Exposure to Weight Management Counseling Among Students at 8 U.S. Medical Schools.

INTRODUCTION: Clinical guidelines support physician intervention consistent with the Ask, Advise, Assess, Assist, Arrange framework for adults who have obesity. However, weight management counseling curricula vary across medical schools. It is unknown how frequently students receive experiences in weight management counseling, such as instruction, observation, and direct experience. METHODS: A cross-sectional survey, conducted in 2017, of 730 third-year medical students in 8 U.S. medical schools assessed the frequency of direct patient, observational, and instructional weight management counseling experiences that were reported as summed scores with a range of 0‒18. Analysis was completed in 2017. RESULTS: Students reported the least experience with receiving instruction (6.5, SD=3.9), followed by direct patient experience (8.6, SD=4.8) and observational experiences (10.3, SD=5.0). During the preclinical years, 79% of students reported a total of ≤3 hours of combined weight management counseling instruction in the classroom, clinic, doctor's office, or hospital. The majority of the students (59%-76%) reported never receiving skills-based instruction for weight management counseling. Of the Ask, Advise, Assess, Assist, Arrange framework, scores were lowest for assisting the patient to achieve their agreed-upon goals (31%) and arranging follow-up contact (22%). CONCLUSIONS: Overall exposure to weight management counseling was less than optimal. Medical school educators can work toward developing a more coordinated approach to weight management counseling.

Students' Report of Preceptor Weight Management Counseling at Eight U.S. Medical Schools.

INTRODUCTION: Primary care providers, using brief counseling, can help patients increase motivation to initiate or maintain weight loss, improve diet, and increase physical activity. However, no prior studies have examined the degree to which primary care preceptors, who are responsible for mentoring medical students during their core clerkships, provide clinical teaching regarding weight management counseling. METHODS: Medical students enrolled in eight U.S. medical schools who had finished their preclinical coursework completed surveys in the spring of 2016 to assess preceptor communication, modeling, feedback, and instruction in weight management counseling, as well as educational cues for patients and chart reminders for physicians. Analysis was completed in 2017 and 2018. RESULTS: Of 738 students completing the survey, the most recent completed clerkships were obstetrics and gynecology (38.1%), family medicine (32.1%), and internal medicine (29.8%). Students in family medicine clerkships reported higher levels of weight management counseling clinical teaching than students completing an internal medicine or obstetrics and gynecology clerkship. Among the main variables of interest across all three clerkships, only 13%-24% of students agreed that preceptors provided clear objectives for learning weight management counseling, and 13%-25% of students agreed that preceptors provided feedback. CONCLUSIONS: Even with a U.S. Preventive Services Task Force recommendation for primary care physicians to provide weight management counseling and endorsement from the major academic primary care societies, students in primary care clerkships report receiving little weight management counseling clinical teaching from their preceptors. The results reinforce the need for medical educators to teach and model weight management counseling for physicians-in-training if they are to achieve Task Force goals. Further research is required to better corroborate self-reported indicators of preceptor to student communication that are described herein.

Design and rationale of the medical students learning weight management counseling skills (MSWeight) group randomized controlled trial.

Physicians have an important role addressing the obesity epidemic. Lack of adequate teaching to provide weight management counseling (WMC) is cited as a reason for limited treatment. National guidelines have not been translated into an evidence-supported, competency-based curriculum in medical schools. Weight Management Counseling in Medical Schools: A Randomized Controlled Trial (MSWeight) is designed to determine if a multi-modal theoretically-guided WMC educational intervention improves observed counseling skills and secondarily improve perceived skills and self-efficacy among medical students compared to traditional education (TE). Eight U.S. medical schools were pair-matched and randomized in a group randomized controlled trial to evaluate whether a multi-modal education (MME) intervention compared to traditional education (TE) improves observed WMC skills. The MME intervention includes innovative components in years 1-3: a structured web-course; a role play exercise, WebPatientEncounter, and an enhanced outpatient internal medicine or family medicine clerkship. This evidence-supported curriculum uses the 5As framework to guide treatment and incorporates patient-centered counseling to engage the patient. The primary outcome is a comparison of scores on an Objective Structured Clinical Examination (OSCE) WMC case among third year medical students. The secondary outcome compares changes in scores of medical students from their first to third year on an assessment of perceived WMC skills and self-efficacy. MSWeight is the first RCT in medical schools to evaluate whether interventions integrated into the curriculum improve medical students' WMC skills. If this educational approach for teaching WMC is effective, feasible and acceptable it can affect how medical schools integrate WMC teaching into their curriculum.

Food Insecurity and Obesity: Exploring the Role of Social Support.

