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Abstract Methemoglobinemia secondary to administration of hydroxyurea is only reported in veterinary medicine as a result of accidental ingestion of high doses, and once at therapeutic dose in human medicine. A 2.5‐year‐old female spayed mixed breed dog was presented for acute signs of neurologic disease and diagnosed with severe erythrocytosis without an identified underlying cause, leading to suspicion of polycythemia vera. The dog was managed with phlebotomies, supportive care, and administration of hydroxyurea. Within 2 h of administration of hydroxyurea (37 mg/kg) administration, respiratory distress with cyanosis, and methemoglobinemia developed. Signs resolved within 24 h but recurred after a second administration of lower dosage of hydroxyurea (17 mg/kg) 20 days later. The dog remained asymptomatic except for mild cyanosis but was humanely euthanized for lack of relevant improvement of signs of neurologic disease. This case report documents the repeated occurrence of methemoglobinemia in a dog after administration of hydroxyurea at therapeutic doses.

Abstract Terrestrial Gamma‐ray Flashes (TGFs) are ten‐to‐hundreds of microsecond bursts of gamma‐rays produced when electrons in strong electric fields in thunderclouds are accelerated to relativistic energies. Space instruments have observed TGFs with source photon brightness down to ∼1017–1016. Based on space and aircraft observations, TGFs have been considered rare phenomena produced in association with very few lightning discharges. Space observations associated with lightning ground observations in the radio band have indicated that there exists a population of dimmer TGFs. Here we show observations of TGFs from aircraft altitude that were not detected by a space instrument viewing the same area. The TGFs were found through Monte Carlo modeling to be associated with 1015–1012 photons at source, which is several orders of magnitude below what can be seen from space. Our results suggest that there exists a significant population of TGFs that are too weak to be observed from space.

Abstract Background There is a possibility that an incorrect diagnosis of hypothyroidism could be made in euthyroid dogs, and the prevalence of hypothyroidism in the dog population remains unknown. Objectives To retrospectively assess the percentage of dogs diagnosed with, and treated for, hypothyroidism at first opinion practice which are likely to be hypothyroid and require levothyroxine supplementation. Animals One hundred two client‐owned dogs were included in this study. Materials and Methods The computerized databases of 7 first opinion practices were searched to identify dogs treated with levothyroxine supplementation. Three European College of Veterinary Internal Medicine—Companian Animals (ECVIM‐CA) diplomates independently assigned 1 of 4 clinical assessments to each case as follows: confirmed or likely hypothyroid, hypothyroidism suspected but not confirmed, hypothyroidism considered unlikely, and no reason to suspect hypothyroidism. They commented as to whether or not they thought levothyroxine supplementation was appropriate. Results The clinical assessments of “confirmed or likely hypothyroid”; “Hypothyroidism suspected but not confirmed”; “Hypothyroidism considered unlikely”; and “No reason to suspect hypothyroidism” was assigned respectively by Clinician 1 to 38.2%, 5.9%, 3.9%, and 52% of cases, by Clinician 2 to 48%, 22.6%, 22.6%, 6.9% of cases, and by Clinician 3 to 55.9%, 11.8%, 13.7% and 18.6%. Clinician 1, Clinician 2, and Clinician 3 considered levothyroxine supplementation not indicated in 58.8%, 52.9%, and 45.1% of cases, respectively. Conclusion These results support the concern that hypothyroidism might be overly and incorrectly diagnosed in first opinion practice, and that thyroid function testing should be performed only in those dogs with a high pretest probability of the disease.

