Defining the Functional Sensitivity for the Siemens Atellica Calcitonin Assay: Insight From a Single-Center Study.

BACKGROUND: Detectable, and especially rising postthyroidectomy serum calcitonin and carcinoembryonic antigen levels, as per American Thyroid Association guidelines, indicate potential disease presence, requiring frequent calcitonin measurement or imaging for early detection of persistent or recurrent medullary thyroid carcinoma. Thus, defining the clinical cutoff value of detection of calcitonin assays relative to imaging and clinical status is crucial for patient care. This study aimed to evaluate postoperative calcitonin levels using the new Siemens Atellica assay system to determine the most appropriate levels for clinical decision-making. METHODS: A retrospective analysis was conducted using Siemens Atellica for calcitonin testing on 56 samples from 40 patients between September 27, 2022 and August 11, 2023. Only calcitonin results performed at least 3 months post-total thyroidectomy were included. Imaging studies, within 6 months of the calcitonin report, were assessed. Carcinoembryonic antigen results were also reviewed. RESULTS: Precision analysis at 2.94 and 5.24 pg/mL revealed coefficients of variation at 16.49% and 8.87%, respectively. For the evidence of post-total thyroidectomy persistent or recurrent medullary thyroid carcinoma confirmed by imaging, using a 1.89 pg/mL cutoff for calcitonin yielded 43% sensitivity and 67% specificity. Using a 5.00 pg/mL cutoff resulted in 0% sensitivity and 100% specificity. CONCLUSIONS: Our findings indicate the potential suitability of a 5 pg/mL calcitonin cutoff on the Siemens Atellica platform for evaluating tumor persistence or recurrence in post-thyroidectomy patients in our institution. However, individual laboratories should establish their own clinical cutoff value when evaluating calcitonin levels for monitoring tumor recurrence post-thyroidectomy.

Endocrine effects of heat exposure and relevance to climate change.

Climate change is increasing both seasonal temperatures and the frequency and severity of heat extremes. As the endocrine system facilitates physiological adaptations to temperature changes, diseases with an endocrinological basis have the potential to affect thermoregulation and increase the risk of heat injury. The effect of climate change and associated high temperature exposure on endocrine axis development and function, and on the prevalence and severity of diseases associated with hormone deficiency or excess, is unclear. This Perspective summarizes current knowledge relating to the hormonal effects of heat exposure in species ranging from rodents to humans. We also describe the potential effect of high temperature exposures on patients with endocrine diseases. Finally, we highlight the need for more basic science, clinical and epidemiological research into the effects of heat on endocrine function and health; this research could enable the development of interventions for people most at risk, in the context of rising environmental temperatures.

Insights into insulin analog cross-reactivity: a comparative study of Siemens Atellica and LC-MS/MS.

BACKGROUND: To address the challenges posed by inconsistent detection of analog insulin in commercially available insulin immunoassays, resulting in potential discrepancies in clinical findings and misdiagnosis during the investigation of factitious hypoglycemia., we aimed to evaluate the ability of the Siemens Atellica automated immunoassay to detect insulin analogs compared with LC-MS/MS. METHODS: Five insulin analogs were analyzed at 10 ng/mL spiked into serum samples, with recombinant human insulin as positive controls. Insulin and C-peptide assays were performed using Siemens Atellica and LC-MS/MS. Recovery rates were calculated. RESULTS: Siemens Atellica immunoassay demonstrated robust cross-reactivity (92-121%) of insulin analogs. In contrast, glargine was detected by LC-MS/MS but other analogs were not observed (<10% recovery). CONCLUSION: Our results indicate that the insulin assay conducted on the Siemens Atellica platform could be used to diagnose factitious hypoglycemia by detecting the specific insulin analogs involved. The findings from our studies indicate the suitability of this method for clinical laboratory use in cases where factitious hypoglycemia is under consideration as a potential diagnosis. Clinicians should take these results into account when interpreting insulin measurements, particularly in instances where insulin analog overdose is suspected.

Pre-exercise hot water immersion increased circulatory heat shock proteins but did not alter muscle damage markers or endurance capacity after eccentric exercise.

