PET/CT-Based Absorbed Dose Maps in 90Y Selective Internal Radiation Therapy Correlate with Spatial Changes in Liver Function Derived from Dynamic MRI.

Functional liver parenchyma can be damaged from treatment of liver malignancies with 90Y selective internal radiation therapy (SIRT). Evaluating functional parenchymal changes and developing an absorbed dose (AD)-toxicity model can assist the clinical management of patients receiving SIRT. We aimed to determine whether there is a correlation between 90Y PET AD voxel maps and spatial changes in the nontumoral liver (NTL) function derived from dynamic gadoxetic acid-enhanced MRI before and after SIRT. Methods: Dynamic gadoxetic acid-enhanced MRI scans were acquired before and after treatment for 11 patients undergoing 90Y SIRT. Gadoxetic acid uptake rate (k1) maps that directly quantify spatial liver parenchymal function were generated from MRI data. Voxel-based AD maps, derived from the 90Y PET/CT scans, were binned according to AD. Pre- and post-SIRT k1 maps were coregistered to the AD map. Absolute and percentage k1 loss in each bin was calculated as a measure of loss of liver function, and Spearman correlation coefficients between k1 loss and AD were evaluated for each patient. Average k1 loss over the patients was fit to a 3-parameter logistic function based on AD. Patients were further stratified into subgroups based on lesion type, baseline albumin-bilirubin scores and alanine transaminase levels, dose-volume effect, and number of SIRT treatments. Results: Significant positive correlations (ρ = 0.53-0.99, P < 0.001) between both absolute and percentage k1 loss and AD were observed in most patients (8/11). The average k1 loss over 9 patients also exhibited a significant strong correlation with AD (ρ ≥ 0.92, P < 0.001). The average percentage k1 loss of patients across AD bins was 28%, with a logistic function model demonstrating about a 25% k1 loss at about 100 Gy. Analysis between patient subgroups demonstrated that k1 loss was greater among patients with hepatocellular carcinoma, higher alanine transaminase levels, larger fractional volumes of NTL receiving an AD of 70 Gy or more, and sequential SIRT treatments. Conclusion: Novel application of multimodality imaging demonstrated a correlation between 90Y SIRT AD and spatial functional liver parenchymal degradation, indicating that a higher AD is associated with a larger loss of local hepatocyte function. With the developed response models, PET-derived AD maps can potentially be used prospectively to identify localized damage in liver and to enhance treatment strategies.

Florbetaben amyloid PET acquisition time: Influence on Centiloids and interpretation.

INTRODUCTION: Amyloid positron emission tomography (PET) acquisition timing impacts quantification. METHODS: In florbetaben (FBB) PET scans of 245 adults with and without cognitive impairment, we investigated the impact of post-injection acquisition time on Centiloids (CLs) across five reference regions. CL equations for FBB were derived using standard methods, using FBB data collected between 90 and 110 min with paired Pittsburgh compound B data. Linear mixed models and t-tests evaluated the impact of acquisition time on CL increases. RESULTS: CL values increased significantly over the scan using the whole cerebellum, cerebellar gray matter, and brainstem as reference regions, particularly in amyloid-positive individuals. In contrast, CLs based on white matter-containing reference regions decreased across the scan. DISCUSSION: The quantification of CLs in FBB PET imaging is influenced by both the overall scan acquisition time and the choice of reference region. Standardized acquisition protocols or the application of acquisition time-specific CL equations should be implemented in clinical protocols. HIGHLIGHTS: Acquisition timing affects florbetaben positron emission tomography (PET) scan quantification, especially in amyloid-positive participants. The impact of acquisition timing on quantification varies across common reference regions. Consistent acquisitions and/or appropriate post-injection adjustments are needed to ensure comparability of PET data.

