Development of a minimum clinical dataset for preoperative comprehensive geriatric assessment using a modified Delphi technique.

OBJECTIVE: To construct a standardised, consensus-guided minimum clinical dataset (MCDS) for preoperative comprehensive geriatric assessment and optimisation (CGA) in Australia and Aotearoa New Zealand. METHODS: We conducted a review of the international perioperative literature to identify CGA domains and tools for potential inclusion in the MCDS. We invited members of the Australian and New Zealand Society for Geriatric Medicine to participate in a Delphi study to obtain consensus on MCDS tools. Participants were asked to rate proposed tools using Likert scales (when >2 tools) or make a binary choice between two proposed tools. Consensus was considered to be achieved when there was at least 75% concordance between the two rounds amongst the participants, and at least one variable attaining over 50% of participants' votes. Domains that did not achieve consensus in Round 1 were carried over to Round 2. RESULTS: There were 73 participants in Round 1 of the Delphi study and 47 participants in Round 2. Consensus was achieved on tool/s recommended for every MCDS domain: Clinical Frailty Scale (frailty); sMMSE, RUDAS, MoCA (cognition); 4AT (delirium); timed-up-and-go (physical function); GDS-15 (mood); Barthel Index (functional status); and MUST (malnutrition). CONCLUSIONS: We recommend clinicians delivering preoperative CGA consider the use of the MCDS we have constructed when assessing older people contemplating surgery, as part of a multicomponent and multidisciplinary approach to optimising perioperative outcomes.

The measurement of autoantibodies to insulin informs diagnosis of diabetes in a childhood population negative for other autoantibodies.

AIMS: Some childhood type 1 diabetes cases are islet autoantibody negative at diagnosis. Potential explanations include misdiagnosis of genetic forms of diabetes or insufficient islet autoantibody testing. Many NHS laboratories offer combinations of three autoantibody markers. We sought to determine the benefit of testing for additional islet autoantibodies, including insulin (IAA) and tetraspanin 7 (TSPAN7A). METHODS: Radiobinding assays (RBAs) were used to test for four islet autoantibodies in children with newly diagnosed type 1 diabetes (n = 486; 54.1% male; median age 10.4 years [range 0.7-18.0]; median duration 1 day [range -183 to 14]). Islet autoantibody negative children were tested for TSPAN7A using a luminescence-based test. Where available, islet cell antibody (ICA) and human leucocyte antigen (HLA) data were considered. RESULTS: Using three autoantibody markers, 21/486 (4.3%) children were autoantibody negative. Testing for IAA classified a further 9/21 (42.9%) children as autoantibody positive. Of the remaining 12 (2.5%) autoantibody negative children, all were TPAN7A negative, seven were ICA negative and one was positive for the protective variant DQB1*0602. One was subsequently diagnosed with Maturity Onset of Diabetes in the Young, but follow-up was not available in all cases. CONCLUSIONS: Using highly sensitive assays, testing for three autoantibodies fails to detect islet autoimmunity in approximately 1/20 children diagnosed with type 1 diabetes. Testing for IAA in children <5 years and GADA in those >10 years was the most effective strategy for detecting islet autoimmunity. The ability to test for all islet autoantibodies should inform clinical decisions and make screening for monogenic diabetes more cost-effective.

Activated but functionally impaired memory Tregs are expanded in slow progressors to type 1 diabetes.

