Rapid on-site molecular Point of Care Testing during influenza outbreaks in aged care facilities improves antiviral use and reduces hospitalisation.

OBJECTIVE: Western Sydney Local Health District (WSLHD) measured the utility and validity of rapid molecular point-of-care testing (POCT) in aged care facilities (ACFs) experiencing influenza-like illness (ILI) outbreaks against routine laboratory testing. METHODS: A descriptive epidemiological study into 82 respiratory outbreaks reported across 63 ACFs within WSLHD supporting approximately 6,500 residents aged ≥65 years and staffed by ∼6,500 employees, from 1 August 2018 to 31 December 2019. RESULTS: WSLHD Public Health Unit performed on-site testing at 27 ACF outbreaks (34%), while 53(66%) ACFs conducted only routine laboratory testing. The Xpert®Xpress Flu/RSV molecular PCR provided a sensitivity and specificity of 100%. Those with on-site testing, antiviral prophylaxis was prescribed at 75% of facilities within 24 hours of testing, as opposed to 32% of those using laboratory testing (p<0.01). There were 24 of 181 ACF residents hospitalised in the POCT group compared to 76 of 357 in the laboratory-only group (OR=0.57; p=0.02). CONCLUSIONS: On-site ACF testing is reliable and practical for early identification of influenza, enabling timely use of antiviral treatment and prophylaxis, and was associated with decreased hospitalisation. PUBLIC HEALTH IMPLICATIONS: Enhanced respiratory surveillance and on-site testing should be strongly considered as part of routine management of respiratory outbreaks in ACFs and may reduce outbreak severity.

Epidemiologic Evidence for Airborne Transmission of SARS-CoV-2 during Church Singing, Australia, 2020.

An outbreak of severe acute respiratory syndrome coronavirus 2 infection occurred among church attendees after an infectious chorister sang at multiple services. We detected 12 secondary case-patients. Video recordings of the services showed that case-patients were seated in the same section, up to 15 m from the primary case-patient, without close physical contact, suggesting airborne transmission.

Factors associated with adverse outcomes during influenza outbreaks in aged care facilities.

OBJECTIVE: To explore factors associated with adverse outcomes during influenza outbreaks in residential aged care facilities. METHODS: A retrospective cohort study of all outbreaks reported to three Sydney metropolitan Public Health Units during 2017. RESULTS: A total of 123 outbreaks affected 1,787 residents and 543 staff. Early notification to a Public Health Unit was associated with shorter outbreak duration (p<0.001; B=0.674). Resident attack rates and resident mortality rates were lower in outbreaks notified early, on univariate analysis (p=0.034 and p=0.048 respectively) but not on an adjusted model. Staff attack rates were significantly associated with resident attack rates (p=0.001; B=0.736). Data on staff vaccination rates was incomplete and reported coverage rates were low (median 39%). Resident vaccination coverage ≥95% was associated with shorter outbreak duration in univariate testing but not on an adjusted model. CONCLUSIONS: Early public health notification is associated with improved outbreak parameters; sick staff may pose a risk to residents, yet vaccination rates are low. Resident vaccination may also be valuable. Implications for public health: Measures that facilitate early PHU involvement in influenza outbreaks should be implemented, such as compulsory reporting requirements and processes that permit easier notification through technology. Actions that enhance staff and resident vaccination coverage should also be undertaken.

Thyroglobulin (Tg) Testing Revisited: Tg Assays, TgAb Assays, and Correlation of Results With Clinical Outcomes.