Acute myeloid leukemia with a novel AKAP9::PDGFRA fusion transformed from essential thrombocythemia: A case report and mini review.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with various combinations of gene mutations, epigenetic abnormalities, and chromosome rearrangement-related gene fusions. Despite the significant degree of heterogeneity in its pathogenesis, many gene fusions and point mutations are recurrent in AML and have been employed in risk stratification over the last several decades. Gene fusions have long been recognized for understanding tumorigenesis and their proven roles in clinical diagnosis and targeted therapies. Advances in DNA sequencing technologies and computational biology have contributed significantly to the detection of known fusion genes as well as for the discovery of novel ones. Several recurring gene fusions in AML have been linked to prognosis, treatment response, and disease progression. In this report, we present a case with a long history of essential thrombocythemia and hallmark CALR mutation transforming to AML characterized by a previously unreported AKAP9::PDGFRA fusion gene. We propose mechanisms by which this fusion may contribute to the pathogenesis of AML and its potential as a molecular target for tyrosine kinase inhibitors.

Exploring Barmah Forest virus pathogenesis: molecular tools to investigate non-structural protein 3 nuclear localization and viral genomic determinants of replication.

Barmah Forest virus (BFV) is a mosquito-borne virus that causes arthralgia with accompanying rash, fever, and myalgia in humans. The virus is mainly found in Australia and has caused outbreaks associated with significant health concerns. As the sole representative of the Barmah Forest complex within the genus Alphavirus, BFV is not closely related genetically to other alphaviruses. Notably, basic knowledge of BFV molecular virology has not been well studied due to a lack of critical investigative tools such as an infectious clone. Here we describe the construction of an infectious BFV cDNA clone based on Genbank sequence and demonstrate that the clone-derived virus has in vitro and in vivo properties similar to naturally occurring virus, BFV field isolate 2193 (BFV2193-FI). A substitution in nsP4, V1911D, which was identified in the Genbank reference sequence, was found to inhibit virus rescue and replication. T1325P substitution in nsP2 selected during virus passaging was shown to be an adaptive mutation, compensating for the inhibitory effect of nsP4-V1911D. The two mutations were associated with changes in viral non-structural polyprotein processing and type I interferon (IFN) induction. Interestingly, a nuclear localization signal, active in mammalian but not mosquito cells, was identified in nsP3. A point mutation abolishing nsP3 nuclear localization attenuated BFV replication. This effect was more prominent in the presence of type I interferon signaling, suggesting nsP3 nuclear localization might be associated with IFN antagonism. Furthermore, abolishing nsP3 nuclear localization reduced virus replication in mice but did not significantly affect disease.IMPORTANCEBarmah Forest virus (BFV) is Australia's second most prevalent arbovirus, with approximately 1,000 cases reported annually. The clinical symptoms of BFV infection include rash, polyarthritis, arthralgia, and myalgia. As BFV is not closely related to other pathogenic alphaviruses or well-studied model viruses, our understanding of its molecular virology and mechanisms of pathogenesis is limited. There is also a lack of molecular tools essential for corresponding studies. Here we describe the construction of an infectious clone of BFV, variants harboring point mutations, and sequences encoding marker protein. In infected mammalian cells, nsP3 of BFV was located in the nuclei. This finding extends our understanding of the diverse mechanisms used by alphavirus replicase proteins to interact with host cells. Our novel observations highlight the complex synergy through which the viral replication machinery evolves to correct mutation errors within the viral genome.

An Individual vs Parent Supported Physical Activity Intervention in Adolescents with Intellectual Disabilities.

INTRODUCTION: Moderate-to-vigorous physical activity (MVPA) is inadequate in adolescents with intellectual and developmental disabilities (IDD). This report describes the results of an 18-mo. clinical trial in adolescents with IDD which compared changes in accelerometer assessed daily MVPA, gross motor quotient and leg press strength between participants randomized to an exercise intervention delivered to adolescents only (AO) or to the adolescent and a parent (A + P). METHODS: The 18-mo. trial included a 6-mo. active intervention, 6-mo. maintenance interventions, and a 6-mo. no-contact follow-up. Adolescents in both arms were asked to attend 40 min. remotely delivered group video exercise sessions (0-6 mos. =3 sessions·wk-1., 7-12 mos. =1 session·wk-1). In the A + P arm, one parent/guardian was asked to attend all group remote video exercise sessions and a monthly remotely delivered 30-min. educations/support session with their adolescent across the 12-mo. intervention. RESULTS: Adolescents (n = 116) with IDD (age ~ 16 yrs., 52% female) were randomized to the AO (n = 59) or A + P (n = 57) arms. Mixed modeling, controlling for baseline MVPA and season, indicated minimal but statistically significant changes in MVPA across 6 (p = 0.006), 12 (p < 0.001), and 18 mos. (p < 0.001). However, the change in MVPA in the two intervention arms did not differ significantly at any time point (all p > 0.05). Similarly, gross motor quotient and leg press strength improved significantly over time (p < 0.001) and these changes did not differ between intervention arms (all p > 0.05). CONCLUSIONS: Parental involvement had no impact on changes in daily MVPA, gross motor quotient or leg press strength in response to a remotely delivered exercise intervention in adolescents with IDD.