AIMS/HYPOTHESIS: Slow progressors to type 1 diabetes are individuals positive for multiple pancreatic islet autoantibodies who have remained diabetes-free for at least 10 years; regulation of the autoimmune response is understudied in this group. Here, we profile CD4+ regulatory T cells (Tregs) in a small but well-characterised cohort of extreme slow progressors with a median age 43 (range 31-72 years), followed up for 18-32 years. METHODS: Peripheral blood samples were obtained from slow progressors (n = 8), age- and sex-matched to healthy donors. One participant in this study was identified with a raised HbA1c at the time of assessment and subsequently diagnosed with diabetes; this donor was individually evaluated in the analysis of the data. Peripheral blood mononuclear cells (PBMCs) were isolated, and to assess frequency, phenotype and function of Tregs in donors, multi-parameter flow cytometry and T cell suppression assays were performed. Unsupervised clustering analysis, using FlowSOM and CITRUS (cluster identification, characterization, and regression), was used to evaluate Treg phenotypes. RESULTS: Unsupervised clustering on memory CD4+ T cells from slow progressors showed an increased frequency of activated memory CD4+ Tregs, associated with increased expression of glucocorticoid-induced TNFR-related protein (GITR), compared with matched healthy donors. One participant with a raised HbA1c at the time of assessment had a different Treg profile compared with both slow progressors and matched controls. Functional assays demonstrated that Treg-mediated suppression of CD4+ effector T cells from slow progressors was significantly impaired, compared with healthy donors. However, effector CD4+ T cells from slow progressors were more responsive to Treg suppression compared with healthy donors, demonstrated by increased suppression of CD25 and CD134 expression on effector CD4+ T cells. CONCLUSIONS/INTERPRETATIONS: We conclude that activated memory CD4+ Tregs from slow progressors are expanded and enriched for GITR expression, highlighting the need for further study of Treg heterogeneity in individuals at risk of developing type 1 diabetes.

Which preoperative screening tool should be applied to older patients undergoing elective surgery to predict short-term postoperative outcomes? Lessons from systematic reviews, meta-analyses and guidelines.

BACKGROUND: Older surgical patients have a higher risk of postoperative mortality and morbidity compared to younger patients. Timely identification of high-risk patients facilitates comprehensive preoperative evaluation, optimization, and resource allocation to help reduce this risk. This review aims to identify a preoperative screening tool for older patients undergoing elective surgery predictive of poor short-term postoperative outcomes. METHODS: A scoping review was conducted. An Ovid MEDLINE search was used to identify systematic reviews or meta-analyses comprising older elective patients in at least two different surgical settings. International guidelines were reviewed for recommendations regarding preoperative tools in this population. RESULTS: Over 50 screening tools were identified. The majority showed a positive association with short-term postoperative mortality and morbidity in older patients. The most commonly described tools were the American Society of Anesthesiologists Physical Status (ASA-PS), frailty tools and domain-specific tools administered as part of comprehensive geriatric assessment (CGA). Due to heterogeneity in outcome measures and statistical methodology the predictive capacity between tools could not be compared. International guidelines described a comprehensive preoperative approach incorporating domain-specific tools rather than recommending a screening tool. CONCLUSION: Multiple tools were associated with poor short-term postoperative outcomes in older elective surgical patients. No single superior tool could be identified. Frailty, cognitive and/or functional tools were most frequently utilized.

Older patients undergoing emergency laparotomy: observations from the National Emergency Laparotomy Audit (NELA) years 1-4.

BACKGROUND: older patients aged ≥65 years constitute the majority of the National Emergency Laparotomy Audit (NELA) population. To better understand this group and inform future service changes, this paper aims to describe patient characteristics, outcomes and process measures across age cohorts and temporally in the 4-year period (2014-2017) since NELA was established. METHODS: patient-level data were populated from the NELA data set years 1-4 and linked with Office of National Statistics mortality data. Descriptive data were compared between groups delineated by age, NELA year and geriatrician review. Primary outcomes were 30- and 90-day mortality, length of stay (LOS) and discharge to care-home accommodation. RESULTS: in total, 93,415 NELA patients were included in the analysis. The median age was 67 years. Patients aged ≥65 years had higher 30-day (15.3 versus 4.9%, P < 0.001) and 90-day mortality (20.4 versus 7.2%, P < 0.001) rates, longer LOS (median 15.2 versus 11.3 days, P < 0.001) and greater likelihood of discharge to care-home accommodation compared with younger patients (6.7 versus 1.9%, P < 0.001). Mortality rate reduction over time was greater in older compared with younger patients. The proportion of older NELA patients seen by a geriatrician post-operatively increased over years 1-4 (8.5 to 16.5%, P < 0.001). Post-operative geriatrician review was associated with reduced mortality (30-day odds ratio [OR] 0.38, confidence interval [CI] 0.35-0.42, P < 0.001; 90-day OR 0.6, CI 0.56-0.65, P < 0.001). CONCLUSIONS: older NELA patients have poorer post-operative outcomes. The greatest reduction in mortality rates over time were observed in the oldest cohorts. This may be due to several interventions including increased perioperative geriatrician input.