CONTEXT: Measurement of thyroglobulin (Tg) by mass spectrometry (Tg-MS) is emerging as a tool for accurate Tg quantification in patients with anti-Tg autoantibodies (TgAbs). OBJECTIVE: The objective of the study was to perform analytical and clinical evaluations of two Tg-MS assays in comparison with immunometric Tg assays (Tg-IAs) and Tg RIAs (Tg-RIAs) in a cohort of thyroid cancer patients. METHODS: A total of 589 samples from 495 patients, 243 TgAb-/252 TgAb+, were tested by Beckman, Roche, Siemens-Immulite, and Thermo-Brahms Tg and TgAb assays, two Tg-RIAs, and two Tg-MS assays. RESULTS: The frequency of TgAb+ was 58%, 41%, 27%, and 39% for Roche, Beckman, Siemens-Immulite, and Thermo-Brahms, respectively. In TgAb- samples, clinical sensitivities and specificities of 100% and 74%-100%, respectively, were observed across all assays. In TgAb+ samples, all Tg-IAs demonstrated assay-dependent Tg underestimation, ranging from 41% to 86%. In TgAb+ samples, the use of a common cutoff (0.5 ng/mL) for the Tg-MS, three Tg-IAs, and the USC-RIA improved the sensitivity for the Tg-MSs and Tg-RIAs when compared with the Tg-IAs. In up to 20% of TgAb+ cases, Tg-IAs failed to detect Tg that was detectable by Tg-MS. In Tg-RIAs false-high biases were observed in TgAb+ samples containing low Tg concentrations. CONCLUSIONS: Tg-IAs remain the method of choice for Tg quantitation in TgAb- patients. In TgAb+ patients with undetectable Tg by immunometric assay, the Tg-MS will detect Tg in up to 20% additional cases. The Tg-RIA will detect Tg in approximately 35% cases, but a significant proportion of these will be clinical false-positive results. The undetectable Tg-MS seen in approximately 40% of TgAb+ cases in patients with disease need further evaluation.

Thyroglobulin measurement by highly sensitive assays: focus on laboratory challenges.

Differentiated thyroid cancer (DTC) is the most common endocrine cancer and its incidence has increased in recent decades. The initial treatment consists of total thyroidectomy followed by ablation of thyroid remnants by radioiodine in most cases. As thyroid cells are the only source of thyroglobulin (Tg), circulating Tg serves as a biochemical marker of persistent or recurrent disease in the follow-up of DTC. Due to the suboptimal clinical detection rate of older Tg assays endogenous or exogenous thyrotropin (TSH) stimulations are recommended for unmasking occult disease. However, the development of new Tg assays with improved analytical sensitivity and precision at low concentrations now allows detection of very low Tg concentrations, reflecting minimal amounts of thyroid tissue, even without the need for TSH stimulation. Even if the use of these assays still has not found its way in current clinical guidelines, such assays are now increasingly used in clinical practice. As serum Tg measurement is a technically challenging assay and criteria to define a 'highly sensitive' assay may be different, a good knowledge of the technical difficulties and interpretation criteria is of paramount importance for both clinical thyroidologists, laboratory physicians and scientists involved in the care of DTC patients.

Thyroglobulin measurement using highly sensitive assays in patients with differentiated thyroid cancer: a clinical position paper.

Differentiated thyroid cancer (DTC) is the most common endocrine cancer and its incidence has increased in recent decades. Initial treatment usually consists of total thyroidectomy followed by ablation of thyroid remnants by iodine-131. As thyroid cells are assumed to be the only source of thyroglobulin (Tg) in the human body, circulating Tg serves as a biochemical marker of persistent or recurrent disease in DTC follow-up. Currently, standard follow-up for DTC comprises Tg measurement and neck ultrasound combined, when indicated, with an additional radioiodine scan. Measurement of Tg after stimulation by endogenous or exogenous TSH is recommended by current clinical guidelines to detect occult disease with a maximum sensitivity due to the suboptimal sensitivity of older Tg assays. However, the development of new highly sensitive Tg assays with improved analytical sensitivity and precision at low concentrations now allows detection of very low Tg concentrations reflecting minimal amounts of thyroid tissue without the need for TSH stimulation. Use of these highly sensitive Tg assays has not yet been incorporated into clinical guidelines but they will, we believe, be used by physicians caring for patients with DTC. The aim of this clinical position paper is, therefore, to offer advice on the various aspects and implications of using these highly sensitive Tg assays in the clinical care of patients with DTC.

A novel albumin gene mutation (R222I) in familial dysalbuminemic hyperthyroxinemia.