Abstract Environmental DNA (eDNA) degradation influences the effectiveness of eDNA‐based biodiversity monitoring, but the factors that determine the rate of decay of eDNA in terrestrial environments are poorly understood. We assessed the persistence of vertebrate eDNA from a mock vertebrate community created with soil from zoo enclosures holding 10 target species from different taxonomic classes (reptiles, birds, and mammals) and of different biomass (little penguin and giraffe). We examined species detection rates resulting from eDNA metabarcoding, as well as relative eDNA concentrations via qPCR, from soil samples over eight time points (0–12 weeks), during exposure to three ambient temperatures (10, 25, and 40°C) and three levels of ultraviolet B (UV‐B) radiation (0%, 50%, and 100% intensity). We recorded considerable variation in detectability between species, independent of temperature, and UV‐B effects. Quantitative polymerase chain reaction (PCR) indicated degradation of eDNA over time for all temperature and UV treatments, although it was still possible to detect eDNA from some species after 12 weeks. Degradation rates were lowest for high UV‐B treatments, presumably due to UV‐B reducing bacterial metabolism. The temperatures investigated did not influence eDNA decay. Our results indicate that eDNA in soil can persist under a range of temperatures and high UV radiation for longer than expected. Sheltered sites with minimal UV‐B radiation, which have previously been considered ideal sites for terrestrial eDNA collection, may not be optimal for eDNA persistence in some cases due to microbial decay. A better understanding of eDNA degradation in terrestrial environments is needed to enhance the accuracy of eDNA metabarcoding for surveying terrestrial vertebrate communities.

Background Essential to a patient‐centered approach to imaging individuals with chest pain is knowledge of differences in radiation effective dose across imaging modalities. Body mass index (BMI) is an important and underappreciated predictor of effective dose. This study evaluated the impact of BMI on estimated radiation exposure across imaging modalities. Methods and Results This was a retrospective analysis of patients with concern for cardiac ischemia undergoing positron emission tomography (PET)/computed tomography (CT), cadmium zinc telluride single‐photon emission CT (SPECT) myocardial perfusion imaging, or coronary CT angiography (CCTA) using state‐of‐the‐art imaging modalities and optimal radiation‐sparing protocols. Radiation exposure was calculated across BMI categories based on established cardiac imaging–specific conversion factors. Among 9046 patients (mean±SD age, 64.3±13.1 years; 55% men; mean±SD BMI, 30.6±6.9 kg/m2), 4787 were imaged with PET/CT, 3092 were imaged with SPECT/CT, and 1167 were imaged with CCTA. Median (interquartile range) radiation effective doses were 4.4 (3.9–4.9) mSv for PET/CT, 4.9 (4.0–6.3) mSv for SPECT/CT, and 6.9 (4.0–11.2) mSv for CCTA. Patients at a BMI 45 kg/m2 compared with

Abstract Globally, the diversity of arthropods and the plants upon which they rely are under increasing pressure due to a combination of biotic and abiotic anthropogenic stressors. Unfortunately, conventional survey methods used to monitor ecosystems are often challenging to conduct on large scales. Pan traps are a commonly used pollinator survey method and environmental DNA (eDNA) metabarcoding of pan trap water may offer a high‐throughput alternative to aid in the detection of both arthropods and the plant resources they rely on. Here, we examined if eDNA metabarcoding can be used to identify arthropods and plant species from pan trap water, and investigated the effect of different DNA extraction methods. We then compared plant species identified by metabarcoding with observation‐based floral surveys and also assessed the contribution of airborne plant DNA (plant DNA not carried by arthropods) using marble traps to reduce putative false positives in the pan trap dataset. Arthropod eDNA was only detected in 17% of pan trap samples and there was minimal overlap between the eDNA results and morphological identifications. In contrast, for plants, we detected 64 taxa, of which 53 were unique to the eDNA dataset, and no differences were identified between the two extraction kits. We were able to significantly reduce the contribution of airborne plant DNA to the final dataset using marble traps. This study demonstrates that eDNA metabarcoding of pan trap water can detect plant resources used by arthropods and highlights the potential for eDNA metabarcoding to be applied to investigations of arthropod‐plant interactions.

