University of California, Los Angeles

Copper dyshomeostasis is associated with various diseases, making in vivo spatiotemporal imaging of mobile Cu(II) dynamics crucial for understanding pathophysiological mechanisms. However, imaging mobile Cu(II) dynamics remains a long‐standing challenge due to the limitations of conventional probes in distinguishing between mobile and bound Cu(II). Herein, we developed a design strategy based on catalytic arylamine radical cation formation, enabling the creation of photoacoustic probes with superior sensitivity and micron‐resolution imaging capabilities in the short‐wave infrared region, specifically in response to mobile Cu(II). In vivo imaging of the brains of Parkinson's disease model mice revealed significant alternations in mobile Cu(II) levels within the cerebral cortex and cerebellar lobules during early disease stages, suggesting that these regions are particularly vulnerable to Cu(II) accumulation in early Parkinson's disease. These findings underscore the significant potential of these probes for investigating mobile Cu(II) dynamics and their role in physiological and pathological processes.

At 7 weeks of life, a connection develops between the left and right anterior cardinal veins. This forms the left brachiocephalic anastomosis (Ghandour et al. 2017). It leads to regression of the left anterior cardinal veins, thus allowing blood to flow from the left side of the body toward the right anterior cardinal vein (Ghandour et al. 2017). Caudally to this transverse anastomosis, near the proximal portion of the right anterior and right common cardinal veins, the superior vena cava (SVC) is derived. Cranially to the transverse anastomosis, the right brachiocephalic vein forms from the right anterior cardinal vein. During embryonic development, the cardinal veins are responsible for venous return and represent the primary drainage. The anterior cardinal veins drain the cephalic portion of the embryo, and the posterior cardinal veins drain the caudal portion. Merging of the anterior and posterior cardinal veins before the sinus venosus creates the short common cardinal veins.

The growth in nuclear medicine for both personalized healthcare and to support drug discovery efforts is creating unprecedented demand for radiopharmaceuticals, bioactive molecules labeled with a radionuclide. Given the highly specialized and costly infrastructure required to produce radiopharmaceuticals (e.g., cyclotrons, hot-cells, automated synthesis modules, specialized analytical equipment), radiopharmaceutical production capabilities are not easily expandable on a short timeframe to meet this rapid growth. As such, new approaches for how radiopharmaceutical syntheses are developed and optimized are urgently needed to meet growing routine clinical production demands on radiochemistry facilities while also continuing innovation of new radiopharmaceuticals. High-throughput experimentation (HTE) holds enormous potential in this regard, and this chapter summarizes the current state-of-the-art of HTE as it pertains to radiochemistry, including both sequential and parallel methods for high-throughput radiolabeling (using vials, multi-well plates, flow chemistry, and droplet-based methods) and analysis (including UPLC, multi-lane radio-TLC, and solid-phase extraction (SPE) approaches). Comparison of the various high-throughput approaches is considered, along with key pros and cons for the different methods, as well as thoughts on how to standardize data acquisition and future outlooks.

The analysis of radiochemical composition is critical in the development and production of radiopharmaceuticals, for example, to assess synthesis performance, perform quality control testing, or analyze radiometabolites. In addition to widely used techniques based on liquid chromatography (e.g., HPLC) and planar chromatography (e.g., TLC), high-performance methods based on electrophoresis are also used in a wide range of applications. This chapter reviews the techniques of gel electrophoresis, paper electrophoresis, capillary electrophoresis, and microchip electrophoresis, and selected applications in the field of radiopharmaceutical analysis.

Performing radiolabeling in microvolume reactors (1–10 μL) instead of conventional reactors (~1 mL) offers significant improvements including increased yield, high molar activity, short synthesis time, reduced reagent consumption, and reduced amount of byproducts that need to be removed during purification. Furthermore, microreactor-based radiochemistry systems are emerging that are far more compact than conventional radiosynthesizers, providing the potential for lower cost radiochemistry facilities and adoption of a wider distributed manufacturing paradigm that can support flexible and scalable manufacturing of a wide variety of radiopharmaceuticals at a given radiopharmacy site. In this chapter, we focus on droplet-based reactors as a way to realize these benefits and review recent work on implementing droplet-based reactions, highlighting technical progress, radiosynthesis applications, and advantages and limitations of each droplet platform.