Beta cell function and ongoing autoimmunity in long-standing, childhood onset type 1 diabetes.

AIMS/HYPOTHESIS: This study aimed to determine the frequency of residual beta cell function in individuals with long-standing type 1 diabetes who were recruited at diagnosis, and relate this to baseline and current islet autoantibody profile. METHODS: Two hour post-meal urine C-peptide:creatinine ratio (UCPCR) and islet autoantibodies were measured in samples collected from 144 participants (median age at diagnosis: 11.7 years; 47% male), a median of 23 years (range 12-29 years) after diagnosis. UCPCR thresholds equivalent to mixed meal-stimulated serum C-peptide >0.001 nmol/l, ≥0.03 nmol/l and ≥0.2 nmol/l were used to define 'detectable', 'minimal' and 'residual/preserved') endogenous insulin secretion, respectively. Autoantibodies against GAD (GADA), islet antigen-2 (IA-2A), zinc transporter 8 (ZnT8A) and insulin (IAA) were measured by radioimmunoassay. RESULTS: Endogenous C-peptide secretion was detectable in 51 participants (35.4%), including residual secretion in seven individuals (4.9%) and minimal secretion in 14 individuals (9.7%). In the 132 samples collected more than 10 years after diagnosis, 86 participants (65.2%) had at least one islet autoantibody: 42 (31.8%) were positive for GADA, 69 (52.3%) for IA-2A and 14 of 104 tested were positive for ZnT8A (13.5%). The level of UCPCR was related to age at diagnosis (p = 0.002) and was independent of diabetes duration, and baseline or current islet autoantibody status. CONCLUSIONS/INTERPRETATION: There is evidence of ongoing autoimmunity in the majority of individuals with longstanding diabetes. Endogenous insulin secretion continues for many years after diagnosis in individuals diagnosed with autoimmune-mediated type 1 diabetes above age 5. These findings suggest that some beta cells are protected from continued autoimmune attack in longstanding type 1 diabetes.

Type 1 Diabetes High-Risk HLA Class II Determination by Polymerase Chain Reaction Sequence-Specific Primers.

The only strategy to select individuals at increased risk for type 1 diabetes for primary prevention trials is through genetic risk assessment. While genome-wide association studies have identified more than 40 loci associated with type 1 diabetes, the single most important genetic determinants lie within the human leucocyte antigen gene family on chromosome 6.In this chapter we describe a protocol for a straightforward, cheap strategy to determine HLA class II mediated risk of type 1 diabetes. This method has proved robust for genotyping whole-genome-amplified DNA as well as DNA extracted directly from human tissues.

Early onset of diabetes in the proband is the major determinant of risk in HLA DR3-DQ2/DR4-DQ8 siblings.

Islet autoimmunity is initiated in infancy, and primary prevention trials require children at high genetic risk to be identified before autoantibodies appear. To inform screening strategies, we evaluated risks of autoimmunity and diabetes associated with HLA DR3-DQ2/DR4-DQ8 in U.K. families. Extended HLA haplotypes were determined in 2,134 siblings from the Bart's-Oxford Study followed to a median age of 22 years. Risks of diabetes and islet autoimmunity (more than two antibodies) were estimated by survival analysis. Of 138 informative DR3-DQ2/DR4-DQ8 siblings, 63% shared both haplotypes with their diabetic proband, 29% shared one, and 8% shared neither. In HLA-identical DR3-DQ2/DR4-DQ8 siblings, the cumulative risk of diabetes by age 15 was 17% (vs. 6% in those sharing one haplotype or none; P = 0.095). Risk varied, however, with the age at the onset of diabetes in the proband; the cumulative risk of autoimmunity and/or diabetes by age 15 was 61% in siblings of probands diagnosed when younger than 10 years old compared with only 4.7% in those diagnosed after age 10 years (P < 0.001). The age of the proband at diagnosis, but not HLA haplotype sharing, was an independent determinant of sibling risk. This suggests that non-HLA genes or epigenetic/environmental factors that accelerate the progression of type 1 diabetes in the proband strongly affect risk in siblings.