BACKGROUND: Women are disproportionately affected by both obesity and food insecurity. Food insecurity occurs when there is limited ability to acquire adequate foods. It is unknown whether social support can reduce the effect of food insecurity on increased obesity. This study seeks to determine whether social support modifies the relationship between food insecurity and obesity. METHODS: We conducted a cross-sectional study in a nationally representative sample of 4672 women aged ≥40 years using National Health and Nutrition Examination Survey (2003-2008). Individual food insecurity was assessed based on the U.S. Department of Agriculture 18-item validated household food security scale. Women were categorized as fully food secure (0 affirmative responses) or food insecure (1-10 affirmative responses). Obesity was defined as body mass index ≥30 kg/m2. Outcomes were analyzed by multivariable logistic regression. RESULTS: Fourteen percent were food insecure. Women with food insecurity had 1.4 the odds of obesity as those who were fully food secure, adjusting for race/ethnicity and health status (95% confidence interval [CI] 1.22-1.62). Food-insecure women were 80% less likely to report strong social support than women who were fully food secure (95% CI 0.11-0.36). Social support as measured in this study did not modify the association between food insecurity and obesity. CONCLUSIONS: Women reporting food insecurity reported lower levels of social support and were more likely to experience obesity. Interventions to reduce obesity in women who are food insecure must consider the limited resources available to these women.

Efficacy of Enzyme and Substrate Reduction Therapy with a Novel Antagonist of Glucosylceramide Synthase for Fabry Disease.

Fabry disease, an X-linked glycosphingolipid storage disorder, is caused by the deficient activity of α-galactosidase A (α-Gal A). This results in the lysosomal accumulation in various cell types of its glycolipid substrates, including globotriaosylceramide (GL-3) and lysoglobotriaosylceramide (globotriaosyl lysosphingolipid, lyso-GL-3), leading to kidney, heart, and cerebrovascular disease. To complement and potentially augment the current standard of care, biweekly infusions of recombinant α-Gal A, the merits of substrate reduction therapy (SRT) by selectively inhibiting glucosylceramide synthase (GCS) were examined. Here, we report the development of a novel, orally available GCS inhibitor (Genz-682452) with pharmacological and safety profiles that have potential for treating Fabry disease. Treating Fabry mice with Genz-682452 resulted in reduced tissue levels of GL-3 and lyso-GL-3 and a delayed loss of the thermal nociceptive response. Greatest improvements were realized when the therapeutic intervention was administered to younger mice before they developed overt pathology. Importantly, as the pharmacologic profiles of α-Gal A and Genz-682452 are different, treating animals with both drugs conferred the greatest efficacy. For example, because Genz-682452, but not α-Gal A, can traverse the blood-brain barrier, levels of accumulated glycosphingolipids were reduced in the brain of Genz-682452-treated but not α-Gal A-treated mice. These results suggest that combining substrate reduction and enzyme replacement may confer both complementary and additive therapeutic benefits in Fabry disease.

α-Galactosidase A knockout mice: progressive organ pathology resembles the type 2 later-onset phenotype of Fabry disease.

Fabry disease is an X-linked lysosomal storage disease caused by deficient activity of α-galactosidase A and the resultant systemic accumulation of globotrioasylceramide (GL-3) and related glycolipids. α-Galactosidase A gene knockout (Gla KO) mice have no α-galactosidase A activity and progressively accumulate GL-3 in tissues and fluids, similarly to FD patients. The nature and temporal effects of the progressive substrate accumulation on tissue histology in these mice have not previously been characterized. Here, we report the pathology of young to old (3 to 17 months old) Gla KO mice and compare these changes with those in strain-matched control animals. Gla KO mice accumulated GL-3 in various tissues and fluids with age. Lysosomal GL-3 inclusions increased with age in multiple cell types, including renal epithelial, intestinal, and vascular smooth muscle cells, and neurons in trigeminal and dorsal root ganglia, as detected by light and electron microscopy. However, unlike the case for male FD patients with the type 1 classic phenotype, GL-3 inclusions were not detected in vascular endothelial cells or cardiomyocytes. The histological changes in Gla KO mice better resemble the type 2 later-onset phenotype observed in patients with residual α-galactosidase A activity. GL-3 accumulation in the small intestine and sensory ganglia of Gla KO mice provides a model for study of enteropathy and neuropathy in Fabry disease.

Merits of combination cortical, subcortical, and cerebellar injections for the treatment of Niemann-Pick disease type A.