The COVID‐19 pandemic profoundly impacted mental health, with psychological distress varying across age and racial/ethnic groups. This study examined trajectories of five distress measures—symptoms of posttraumatic stress (PTS), anxiety, depression, anger, and somatization—over the first 2 years of the pandemic, adjusting for prepandemic mental health. Participants in a nationally representative, probability‐based U.S. sample (N = 4,298, age range: 18–97 years) completed four online surveys from March 2020 to June 2022. Multilevel models revealed that symptom levels and changes over time varied by age group across outcomes. Across time, PTS and anxiety symptoms declined for most age groups at different rates, F(6, 85,660) = 6.21, p < .001. Younger adults initially reported higher PTS symptom levels at Wave 1, Bs = 0.10–0.14, p < .001, but levels converged across age groups by Wave 4. Rates of anxiety symptoms were similar across age groups at Wave 4 except for older adults, who reported significantly lower levels. Depressive symptoms and anger increased in the initial waves but declined by Wave 4, Bs = −0.25–0.02, p < .001. For all participants, somatization increased after Wave 1, B = −0.30, p < .001, and never returned to initial levels, B = −0.04, p < .001. Additionally, somatization was the only symptom with similar levels across age groups at each wave. Across race/ethnicity, Hispanic adults reported higher distress and less decline over time. Findings highlight distinct symptom trajectories across the pandemic, with generally lower distress levels among the oldest adults.

Background Alzheimer‘s disease (AD) is the leading cause of cognitive impairment and dementia in elderly patients worldwide. There is increasing evidence that periodontal disease may have an important role in the complex, multifactorial pathogenesis of AD. Aim This narrative review aims to (1) highlight the current understanding of the role of periodontal disease in AD, including molecular and immunological evidence, epidemiological studies, and biological mechanisms linking periodontal disease to AD; and (2) explore the potential impact of periodontal therapy as part of an individualized, multitherapeutic approach to AD. Materials and methods A literature search of the PubMed database was conducted using Boolean search strategies to identify publications related to the potential connections between periodontal disease and AD. Results Most of the evidence for a link between periodontal disease and AD is limited to preclinical research and epidemiological investigations. A direct causal link has not yet been demonstrated in human clinical studies, but periodontal pathogenic bacteria have been detected in brain tissue and cerebrospinal fluid of patients with AD. Further, colocalization of gingipain proteases secreted by Porphyromonas gingivalis has been found in AD pathological lesions. Epidemiological studies support associations between periodontal disease and increased risk/prevalence of cognitive decline, AD, and AD mortality. Two mechanistic theories have been proposed to explain the connection between periodontitis and AD: the “microbial involvement” theory focuses on periodontal disease–associated pathogenic bacteria, whereas the “inflammatory cascade” theory focuses on proinflammatory mediators as drivers of neuroinflammation that may exacerbate pathologic lesions associated with AD. Preclinical studies of periodontal therapies targeting oral microbiota or their byproducts have investigated small‐molecule gingipain inhibitors and novel therapeutics that restore oral microbial homeostasis (e.g., probiotic bacteriocin nisin). In animal models, gingipain inhibitors and nisin showed inhibitory effects on formation of pathological lesions of AD or neuroinflammation and microbiome changes, respectively; however, no impact on cognition was found with use of gingipain inhibitors in patients with mild‐to‐moderate AD. Conclusions Additional studies are needed to better understand the potential causal relationship between periodontal disease and AD, including further exploration of therapies targeting the oral–brain axis.

Psoriasis body surface area (BSA) of 10% or more has been a major criterion for determining systemic therapy eligibility. However, patients with BSA < 10% and even ≤ 3% may have high disease burden and difficulties accessing biologics. To assess psoriasis burden among patients with BSA ≤ 10%, this study characterized patient-reported outcomes (PROs) across BSA categories among systemic treatment-naïve patients initiating biologic therapy. Patients from the CorEvitas Psoriasis Registry initiating biologics between April 2015 and September 2023 were categorized according to low (< 3%), medium (3–10%), or high (> 10%) BSA involvement. Measures assessed at initiation of biologic therapy included health-related quality of life, itch, pain, fatigue, psoriatic arthritis, psoriasis disease characteristics, and medical history. Overlap between BSA groups for each outcome was calculated via non-parametric Mann–Whitney statistic transformation (range 0.0–1.0; 0.5 indicates complete similarity [i.e., for a comparison between low and high BSA groups, overlap of 0.5 means there is 50% probability that a randomly selected patient with low BSA would have the same or greater PRO burden as one with high BSA]; 0 or 1 indicates complete dissimilarity) to determine whether each measure differed in randomly selected patients with low or medium versus high BSA. Of 1640 patients who initiated biologics, 7.0% had low BSA, 46.9% had medium BSA, and 46.2% had high BSA involvement. PRO overlap statistics ranged from 0.52 to 0.59 and from 0.60 to 0.70 for randomly selected patients with high versus medium and low BSA, respectively, indicating patients with high and medium BSA are likely to have similar levels of disease burden, and patients with high BSA are slightly more likely to have higher disease burden than those with low BSA. Near complete overlap (range 0.44–0.58) was observed for psoriasis disease characteristics and medical history in the low versus high and medium BSA groups. Observed overlap in PROs across BSA categories shows that patients with low BSA can experience similarly poor quality of life and high symptom burden to those with higher BSA. These findings support the appropriateness of considering biologic therapies for patients with low BSA and indicators of high disease burden. ClinicalTrials.gov: NCT02707341.