Humoral responses to islet antigen-2 and zinc transporter 8 are attenuated in patients carrying HLA-A*24 alleles at the onset of type 1 diabetes.

The HLA-A*24 allele has shown negative associations with autoantibodies to islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) in patients with established type 1 diabetes. Understanding how this HLA class I allele affects humoral islet autoimmunity gives new insights into disease pathogenesis. We therefore investigated the epitope specificity of associations between HLA-A*24 and islet autoantibodies at disease onset. HLA-A*24 genotype and autoantibody responses to insulin (IAA), glutamate decarboxylase (GADA), IA-2, IA-2ß, and ZnT8 were analyzed in samples collected from patients with recent-onset type 1 diabetes. After correction for age, sex, and HLA class II genotype, HLA-A*24 was shown to be a negative determinant of IA-2A and ZnT8A. These effects were epitope specific. Antibodies targeting the protein tyrosine phosphatase domains of IA-2 and IA-2ß, but not the IA-2 juxtamembrane region, were less common in patients carrying HLA-A*24 alleles. The prevalence of ZnT8A specific or cross-reactive with the ZnT8 tryptophan-325 polymorphic residue, but not those specific to arginine-325, was reduced in HLA-A*24-positive patients. No associations were found between HLA-A*24 and IAA or GADA. Association of an HLA class I susceptibility allele with altered islet autoantibody phenotype at diagnosis suggests CD8 T-cell and/or natural killer cell-mediated killing modulates humoral autoimmune responses.

Early-onset, coexisting autoimmunity and decreased HLA-mediated susceptibility are the characteristics of diabetes in Down syndrome.

OBJECTIVE: Down syndrome (DS) is associated with an increased risk of diabetes, particularly in young children. HLA-mediated risk is however decreased in children with DS and diabetes (DSD). We hypothesized that early-onset diabetes in children with DS is etiologically different from autoimmune diabetes. RESEARCH DESIGN AND METHODS: Clinical and immunogenetic markers of autoimmune diabetes were studied in 136 individuals with DSD and compared with 194 age- and sex-matched individuals with type 1 diabetes, 222 with DS, and 671 healthy controls. HLA class II was analyzed by sequence-specific primed PCR. Islet autoantibodies were measured by radioimmunoassay. RESULTS: Age at onset of diabetes was biphasic, with 22% of DS children diagnosed before 2 years of age, compared with only 4% in this age-group with type 1 diabetes in the general population (P < 0.0001). The frequency of the highest-risk type 1 diabetes-associated HLA genotype, DR3-DQ2/DR4-DQ8, was decreased in both early- and later-onset DSD compared with age-matched children with type 1 diabetes (P < 0.0001), although HLA DR3-DQ2 genotypes were increased (P = 0.004). Antibodies to GAD were observed in all five samples tested from children diagnosed at ≤2 years of age, and persistent islet autoantibodies were detected in 72% of DSD cases. Thyroid and celiac disease were diagnosed in 74 and 14%, respectively, of the DSD cohort. CONCLUSIONS: Early-onset diabetes in children with DS is unlikely to be etiologically different from autoimmune diabetes occurring in older DS children. Overall, these studies demonstrate more extreme autoimmunity in DSD typified by early-onset diabetes with multiple autoimmunity, persistent islet autoantibodies, and decreased HLA-mediated susceptibility.