Parsing patterns: Emerging roles of tissue self-organization in health and disease.

Patterned morphologies, such as segments, spirals, stripes, and spots, frequently emerge during embryogenesis through self-organized coordination between cells. Yet, complex patterns also emerge in adults, suggesting that the capacity for spontaneous self-organization is a ubiquitous property of biological tissues. We review current knowledge on the principles and mechanisms of self-organized patterning in embryonic tissues and explore how these principles and mechanisms apply to adult tissues that exhibit features of patterning. We discuss how and why spontaneous pattern generation is integral to homeostasis and healing of tissues, illustrating it with examples from regenerative biology. We examine how aberrant self-organization underlies diverse pathological states, including inflammatory skin disorders and tumors. Lastly, we posit that based on such blueprints, targeted engineering of pattern-driving molecular circuits can be leveraged for synthetic biology and the generation of organoids with intricate patterns.

Cumulative route improvements spontaneously emerge in artificial navigators even in the absence of sophisticated communication or thought.

Homing pigeons (Columba livia) navigate by solar and magnetic compass, and fly home in idiosyncratic but stable routes when repeatedly released from the same location. However, when experienced pigeons fly alongside naive counterparts, their path is altered. Over several generations of turnover (pairs in which the most experienced individual is replaced with a naive one), pigeons show cumulative improvements in efficiency. Here, I show that such cumulative route improvements can occur in a much simpler system by using agent-based simulation. Artificial agents are in silico entities that navigate with a minimal cognitive architecture of goal-direction (they know roughly where the goal is), social proximity (they seek proximity to others and align headings), route memory (they recall landmarks with increasing precision), and continuity (they avoid erratic turns). Agents' behaviour qualitatively matched that of pigeons, and quantitatively fitted to pigeon data. My results indicate that naive agents benefitted from being paired with experienced agents by following their previously established route. Importantly, experienced agents also benefitted from being paired with naive agents due to regression to the goal: naive agents were more likely to err towards the goal from the perspective of experienced agents' memorised paths. This subtly biased pairs in the goal direction, resulting in intergenerational improvements of route efficiency. No cumulative improvements were evident in control studies in which agents' goal-direction, social proximity, or memory were lesioned. These 3 factors are thus necessary and sufficient for cumulative route improvements to emerge, even in the absence of sophisticated communication or thought.

Interval Metastases After Neoadjuvant Chemoradiotherapy for Patients with Locally Advanced Esophageal Cancer: A Multicenter Observational Cohort Study.

BACKGROUND: Despite trimodality treatment, 10% to 20% of patients with esophageal cancer experience interval metastases after surgery. Restaging may identify patients who should not proceed to surgery, as well as a subgroup with limited metastases for whom long-term disease-control can be obtained. This study aimed to determine the proportion of patients with interval metastases after neoadjuvant chemoradiotherapy (nCRT) and to evaluate treatment and survival. METHODS: Patients who had cT2-4aN0-3M0 esophageal cancer treated with nCRT were identified from a trial database. Metastases detected up to 14 weeks after nCRT on 18F-FDG-PET/CT or during surgery were categorized as oligometastases (≤3 lesions located in one single organ or one extra-regional lymph node station) or as non-oligometastases. The primary outcome was the proportion of patients with metastases after nCRT. The secondary outcomes were overall survival (OS) and the site and treatment of metastases. RESULTS: Between 2013 and 2021, 973 patients received nCRT, and 10.3% had interval metastases. Of 100 patients, 30 (30%) had oligometastases, located mostly in non-regional lymph nodes (33.3%) or bones (26.7%). The median OS of this group was 13.8 months (95% confidence interval [CI] 9.2-27.1 months). Of 30 patients, 12 (40%) with oligometastases underwent potentially curative treatment, with a median OS of 22.8 months (95% CI 10.4-NA). The patients with non-oligometastases underwent mostly systemic therapy or BSC and had a median OS of 9 months (95% CI 7.4-10.9 months). CONCLUSIONS: Interval metastases were detected in about 10% of patients after nCRT, underscoring the importance of re-staging with 18F-FDG-PET/CT for those who proceed to surgery. A favorable survival might be accomplished for a subgroup of patients with oligometastases.

Association Between a National Behavioral Weight Management Program and Veterans Affairs Health Expenditures.