Mechanisms of action of microbicides commonly used in infection prevention and control.

SUMMARYUnderstanding how commonly used chemical microbicides affect pathogenic microorganisms is important for formulation of microbicides. This review focuses on the mechanism(s) of action of chemical microbicides commonly used in infection prevention and control. Contrary to the typical site-specific mode of action of antibiotics, microbicides often act via multiple targets, causing rapid and irreversible damage to microbes. In the case of viruses, the envelope or protein capsid is usually the primary structural target, resulting in loss of envelope integrity or denaturation of proteins in the capsid, causing loss of the receptor-binding domain for host cell receptors, and/or breakdown of other viral proteins or nucleic acids. However, for certain virucidal microbicides, the nucleic acid may be a significant site of action. The region of primary damage to the protein or nucleic acid is site-specific and may vary with the virus type. Due to their greater complexity and metabolism, bacteria and fungi offer more targets. The rapid and irreversible damage to microbes may result from solubilization of lipid components and denaturation of enzymes involved in the transport of nutrients. Formulation of microbicidal actives that attack multiple sites on microbes, or control of the pH, addition of preservatives or potentiators, and so on, can increase the spectrum of action against pathogens and reduce both the concentrations and times needed to achieve microbicidal activity against the target pathogens.

Self-Replication Without Hydrogen-Bonds: An Exobiotic Design.

Life on Earth uses DNA as the central template for self-replication, genetic encoding, and information transfer. However, there are no physical laws precluding life's existence elsewhere in space, and alternative life forms may not need DNA. In the search for exobiology, knowing what to look for as a biosignature remains a challenge-especially if it is not from the obvious list of biologic building blocks. Clues from chemicals recently discovered on Mars and in the Taurus Molecular Cloud 1 (TMC-1), show that intriguing organic compounds exist beyond Earth, which could provide a starting point for unconventional exobiotic designs. Here we present a new self-replicating system with structural similarities to recently discovered compounds on Mars and TMC-1. Rather than using DNA's hydrogen-bonding motif for reliable base-paring, our design employs sulfur-nitrogen interactions to selectively template unique benzothiadiazole units in sequence. We synthesized and studied two versions of this system, one reversible and the other irreversible, and found experimental evidence of self-replication in d-chloroform solvent. These results are part of a larger pursuit in our lab for developing a basis for a potential exobiological system using starting blocks closely related to these cosmic compounds.

Transparency and reproducibility in the Adolescent Brain Cognitive Development (ABCD) study.

BACKGROUND: Transparency can build trust in the scientific process, but scientific findings can be undermined by poor and obscure data use and reporting practices. The purpose of this work is to report how data from the Adolescent Brain Cognitive Development (ABCD) Study has been used to date, and to provide practical recommendations on how to improve the transparency and reproducibility of findings. METHODS: Articles published from 2017 to 2023 that used ABCD Study data were reviewed using more than 30 data extraction items to gather information on data use practices. Total frequencies were reported for each extraction item, along with computation of a Level of Completeness (LOC) score that represented overall endorsement of extraction items. Univariate linear regression models were used to examine the correlation between LOC scores and individual extraction items. Post hoc analysis included examination of whether LOC scores were correlated with the logged 2-year journal impact factor. RESULTS: There were 549 full-length articles included in the main analysis. Analytic scripts were shared in 30 % of full-length articles. The number of participants excluded due to missing data was reported in 60 % of articles, and information on missing data for individual variables (e.g., household income) was provided in 38 % of articles. A table describing the analytic sample was included in 83 % of articles. A race and/or ethnicity variable was included in 78 % of reviewed articles, while its inclusion was justified in only 41 % of these articles. LOC scores were highly correlated with extraction items related to examination of missing data. A bottom 10 % of LOC score was significantly correlated with a lower logged journal impact factor when compared to the top 10 % of LOC scores (ß=-0.77, 95 % -1.02, -0.51; p-value < 0.0001). CONCLUSION: These findings highlight opportunities for improvement in future papers using ABCD Study data to readily adapt analytic practices for better transparency and reproducibility efforts. A list of recommendations is provided to facilitate adherence in future research.