Pre-exercise passive heating attenuates muscle damage caused by eccentric exercise in rats where the induction of heat shock proteins (HSPs) confers a myoprotective effect. We investigated whether pre-exercise hot water immersion (HWI) confers similar benefits in humans. Eleven recreational male athletes were immersed in 41°C water up to 60 min or until rectal temperatures reached 39.5°C. After a 6 h rest, the participants performed an eccentric downhill run for 1 h at -4% gradient to induce muscle damage. An endurance capacity test at 75% VO2max was conducted 18 h later. The control trial was similar except that participants were immersed at 34°C. Blood samples were collected to assess HSPs levels, creatine kinase, and lactate dehydrogenase activities. Plasma eHSP70 was higher post-immersion in HWI trials (1.3 ± 0.4 vs 1.1 ± 0.4; p = 0.005). Plasma eHSP27 was higher before (p = 0.049) and after (p = 0.015) endurance test in HWI. Leukocytic p-HSP27 was increased 18 h after HWI (0.97 ± 0.14 vs 0.67 ± 0.11; p = 0.04). Creatine kinase and lactate dehydrogenase activities were increased by 3-fold and 1.5-fold, respectively, after endurance test in HWI but did not differ across trials (p > 0.05). Mean heart rates were higher during eccentric run and endurance test in HWI as compared to control (p < 0.05). Endurance capacity was similar between trials (57.3 ± 11.5 min vs 55.0 ± 13.5 min; p = 0.564). Pre-exercise heating increased the expression of plasma eHSPs and leukocytic p-HSP27 but did not reduce muscle damage nor enhance endurance capacity.

Designing Microporous Layers for Electrolyzers Using Stochastic Approach.

Electrochemical energy conversion devices, such as water and carbon dioxide electrolyzers, offer significant advantages in achieving net-zero emissions and in mitigating further increases in global temperature. However, their widespread adoption necessitates enhancements in performance and durability. Microporous layers (MPLs) have been gaining attention as a promising means to enhance the performance and durability of membrane-electrode-assembly (MEA) based electrolyzers, but their nontrivial mechanisms and complexity in fabrication pose challenges for optimizing the microporous layer structure experimentally. This study introduces a stochastic model for generating MPLs in application to electrolyzers. The model produces 3D reconstructions of MPLs, with porosity and particle size as input parameters, and is capable of generating biased MPLs by taking the pre-existing 3D reconstruction as an input. The model applies a dilation and erosion algorithm to replicate sinter-necks formed in the MPL during the sintering process, and captures their impact on structural and transport properties. In this work, three types of MPLs are generated by using the presented model, which include single-layer MPLs, MPLs with pore formers, and bilayer MPLs. Surface roughness analysis and pore network simulations on the MPLs highlight the significance of particle size in the MPL design. Using finer particles at higher porosities are favored over using larger particles at lower porosities. Such findings are examples of the valuable insights offered from the presented stochastic model, and the model will guide seminal discovery of next-generation MPLs that will greatly progress the shift toward net-zero electrochemical energy conversion technologies.

The relative vaccine effectiveness of high-dose vs standard-dose influenza vaccines in preventing hospitalization and mortality: A meta-analysis of evidence from randomized trials.

OBJECTIVES: To summarize current evidence of high-dose influenza vaccine (HD-IV) vs standard-dose (SD-IV) regarding severe clinical outcomes. METHODS: A prespecified meta-analysis was conducted to assess relative vaccine effectiveness (rVE) of HD-IV vs SD-IV in reducing the rates of (1) pneumonia and influenza (P&I) hospitalization, (2) all hospitalizations, and (3) all-cause death in adults ≥ 65 years in randomized controlled trials. Pooled effect sizes were estimated using fixed-effects models with the inverse variance method. RESULTS: Five randomized trials were included encompassing 105,685 individuals. HD-IV vs SD-IV reduced P&I hospitalizations (rVE: 23.5 %, [95 %CI: 12.3 to 33.2]). HD-IV vs SD-IV also reduced rate of all-cause hospitalizations (rVE: 7.3 %, [95 %CI: 4.5 to 10.0]). No significant differences were observed in death rates (rVE = 1.6 % ([95 %CI: -2.0 to 5.0]) in HD-IV vs SD-IV. Sensitivity analyses omitting trials with participants sharing the same comorbidity, trials with ≥ 100 events, and random-effects models provided comparable estimates for all outcomes. CONCLUSIONS: HD-IV reduced the incidence of P&I and all-cause hospitalization vs SD-IV in adults ≥ 65 years in randomized trials, through no significant difference was observed in all-cause death rates. These findings, supported by evidence from several randomized studies, can benefit from replication in a fully powered, individually randomized trial.

