What are Internal medicine residents' attitudes toward obesity as a disease, people living with obesity, and obesity treatment?

Objective: Despite the rising prevalence of people living with obesity, physicians are providing suboptimal care to these individuals, which may be a consequence of inadequate education in weight management and negative attitudes toward people living with obesity. Internal Medicine (IM) residency is an ideal setting to address physicians' attitudes toward people living with obesity. However, there is a paucity of recent literature on this topic. This study sought to assess the current attitudes of IM residents toward obesity as a disease, people living with obesity, and obesity treatment. Methods: A cross-sectional survey was conducted in 2020 across two IM programs assessing residents' attitudes toward obesity as a disease, people living with obesity, and obesity treatment. RESULTS: Among 42 residents who participated in the survey, 64% were women; 31 percent were Post Graduate Year 1, 31% PGY-2, and 38% PGY-3. Mean attitude scores were high on statements regarding obesity as a chronic disease [4.7 (SD 0.4)] and its association with serious medical conditions [4.9 (SD 0.3)]. Residents had overall positive attitudes toward people living with obesity. In contrast, residents felt negatively regarding their level of success in helping patients lose weight [2.0 (SD 0.7)]. CONCLUSIONS: While residents recognized obesity as a chronic disease and had positive attitudes toward people living with obesity, their low ratings regarding weight management success suggest that targeted educational efforts are needed to increase obesity treatment self-efficacy.

An obesity medicine curriculum increases the obesity care self-efficacy of internal medicine residents in the primary care setting.

Primary care physicians (PCPs) report insufficient knowledge and training gaps in obesity care. Internal Medicine (IM) residency offers an opportunity to address this educational gap for future PCPs. We designed an innovative, multicomponent curriculum on obesity medicine (OM) in the primary care setting for IM residents. We then conducted a prospective, 6-month, two-arm study within two residency programs in Maryland evaluating feasibility (use, appropriateness for IM training, and satisfaction) of the curriculum as well as changes in self-efficacy within seven obesity care domains, assessed on 4-point scales (1-not at all confident to 4-very confident). One residency program received the curriculum and the other served as the control group. We recruited 35 IM residents to participate (17 intervention, 18 control). Among intervention residents, 42% used all curricular components; appropriateness and satisfaction with the curriculum were high. Compared with controls, intervention residents had statistically significant increases in five obesity care self-efficacy domains: nutrition (intervention 0.8 vs. control 0.2, p = .02), behaviour change (1.2 vs. 0.4, p < .01), weight-gain-promoting medications (0.8 vs. 0.1, p = .01), anti-obesity medications (1.2 vs. 0.5, p = .03), and bariatric surgical counselling (0.9 vs. 0.4, p = .03). There were no significant changes in physical activity or post-bariatric surgical care domains. Our OM curriculum is feasible with IM residents and increases residents' obesity care self-efficacy beyond what is achieved with usual IM training.

Commercial Weight Loss Programs in the Management of Obesity: an Update.

PURPOSE OF REVIEW: Comprehensive lifestyle programs are cornerstones of obesity management, but clinician referrals may be limited by program availability. Commercial weight loss programs may be an alternative, but clinicians may be unaware of their efficacy and safety. This review describes the evidence for commercial programs, particularly 12-month weight loss, among individuals with obesity. RECENT FINDINGS: Several programs are concordant with evidence-based recommendations (i.e., lower-calorie diet, increased physical activity, and behavioral strategies). Among the guideline-concordant programs, National Diabetes Prevention Program, WW, Jenny Craig, Medifast, and OPTIFAST have demonstrated 12-month weight loss efficacy and safety. While other programs show promise, more evidence is needed before clinician referral may be recommended. Clinical practice guidelines support referrals to commercial weight loss programs that have peer-reviewed evidence to support their efficacy and safety. Clinicians should consider the available evidence, patient preference, and cost when considering referrals to these programs for weight management.

Association between the soluble receptor for advanced glycation end products (sRAGE) and NAFLD in participants in the Atherosclerosis Risk in Communities Study.