Objective To evaluate the first 3 years of compliance with the American College of Surgeons Commission on Cancer (CoC) Operative Standards. Background CoC implemented evidence-based standards to improve the quality of sentinel lymph node biopsy and axillary lymph node dissection for breast cancer (Operative Standards 5.3 and 5.4), wide local excision for melanoma (5.5), colectomy for colon cancer (5.6), proctectomy for rectal cancer (5.7), and pulmonary resection for lung cancer (5.8) at approximately 1,400 programs treating>74% of US cancer patients. Each Operative Standard defines a technical element of the operation and structured documentation. Methods Compliance data are from site visits conducted between January 1, 2022, and December 31, 2024 (implementation/site visits began in 2021/2022 for 5.7 and 5.8 and 2023/2024 for 5.3-5.6). Compliance with each Operative Standard was determined by evaluation of 7 operative (5.3-5.6) or pathology (5.7, 5.8) reports. Deficiency in technical performance, documentation, or both was considered noncompliance. Results Reviewers conducted 974 site visits of Comprehensive Community (44%), Community (23%), Academic Comprehensive (16%), network (12%), NCI-Designated Comprehensive (4%), and other (1%) cancer programs. Program compliance rates ranged from 53% to 88%. Documentation noncompliance was more common for standards 5.3-5.6 (based on operative reports), and technical noncompliance was more common for 5.7 and 5.8 (based on pathology reports). Compliance significantly ( P =0.006) varied by program type for 5.8 (highest: 66% at NCI-designated Comprehensive programs; lowest: 37% at Community Cancer programs). Conclusions Early compliance with CoC Operative Standards varied, indicating local and large-scale national quality improvement efforts are needed.

Objective To establish a femoral cortical thickness index (CTI) for dogs undergoing total hip replacement (THR), determine the reproducibility of the established CTI measurements, and assess the efficacy of CTI as a preoperative variable in the femoral fracture/fissure occurrence in dogs undergoing THR. Study design Retrospective study. Animals A total of 224 dogs with THR. Methods Medical records for dogs undergoing THR were reviewed retrospectively, analyzing only the first side in dogs with bilateral THR. Three measuring points were defined on preoperative mediolateral radiographs: immediately distal to the lesser trochanter, one‐quarter‐, and midway down the femur. The CTI was calculated from the mean cortical and femoral diaphyseal diameters at the established locations. A total of 10 dogs with varying CTI scores were selected for interobserver comparisons and pre−/ postoperative analyses. The relationship between CTI and perioperative fissure/fracture risk was then evaluated. Results Interobserver and pre−/ postoperative measurement comparisons showed near‐perfect correlation. Analysis of 224 dogs revealed a significant association between lower CTI and incidence of perioperative fractures ( p < .0001). The mean CTI for all dogs was 0.285, while it was statistically lower at 0.246 for dogs that sustained fissures/fractures. No other statistically significant risk factors were identified. Conclusion This study quantitatively assessed femoral cortical thickness in dogs undergoing THR. The findings confirmed that lower CTI is a repeatable and accurate predisposing factor for perioperative fissure/fracture risk in canine THR. Clinical significance Factoring CTI into the clinical decision making may minimize fracture risk, especially in dogs with other possible risk factors such as abnormal BCS.