Evaluation of Age and Sex Differences in Contemporary versus High-Sensitivity Troponin I Measurement in Hospitalized Patients.

Background: With the transition from the contemporary (cTnI) to high-sensitivity troponin assay (hs-cTnI), concerns have arisen regarding the diagnostic differences between these two assays due to analytical distinctions. This study aims to evaluate the age and sex differences between these two assays, as well as the differences resulting from using two different 99th percentile values of the high-sensitivity troponin assay. Method: A retrospective observational study was conducted at an academic medical center, encompassing a total of 449 lithium heparin plasma samples included in the dataset. Both contemporary and high-sensitivity troponin were simultaneously measured using Siemens ADVIA Centaur analyzers. Two sets of sex-specific 99th percentile URLs from the Siemens study (cutoff-1) and Universal Sample Bank data (cutoff-2) were used for the data analysis. Results: The use of cutoff-1 or cutoff-2 had a negligible impact on troponin classification. Troponin elevation significantly increased in individuals > 50 years old for males and >40 years old for females, with both troponin assays. A receiver operating characteristic analysis did not find significant differences between the two assays. The Kaplan-Meier curves showed no differences in survival in cTnI according to the non-sex-specific 99th URL or hs-cTnI (cutoff-2) but showed a slight difference in survival in hs-cTnI (cutoff-1). Conclusions: Overall, there were no significant differences in age and sex in the diagnostic performance between the contemporary and high-sensitivity troponin assays. Selection criteria for the establishment of the 99th percentile URL should be standardized to avoid the misinterpretation of the troponin results.

Elevated brain temperature under severe heat exposure impairs cortical motor activity and executive function.

BACKGROUND: Excessive heat exposure can lead to hyperthermia in humans, which impairs physical performance and disrupts cognitive function. While heat is a known physiological stressor, it is unclear how severe heat stress affects brain physiology and function. METHODS: Eleven healthy participants were subjected to heat stress from prolonged exercise or warm water immersion until their rectal temperatures (Tre) attained 39.5°C, inducing exertional or passive hyperthermia, respectively. In a separate trial, blended ice was ingested before and during exercise as a cooling strategy. Data were compared to a control condition with seated rest (normothermic). Brain temperature (Tbr), cerebral perfusion, and task-based brain activity were assessed using magnetic resonance imaging techniques. RESULTS: Tbr in motor cortex was found to be tightly regulated at rest (37.3°C ± 0.4°C (mean ± SD)) despite fluctuations in Tre. With the development of hyperthermia, Tbr increases and dovetails with the rising Tre. Bilateral motor cortical activity was suppressed during high-intensity plantarflexion tasks, implying a reduced central motor drive in hyperthermic participants (Tre = 38.5°C ± 0.1°C). Global gray matter perfusion and regional perfusion in sensorimotor cortex were reduced with passive hyperthermia. Executive function was poorer under a passive hyperthermic state, and this could relate to compromised visual processing as indicated by the reduced activation of left lateral-occipital cortex. Conversely, ingestion of blended ice before and during exercise alleviated the rise in both Tre and Tbr and mitigated heat-related neural perturbations. CONCLUSION: Severe heat exposure elevates Tbr, disrupts motor cortical activity and executive function, and this can lead to impairment of physical and cognitive performance.

Engineering Bipolar Interfaces for Water Electrolysis Using Earth-Abundant Anodes.