BACKGROUND: Inflammation is key in the pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD) - a common progressive liver disease. The soluble receptor for advanced glycation end products (sRAGE) attenuates inflammatory signaling; low levels of sRAGE are correlated with increased inflammation. AIM: We sought to describe associations between sRAGE and NAFLD. METHODS: We conducted a cross-sectional analysis of 1088 Atherosclerosis Risk in Communities (ARIC) Study participants and used logistic regression to investigate the associations between sRAGE and NAFLD defined by elevated liver enzymes and fibrosis score. RESULTS: In this community-based sample (n = 1,088, mean age 56 years, 61% female, 78% Caucasian), persons in the lowest vs. highest quartile of sRAGE had significantly higher odds of elevated ALT (OR 2.82, 95% CI 1.18-6.76) but not elevated AST (OR 1.16, 95% CI 0.45-2.99); persons in the lowest vs. highest quartile had significantly lower odds of elevated FIB-4 index (OR 0.56, 95% CI 0.37-0.84). CONCLUSIONS: We found an inverse cross-sectional association between sRAGE and liver inflammation; this is consistent with prior studies linking low sRAGE to inflammatory states. However, we observed a direct association between sRAGE and fibrosis. Our findings suggest that sRAGE is dynamic in NAFLD and patterns may vary with different stages of disease.

ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma.

Genetic studies have established anaplastic lymphoma kinase (ALK), a cell surface receptor tyrosine kinase, as a tractable molecular target in neuroblastoma. We describe comprehensive genomic, biochemical, and computational analyses of ALK mutations across 1,596 diagnostic neuroblastoma samples. ALK tyrosine kinase domain mutations occurred in 8% of samples--at three hot spots and 13 minor sites--and correlated significantly with poorer survival in high- and intermediate-risk neuroblastoma. Biochemical and computational studies distinguished oncogenic (constitutively activating) from nononcogenic mutations and allowed robust computational prediction of their effects. The mutated variants also showed differential in vitro crizotinib sensitivities. Our studies identify ALK genomic status as a clinically important therapeutic stratification tool in neuroblastoma and will allow tailoring of ALK-targeted therapy to specific mutations.

Genome-wide linkage analysis to identify genetic modifiers of ALK mutation penetrance in familial neuroblastoma.

BACKGROUND: Neuroblastoma (NB) is an important childhood cancer with a strong genetic component related to disease susceptibility. Approximately 1% of NB cases have a positive family history. Following a genome-wide linkage analysis and sequencing of candidate genes in the critical region, we identified ALK as the major familial NB gene. Dominant mutations in ALK are found in more than 50% of familial NB cases. However, in the families used for the linkage study, only about 50% of carriers of ALK mutations are affected by NB. METHODS: To test whether genetic variation may explain the reduced penetrance of the disease phenotype, we analyzed genome-wide genotype data in ALK mutation-positive families using a model-based linkage approach with different liability classes for carriers and non-carriers of ALK mutations. RESULTS: The region with the highest LOD score was located at chromosome 2p23-p24 and included the ALK locus under models of dominant and recessive inheritance. CONCLUSIONS: This finding suggests that variants in the non-mutated ALK gene or another gene linked to it may affect penetrance of the ALK mutations and risk of developing NB in familial cases.

RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in neuroblastoma.

Neuroblastoma is a childhood cancer that is often fatal despite intense multimodality therapy. In an effort to identify therapeutic targets for this disease, we performed a comprehensive loss-of-function screen of the protein kinome. Thirty kinases showed significant cellular cytotoxicity when depleted, with loss of the cell cycle checkpoint kinase 1 (CHK1/CHEK1) being the most potent. CHK1 mRNA expression was higher in MYC-Neuroblastoma-related (MYCN)-amplified (P < 0.0001) and high-risk (P = 0.03) tumors. Western blotting revealed that CHK1 was constitutively phosphorylated at the ataxia telangiectasia response kinase target site Ser345 and the autophosphorylation site Ser296 in neuroblastoma cell lines. This pattern was also seen in six of eight high-risk primary tumors but not in control nonneuroblastoma cell lines or in seven of eight low-risk primary tumors. Neuroblastoma cells were sensitive to the two CHK1 inhibitors SB21807 and TCS2312, with median IC(50) values of 564 nM and 548 nM, respectively. In contrast, the control lines had high micromolar IC(50) values, indicating a strong correlation between CHK1 phosphorylation and CHK1 inhibitor sensitivity (P = 0.0004). Furthermore, cell cycle analysis revealed that CHK1 inhibition in neuroblastoma cells caused apoptosis during S-phase, consistent with its role in replication fork progression. CHK1 inhibitor sensitivity correlated with total MYC(N) protein levels, and inducing MYCN in retinal pigmented epithelial cells resulted in CHK1 phosphorylation, which caused growth inhibition when inhibited. These data show the power of a functional RNAi screen to identify tractable therapeutical targets in neuroblastoma and support CHK1 inhibition strategies in this disease.

Copy number variation at 1q21.1 associated with neuroblastoma.