CONTEXT: Familial dysalbuminemic hyperthyroxinemia, characterized by abnormal circulating albumin with increased T4 affinity, causes artefactual elevation of free T4 concentrations in euthyroid individuals. OBJECTIVE: Four unrelated index cases with discordant thyroid function tests in different assay platforms were investigated. DESIGN AND RESULTS: Laboratory biochemical assessment, radiolabeled T4 binding studies, and ALB sequencing were undertaken. (125)I-T4 binding to both serum and albumin in affected individuals was markedly increased, comparable with known familial dysalbuminemic hyperthyroxinemia cases. Sequencing showed heterozygosity for a novel ALB mutation (arginine to isoleucine at codon 222, R222I) in all four cases and segregation of the genetic defect with abnormal biochemical phenotype in one family. Molecular modeling indicates that arginine 222 is located within a high-affinity T4 binding site in albumin, with substitution by isoleucine, which has a smaller side chain predicted to reduce steric hindrance, thereby facilitating T4 and rT3 binding. When tested in current immunoassays, serum free T4 values from R222I heterozygotes were more measurably abnormal in one-step vs two-step assay architectures. Total rT3 measurements were also abnormally elevated. CONCLUSIONS: A novel mutation (R222I) in the ALB gene mediates dominantly inherited dysalbuminemic hyperthyroxinemia. Susceptibility of current free T4 immunoassays to interference by this mutant albumin suggests likely future identification of individuals with this variant binding protein.

Sustained outbreak of measles in New South Wales, 2012: risks for measles elimination in Australia.

OBJECTIVE: On 7 April 2012, a recently returned traveller from Thailand to Australia was confirmed to have measles. An outbreak of measles subsequently occurred in the state of New South Wales, prompting a sustained and coordinated response by public health authorities. The last confirmed case presented on 29 November 2012. This report describes the outbreak and its characteristics. METHODS: Cases were investigated following Australian protocols, including case interviews and assessment of contacts for post-exposure prophylaxis. RESULTS: Of the 168 cases identified, most occurred in south-western and western Sydney (92.9%, n = 156). Notable features of this outbreak were the disproportionately high number of cases in the 10-19-year-old age group (29.2%, n = 49), the overrepresentation among people of Pacific Islander descent (21.4%, n = 36) and acquisition in health-care facilities (21.4%, n = 36). There were no reported cases of encephalitis and no deaths. DISCUSSION: This was the largest outbreak of measles in Australia since 1997. Its occurrence highlights the need to maintain vigilant surveillance systems for early detection and containment of measles cases and to maintain high population immunity to measles through routine childhood immunization. Vaccination campaigns targeting susceptible groups may also be necessary to sustain Australia's measles elimination status.

Sustained outbreak of measles in New South Wales, 2012: risks for measles elimination in Australia

Objective：On 7 April 2012, a recently returned traveller from Thailand to Australia was confirmed to have measles. An outbreak of measles subsequently occurred in the state of New South Wales, prompting a sustained and coordinated response by public health authorities. The last confirmed case presented on 29 November 2012. This report describes the outbreak and its characteristics.Methods：Cases were investigated following Australian protocols, including case interviews and assessment of contacts for post-exposure prophylaxis.Results：Of the 168 cases identified, most occurred in south-western and western Sydney (92.9%, n = 156). Notable features of this outbreak were the disproportionately high number of cases in the 10–19-year-old age group (29.2%, n = 49), the overrepresentation among people of Pacific Islander descent (21.4%, n = 36) and acquisition in health-care facilities (21.4%, n = 36). There were no reported cases of encephalitis and no deaths.Discussion: This was the largest outbreak of measles in Australia since 1997. Its occurrence highlights the need to maintain vigilant surveillance systems for early detection and containment of measles cases and to maintain high population immunity to measles through routine childhood immunization. Vaccination campaigns targeting susceptible groups may also be necessary to sustain Australia’s measles elimination status.

Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer.