Niemann-Pick disease Type A (NPA) is a neuronopathic lysosomal storage disease (LSD) caused by the loss of acid sphingomyelinase (ASM). The goals of the current study are to ascertain the levels of human ASM that are efficacious in ASM knockout (ASMKO) mice, and determine whether these levels can be attained in non-human primates (NHPs) using a multiple parenchymal injection strategy. Intracranial injections of different doses of AAV1-hASM in ASMKO mice demonstrated that only a small amount of enzyme (<0.5 mg hASM/g tissue) was sufficient to increase survival, and that increasing the amount of hASM did not enhance this survival benefit until a new threshold level of >10 mg hASM/g tissue was reached. In monkeys, injection of 12 tracts of AAV1-hASM resulted in efficacious levels of enzyme in broad regions of the brain that was aided, in part, by axonal transport of adeno-associated virus (AAV) and movement through the perivascular space. This study demonstrates that a combination cortical, subcortical, and cerebellar injection protocol could provide therapeutic levels of hASM to regions of the NHP brain that are highly affected in NPA patients. The information from this study might help design new AAV-mediated enzyme replacement protocols for NPA and other neuronopathic LSDs in future clinical trials.

Iminosugar-based inhibitors of glucosylceramide synthase prolong survival but paradoxically increase brain glucosylceramide levels in Niemann-Pick C mice.

Niemann Pick type C (NPC) disease is a progressive neurodegenerative disease caused by mutations in NPC1 or NPC2, the gene products of which are involved in cholesterol transport in late endosomes. NPC is characterized by an accumulation of cholesterol, sphingomyelin and glycosphingolipids in the visceral organs, primarily the liver and spleen. In the brain, there is a redistribution of unesterified cholesterol and a concomitant accumulation of glycosphingolipids. It has been suggested that reducing the aberrant lysosomal storage of glycosphingolipids in the brain by a substrate reduction therapy (SRT) approach may prove beneficial. Inhibiting glucosylceramide synthase (GCS) using the iminosugar-based inhibitor miglustat (NB-DNJ) has been reported to increase the survival of NPC mice. Here, we tested the effects of Genz-529468, a more potent iminosugar-based inhibitor of GCS, in the NPC mouse. Oral administration of Genz-529468 or NB-DNJ to NPC mice improved their motor function, reduced CNS inflammation, and increased their longevity. However, Genz-529468 offered a wider therapeutic window and better therapeutic index than NB-DNJ. Analysis of the glycolipids in the CNS of the iminosugar-treated NPC mouse revealed that the glucosylceramide (GL1) but not the ganglioside levels were highly elevated. This increase in GL1 was likely caused by the off-target inhibition of the murine non-lysosomal glucosylceramidase, Gba2. Hence, the basis for the observed effects of these inhibitors in NPC mice might be related to their inhibition of Gba2 or another unintended target rather than a result of substrate reduction.

Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease.

The neuropathic glycosphingolipidoses are a subgroup of lysosomal storage disorders for which there are no effective therapies. A potential approach is substrate reduction therapy using inhibitors of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide and related glycosphingolipids that accumulate in the lysosomes. Genz-529468, a blood-brain barrier-permeant iminosugar-based GCS inhibitor, was used to evaluate this concept in a mouse model of Sandhoff disease, which accumulates the glycosphingolipid GM2 in the visceral organs and CNS. As expected, oral administration of the drug inhibited hepatic GM2 accumulation. Paradoxically, in the brain, treatment resulted in a slight increase in GM2 levels and a 20-fold increase in glucosylceramide levels. The increase in brain glucosylceramide levels might be due to concurrent inhibition of the non-lysosomal glucosylceramidase, Gba2. Similar results were observed with NB-DNJ, another iminosugar-based GCS inhibitor. Despite these unanticipated increases in glycosphingolipids in the CNS, treatment nevertheless delayed the loss of motor function and coordination and extended the lifespan of the Sandhoff mice. These results suggest that the CNS benefits observed in the Sandhoff mice might not necessarily be due to substrate reduction therapy but rather to off-target effects.

Vesicular monoamine transporter-1 (VMAT-1) mRNA and immunoreactive proteins in mouse brain.

