Ambulatory Care Skills: Do Residents Feel Prepared?

Abstract: Objective: To determine resident comfort and skill in performing ambulatory care skills. Methods: Descriptive survey of common ambulatory care skills administered to internal medicine faculty and residents at one academic medical center. Respondents were asked to rate their ability to perform 12 physical exam skills and 6 procedures, and their comfort in performing 7 types of counseling, and obtaining 6 types of patient history (4 point Likert scale for each). Self-rated ability or comfort was compared by gender, status (year of residency, faculty), and future predicted frequency of use of the skill. Results: Residents reported high ability levels for physical exam skills common to both the ambulatory and hospital setting. Fewer felt able to perform musculoskeletal, neurologic or eye exams easily alone. Procedures generally received low ability ratings. Similarly, residents’ comfort in performing common outpatient counseling was also low. More residents reported feeling very comfortable in obtaining history from patients. We found little variation by gender, year of training, or predicted frequency of use. Conclusion: Self-reported ability and comfort for many common ambulatory care skills is low. Further evaluation of this finding in other training programs is warranted

Family-Based Association Analysis Confirms the Role of the Chromosome 9q21.32 Locus in the Susceptibility of Diabetic Nephropathy

A genome-wide association scan of type 1 diabetic patients from the GoKinD collections previously identified four novel diabetic nephropathy susceptibility loci that have subsequently been shown to be associated with diabetic nephropathy in unrelated patients with type 2 diabetes. To expand these findings, we examined whether single nucleotide polymorphisms (SNPs) at these susceptibility loci were associated with diabetic nephropathy in patients from the Joslin Study of Genetics of Nephropathy in Type 2 Diabetes Family Collection. Six SNPs across the four loci identified in the GoKinD collections and 7 haplotype tagging SNPs, were genotyped in 66 extended families of European ancestry. Pedigrees from this collection contained an average of 18.5 members, including 2 to 14 members with type 2 diabetes. Among diabetic family members, the 9q21.32 locus approached statistical significance with advanced diabetic nephropathy (P = 0.037 [adjusted P = 0.222]). When we expanded our definition of diabetic nephropathy to include individuals with high microalbuminuria, the strength of this association improved significantly (P = 1.42×10−3 [adjusted P = 0.009]). This same locus also trended toward statistical significance with variation in urinary albumin excretion in family members with type 2 diabetes (P = 0.032 [adjusted P = 0.192]) and in analyses expanded to include all relatives (P = 0.019 [adjusted P = 0.114]). These data increase support that SNPs identified in the GoKinD collections on chromosome 9q21.32 are true diabetic nephropathy susceptibility loci

Significant linkage at chromosome 19q for otitis media with effusion and/or recurrent otitis media (COME/ROM)

<p>Abstract</p> <p>Background</p> <p>In previous analyses, we identified a region of chromosome 19 as harboring a susceptibility locus for chronic otitis media with effusion and/or recurrent otitis media (COME/ROM). Our aim was to further localize the linkage signal and ultimately identify the causative variant or variants. We followed up our previous linkage scan with dense SNP genotyping across in a 5 Mb region. A total of 607 individuals from 139 families, including 159 affected sib pairs and 62 second-degree affected relative pairs, were genotyped at 1,091 SNPs. We carried out a nonparametric linkage analysis, modeling marker-to-marker linkage disequilibrium.</p> <p>Results</p> <p>The maximum log of the odds (LOD) score increased to 3.75 (P = 1.6 × 10^-5) at position 63.4 Mb, with a LOD-1 support interval between 61.6 Mb and 63.8 Mb, providing significant evidence of linkage between this region and COME/ROM. The support interval contains over 90 known genes, including several genes involved in the inflammasome protein complex, a key regulator of the innate immune response to harmful exogenous or endogenous stimuli. Parametric linkage analysis suggests that for a sib of an affected individual, the recurrence risk of COME/ROM due to this linkage region is twice the recurrence risk in the population. We examined potential associations between the SNPs genotyped in this region and COME/ROM, however none provided evidence for association.</p> <p>Conclusion</p> <p>This study has refined the 19q region of linkage with COME/ROM, and association results suggest that the linkage signal may be due to rare variants.</p

Confirmation of Genetic Associations at ELMO1 in the GoKinD Collection Supports Its Role as a Susceptibility Gene in Diabetic Nephropathy