Developing efficient and low-cost water electrolyzers for clean hydrogen production to reduce the carbon footprint of traditional hard-to-decarbonize sectors is a grand challenge toward tackling climate change. Bipolar-based water electrolysis combines the benefits of kinetically more favorable half-reactions and relatively inexpensive cell components compared to incumbent technologies, yet it has been shown to have limited performance. Here, we develop and test a bipolar-interface water electrolyzer (BPIWE) by combining an alkaline anode porous transport electrode with an acidic catalyst-coated membrane. The role of TiO2 as a water dissociation (WD) catalyst is investigated at three representative loadings, which indicates the importance of balancing ionic conductivity and WD activity derived from the electric field for optimal TiO2 loading. The optimized BPIWE exhibits negligible performance degradation up to 500 h at 400 mA cm-2 fed with pure water using earth-abundant anode materials. Our experimental findings provide insights into designing bipolar-based electrochemical devices.

Climate change and population health in Singapore: a systematic review.

Gaseous emissions have contributed to global warming, an increase in the frequency of extreme weather events and poorer air quality. The associated health impacts have been well reported in temperate regions. In Singapore, key climate change adaptation measures and activities include coastal and flood protection, and mitigating heat impacts. We systematically reviewed studies examining climate variability and air quality with population health in Singapore, a tropical city-state in South-East Asia (SEA), with the aim to identify evidence gaps for policymakers. We included 14 studies with respiratory illnesses, cardiovascular outcomes, foodborne disease and dengue. Absolute humidity (3 studies) and rainfall (2 studies) were positively associated with adverse health. Extreme heat (2 studies) was inversely associated with adverse health. The effects of mean ambient temperature and relative humidity on adverse health were inconsistent. Nitrogen dioxide and ozone were positively associated with adverse health. Climate variability and air quality may have disease-specific, differing directions of effect in Singapore. Additional high quality studies are required to strengthen the evidence for policymaking. Research on effective climate action advocacy and adaptation measures for community activities should be strengthened. Funding: There was no funding source for this study.

Simultaneous multimaterial operando tomography of electrochemical devices.

The performance of electrochemical energy devices, such as fuel cells and batteries, is dictated by intricate physiochemical processes within. To better understand and rationally engineer these processes, we need robust operando characterization tools that detect and distinguish multiple interacting components/interfaces in high contrast. Here, we uniquely combine dual-modality tomography (simultaneous neutron and x-ray tomography) and advanced image processing (iterative reconstruction and metal artifact reduction) for high-contrast multimaterial imaging, with signal and contrast enhancements of up to 10 and 48 times, respectively, compared to conventional single-modality imaging. Targeted development and application of these methods to electrochemical devices allow us to resolve operando distributions of six interacting fuel cell components (including void space) with the highest reported pairwise contrast for simultaneous yet decoupled spatiotemporal characterization of component morphology and hydration. Such high-contrast tomography ushers in key gold standards for operando electrochemical characterization, with broader applicability to numerous multimaterial systems.

Active maintenance of CD8+ T cell naivety through regulation of global genome architecture.

The differentiation of naive CD8+ T lymphocytes into cytotoxic effector and memory CTL results in large-scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organization underpin these transcriptional programs. We use Hi-C to map changes in the spatial organization of long-range genome contacts within naive, effector, and memory virus-specific CD8+ T cells. We observe that the architecture of the naive CD8+ T cell genome is distinct from effector and memory genome configurations, with extensive changes within discrete functional chromatin domains associated with effector/memory differentiation. Deletion of BACH2, or to a lesser extent, reducing SATB1 DNA binding, within naive CD8+ T cells results in a chromatin architecture more reminiscent of effector/memory states. This suggests that key transcription factors within naive CD8+ T cells act to restrain T cell differentiation by actively enforcing a unique naive chromatin state.

Tezepelumab Efficacy in Patients with Severe, Uncontrolled Asthma with Comorbid Nasal Polyps in NAVIGATOR.