AZD3152 neutralizes SARS-CoV-2 historical and contemporary variants and is protective in hamsters and well tolerated in adults.

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in variants that can escape neutralization by therapeutic antibodies. Here, we describe AZD3152, a SARS-CoV-2-neutralizing monoclonal antibody designed to provide improved potency and coverage against emerging variants. AZD3152 binds to the back left shoulder of the SARS-CoV-2 spike protein receptor binding domain and prevents interaction with the human angiotensin-converting enzyme 2 receptor. AZD3152 potently neutralized a broad panel of pseudovirus variants, including the currently dominant Omicron variant JN.1 but has reduced potency against XBB subvariants containing F456L. In vitro studies confirmed F456L resistance and additionally identified T415I and K458E as escape mutations. In a Syrian hamster challenge model, prophylactic administration of AZD3152 protected hamsters from weight loss and inflammation-related lung pathologies and reduced lung viral load. In the phase 1 sentinel safety cohort of the ongoing SUPERNOVA study (ClinicalTrials.gov: NCT05648110), a single 600-mg intramuscular injection of AZD5156 (containing 300 mg each of AZD3152 and cilgavimab) was well tolerated in adults through day 91. Observed serum concentrations of AZD3152 through day 91 were similar to those observed with cilgavimab and consistent with predictions for AZD7442, a SARS-CoV-2-neutralizing antibody combination of cilgavimab and tixagevimab, in a population pharmacokinetic model. On the basis of its pharmacokinetic characteristics, AZD3152 is predicted to provide durable protection against symptomatic coronavirus disease 2019 caused by susceptible SARS-CoV-2 variants, such as JN.1, in humans.

Ethylene Oxide in Southeastern Louisiana's Petrochemical Corridor: High Spatial Resolution Mobile Monitoring during HAP-MAP.

Ethylene oxide ("EtO") is an industrially made volatile organic compound and a known human carcinogen. There are few reliable reports of ambient EtO concentrations around production and end-use facilities, however, despite major exposure concerns. We present in situ, fast (1 Hz), sensitive EtO measurements made during February 2023 across the southeastern Louisiana industrial corridor. We aggregated mobile data at 500 m spatial resolution and reported average mixing ratios for 75 km of the corridor. Mean and median aggregated values were 31.4 and 23.3 ppt, respectively, and a majority (75%) of 500 m grid cells were above 10.9 ppt, the lifetime exposure concentration corresponding to 100-in-one million excess cancer risk (1 × 10-4). A small subset (3.3%) were above 109 ppt (1000-in-one million cancer risk, 1 × 10-3); these tended to be near EtO-emitting facilities, though we observed plumes over 10 km from the nearest facilities. Many plumes were highly correlated with other measured gases, indicating potential emission sources, and a subset was measured simultaneously with a second commercial analyzer, showing good agreement. We estimated EtO for 13 census tracts, all of which were higher than EPA estimates (median difference of 21.3 ppt). Our findings provide important information about EtO concentrations and potential exposure risks in a key industrial region and advance the application of EtO analytical methods for ambient sampling and mobile monitoring for air toxics.

Human-Induced Range Expansions Result in a Recent Hybrid Zone between Sister Species of Ducks.