Abstract INTRODUCTION This study evaluated the performance of the Lumipulse plasma beta‐amyloid (Aβ) 42/40 and pTau181 compared to other assays to detect an abnormal amyloid‐positron emission tomography (PET). METHODS Plasma samples from cognitively unimpaired (N = 179) and MCI/AD dementia (N = 36) individuals were retrospectively evaluated. Plasma Aβ42/40 and pTau181 were measured using the Lumipulse and Simoa immunoassays. An immunoprecipitation mass spectrometry (IP‐MS) assay for plasma Aβ42/40 was also evaluated. Amyloid‐PET status was the outcome measure. RESULTS Lumipulse and IP‐MS Aβ42/40 exhibited the highest diagnostic accuracy for detecting an abnormal amyloid‐PET (areas under the curve [AUCs] of 0.81 and 0.84, respectively). The Lumipulse and Simoa pTau181 assays exhibited lower performance (AUCs of 0.74 and 0.72, respectively). The Simoa Aβ42/40 assay demonstrated the lowest diagnostic accuracy (AUC 0.57). Combining Aβ42/40 and pTau181 did not significantly improve performance over Aβ42/40 alone for Lumipulse (AUC 0.83) or over pTau181 alone for Simoa (AUC 0.71) DISCUSSION The Lumipulse Aβ42/40 assay showed similar performance to the IP‐MS Aβ42/40 assay for detection of an abnormal amyloid‐PET; and both assays performed better than the two p‐tau181 immunoassays. The Simoa Aβ42/Aβ40 assay was the least accurate at predicting an abnormal amyloid‐PET status. Highlights Lumipulse plasma Aβ42/Aβ40 AUC for abnormal amyloid‐PET detection was 0.81. This performance was comparable to previously reported IP‐MS and higher than Simoa. Performance of Alzheimer's disease blood biomarkers varies between assays.

Abstract Introduction Current approaches for treating sporadic Alzheimer's disease (sAD) focus on removal of amyloid beta 1‐42 (Aβ1‐42) or phosphorylated tau, but additional strategies are needed to reduce neuropathology at earlier stages prior to neuronal damage. Longstanding data show that calcium dysregulation is a key etiological factor in sAD, and the cortical neurons most vulnerable to tau pathology show magnified calcium signaling, for example in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In primate dlPFC and ERC, type 3 metabotropic glutamate receptors (mGluR3s) are predominately post‐synaptic, on spines, where they regulate cAMP‐calcium signaling, a process eroded by inflammatory glutamate carboxypeptidase II (GCPII) actions. The current study tested whether enhancing mGluR3 regulation of calcium via chronic inhibition of GCPII would reduce tau hyperphosphorylation in aged macaques with naturally‐occurring tau pathology. Methods Aged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)), Aged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)), Results Aged macaques that received 2‐MPPA had significantly lower pT217Tau levels in dlPFC and ERC, and had lowered plasma pT217Tau levels from baseline. pT217Tau levels correlated significantly with GCPII activity in dlPFC. Both 2‐MPPA‐ and vehicle‐treated monkeys showed cognitive improvement; 2‐MPPA had no apparent side effects. Exploratory CSF analyses indicated reduced pS202Tau with 2‐MPPA administration, confirmed in dlPFC samples. Discussion These data provide proof‐of‐concept support that GCPII inhibition can reduce tau hyperphosphorylation in the primate cortices most vulnerable in sAD. GCPII inhibition may be particularly helpful in reducing the risk of sAD caused by inflammation. These data in nonhuman primates should encourage future research on this promising mechanism. Highlights Inflammation is a key driver of sporadic Alzheimer's disease. GCPII inflammatory signaling in brain decreases mGluR3 regulation of calcium. Chronic inhibition of GCPII inflammatory signaling reduced pT217Tau in aged monkeys. GCPII inhibition is a novel strategy to help prevent tau pathology at early stages.

Abstract Focal cortical dysplasia (FCD) is one of the most common malformations causing refractory epilepsy. Dysregulation of glutamatergic systems plays a critical role in the hyperexcitability of dysplastic neurons in FCD lesions. The pharmacoresistant nature of epilepsy associated with FCD may be due to a lack of well‐tolerated and precise antiepileptic drugs that can target glutamate receptors. Here, for the first time in human FCD brain slices, we show that the established, noncompetitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor antagonist, perampanel has potent antiepileptic action. Moreover, we demonstrate that this effect is due to a reduction in burst firing behavior in human FCD microcircuits. These data support a potential role for the treatment of refractory epilepsy associated with FCD in human patients.