BACKGROUND: It is not known whether low-dose radioiodine (1.1 GBq [30 mCi]) is as effective as high-dose radioiodine (3.7 GBq [100 mCi]) for treating patients with differentiated thyroid cancer or whether the effects of radioiodine (especially at a low dose) are influenced by using either recombinant human thyrotropin (thyrotropin alfa) or thyroid hormone withdrawal. METHODS: At 29 centers in the United Kingdom, we conducted a randomized noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Patients (age range, 16 to 80 years) had tumor stage T1 to T3, with possible spread to nearby lymph nodes but without metastasis. End points were the rate of success of ablation at 6 to 9 months, adverse events, quality of life, and length of hospital stay. RESULTS: A total of 438 patients underwent randomization; data could be analyzed for 421. Ablation success rates were 85.0% in the group receiving low-dose radioiodine versus 88.9% in the group receiving the high dose and 87.1% in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid hormone withdrawal. All 95% confidence intervals for the differences were within ±10 percentage points, indicating noninferiority. Similar results were found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose radioiodine plus thyrotropin alfa (90.2%). More patients in the high-dose group than in the low-dose group were hospitalized for at least 3 days (36.3% vs. 13.0%, P<0.001). The proportions of patients with adverse events were 21% in the low-dose group versus 33% in the high-dose group (P=0.007) and 23% in the thyrotropin alfa group versus 30% in the group undergoing thyroid hormone withdrawal (P=0.11). CONCLUSIONS: Low-dose radioiodine plus thyrotropin alfa was as effective as high-dose radioiodine, with a lower rate of adverse events. (Funded by Cancer Research UK; ClinicalTrials.gov number, NCT00415233.).

An evaluation of measured and calculated serum free cortisol in a group of patients with known adrenal suppression.

BACKGROUND: Since more than 90% of cortisol is bound to protein, serum free cortisol (SFC) may be a more appropriate marker of adrenal status than total cortisol. However, measurement of SFC is technically difficult and calculated SFC may offer a more practical alternative. METHODS: SFC, measured by equilibrium dialysis coupled with immunoassay, and calculated using Coolens' equation from total cortisol and corticosteroid binding globulin (CBG) concentrations, was compared in short Synacthen test (SST) serum from 42 patients, of whom 20 demonstrated a suppressed adrenal response. RESULTS: Considering the patient group as a whole, calculated SFC was found to be significantly lower than measured SFC, pre- and post-Synacthen (P < 0.05 and <0.001, respectively). Upon classifying the patients as pass or fail based on total cortisol response to Synacthen, the difference in calculated and measured SFC only reached statistical significance for post-Synacthen concentrations in the pass group (P < 0.01), suggesting a greater discrepancy at higher cortisol concentrations. There was no difference in CBG levels between the pass and fail groups and both measured and calculated SFC gave a diminished 30 min response in subjects deemed to have failed the SST. CONCLUSION: Coolens' equation was found to underestimate measured SFC in this cohort of outpatients, as has been previously demonstrated, particularly in patients with a pronounced acute phase response. Although calculated SFC gave a diminished response in individuals deemed to have failed the SST, the concentration-dependent nature of the discrepancy may limit the usefulness of this method for assessing adrenal status.

Toward standardization of insulin immunoassays.

BACKGROUND: Measurement of circulating insulin may improve the classification and management of diabetes mellitus and assist in treating people with insulin resistance. METHODS: A work group convened by the American Diabetes Association evaluated results for a panel of 39 single donor sera measured by 10 commercial insulin methods from 9 manufacturers against an isotope dilution-liquid chromatography/tandem mass spectrometry (IDMS) measurement procedure calibrated using purified recombinant insulin. We used a candidate primary (pure substance) reference material, pooled serum, and single donor sera to evaluate approaches to achieve improved agreement of results between the routine and reference measurement procedures. RESULTS: Four of 10 methods had >or=95% of individual serum results within 32% of the IDMS concentrations. However, the bias vs IDMS was more than 15.5% for 7 of 10 methods in 36%-100% of individual samples. A purified recombinant insulin preparation used as a common calibrator did not improve harmonization of results among routine methods but was not used as instructed by all participants. Calibration using serum pools achieved bias <15.5% for nearly all results in the concentration range covered by the pools (>60 pmol/L). Calibration using a panel of individual sera was the most effective to improve harmonization of results over the full measuring range. CONCLUSIONS: Agreement among methods can be improved by establishing traceability to the IDMS procedure using a panel of native sera. Pooled sera may be useful as trueness control materials. The usefulness of the pure insulin primary reference material [candidate reference material for insulin (cRMI)] requires clarification of protocols used by manufacturers.

Preanalytical, analytical, and computational factors affect homeostasis model assessment estimates.