OBJECTIVE: The association between participation in a behavioral weight intervention and health expenditures has not been well characterized. We compared Veterans Affairs (VA) expenditures of individuals participating in MOVE!, a VA behavioral weight loss program, and matched comparators 2 years before and 2 years after MOVE! initiation. METHODS: Retrospective cohort study of Veterans who had one or more MOVE! visits in 2008-2017 who were matched contemporaneously to up to 3 comparators with overweight or obesity through sequential stratification on an array of patient characteristics, including sex. Baseline patient characteristics were compared between the two cohorts through standardized mean differences. VA expenditures in the 2 years before MOVE! initiation and 2 years after initiation were modeled using generalized estimating equations with a log link and distribution with variance proportional to the standard deviation (gamma). RESULTS: MOVE! participants (n=499,696) and comparators (n=1,336,172) were well-matched, with an average age of 56, average body mass index of 35, and similar total VA expenditures in the fiscal year before MOVE! initiation ($9662 for MOVE! participants and $10,072 for comparators, standardized mean difference=-0.019). MOVE! participants had total expenditures that were statistically lower than matched comparators in the 6 months after initiation but modestly higher in the 6 months to 2 years after initiation, though differences were small in magnitude (1.0%-1.6% differences). CONCLUSIONS: The VA's system-wide behavioral weight intervention did not realize meaningful short-term health care cost savings for participants.

Identifying Patterns of Primary Care In-Person and Telemedicine Use in the Veterans Health Administration: A Latent Class Analysis.

BACKGROUND: The Veterans Health Administration increased synchronous telemedicine (video and telephone visits) in primary care in response to the COVID-19 pandemic. OBJECTIVE: Our objective was to determine veteran use patterns of in-person and telemedicine primary care when all modalities were available. DESIGN: A retrospective cohort analysis. We performed a latent class analysis of primary care visits over a 1-year period to identify veteran subgroup (i.e., class) membership based on amount of primary care use and modality used. Then, we used multinomial logistic regression with a categorical outcome to identify patient characteristics associated with class identification. PARTICIPANTS: A random national sample consisting of 564,580 primary care empaneled veterans in June 2021. MAIN MEASURES: Latent class membership. KEY RESULTS: We identified three latent classes: those with few primary care visits that were predominantly telephone-based (45%), intermediate number of visits of all modalities (50%), and many visits of all modalities (5%). In an adjusted model, characteristics associated with the "few" visits class, compared to the intermediate class, were older age, male sex, White race, further driving distance to primary care, higher Gagne, optimal internet speed, and unmarried status (OR 1.002, 1.52, 1.13, 1.004, 1.04, 1.05, 1.06, respectively; p < .05). Characteristics associated with membership in the "many" visits class, compared to the intermediate class, were Hispanic race, higher JEN Frailty Index and Gagne (OR 1.12, 1.11, 1.02, respectively; p < .05), and higher comorbidity by Care Assessment Need score quartile (Q2 1.73, Q3 2.80, Q4 4.12; p < 0.05). CONCLUSIONS: Veterans accessing primary care in-person or via telemedicine do so primarily in three ways: (1) few visits, predominantly telephone; (2) intermediate visits, all modalities, (3) many visits, all modalities. We found no groups of veterans receiving a majority of primary care through video.

Defining and Improving Outcomes Measurement for Virtual Care: Report from the VHA State-of-the-Art Conference on Virtual Care.

Virtual care, including synchronous and asynchronous telehealth, remote patient monitoring, and the collection and interpretation of patient-generated health data (PGHD), has the potential to transform healthcare delivery and increase access to care. The Veterans Health Administration (VHA) Office of Health Services Research and Development (HSR&D) convened a State-of-the-Art (SOTA) Conference on Virtual Care to identify future virtual care research priorities. Participants were divided into three workgroups focused on virtual care access, engagement, and outcomes. In this article, we report the findings of the Outcomes Workgroup. The group identified virtual care outcome areas with sufficient evidence, areas in need of additional research, and areas that are particularly well-suited to be studied within VHA. Following a rigorous process of literature review and consensus, the group focused on four questions: (1) What outcomes of virtual care should we be measuring and how should we measure them?; (2) how do we choose the "right" care modality for the "right" patient?; (3) what are potential consequences of virtual care on patient safety?; and (4) how can PGHD be used to benefit provider decision-making and patient self-management?. The current article outlines key conclusions that emerged following discussion of these questions, including recommendations for future research.

Imaging Neuropeptide Release from Drosophila Clock and Motor Neurons.

Electrophysiological studies of synaptic function do not robustly report release of neuropeptides and neurotrophins. These limitations have been overcome with the presynaptic expression of optical release reporters based on green fluorescent protein and fluorogen-activating protein. Here we describe how to image neuropeptide release in Drosophila at the neuromuscular junction and in the adult brain.