Purpose: Tezepelumab, a human monoclonal antibody, blocks thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab reduced annualized asthma exacerbation rates (AAERs) versus placebo, irrespective of baseline disease characteristics, and improved lung function and symptom control versus placebo in adults and adolescents with severe, uncontrolled asthma. We assessed the efficacy of tezepelumab in patients with severe asthma with or without nasal polyps (NPs) in the 2 years before randomization in NAVIGATOR. Methods: Patients with severe asthma (N=1059) were randomized (1:1) and received tezepelumab 210 mg or placebo every 4 weeks subcutaneously for 52 weeks. Prespecified exploratory analyses included: AAER over 52 weeks and changes from baseline to week 52 in pre-bronchodilator forced expiratory volume in 1 second, Sino-Nasal Outcome Test (SNOT)-22 scores, and asthma control and health-related quality life (HRQoL) outcomes in NP subgroups. Changes from baseline in fractional exhaled nitric oxide (FeNO), blood eosinophil counts, total immunoglobulin E (IgE), eosinophil-derived neurotoxin (EDN), matrix metalloproteinase-10 (MMP-10), and serum interleukin (IL)-5, IL-6, IL-8 and IL-13 were assessed (post hoc). Results: Tezepelumab reduced the AAER over 52 weeks versus placebo by 85% (95% confidence interval [CI]: 72, 92; n=118) and 51% (95% CI: 40, 60; n=941) in patients with and without NPs, respectively. At week 52, tezepelumab improved lung function, asthma control and HRQoL versus placebo in patients with and without NPs. Tezepelumab reduced SNOT-22 total scores (least-squares mean difference versus placebo [95% CI]) in patients with NPs at 28 weeks (-12.57 points [-19.40, -5.73]) and 52 weeks (-10.58 points [-17.75, -3.41]). At week 52, tezepelumab reduced blood eosinophil counts and FeNO, IgE, IL-5, IL-13, EDN and MMP-10 levels versus placebo, irrespective of NP status. Conclusion: Tezepelumab resulted in clinically meaningful improvements in sino-nasal symptoms and asthma outcomes in patients with severe asthma with comorbid NPs.

Mepolizumab in Patients With Severe Asthma and Comorbidities: 1-Year REALITI-A Analysis.

BACKGROUND: Severe asthma is complex; comorbidities may influence disease outcomes. OBJECTIVE: To assess mepolizumab effectiveness in patients with severe asthma and comorbidities. METHODS: REALITI-A was a 2-year international, prospective study enrolling adults with asthma newly prescribed mepolizumab (100 mg subcutaneously) at physician's discretion. This post hoc analysis assessed 1-year outcomes stratified by comorbidities at enrollment: chronic rhinosinusitis with nasal polyps (CRSwNP), gastroesophageal reflux disease (GERD), depression/anxiety, and chronic obstructive pulmonary disease (COPD). Outcomes included the rate of clinically significant asthma exacerbations (CSEs; requiring systemic corticosteroids and/or hospital/emergency room admission) between the 12 months pre- and post-mepolizumab treatment and changes from baseline in daily maintenance oral corticosteroid dose (mo 12), Asthma Control Questionnaire-5 score (mo 12) and forced expiratory volume in 1 second (FEV1; mo 9-12). RESULTS: At enrollment (n = 822), 321 of 822 (39%), 309 of 801 (39%), 203 of 785 (26%), and 81 of 808 (10%) patients had comorbid CRSwNP, GERD, depression/anxiety, and COPD, respectively. Post- versus pre-treatment across all comorbidity subgroups: the rate of CSEs decreased by 63% or more; among 298 (39%) patients on maintenance oral corticosteroids at baseline, median dose decreased by 50% or more; Asthma Control Questionnaire-5 score decreased by 0.63 or more points; FEV1 increased by 74 mL or more. Patients with versus without CRSwNP had the greatest improvements (eg, rate of CSEs decreased by 75%). Patients without GERD, depression/anxiety, or COPD had greater improvements than those with the respective comorbidities, except for FEV1 in patients with COPD. CONCLUSIONS: Mepolizumab improved disease outcomes in patients with severe asthma irrespective of comorbidities, with additional benefit for patients with CRSwNP.

Ionomer-free and recyclable porous-transport electrode for high-performing proton-exchange-membrane water electrolysis.