OBJECTIVE: We investigated how beta-cell function and insulin sensitivity or resistance are affected by the type of blood sample collected or choice of insulin assay and homeostatis model assessment (HOMA) calculator (http://www.dtu.ox.ac.uk). RESEARCH DESIGN AND METHODS: Insulin was measured using 11 different assays in serum and 1 assay in heparinized plasma. Fasting subjects with normoglycemia (n = 12), pre-diabetes, i.e., impaired fasting glucose or impaired glucose tolerance (n = 18), or type 2 diabetes (n = 67) were recruited. Patients treated with insulin or those who were insulin antibody-positive were excluded. HOMA estimates were calculated using specific insulin (SI) or radioimmunoassay (RIA) calculators (version 2.2). RESULTS: All glucose values were within model (HOMA) limits but not all insulin results, as 4.3% were <20 pmol/l and 1% were >300 pmol/l. beta-Cell function derived from different insulin assays ranged from 67 to 122% (median) for those with normoglycemia (P = 0.026), from 89 to 138% for those with pre-diabetes (P = 0.990), and from 50 to 81% for those with type 2 diabetes (P < 0.0001). Furthermore, insulin resistance ranged from 0.8 to 2.0 (P = 0.0007), from 1.9 to 3.2 (P = 0.842), and from 1.5 to 2.9 (P < 0.0001), respectively. This twofold variation in HOMA estimates from the various insulin assays studied in serum may be significant metabolically. Insulin was 15% lower in heparinized plasma (used in the original HOMA study) compared with serum, which is now more commonly used. beta-Cell function differed by 11% and insulin resistance by 15% when estimates derived from specific insulin were calculated using the RIA rather than the SI calculator. CONCLUSIONS: To enable comparison of HOMA estimates among individuals and different research studies, preanalytical factors and calculator selection should be standardized with insulin assays traceable to an insulin reference method procedure.

Mutations in the glucokinase gene of the fetus result in reduced placental weight.

OBJECTIVE: In human pregnancy, placental weight is strongly associated with birth weight. It is uncertain whether there is regulation of the placenta by the fetus or vice versa. We aimed to test the hypothesis that placental growth is mediated, either directly or indirectly, by fetal insulin. RESEARCH DESIGN AND METHODS: Birth weight and placental weight were measured in 43 offspring of 21 parents with mutations in the glucokinase (GCK) gene (25 had inherited the mutation and 18 had not), which results in reduced fetal insulin secretion. Birth weight, placental weight, umbilical cord insulin, and maternal glucose and insulin concentrations were measured in 573 nondiabetic, healthy, term pregnancies. RESULTS: GCK mutation carriers were lighter and also had smaller placentas (610 vs. 720 g, P = 0.042). This difference was also seen in 17 discordant sibling pairs (600 vs. 720 g, P = 0.003). GCK mRNA was not detected in the placenta by RT-PCR. In the normal pregnancies, placental weight was strongly correlated with birth weight (r = 0.61, P < 0.001). Cord insulin concentrations were directly related to placental weight (r = 0.28) and birth weight (r = 0.36) (P < 0.001 for both). CONCLUSIONS: These results suggest that insulin, directly or indirectly, plays a role in placental growth, especially as a mutation in the GCK gene, which is known to only alter fetal insulin secretion, results in altered placental weight. This finding is consistent with the preferential localization of the insulin receptors in the fetal endothelium of the placenta in the last trimester of pregnancy.

Measurement of cord insulin and insulin-related peptides suggests that girls are more insulin resistant than boys at birth.