GFP and FAP imaging of neuropeptide release in Drosophila.

Genetics in Drosophila have revealed the role of neuropeptides in development and behavior. However, determining when and where neuropeptides are released has been challenging. Furthermore, the cell biology underlying neuropeptide release has largely been unexplored. Thus, it has not been possible to determine whether changes in neuropeptide immunofluorescence reflect traffic and/or release, and in neurons where such changes are not detectable, conclusions about neuropeptide release have been formulated based on the assumption that electrical and Ca2+ recordings are accurate and quantitative predictors of release. Recently, the advent of optical detection of neuropeptides tagged with fluorescent proteins and fluorogen-activating proteins (FAPs) has made it feasible to directly image vesicle traffic and exocytosis that mediates neuropeptide release in peripheral synapses and in the brain. In fact, these approaches have led to the discovery of unexpected insights concerning neuropeptide release. Here procedures are presented for optimizing fluorescence imaging of neuropeptides tagged with green fluorescent protein or a FAP.

Long-term disgust habituation with limited generalisation in care home workers.

Countless workers handle bodily effluvia and body envelope violations every working day, and consequentially face deeply unpleasant levels of disgust. Understanding if and how they adapt can help inform policies to improve worker satisfaction and reduce staff turnover. So far, limited evidence exist that self-reported disgust is reduced (or lower to begin with) among those employed in high-disgust environments. However, it is unclear if this is due to demand effects or translates into real behavioural changes. Here, we tested healthcare assistants (N = 32) employed in UK care homes and a control sample (N = 50). We replicated reduced self-reported pathogen disgust sensitivity in healthcare workers compared to controls. We also found it negatively correlated with career duration, suggesting long-term habituation. Furthermore, we found that healthcare assistants showed no behavioural disgust avoidance on a web-based preferential looking task (equivalent to eye tracking). Surprisingly, this extended to disgust elicitors found outside care homes, suggesting generalisation of disgust habituation. While we found no difference between bodily effluvia (core disgust) and body envelope violations (gore disgust), generalisation did not extend to other domains: self-reported sexual and moral disgust sensitivity were not different between healthcare assistants and the control group, nor was there a correlation with career duration. In sum, our work confirms that people in high-frequency disgust employment are less sensitive to pathogen disgust. Crucially, we provide preliminary evidence that this is due to a process of long-term habituation with generalisation to disgust-elicitors within the pathogen domain, but not beyond it.

Disability and Place of Death in Older Americans: The Moderating Role of Household Wealth.

CONTEXT: Home-based deaths are increasing, yet, how wealth influences where people die in the presence of disability remains unknown. OBJECTIVE: To examine place of death by help with (instrumental) activities of daily living (I/ADLs) at the end of life (EOL) and the modifying role of wealth. METHODS: Retrospective study of decedents from the Health and Retirement Study (n = 13,210). The exposure was intensity of help with I/ADLs at the EOL (no help/ lower intensity/higher intensity). The outcome was place of death (hospital/nursing home/home). Household wealth was an effect modifier with six categories: ≤$0, first-fifth quintile. Covariates included age, gender, race, marital status at the EOL, last place of residence, and receipt of hospice care. We used multinomial logit regression models with estimates reported as average marginal effects (AMEs). RESULTS: Mean age was 79.8 years; 53.2% were female. In the adjusted models, compared to not receiving help at EOL, receiving higher-intensity help was associated with a lower probability of dying in a hospital (AME = -3.8 percentage points (pp), 95% CI = -6.3 to -1.3) and a higher probability of dying at home (AME = 3.6 pp, 95% CI = 1.4-5.7). Associations were most pronounced among decedents in the top two wealth quintiles; older adults who received higher-intensity help had a lower probability of dying in a hospital (AME = -9.0 pp, 95% CI = -14.8 to -3.1), and a higher probability of dying at home (AME = 8.4 pp, 95% CI = 3.8-13.0). CONCLUSION: Receiving higher intensity of help with I/ADLs was associated with lower likelihood of dying in a hospital, and higher likelihood of dying at home, particularly among older adults with greater wealth.

Circadian Vesicle Capture Prepares Clock Neuron Synapses for Daily Phase-Delayed Neuropeptide Release.