Objective: To examine the association between single nucleotide polymorphisms (SNPs) in the engulfment and cell motility 1 (ELMO1) gene, a locus previously shown to be associated with diabetic nephropathy in two ethnically distinct type 2 diabetic populations, and the risk of nephropathy in type 1 diabetes. Research Design and Methods: Genotypic data from a genome-wide association scan (GWAS) of the Genetics of Kidneys in Diabetes (GoKinD) study collection were analyzed for associations across the ELMO1 locus. In total, genetic associations were assessed using 118 SNPs and 1,705 individuals of European ancestry with type 1 diabetes (885 normoalbuminuric control subjects and 820 advanced diabetic nephropathy case subjects). Results: The strongest associations in ELMO1 occurred at rs11769038 (odds ratio [OR] 1.24; P = 1.7 × 10−3) and rs1882080 (OR 1.23; P = 3.2 × 10−3) located in intron 16. Two additional SNPs, located in introns 18 and 20, respectively, were also associated with diabetic nephropathy. No evidence of association for variants previously reported in type 2 diabetes was observed in our collection. Conclusions: Using GWAS data from the GoKinD collection, we comprehensively examined evidence of association across the ELMO1 locus. Our investigation marks the third report of associations in ELMO1 with diabetic nephropathy, further establishing its role in the susceptibility of this disease. There is evidence of allelic heterogeneity, contributed by the diverse genetic backgrounds of the different ethnic groups examined. Further investigation of SNPs at this locus is necessary to fully understand the commonality of these associations and the mechanism(s) underlying their role in diabetic nephropathy

Effect of substituting IPV for tOPV on immunity to poliovirus in Bangladeshi infants: An open-label randomized controlled trial

AbstractBackgroundThe Polio Endgame strategy includes phased withdrawal of oral poliovirus vaccines (OPV) coordinated with introduction of inactivated poliovirus vaccine (IPV) to ensure population immunity. The impact of IPV introduction into a primary OPV series of immunizations in a developing country is uncertain.MethodsBetween May 2011 and November 2012, we enrolled 700 Bangladeshi infant-mother dyads from Dhaka slums into an open-label randomized controlled trial to test whether substituting an injected IPV dose for the standard Expanded Program on Immunization (EPI) fourth tOPV dose at infant age 39 weeks would reduce fecal shedding and enhance systemic immunity. The primary endpoint was mucosal immunity to poliovirus at age one year, measured by fecal excretion of any Sabin virus at five time points up to 25 days post-52 week tOPV challenge, analyzed by the intention to treat principle.FindingsWe randomized 350 families to the tOPV and IPV vaccination arms. Neither study arm resulted in superior intestinal protection at 52 weeks measured by the prevalence of infants shedding any of three poliovirus serotypes, but the IPV dose induced significantly higher seroprevalence and seroconversion rates. This result was identical for poliovirus detection by cell culture or RT-qPCR. The non-significant estimated culture-based shedding risk difference was −3% favoring IPV, and the two vaccination schedules were inferred to be equivalent within a 95% confidence margin of −10% to +4%. Results for shedding analyses stratified by poliovirus type were similar.ConclusionsNeither of the vaccination regimens is superior to the other in enhancing intestinal immunity as measured by poliovirus shedding at 52 weeks of age and the IPV regimen provides similar intestinal immunity to the four tOPV series, although the IPV regimen strongly enhances humoral immunity. The IPV-modified regimen may be considered for vaccination programs without loss of intestinal protection

The core clock gene, Bmal1, and its downstream target, the SNARE regulatory protein secretagogin, are necessary for circadian secretion of glucagon-like peptide-1.

OBJECTIVES:The incretin hormone glucagon-like peptide-1 (GLP-1) is secreted from intestinal L-cells upon nutrient intake. While recent evidence has shown that GLP-1 is released in a circadian manner in rats, whether this occurs in mice and if this pattern is regulated by the circadian clock remain to be elucidated. Furthermore, although circadian GLP-1 secretion parallels expression of the core clock gene Bmal1, the link between the two remains largely unknown. Secretagogin (Scgn) is an exocytotic SNARE regulatory protein that demonstrates circadian expression and is essential for insulin secretion from β-cells. The objective of the current study was to establish the necessity of the core clock gene Bmal1 and the SNARE protein SCGN as essential regulators of circadian GLP-1 secretion. METHODS:Oral glucose tolerance tests were conducted at different times of the day on 4-hour fasted C57BL/6J, Bmal1 wild-type, and Bmal1 knockout mice. Mass spectrometry, RNA-seq, qRT-PCR and/or microarray analyses, and immunostaining were conducted on murine (m) and human (h) primary L-cells and mGLUTag and hNCI-H716 L-cell lines. At peak and trough GLP-1 secretory time points, the mGLUTag cells were co-stained for SCGN and a membrane-marker, ChIP was used to analyze BMAL1 binding sites in the Scgn promoter, protein interaction with SCGN was tested by co-immunoprecipitation, and siRNA was used to knockdown Scgn for GLP-1 secretion assay. RESULTS:C57BL/6J mice displayed a circadian rhythm in GLP-1 secretion that peaked at the onset of their feeding period. Rhythmic GLP-1 release was impaired in Bmal1 knockout (KO) mice as compared to wild-type controls at the peak (p < 0.05) but not at the trough secretory time point. Microarray identified SNARE and transport vesicle pathways as highly upregulated in mGLUTag L-cells at the peak time point of GLP-1 secretion (p < 0.001). Mass spectrometry revealed that SCGN was also increased at this time (p < 0.001), while RNA-seq, qRT-PCR, and immunostaining demonstrated Scgn expression in all human and murine primary L-cells and cell lines. The mGLUTag and hNCI-H716 L-cells exhibited circadian rhythms in Scgn expression (p < 0.001). The ChIP analysis demonstrated increased binding of BMAL1 only at the peak of Scgn expression (p < 0.01). Immunocytochemistry showed the translocation of SCGN to the cell membrane after stimulation at the peak time point only (p < 0.05), while CoIP showed that SCGN was pulled down with SNAP25 and β-actin, but only the latter interaction was time-dependent (p < 0.05). Finally, Scgn siRNA-treated cells demonstrated significantly blunted GLP-1 secretion (p < 0.01) in response to stimulation at the peak time point only. CONCLUSIONS:These data demonstrate, for the first time, that mice display a circadian pattern in GLP-1 secretion, which is impaired in Bmal1 knockout mice, and that Bmal1 regulation of Scgn expression plays an essential role in the circadian release of the incretin hormone GLP-1