OBJECTIVE: We aimed to examine sex differences in insulin and insulin propeptide concentrations at birth using validated cord blood collection. RESEARCH DESIGN AND METHODS: We tested the impact on insulin and insulin propeptides of taking 13 cord blood samples in heparin and EDTA and then centrifuging and separating plasma after 1, 2, 24, or 48 h at room temperature (heparin) or 4 degrees C (EDTA). Cord plasma insulin and insulin propeptides concentrations were measured in 440 babies and correlated with offspring anthropometry measured at birth. RESULTS: Cord insulin concentrations significantly decreased (74% those at baseline by 24 h; P = 0.01) in the samples taken in heparin and stored at room temperature, but those taken on EDTA and refrigerated remained stable for up to 48 h. Insulin propeptides were stable in both. Cord plasma insulin and insulin propeptides measured in EDTA were related to all measures of birth size and maternal glycemia and BMI (r > 0.11; P < 0.03 for all) and were higher in those delivered via caesarean section. Girls were lighter (3,497 vs. 3,608 g; P = 0.01) but had higher cord insulin (46.7 vs. 41.2 pmol/l; P = 0.031), total proinsulin (34.1 vs. 25.8 pmol/l; P < 0.001), and intact proinsulin (9.5 vs. 8.3 pmol/l; P = 0.004) concentrations than boys; this was further confirmed when cord insulin concentrations of boys and girls were compared after pair matching for birth weight (insulin 49.7 vs. 42.1 pmol/l; P = 0.004). CONCLUSIONS: When using appropriate sample collection methods, female newborns have higher insulin concentrations than male newborns, despite being smaller, suggesting intrinsic insulin resistance in girls.

Comparison of 11 human insulin assays: implications for clinical investigation and research.

BACKGROUND: The American Diabetes Association task force on standardization of insulin assays in 1996 showed wide variation in assay bias. Newer assays are specific for insulin, with several now available on automated immunoassay analyzers. METHODS: In 2004, we compared 11 commercially available insulin assays by analyzing 150 serum samples (99 fasting/51 postprandial) from study participants with various degrees of glucose intolerance (exclusions being type 1 diabetes, insulin treatment, or presence of insulin antibodies). All assays were calibrated against International Reference Preparation 66/304. One assay was not specific for insulin and another was an RIA; 10 assays used enzyme/chemiluminescent labels. Bland-Altman difference plots were modified to use the mean insulin from all assays on the x-axis as a common comparator. RESULTS: As in the 1996 study, insulin values from the different assays varied by a factor of 2, with the nonspecific assay ranking in the middle of the distribution. Spearman rank correlation coefficients, for ranking samples vs the mean, were 0.983-0.997. Both offsets and concentration-dependent differences were seen in the modified difference plots. Imprecision (mean CV) for automated assays (3%) was not significantly different from manual assays (5%). Similar values were obtained when one automated assay was run in laboratories in both the UK and the US. Results of 1 assay showed lower insulin concentrations in heparinized plasma than in serum. CONCLUSIONS: Assay performance must be considered before comparing insulin results. The 2-fold variation in insulin results may be related to specificity, manufacturers' calibration procedures or conversion factors.

The long-term predictive accuracy of the short synacthen (corticotropin) stimulation test for assessment of the hypothalamic-pituitary-adrenal axis.

CONTEXT: The high-dose short Synacthen (corticotropin) test (SST) is widely used to investigate suspected secondary adrenal insufficiency, but concern remains about falsely reassuring results. OBJECTIVE: Our objective was to evaluate the long-term safety of the SST. METHOD: We retrospectively evaluated the clinical outcome in 178 patients who achieved 30-min cortisol values in the lowest 15th percentile of normal healthy responses. Thirty patients were later excluded because of missing case notes (20 patients) or unsubstantiated pituitary pathology (10 patients). The remaining 148 patients were divided into two groups: group 1, patients with cortisol response between the 5th and 15th percentiles of normal response (551-635 nmol/liter, 98 patients); and group 2, patients with borderline response between the 2.5th and 5th percentiles (510-550 nmol/liter, 50 patients). Patients did not receive routine glucocorticoid therapy, but those in group 2 were advised to take hydrocortisone in case of intercurrent illness. RESULTS: The median follow-up period from the initial SST was 4.2 yr (range, 4 months to 7 yr). A total of 137 patients showed no clinical or biochemical evidence of adrenal insufficiency during follow-up. Of the remaining 11 patients, seven became hypoadrenal after subsequent pituitary surgery or radiotherapy, one patient in group 1 developed adrenal insufficiency at 2 yr, and one patient in group 2 developed adrenal insufficiency at 6 months. The other two patients who were in group 2 had clinical diagnostic uncertainty. CONCLUSION: The high-dose SST is safe for the purpose of excluding clinically significant secondary adrenal insufficiency and is indicated as the first line of investigation for this purpose.