Drosophila sLNv clock neurons release the neuropeptide PDF to control circadian rhythms. Strikingly, PDF content in sLNv terminals is rhythmic with a peak in the morning hours prior to the onset of activity-dependent release. Because synaptic PDF accumulation, rather than synaptic release, aligns with the late-night elevations in both sLNv neuron excitability and Ca2+, we explored the dependence of presynaptic neuropeptide accumulation on neuropeptide vesicle transport, electrical activity and the circadian clock. Live imaging reveals that anterograde axonal transport is constant throughout the day and capture of circulating neuropeptide vesicles rhythmically boosts presynaptic neuropeptide content hours prior to release. The late-night surge in vesicle capture, like release, requires electrical activity and results in a large releasable pool of presynaptic vesicles to support the later burst of neuropeptide release. The circadian clock is also required suggesting that it controls the switch from vesicle capture to exocytosis, which are normally coupled activity-dependent processes. This toggling of activity transduction maximizes rhythmic synaptic neuropeptide release needed for robust circadian behavior and resolves the previously puzzling delay in timing of synaptic neuropeptide release relative to changes in sLNv clock neuron physiology.

Feasibility of keeping Mars warm with nanoparticles.

One-third of Mars' surface has shallow-buried H2O, but it is currently too cold for use by life. Proposals to warm Mars using greenhouse gases require a large mass of ingredients that are rare on Mars' surface. However, we show here that artificial aerosols made from materials that are readily available at Mars-for example, conductive nanorods that are ~9 micrometers long-could warm Mars >5 × 103 time smore effectively than the best gases. Such nanoparticles forward-scatter sunlight and efficiently block upwelling thermal infrared. Like the natural dust of Mars, they are swept high into Mars' atmosphere, allowing delivery from the near-surface. For a 10-year particle lifetime, two climate models indicate that sustained release at 30 liters per second would globally warm Mars by ≳30 kelvin and start to melt the ice. Therefore, if nanoparticles can be made at scale on (or delivered to) Mars, then the barrier to warming of Mars appears to be less high than previously thought.

Disparities in telemedicine use among Native Hawaiian and Pacific Islander individuals insured through Medicaid.

States have implemented policy changes to increase access to telemedicine services for individuals receiving Medicaid benefits. Native Hawaiian and Pacific Islander (NHPI) individuals experienced disproportionate harms from COVID-19 and have long experienced disparities in health care access compared with other racial and ethnic groups, making the issue of telemedicine access particularly salient for NHPI individuals on Medicaid. Utilizing 100% 2020-2021 Medicaid claims, we compared trends in telemedicine use between NHPI and non-Hispanic White individuals on Medicaid in Washington State and conducted a decomposition analysis to identify drivers of underlying disparities. In both years, NHPI individuals were 38%-39% less likely to use any telemedicine than White individuals after adjusting for patient- and area-level characteristics. Decomposition analysis revealed that most of this difference was due to differential effects of characteristics, rather than group differences in characteristics. Namely, several characteristics that were associated with increased telemedicine use had more muted associations for NHPI vs White individuals, such as English as the primary spoken language and female sex. These findings suggest the presence of limited acceptability of or group-specific barriers to telemedicine for NHPI individuals, including potential discrimination in being offered telemedicine visits. These issues should be understood and mitigated through close collaboration between health care leaders and NHPI communities.

The weapons potential of high-assay low-enriched uranium.

Recent promotion of new reactor technologies appears to disregard decades-old concerns about nuclear proliferation.

Factors Associated With Use of the Preventive Health Inventory in US Veterans.

Importance: The COVID-19 pandemic caused significant declines in the quality of preventive and chronic disease care. The Veterans Health Administration (VHA) used the Preventive Health Inventory (PHI), a multicomponent care management intervention, to catch up on care disrupted by the pandemic. Objective: To identify key factors associated with PHI use. Design, Setting, and Participants: This cohort study of veterans receiving primary care used administrative data from national VHA primary care clinics for February 1, 2021, through February 1, 2022. Exposure: Patient PHI receipt. Main Outcomes and Measures: The main outcomes were patient, practitioner, and clinic factors associated with PHI receipt. Binomial generalized linear models with fixed effects for clinic were used to analyze factors associated with receipt of PHI. Least absolute shrinkage and selection operator procedures were used for variable selection. Results: A total of 4 358 038 veterans (mean [SD] age, 63.7 [16.0] years; 90% male; 76% non-Hispanic White) formed the study cohort, of whom 389 757 (9%) received the PHI. Veterans who received the PHI had higher mean Care Assessment Need (CAN) scores, which indicate the likelihood of hospitalization or death within 1 year (mean [SD], 51.9 [28.6] vs 47.2 [28.6]; standardized mean difference [SMD], -0.16). They were also more likely to live in urban areas (77% vs 64%; SMD, 0.28) and have a shorter drive distance to primary care (mean [SD], 13.2 [12.4] vs 15.7 [14.6] miles; SMD, 0.19). The mean outpatient use was higher among PHI recipients compared with non-PHI recipients (mean [SD], 18.4 [27.8] vs 15.1 [24.1] visits; SMD, -0.13). In addition, veterans with primary care practitioners with higher caseloads were more likely to receive the PHI (mean [SD], 778 [231] vs 744 [249] patients; SMD, -0.14), and they were more likely to be seen at larger clinics (mean [SD], 9670 [6876] vs 8786 [6892] patients; SMD, -0.13). Prior outpatient use and CAN score were associated with PHI receipt in the final model. Conclusions and Relevance: In this cohort study of the VHA's PHI, patients with higher CAN scores and more outpatient use in the previous year were more likely to receive the PHI. This study identifies potential intervention points to improve care coordination for veterans.