Landscapes are consistently under pressure from human-induced ecological change, often resulting in shifting species distributions. For some species, changing the geographical breadth of their niche space results in matching range shifts to regions other than those in which they are formally found. In this study, we employ a population genomics approach to assess potential conservation issues arising from purported range expansions into the south Texas Brush Country of two sister species of ducks: mottled (Anas fulvigula) and Mexican (Anas diazi) ducks. Specifically, despite being non-migratory, both species are increasingly being recorded outside their formal ranges, with the northeastward and westward expansions of Mexican and mottled ducks, respectively, perhaps resulting in secondary contact today. We assessed genetic ancestry using thousands of autosomal loci across the ranges of both species, as well as sampled Mexican- and mottled-like ducks from across overlapping regions of south Texas. First, we confirm that both species are indeed expanding their ranges, with genetically pure Western Gulf Coast mottled ducks confirmed as far west as La Salle county, Texas, while Mexican ducks recorded across Texas counties near the USA-Mexico border. Importantly, the first confirmed Mexican × mottled duck hybrids were found in between these regions, which likely represents a recently established contact zone that is, on average, ~100 km wide. We posit that climate- and land use-associated changes, including coastal habitat degradation coupled with increases in artificial habitats in the interior regions of Texas, are facilitating these range expansions. Consequently, continued monitoring of this recent contact event can serve to understand species' responses in the Anthropocene, but it can also be used to revise operational survey areas for mottled ducks.

AAV9-Mediated Intra-Striatal Delivery of GNAO1 Reduces Hyperlocomotion in Gnao1 Heterozygous R209H Mutant Mice.

Mutations in the GNAO1 gene, which encodes the abundant brain G-protein Gαo, result in neurologic disorders characterized by developmental delay, epilepsy, and movement abnormalities. There are over 50 mutant alleles associated with GNAO1 disorders; the R209H mutation results in dystonia, choreoathetosis, and developmental delay without seizures. Mice heterozygous for the human mutant allele (Gnao1 +/R209H) exhibit hyperactivity in open field tests but no seizures. We developed self-complimentary adeno-associated virus vectors (scAAV9) expressing two splice variants of human GNAO1 Gαo isoforms 1 (GoA, GNAO1.1) and 2 (GoB, GNAO1.2). Bilateral intra-striatal injections of either scAAV9-GNAO1.1 or scAAV9-GNAO1.2 significantly reversed mutation-associated hyperactivity in open field tests. GNAO1 overexpression did not increase seizure susceptibility, a potential side-effect of GNAO1 vector treatment. This represents the first report of successful preclinical gene therapy for GNAO1 encephalopathy applied in vivo Further studies are needed to uncover the molecular mechanism that results in behavior improvements after scAAV9-mediated Gαo expression and to refine the vector design. Significance Statement GNAO1 mutations cause a spectrum of developmental, epilepsy, and movement disorders. Here, we show that intra-striatal delivery of scAAV9-GNAO1 to express the wild-type Gαo protein reduces the hyperactivity of the Gnao1 +/R209H mouse model, which carries one of the most common movement disorder-associated mutations. This is the first report of a gene therapy for GNAO1 encephalopathy applied in vivo on a patient-allele model.

Automated segmentation of ventricular volumes and subarachnoid hemorrhage from computed tomography images: Evaluation of a rule-based pipeline approach.

Changes in ventricular size, related to brain edema and hydrocephalus, as well as the extent of hemorrhage are associated with adverse outcomes in patients with subarachnoid hemorrhage (SAH). Frequently, these are measured manually using consecutive non-contrast computed tomography scans. Here, we developed a rule-based approach which incorporates both intensity and spatial normalization and utilizes user-defined thresholds and anatomical templates to segment both lateral ventricle (LV) and SAH blood volumes automatically from CT images. The algorithmic segmentations were evaluated against two expert neuroradiologists on representative slices from 20 admission scans from aneurysmal SAH patients. Previous methods have been developed to automate this time-consuming task, but they lack user feedback and are hard to implement due to large-scale data and complex design processes. Our results using automatic ventricular segmentation aligned well with expert reviewers with a median Dice coefficient of 0.81, AUC of 0.91, sensitivity of 81%, and precision of 84%. Automatic segmentation of SAH blood was most reliable near the base of the brain with a median Dice coefficient of 0.51, an AUC of 0.75, precision of 68%, and sensitivity of 50%. Ultimately, we developed a rule-based method that is easily adaptable through user feedback, generates spatially normalized segmentations that are comparable regardless of brain morphology or acquisition conditions, and automatically segments LV with good overall reliability and basal SAH blood with good precision. Our approach could benefit longitudinal studies in patients with SAH by streamlining assessment of edema and hydrocephalus progression, as well as blood resorption.

Characterizing the safety profile of vagus nerve stimulation devices for epilepsy from 21,448 manufacturer and user reports.