Common copy number variations (CNVs) represent a significant source of genetic diversity, yet their influence on phenotypic variability, including disease susceptibility, remains poorly understood. To address this problem in human cancer, we performed a genome-wide association study of CNVs in the childhood cancer neuroblastoma, a disease in which single nucleotide polymorphism variations are known to influence susceptibility. We first genotyped 846 Caucasian neuroblastoma patients and 803 healthy Caucasian controls at approximately 550,000 single nucleotide polymorphisms, and performed a CNV-based test for association. We then replicated significant observations in two independent sample sets comprised of a total of 595 cases and 3,357 controls. Here we describe the identification of a common CNV at chromosome 1q21.1 associated with neuroblastoma in the discovery set, which was confirmed in both replication sets. This CNV was validated by quantitative polymerase chain reaction, fluorescent in situ hybridization and analysis of matched tumour specimens, and was shown to be heritable in an independent set of 713 cancer-free parent-offspring trios. We identified a previously unknown transcript within the CNV that showed high sequence similarity to several neuroblastoma breakpoint family (NBPF) genes and represents a new member of this gene family (NBPF23). This transcript was preferentially expressed in fetal brain and fetal sympathetic nervous tissues, and the expression level was strictly correlated with CNV state in neuroblastoma cells. These data demonstrate that inherited copy number variation at 1q21.1 is associated with neuroblastoma and implicate a previously unknown neuroblastoma breakpoint family gene in early tumorigenesis of this childhood cancer.

Common variations in BARD1 influence susceptibility to high-risk neuroblastoma.

We conducted a SNP-based genome-wide association study (GWAS) focused on the high-risk subset of neuroblastoma. As our previous unbiased GWAS showed strong association of common 6p22 SNP alleles with aggressive neuroblastoma, we restricted our analysis here to 397 high-risk cases compared to 2,043 controls. We detected new significant association of six SNPs at 2q35 within the BARD1 locus (P(allelic) = 2.35 x 10(-9)-2.25 x 10(-8)). We confirmed each SNP association in a second series of 189 high-risk cases and 1,178 controls (P(allelic) = 7.90 x 10(-7)-2.77 x 10(-4)). We also tested the two most significant SNPs (rs6435862, rs3768716) in two additional independent high-risk neuroblastoma case series, yielding combined allelic odds ratios of 1.68 each (P = 8.65 x 10(-18) and 2.74 x 10(-16), respectively). We also found significant association with known BARD1 nonsynonymous SNPs. These data show that common variation in BARD1 contributes to the etiology of the aggressive and most clinically relevant subset of human neuroblastoma.

Identification of ALK as a major familial neuroblastoma predisposition gene.

Neuroblastoma is a childhood cancer that can be inherited, but the genetic aetiology is largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at chromosome bands 2p23-24 using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate germline missense mutations in the tyrosine kinase domain of ALK that segregated with the disease in eight separate families. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the ten mutations map to critical regions of the kinase domain and were predicted, with high probability, to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK, as well as in two out of six wild-type cell lines for ALK. Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy.

Chromosome 6p22 locus associated with clinically aggressive neuroblastoma.

BACKGROUND: Neuroblastoma is a malignant condition of the developing sympathetic nervous system that most commonly affects young children and is often lethal. Its cause is not known. METHODS: We performed a genomewide association study by first genotyping blood DNA samples from 1032 patients with neuroblastoma and 2043 control subjects of European descent using the Illumina HumanHap550 BeadChip. Samples from three independent groups of patients with neuroblastoma (a total of 720 patients) and 2128 control subjects were then genotyped to replicate significant associations. RESULTS: We observed a significant association between neuroblastoma and the common minor alleles of three consecutive single-nucleotide polymorphisms (SNPs) at chromosome band 6p22 and containing the predicted genes FLJ22536 and FLJ44180 (P=1.71x10(-9) to 7.01x10(-10); allelic odds ratio, 1.39 to 1.40). Homozygosity for the at-risk G allele of the most significantly associated SNP, rs6939340, resulted in an increased likelihood of the development of neuroblastoma (odds ratio, 1.97; 95% confidence interval, 1.58 to 2.45). Subsequent genotyping of the three 6p22 SNPs in three independent case series confirmed our observation of an association (P=9.33x10(-15) at rs6939340 for joint analysis). Patients with neuroblastoma who were homozygous for the risk alleles at 6p22 were more likely to have metastatic (stage 4) disease (P=0.02), amplification of the MYCN oncogene in the tumor cells (P=0.006), and disease relapse (P=0.01). CONCLUSIONS: A common genetic variation at chromosome band 6p22 is associated with susceptibility to neuroblastoma.