Common names of species are important for communicating with the general public. In principle, these names should provide an accessible way to engage with and identify species. The common names of species have historically been labile without standard guidelines, even within a language. Currently, there is no systematic assessment of how often common names communicate identifiable and biologically relevant characteristics about species. This is a salient issue in ornithology, where common names are used more often than scientific names for species of birds in written and spoken English, even by professional researchers. To gain a better understanding of the types of terminology used in the English-language common names of bird species, a group of 85 professional ornithologists and non-professional contributors classified unique descriptors in the common names of all recognized species of birds. In the AvianLexiconAtlas database produced by this work, each species’ common name is assigned to one of ten categories associated with aspects of avian biology, ecology, or human culture. Across 10,906 species of birds, 89% have names describing the biology of the species, while the remaining 11% of species have names derived from human cultural references, human names, or local non-English languages. Species with common names based on features of avian biology are more likely to be related to each other or be from the same geographic region. The crowdsourced data collection also revealed that many common names contain specialized or historic terminology unknown to many of the data collectors, and we include these terms in a glossary and gazetteer alongside the dataset. The AvianLexiconAtlas can be used as a quantitative resource to assess the state of terminology in English-language common names of birds. Future research using the database can shed light on historical approaches to nomenclature and how people engage with species through their names.

We study the implications of optimal insurance provision for long‐run welfare and inequality in economies with persistent private information. A principal insures an agent whose private type follows an ergodic, finite‐state Markov chain. The optimal contract always induces immiseration: the agent's consumption and utility decrease without bound. Under positive serial correlation, it also backloads high‐powered incentives: the sensitivity of the agent's utility with respect to his reports increases without bound. These results extend—and help elucidate the limits of—the hallmark immiseration results for economies with i.i.d. private information. Numerically, we find that persistence yields faster immiseration, higher inequality, and novel short‐run distortions. Our analysis uses recursive methods for contracting with persistent types and allows for binding global incentive constraints.

Voltammetry is widely used to detect and quantify oxidizable or reducible species in complex environments. The neurotransmitter serotonin epitomizes an analyte that is challenging to detect in situ due to its low concentrations and the co-existence of similarly structured analytes and interferents. We developed rapid-pulse voltammetry for brain neurotransmitter monitoring due to the high information content elicited from voltage pulses. Generally, the design of voltammetry waveforms remains challenging due to prohibitively large combinatorial search spaces and a lack of design principles. Here, we illustrate how Bayesian optimization can be used to hone searches for optimized rapid pulse waveforms. Our machine-learning-guided workflow (SeroOpt) outperformed random and human-guided waveform designs and is tunable a priori to enable selective analyte detection. We interpreted the black box optimizer and found that the logic of machine-learning-guided waveform design reflected domain knowledge. Our approach is straightforward and generalizable for all single and multi-analyte problems requiring optimized electrochemical waveform solutions. Overall, SeroOpt enables data-driven exploration of the waveform design space and a new paradigm in electroanalytical method development.

Background Long-term sequelae after SARS-CoV-2 infection may impact health-related quality-of-life (HRQoL), yet it is unknown how HRQoL changes during recovery. We compared patient-reported HRQoL among adults with COVID-19–like illness who tested SARS-CoV-2 positive (COVID+) with those who tested negative (COVID−). Methods Participants in this prospective, multicenter, longitudinal registry study were enrolled from December 2020 through August 2022 and completed 3-month follow-up assessments until 12 months after enrollment. Participants were adults (≥18 years) with acute symptoms suggestive of COVID-19 who received a Food and Drug Administration–approved SARS-CoV-2 test. Participants received questions from PROMIS-29 (subscales: physical function, anxiety, depression, fatigue, social participation, sleep disturbance, and pain interference) and PROMIS SF-8a (cognitive function). Latent transition analysis was used to identify meaningful patterns in HRQoL scores over time; 4 HRQoL categories were compared descriptively and using multivariable regression. Inverse probability weighting was used to adjust for covariate imbalance. Results There were 1096 (75%) COVID+ and 371 (25%) COVID−. Four distinct well-being classes emerged: optimal overall, poor mental, poor physical, and poor overall HRQoL. COVID+ participants were more likely to return to the optimal HRQoL class compared to COVID− participants. The most substantial transition from poor physical to optimal HRQoL occurred by 3 months, whereas movement from poor mental to optimal HRQoL occurred by 9 months. Conclusions In adults with COVID-19–like illness, COVID+ participants demonstrated meaningful recovery in their physical HRQoL by 3 months after infection, but mental HRQoL took longer to improve. Suboptimal HRQoL at 3 to 12 months after infection remained in approximately 20%. Trial Registration NCT04610515.