OBJECTIVE: This study summarizes medical device reports (MDRs) associated with adverse events for vagus nerve stimulation (VNS) devices indicated for epilepsy as reported by the Manufacturer and User Facility Device Experience (MAUDE) database of the US Food and Drug Administration. METHODS: The MAUDE database was surveyed for MDRs from November 2013 to September 2022 regarding VNS devices for epilepsy. Event descriptions, device problems, correlated patient consequences, and device models were grouped and analyzed in Python. Based on event description, revision surgeries and other unique events were identified. Revenue from VNS device sales was used to approximate growth in their use over time. RESULTS: A total of 21,448 MDRs met the inclusion criteria. High VNS impedance, the most prevalent device malfunction overall (17.0% of MDRs), was the most common factor for 18 of the 102 encountered patient problems and led to 1001 revision surgeries (3371 total revisions). Included in those 18 device malfunctions were 3 of the top 6 occurring patient problems: seizure recurrence (9.9% associated with high impedance; encompassed focal, absence, and grand mal subtypes), death (1.3%), and generalized pain (7.9%). The next 4 top cited device malfunctions-lead fracture (13.7% of MDRs), operational issue (6.6%), battery problem holding charge (4.2%), and premature end-of-life indicator (2.9%)-differed widely in their percentage of cases that did not impact patients (77.4%, 57.3%, 48.9%, and 92.2%, respectively), highlighting differing malfunction severities. Seizure recurrence, the most prevalent patient impact, was the outcome most associated with 32 of the 68 encountered device problems, including high impedance (12.8%), lead fracture (12.2%), operational issue (18.4%), battery problem holding charge (31.2%), and premature end-of-life indicator (8.9%), which comprised the top 5 occurring device problems. In general, MDRs spanned a diverse range including device age, hardware, software, and surgeon or manufacturer error. Trends were seen over time with declining annual MDRs coupled with a rise in the use of VNS devices as gauged by revenue growth. Shifting device and patient problem profiles were also seen in successive models, reflecting engineering updates. CONCLUSIONS: This study characterizes the most common and consequential side effects of VNS devices for epilepsy while clarifying likely causes. In addition, the outcomes of 68 distinct device malfunctions were identified, including many not ubiquitously present in literature, lending critical perspective to clinical practice.

Comparing classic-onset corticobasal syndrome to speech/language-onset corticobasal syndrome.

INTRODUCTION: Patients with classic-onset corticobasal syndrome (CBS) present with asymmetric limb apraxia and parkinsonism. We have, however, observed patients who initially present with speech and/or language (SL) problems and several years later develop CBS (i.e., SL-onset CBS). We aimed to compare clinical, neuroimaging and pathological characteristics of classic-onset CBS with SL-onset CBS. METHODS: We conducted a retrospective cohort study of 62 patients who met criteria for CBS (17 presented with classic-onset CBS and 45 had SL-onset CBS). We compared demographics, clinical characteristics, and grey and white matter volume loss with SPM12 between groups and assessed pathology and corticobasal degeneration (CBD) pathological lesion counts in patients who had died and undergone autopsy. RESULTS: Median age at CBS diagnosis was 66.4 years in classic-onset CBS and 73.6 years in SL-onset CBS. Classic-onset CBS had higher frequencies of dystonia, myoclonus, and alien limb phenomenon, while SL-onset CBS had a higher frequency of vertical supranuclear gaze palsy. Both groups showed smaller frontoparietal volumes than controls, with SL-onset CBS having greater volume loss in the left supplementary motor area than classic-onset CBS. All three classic-onset CBS cases with autopsy (100 %) had CBD pathology while 8/21 of SL-onset CBS cases (38 %) had CBD. Pathological lesion burden (including astrocytic plaques) did not differ between classic-onset and SL-onset CBS. CONCLUSION: Classic-onset and SL-onset CBS appear to be different syndromes, with the former being a more profuse motor syndrome. The more widespread volume loss in SL-onset CBS likely reflects longer disease course.

Reidentification of Participants in Shared Clinical Data Sets: Experimental Study.

