from the Pediatric Transplant Registry at our institution since May 2000 was performed. The indications for renal transplant included focal segmental glomerulosclerosis, renal dysplasia and reflux nephropathy. One patient had factor V Leiden mutation and two patients had protein S deficiency. Patients were anticoagulated in the peri-operative and post-transplant period. All index transplants were performed with living donor kidneys. There were no adverse outcomes in children with thrombophilias despite having significantly lower weight at the time of transplant vs. children without thrombophilia. The incidence of graft thrombosis in the pediatric renal transplant recipients is high. We identify a potential cause of thrombosis in children not well documented in the literature. A high index of suspicion combined with preoperative screening and diagnosis of thrombophilias and an appropriate treatment plan may decrease the incidence of graft thrombosis in infants and small children undergoing renal transplantation.