OBJECTIVE: Vesicular monoamine transporter 1 (VMAT-1) mRNA and protein were examined (1) to determine whether adult mouse brain expresses full-length VMAT-1 mRNA that can be translated to functional transporter protein and (2) to compare immunoreactive VMAT-1 proteins in brain and adrenal. METHODS: VMAT-1 mRNA was detected in mouse brain with RT-PCR. The cDNA was sequenced, cloned into an expression vector, transfected into COS-1 cells, and cell protein was assayed for VMAT-1 activity. Immunoreactive proteins were examined on western blots probed with four different antibodies to VMAT-1. RESULTS: Sequencing confirmed identity of the entire coding sequences of VMAT-1 cDNA from mouse medulla oblongata/pons and adrenal to a Gen-Bank reference sequence. Transfection of the brain cDNA into COS-1 cells resulted in transporter activity that was blocked by the VMAT inhibitor reserpine and a proton ionophore, but not by tetrabenazine, which has a high affinity for VMAT-2. Antibodies to either the C- or N- terminus of VMAT-1 detected two proteins (73 and 55 kD) in transfected COS-1 cells. The C-terminal antibodies detected both proteins in extracts of mouse medulla/pons, cortex, hypothalamus, and cerebellum but only the 73 kD protein and higher molecular weight immunoreactive proteins in mouse adrenal and rat PC12 cells, which are positive controls for rodent VMAT-1. CONCLUSIONS: These findings demonstrate that a functional VMAT-1 mRNA coding sequence is expressed in mouse brain and suggest processing of VMAT-1 protein differs in mouse adrenal and brain.

Systemic administration of AAV8-α-galactosidase A induces humoral tolerance in nonhuman primates despite low hepatic expression.

In mice, liver-restricted expression of lysosomal enzymes from adeno-associated viral serotype 8 (AAV8) vectors results in reduced antibodies to the expressed proteins. To ask whether this result might translate to patients, nonhuman primates (NHPs) were injected systemically with AAV8 encoding α-galactosidase A (α-gal). As in mice, sustained expression in monkeys attenuated antibody responses to α-gal. However, this effect was not robust, and sustained α-gal levels were 1-2 logs lower than those achieved in male mice at the same vector dose. Because our mouse studies had shown that antibody levels were directly related to expression levels, several strategies were evaluated to increase expression in monkeys. Unlike mice, expression in monkeys did not respond to androgens. Local delivery to the liver, immune suppression, a self-complementary vector and pharmacologic approaches similarly failed to increase expression. While equivalent vector copies reached mouse and primate liver and there were no apparent differences in vector form, methylation or deamination, transgene expression was limited at the mRNA level in monkeys. These results suggest that compared to mice, transcription from an AAV8 vector in monkeys can be significantly reduced. They also suggest some current limits on achieving clinically useful antibody reduction and therapeutic benefit for lysosomal storage diseases using a systemic AAV8-based approach.

Substrate reduction augments the efficacy of enzyme therapy in a mouse model of Fabry disease.

Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency in the activity of the lysosomal hydrolase α-galactosidase A (α-gal). This deficiency results in accumulation of the glycosphingolipid globotriaosylceramide (GL-3) in lysosomes. Endothelial cell storage of GL-3 frequently leads to kidney dysfunction, cardiac and cerebrovascular disease. The current treatment for Fabry disease is through infusions of recombinant α-gal (enzyme-replacement therapy; ERT). Although ERT can markedly reduce the lysosomal burden of GL-3 in endothelial cells, variability is seen in the clearance from several other cell types. This suggests that alternative and adjuvant therapies may be desirable. Use of glucosylceramide synthase inhibitors to abate the biosynthesis of glycosphingolipids (substrate reduction therapy, SRT) has been shown to be effective at reducing substrate levels in the related glycosphingolipidosis, Gaucher disease. Here, we show that such an inhibitor (eliglustat tartrate, Genz-112638) was effective at lowering GL-3 accumulation in a mouse model of Fabry disease. Relative efficacy of SRT and ERT at reducing GL-3 levels in Fabry mouse tissues differed with SRT being more effective in the kidney, and ERT more efficacious in the heart and liver. Combination therapy with ERT and SRT provided the most complete clearance of GL-3 from all the tissues. Furthermore, treatment normalized urine volume and uromodulin levels and significantly delayed the loss of a nociceptive response. The differential efficacies of SRT and ERT in the different tissues indicate that the combination approach is both additive and complementary suggesting the possibility of an improved therapeutic paradigm in the management of Fabry disease.

Inhibition of glycogen biosynthesis via mTORC1 suppression as an adjunct therapy for Pompe disease.

Pompe disease, also known as glycogen storage disease (GSD) type II, is caused by deficiency of lysosomal acid alpha-glucosidase (GAA). The resulting glycogen accumulation causes a spectrum of disease severity ranging from a rapidly progressive course that is typically fatal by 1-2years of age to a more slowly progressive course that causes significant morbidity and early mortality in children and adults. Recombinant human GAA (rhGAA) improves clinical outcomes with variable results. Adjunct therapy that increases the effectiveness of rhGAA may benefit some Pompe patients. Co-administration of the mTORC1 inhibitor rapamycin with rhGAA in a GAA knockout mouse reduced muscle glycogen content more than rhGAA or rapamycin alone. These results suggest mTORC1 inhibition may benefit GSDs that involve glycogen accumulation in muscle.