The authors offer a model for curriculum for education and training in substance-assisted psychotherapy (SAP), that is, psychedelic, psycholytic, and entactogen/MDMA (3,4-methylenedioxymethamphetamine)-assisted psychotherapy, addressing both the detailed contents of training and the question of experiential training. All authors of this model have an abiding interest and extensive experience in both the theory and practical aspects of SAP and questions relating to training. The model curriculum has been written through an international consensus building process and represents a consensus statement about the topic. The model includes an enumeration of theoretical themes and topics, which we suggest for inclusion in an SAP curriculum. The practical part of the curriculum includes experiential training with the following components: (1) apprenticeship observation: learning from observing experienced therapists, (2) ongoing clinical supervision: conducting treatment under direct supervision of experienced SAP therapists, and (3) a proposal for the inclusion of self-experiences for the trainees. Other parts address the use of peer supervision and conventional supervision. The authors are aware of the abiding need for respect of intercultural differences. We are conscious that the proposed model is one largely adapted to western industrialized countries with established graduate level education and training procedures for psychotherapists. However, the model curriculum includes teachings about the use of related substances and treatment techniques in indigenous cultures and traditions. This curriculum model may be valuable to psychedelic researchers, those endeavoring to train therapists for research studies, and those preparing for the clinical work to follow, once SAP is conducted outside of research settings.

Influenza virus infections generate antibodies that cross-react with antigenically similar viruses. However, the breadth of cross-reactivity is unclear. Here we analysed 200,000 haemagglutination inhibition (HAI) titrations from ferrets singly infected with A(H3N2) or A(H1N1)pdm09. We identified consistent influenza A virus subtype-specific patterns where breadth of HAI antibody cross-reactivity was associated with isolation time between tested and immunizing viruses. This was independent of virus strains, passage history and genetic mutations. A 6-year interval between virus isolation resulted in minimal HAI titres for A(H3N2), while A(H1N1)pdm09 demonstrated broader cross-reactivity with moderate titre reductions over the same interval. Analysis of HA substitutions revealed more amino acid substitutions between viruses for A(H3N2) and a greater reduction in HAI titres per substitution compared with A(H1N1). Longitudinal analysis of human antisera across age groups suggests that repeat A(H3N2) exposure increased HAI responses within the cross-reactivity range, with greater increases for more recent viruses. These results provide a framework for antigenically evolving pathogens such as influenza viruses.

Though racial disparities in shortened life expectancy have been well established, racial disparities in the burden of bereavement after such premature deaths are severely understudied. This is, in part, due to a lack of measurement tools for characterizing lifetime exposure to loss. We propose three indices that simultaneously quantify premature and cumulative lifetime loss—two typically unmeasured dimensions of loss. Using a longitudinal US sample of 27,985 participants from the Health and Retirement Study (1992 to 2020) who experienced at least one lifetime loss, hierarchical linear models accounting for participants nested within households showed that Black participants and Native American participants had higher premature and cumulative burden of family member loss over the lifetime than all other racial groups across all three indices. These effects remained for Black participants after controlling for covariates such as parental education, household size, and years in the study. Second, we found that loss burden at study enrollment prospectively related to all-cause mortality. Depending on prematurity, each additional loss related to higher odds of dying during the study period after controlling for covariates such as chronic health conditions. Together, our work leverages prospective, longitudinal methodologies to identify racial disparities in exposure to earlier and repeated death and its impact on mortality among the bereaved. The proposed measurement approach has future applications for understanding how loss exposure—both “too soon” and “too much”—predicts poor health and earlier mortality.

Sarcomas, including osteosarcoma and soft tissue sarcoma, are heterogeneous and rare diseases with limited treatment options and a high metastatic potential. Despite advancements in immunotherapy and targeted therapies, many sarcoma patients have limited durable responses to these treatments. Therefore, individualized precision medicine and novel drug discovery are greatly needed. To address this unmet need, we have developed a patient-derived orthotopic xenograft (PDOX) mouse model of sarcomas using surgical orthotopic implantation. The PDOX models more accurately recapitulate the complex characteristics of human tumors compared to traditional subcutaneous xenografts. This enhanced fidelity is due to the preservation of the original tumor's histology and the accurate representation of the tumor microenvironment within the orthotopic implantation site. The present report summarizes our research group's experience with the sarcoma PDOX model and underscores its significant potential for identifying effective therapeutics. We have obtained numerous promising and unexpected results, including the identification of active chemotherapy drugs, novel drug combinations, and experimental therapeutics tailored to individual patients. In the current era of growing advancements in precision medicine, PDOX models offer a unique opportunity for developing individualized and innovative therapy specifically tailored to the individual needs of sarcoma patients.