HLA Class I and Genetic Susceptibility to Type 1 Diabetes: Results From the Type 1 Diabetes Genetics Consortium

OBJECTIVE-We report here genotyping data and type 1 diabetes association analyses for HLA class I loci (A, B, and C) on 1,753 multiplex pedigrees from the Type 1 Diabetes Genetics Consortium (T1DGC), a large international collaborative study. RESEARCH DESIGN AND METHODS-Complete eight-locus HLA genotyping data were generated. Expected patient class I (HLA-A, -B, and -C) allele frequencies were calculated, based on linkage disequilibrium (LD) patterns with observed HLA class II DRB1-DQA1-DQB1 haplotype frequencies. Expected frequencies were compared to observed allele frequencies in patients. RESULTS-Significant type 1 diabetes associations were observed at all class I HLA loci. After accounting for LD with HLA class II, the most significantly type 1 diabetes-associated alleles were B*5701 (odds ratio 0.19; P = 4 x 10(-11)) and B*3906 (10.31; P = 4 X 10(-10)). Other significantly type 1 diabetes-associated alleles included A*2402, A*0201, B*1801, and C*0501 (predisposing) and A*1101, A*3201, A*6601, B*0702, B*4403, B*3502, C*1601, and C*0401 (protective). Some alleles, notably B*3906, appear to modulate the risk of all DRB1-DQA1-DQB1 haplotypes on which they reside, suggesting a class I effect that is independent of class H. Other class I type 1 diabetes associations appear to be specific to individual class H haplotypes. Some apparent associations (e.g., C*1601) could be attributed to strong LD to another class I susceptibility locus (B*4403). CONCLUSIONS-These data indicate that HLA class I alleles, in addition to and independently from HLA class H alleles, are associated with type 1 diabetes. Diabetes 59:2972-2979, 201

HLA DPA1, DPB1 Alleles and Haplotypes Contribute to the Risk Associated With Type 1 Diabetes: Analysis of the Type 1 Diabetes Genetics Consortium Families

OBJECTIVE-To determine the relative risk associated with DPA1 and DPB1 alleles and haplotypes in type I diabetes. RESEARCH DESIGN AND METHODS-The frequency of DPA1 and DPB1 alleles and haplotypes in type I diabetic patients was compared to the family based control frequency in 1,771 families directly and conditional on FILA (B)-DRB1-DQA1-DQB1 linkage disequilibrium. A relative predispositional analysis (RPA) was performed in the presence or absence of the primary HLA DR-DQ associations and the contribution of DP haplotype to individual DR-DQ haplotype risks examined. RESULTS-Eight DPAI and thirty-eight DPB1 alleles forming seventy-four DPA1-DPB1 haplotypes were observed, nineteen DPB1 alleles were associated with multiple DPA1 alleles Following both analyses, type I diabetes susceptibility was significantly associated with DPB1*0301 (DPA1*0103-DPB1*0301) and protection with DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 but not DPA1*0201-DPB1*0101. In addition, DPB1*0202 (DPA1*0103-DPB1*0202) and DPB1*0201 (DPA1*0103-DPB1*0201) were significantly associated with susceptibility in the presence of the high risk and protective DR-DQ haplotypes Three associations (DPB1*0301, *0402, and *0202) remained statistically significant when only the extended HLA-A1-B8-DR3 haplotype was considered, suggesting that DPB1 alone may delineate the risk associated with this otherwise conserved haplotype CONCLUSIONS-HLA DP allelic and haplotypic diversity contributes significantly to the risk for type I diabetes; DPB1*0301 (DPA1*0103-DPB1*0301) is associated with susceptibility and DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 with protection Additional evidence is presented for the susceptibility association of DPB1*0202 (DPA1*0103-DPB1*0202) and for a contributory role of individual amino acids and DPA1 or a gene in linkage disequilibrium in DR3-DPB1*0101 positive haplotypes Diabetes 59:2055-2062, 201