BACKGROUND: Large curated data sets are required to leverage speech-based tools in health care. These are costly to produce, resulting in increased interest in data sharing. As speech can potentially identify speakers (ie, voiceprints), sharing recordings raises privacy concerns. This is especially relevant when working with patient data protected under the Health Insurance Portability and Accountability Act. OBJECTIVE: We aimed to determine the reidentification risk for speech recordings, without reference to demographics or metadata, in clinical data sets considering both the size of the search space (ie, the number of comparisons that must be considered when reidentifying) and the nature of the speech recording (ie, the type of speech task). METHODS: Using a state-of-the-art speaker identification model, we modeled an adversarial attack scenario in which an adversary uses a large data set of identified speech (hereafter, the known set) to reidentify as many unknown speakers in a shared data set (hereafter, the unknown set) as possible. We first considered the effect of search space size by attempting reidentification with various sizes of known and unknown sets using VoxCeleb, a data set with recordings of natural, connected speech from >7000 healthy speakers. We then repeated these tests with different types of recordings in each set to examine whether the nature of a speech recording influences reidentification risk. For these tests, we used our clinical data set composed of recordings of elicited speech tasks from 941 speakers. RESULTS: We found that the risk was inversely related to the number of comparisons an adversary must consider (ie, the search space), with a positive linear correlation between the number of false acceptances (FAs) and the number of comparisons (r=0.69; P<.001). The true acceptances (TAs) stayed relatively stable, and the ratio between FAs and TAs rose from 0.02 at 1 × 105 comparisons to 1.41 at 6 × 106 comparisons, with a near 1:1 ratio at the midpoint of 3 × 106 comparisons. In effect, risk was high for a small search space but dropped as the search space grew. We also found that the nature of a speech recording influenced reidentification risk, with nonconnected speech (eg, vowel prolongation: FA/TA=98.5; alternating motion rate: FA/TA=8) being harder to identify than connected speech (eg, sentence repetition: FA/TA=0.54) in cross-task conditions. The inverse was mostly true in within-task conditions, with the FA/TA ratio for vowel prolongation and alternating motion rate dropping to 0.39 and 1.17, respectively. CONCLUSIONS: Our findings suggest that speaker identification models can be used to reidentify participants in specific circumstances, but in practice, the reidentification risk appears small. The variation in risk due to search space size and type of speech task provides actionable recommendations to further increase participant privacy and considerations for policy regarding public release of speech recordings.

Evaluating the Implementation of the Pediatric Acute Care Education (PACE) Program in Northwestern Tanzania: A Mixed-Methods Study Guided by Normalization Process Theory.

Background: In low- and -middle-income countries (LMICs) like Tanzania, the competency of healthcare providers critically influences the quality of pediatric care. To address this, we introduced PACE (Pediatric Acute Care Education), an adaptive e-learning program tailored to enhance provider competency in line with Tanzania's national guidelines for managing seriously ill children. Adaptive e-learning presents a promising alternative to traditional in-service education, yet optimal strategies for its implementation in LMIC settings remain to be fully elucidated. Objectives: This study aimed to (1) evaluate the initial implementation of PACE in Mwanza, Tanzania, using the constructs of Normalization Process Theory (NPT), and (2) provide insights into its feasibility, acceptability, and scalability potential. Methods: A mixed-methods approach was employed across three healthcare settings in Mwanza: a zonal hospital and two health centers. NPT was utilized to navigate the complexities of implementing PACE. Data collection involved a customized NoMAD survey, focus groups and in-depth interviews with healthcare providers. Results: The study engaged 82 healthcare providers through the NoMAD survey and 79 in focus groups and interviews. Findings indicated high levels of coherence and cognitive participation, demonstrating that PACE is well-understood and resonates with existing healthcare goals. Providers expressed a willingness to integrate PACE into their practice, distinguishing it from existing educational methods. However, challenges related to resources and infrastructure, particularly affecting collective action, were noted. The short duration of the study limited the assessment of reflexive monitoring, though early indicators point towards the potential for PACE's long-term sustainability. Conclusion: This study offers vital insights into the feasibility and acceptability of implementing PACE in a Tanzanian context. While PACE aligns well with healthcare objectives, addressing resource and infrastructure challenges is crucial for its successful and sustainable implementation. Furthermore, the study underscores the value of NPT as a framework in guiding implementation processes, with broader implications for implementation science and pediatric acute care in LMICs.