Abstract Objective Tau hyperphosphorylation at threonine 217 (pT217) in cerebrospinal fluid (CSF) has recently been linked to early amyloidosis and could serve as a highly sensitive biomarker for Alzheimer’s disease (AD). However, it remains unclear whether other tauopathies induce pT217 modifications. To determine if pT217 modification is specific to AD, CSF pT217 was measured in AD and other tauopathies. Methods Using immunoprecipitation and mass spectrometry methods, we compared CSF T217 phosphorylation occupancy (pT217/T217) and amyloid‐beta (Aβ) 42/40 ratio in cognitively normal individuals and those with symptomatic AD, progressive supranuclear palsy, corticobasal syndrome, and sporadic and familial frontotemporal dementia. Results Individuals with AD had high CSF pT217/T217 and low Aβ42/40. In contrast, cognitively normal individuals and the majority of those with 4R tauopathies had low CSF pT217/T217 and normal Aβ 42/40. We identified a subgroup of individuals with increased CSF pT217/T217 and normal Aβ 42/40 ratio, most of whom were MAPT R406W mutation carriers. Diagnostic accuracies of CSF Aβ 42/40 and CSF pT217/T217, alone and in combination were compared. We show that CSF pT217/T217 × CSF Aβ 42/40 is a sensitive composite biomarker that can separate MAPT R406W carriers from cognitively normal individuals and those with other tauopathies. Interpretation MAPT R406W is a tau mutation that leads to 3R+4R tauopathy similar to AD, but without amyloid neuropathology. These findings suggest that change in CSF pT217/T217 ratio is not specific to AD and might reflect common downstream tau pathophysiology common to 3R+4R tauopathies.

Abstract Local people can act as sentinels for change, especially for wildlife populations not monitored by centralized governments. Responding to concern expressed by the Kitasoo Xai'xais (KX) First Nation over a decline in mountain goat (Oreamnos americanus) sightings, our community‐academic partnership assessed the conservation status of goats in KX territory and beyond in British Columbia by evaluating three independent information sources. Aerial surveys (2019 and 2020) over 542 km2 revealed a low‐density population (mean 0.25, SD 0.12 goats/km2), typical of peripheral coastal range. Interviews with KX Knowledge Holders revealed that sightings from sea level have declined sharply over 40 years, a period during which temperatures have increased and snowpack has decreased. Finally, Kill data (1980–2018) showed that kills/hunter/day initially increased among guided hunters before plateauing, but declined among resident hunters (~70% of hunt days) in both coastal and interior BC. Convergent patterns among datasets suggest that coastal goats declined in abundance and/or reduced use of low‐elevation habitat, disrupting a millennia‐old relationship between KX people and goats, thereby posing a conservation concern. Broadly, our work shows that detecting threats to peripheral populations, and wildlife in general, can be informed and empowered by the knowledge of place‐based peoples and associated decentralized management. Kitasoo Xai'xais First Nation mountain goat research illustrates roles of Indigenous peoples as sentinels of population and ecosystem change.

Abstract Introduction Some guidelines allow for the use of either insulin or noninsulin antidiabetic agents for gestational diabetes, but only insulin is recommended for pregnant women with preexisting type 2 diabetes mellitus (T2DM). We aimed to document treatment patterns in routine care for women with preexisting T2DM. Methods We identified pregnancy cohorts within 2 US claims databases for publicly and privately insured individuals: the Medicaid Analytical eXtract (2000–2014) and OptumClinformatics (2004–2014). T2DM was classified with a validated algorithm using ICD‐9‐CM and CPT codes. We assessed medication usage over the years of the study, and changes in medication use before and after the beginning of pregnancy, using prescription fills as a proxy for the use of insulin, metformin, sulphonylureas and other noninsulin antidiabetic agents before pregnancy and during each trimester. Results Among 12,631 women with T2DM, insulin use in pregnancy was stable over the study years (55%–60% in the 2nd trimester), but 2nd trimester use of metformin increased from