Differences in healthcare costs over 10 years following discharge from military service by weight trajectory.

The prevalence of overweight and obesity among military personnel has increased substantially in the past two decades. Following military discharge many personnel can receive integrated health care from the Veterans Health Administration. Prior research related to the economic impacts of obesity has not examined health care costs following the transition into civilian life following military discharge. To address this evidence gap, this study sought to compare longitudinal costs over 10 years across weight categories among VA enrollees recently discharged from the military.

Factors associated with primary care physician turnover in the VA.

OBJECTIVES: To quantify the association between primary care team workload satisfaction and primary care physician (PCP) turnover and examine potential mediation of workplace climate factors using survey and administrative data. STUDY DESIGN: Longitudinal observational study using data from 2008 to 2016. METHODS: The outcome variable was PCP turnover. The main explanatory variable was satisfaction with amount of workload. We included 7 additional workplace climate measures (eg, satisfaction with direct supervision) as mediators. We included characteristics of PCPs (eg, PCP years of experience, gender), salary, and clinic factors (eg, urban vs rural geography, community vs hospital based) as covariates. RESULTS: US Department of Veterans Affairs (VA) PCPs working at 787 VA primary care clinics nationally were recruited for this study. Over the 9-year study period, 8362 unique PCPs were employed in the VA. The unadjusted mean quarterly turnover rate was 1.83%, and the mean (SD) workload satisfaction score was 3.58 ( 0.24) on a 5-point Likert scale over the study period. In adjusted analysis, a 1-point increase in workload satisfaction was associated with a decrease of 0.73 (95% CI, 0.36-1.10) percentage points in the probability of turnover in a calendar quarter. In the mediation analysis, we found that workload satisfaction impacted turnover through only 1 of the 7 workplace climate measures: satisfaction with direction by senior managers. CONCLUSIONS: Our study findings highlight the key role that achieving primary care workload satisfaction can play in reducing PCP turnover. Identification of direction by senior managers as an underlying mechanism is an important finding for strategic planning to mitigate PCP turnover.

The Importance of Autonomy and Performance Goals in Perceived Workload Among Behavioral Health Providers.

OBJECTIVE: The authors sought to assess workplace characteristics associated with perceived reasonable workload among behavioral health care providers in the Veterans Health Administration. METHODS: The authors evaluated perceived reasonable workload and workplace characteristics from the 2019 All Employee Survey (AES; N=14,824) and 2019 Mental Health Provider Survey (MHPS; N=10,490) and facility-level staffing ratios from Mental Health Onboard Clinical Dashboard data. Nine AES and 15 MHPS workplace predictors of perceived reasonable workload, 11 AES and six MHPS demographic predictors, and facility-level staffing ratios were included in mixed-effects logistic regression models. RESULTS: In total, 8,874 (59.9%) AES respondents and 5,915 (56.4%) MHPS respondents reported having a reasonable workload. The characteristics most strongly associated with perceived reasonable workload were having attainable performance goals (average marginal effect [AME]=0.10) in the AES and ability to schedule patients as frequently as indicated (AME=0.09) in the MHPS. Other AES characteristics significantly associated with reasonable workload included having appropriate resources, support for personal life, skill building, performance recognition, concerns being addressed, and no supervisor favoritism. MHPS characteristics included not having collateral duties that reduce care time, staffing levels not affecting care, support staff taking over some responsibilities, having spirit of teamwork, primary care-mental health integration, participation in performance discussions, well-coordinated mental health care, effective veteran programs, working at the top of licensure, and feeling involved in improving access. Facility-level staffing ratios were not significantly associated with perceived reasonable workload. CONCLUSIONS: Leadership may consider focusing resources on initiatives that support behavioral health providers' autonomy to schedule patients as clinically indicated and develop attainable performance goals.