Clean hydrogen production requires large-scale deployment of water-electrolysis technologies, particularly proton-exchange-membrane water electrolyzers (PEMWEs). However, as iridium-based electrocatalysts remain the only practical option for PEMWEs, their low abundance will become a bottleneck for a sustainable hydrogen economy. Herein, we propose high-performing and durable ionomer-free porous transport electrodes (PTEs) with facile recycling features enabling Ir thrifting and reclamation. The ionomer-free porous transport electrodes offer a practical pathway to investigate the role of ionomer in the catalyst layer and, from microelectrode measurements, point to an ionomer poisoning effect for the oxygen evolution reaction. The ionomer-free porous transport electrodes demonstrate a voltage reduction of > 600 mV compared to conventional ionomer-coated porous transport electrodes at 1.8 A cm-2 and <0.1 mgIr cm-2, and a voltage degradation of 29 mV at average rate of 0.58 mV per 1000-cycles after 50k cycles of accelerated-stress tests at 4 A cm-2. Moreover, the ionomer-free feature enables facile recycling of multiple components of PEMWEs, which is critical to a circular clean hydrogen economy.

Workplace absenteeism due to COVID-19 and influenza across Canada: A mathematical model.

The continual distress of COVID-19 cannot be overemphasized. The pandemic economic and social costs are alarming, with recent attributed economic loss amounting to billions of dollars globally. This economic loss is partly driven by workplace absenteeism due to the disease. Influenza is believed to be a culprit in reinforcing this phenomenon as it may exist in the population concurrently with COVID-19 during the influenza season. Furthermore, their joint infection may increase workplace absenteeism leading to additional economic loss. The objective of this project will aim to quantify the collective impact of COVID-19 and influenza on workplace absenteeism via a mathematical compartmental disease model incorporating population screening and vaccination. Our results indicate that appropriate PCR testing and vaccination of both COVID-19 and seasonal influenza may significantly alleviate workplace absenteeism. However, with COVID-19 PCR testing, there may be a critical threshold where additional tests may result in diminishing returns. Regardless, we recommend on-going PCR testing as a public health intervention accompanying concurrent COVID-19 and influenza vaccination with the added caveat that sensitivity analyses will be necessary to determine the optimal thresholds for both testing and vaccine coverage. Overall, our results suggest that rates of COVID-19 vaccination and PCR testing capacity are important factors for reducing absenteeism, while the influenza vaccination rate and the transmission rates for both COVID-19 and influenza have lower and almost equal affect on absenteeism. We also use the model to estimate and quantify the (indirect) benefit that influenza immunization confers against COVID-19 transmission.

Vernal keratoconjunctivitis: Current immunological and clinical evidence and the potential role of omalizumab.

Vernal keratoconjunctivitis (VKC) is a severe ocular allergic disease characterized by chronic inflammation of the cornea and conjunctiva that may lead to loss of visual acuity and blindness. The disease occurs primarily in children and is more common in geographical regions characterized by warm temperatures and high humidity. The clinical manifestations of VKC, when inadequately treated, may lead to severe complications and corneal damage. The prevalence of allergen sensitization, specific serum immunoglobulin E (IgE), and specific tear IgE was reported in approximately 55%-60% of patients with VKC, confirming the involvement of IgE-mediated and non-IgE-mediated mechanisms in the pathophysiology of the condition. This article explores current knowledge on the immunological pathways of VKC and the role of the monoclonal anti-IgE antibody, omalizumab, in its management. The review evaluated the effects of omalizumab beyond the direct IgE-mediated reactions and discusses its potential as a therapeutic target for VKC. Multiple retrospective analyses, case series, and case reports have reported the effectiveness of omalizumab in the management of VKC. A summary of the clinical data from these studies revealed that in children with VKC omalizumab treatment was well tolerated with improvement or resolution of ocular symptoms, reduction in steroid use, and enhancement of quality of life. Omalizumab may serve as a promising treatment option for VKC due to its ability to target both IgE-mediated and non-IgE-mediated pathophysiological pathways. Larger, controlled clinical trials are needed to support these findings.