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Abstract The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The primary advantage of using the “dose and LET” physical system is its relative simplicity, especially for presenting and recording results. Inclusion of additional information such as the energy spectrum of charged particles renders this approach adequate to describe the biological effects of large dose levels from homogeneous sources. The primary disadvantage of this system is that it does not provide a unique description of the stochastic nature of radiation interactions. We and others have used dose-averaged LET (LET d ) as a correlative physical quantity to the relative biological effectiveness (RBE) of proton beams. This approach is based on established experimental findings that proton RBE increases with LET d . However, this approach might not be applicable to intensity-modulated proton therapy or other applications in which the proton energy spectrum is highly heterogeneous. In the current study, we irradiated cancer cells with scanning proton beams with identical LET d (3.4 keV/µm) but arising from two different proton energy/LET spectra (a narrow spectrum in group 1 and a widespread heterogeneous spectrum in group 2). Clonogenic survival after irradiation revealed significant differences in RBE at any cell surviving fraction: e.g., at a surviving fraction of 0.1, the RBE was 0.97 ± 0.03 in group 1 and 1.16 ± 0.04 in group 2 (p≤0.01), validating our hypothesis that LET d alone may not adequately indicate proton RBE. Further analysis showed that microdosimetric spectrum (the probability density function of the stochastic physical quantity lineal energy y) was helpful for interpreting observed differences in biological effects. However, more accurate use of microdosimetric spectrum to quantify RBE requires a cell line–specific mechanistic model.

Abstract Photonics offers a transformative approach to artificial intelligence (AI) and neuromorphic computing by enabling low-latency, high-speed, and energy-efficient computations. However, conventional photonic tensor cores face significant challenges in constructing large-scale photonic neuromorphic networks. Here, we propose a fully integrated photonic tensor core, consisting of only two thin-film lithium niobate (TFLN) modulators, a III-V laser, and a charge-integration photoreceiver. Despite its simple architecture, it is capable of implementing an entire layer of a neural network with a computational speed of 120 GOPS, while also allowing flexible adjustment of the number of inputs (fan-in) and outputs (fan-out). Our tensor core supports rapid in-situ training with a weight update speed of 60 GHz. Furthermore, it successfully classifies (supervised learning) and clusters (unsupervised learning) 112 × 112-pixel images through in-situ training. To enable in-situ training for clustering AI tasks, we offer a solution for performing multiplications between two negative numbers.

Abstract Hairy cell leukemia is an uncommon B‐cell malignancy with excellent response to purine analogs and to targeted therapies such as ibrutinib and vemurafenib. However, purine analogs are known to be highly immunosuppressive and the infection burden in this patient population with current therapies is unknown. We therefore conducted a retrospective cohort study following 149 patients. Median follow‐up time was 6.9 years. Thirty‐six percent developed an opportunistic or serious infection requiring hospitalization. Most cases were bacterial and most coincided with neutropenia and/or CD4 T‐lymphopenia. No single treatment agent was significantly associated with increased or decreased incidence of infection. Reassuringly, the cumulative incidence of infections plateaued 2 months after initial treatment suggesting clinically significant immune recovery. Only one patient in our cohort passed away due to infection. Estimated 10‐year overall survival was 99% suggesting that infections may not cause as much mortality as was seen prior to current therapies.

Abstract Background Before SARS-CoV-2 vaccination availability, medical center employees were at high risk of COVID-19. However, risk factors for SARS-CoV-2 infection in medical center employees, both healthcare and non-healthcare workers, are poorly understood. Methods From September-December 2020, free IgG antibody testing was offered to all employees at a large urban medical center. Participants were asked to complete a questionnaire on work and non-work related risk factors for COVID-19 infection. Results SARS-CoV-2 seropositivity was found in 4.7%. Seropositivity was associated with close contact with COVID-19 cases with or without the use of adequate personal protective equipment (PPE), (OR 3.1 [95% CI 1.4–6.9] and OR 4.7 [95% CI 2.0–11.0] respectively), never wearing a mask outside of work (OR 10.1 [95% CI 1.9–57]), and Native Hawaiian/Pacific Islander race (OR 6.3 95% CI (1.6–25)]. Conclusions Among workers in a large urban medical center, SARS-CoV-2 seropositivity was associated with work-related COVID-19 close contacts and low mask use outside of work, suggesting that non-workplace close contacts are also relevant routes of COVID-19 spread among healthcare workers.

Monkeypox virus (MPXV) is zoonotic and capable of infecting many mammal species. However, whether common companion animals are susceptible to MPXV infection is unclear. During July 2022–March 2023, we collected animal and environmental swab samples within homes of confirmed human mpox case-patients and tested for MPXV and human DNA by PCR. We also used ELISA for orthopoxvirus antibody detection. Overall, 12% (22/191) of animal and 25% (14/56) of environmental swab samples from 4 households, including samples from 4 dogs and 1 cat, were positive for MPXV DNA, but we did not detect viable MPXV or orthopoxvirus antibodies. Among MPXV PCR-positive swab samples, 82% from animals and 93% from environment amplified human DNA with a statistically significant correlation in observed cycle threshold values. Our findings demonstrate likely DNA contamination from the human mpox cases. Despite the high likelihood for exposure, we found no indications that companion animals were infected with MPXV.

Abstract Background Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p

Abstract Background X-linked acrogigantism (X-LAG; MIM: 300942) is a severe form of pituitary gigantism caused by chromosome Xq26.3 duplications involving GPR101. X-LAG-associated duplications disrupt the integrity of the topologically associating domain (TAD) containing GPR101 and lead to the formation of a neo-TAD that drives pituitary GPR101 misexpression and gigantism. As X-LAG is fully penetrant and heritable, duplications involving GPR101 identified on prenatal screening studies, like amniocentesis, can pose an interpretation challenge for medical geneticists and raise important concerns for patients and families. Therefore, providing robust information on the functional genomic impact of such duplications has important research and clinical value with respect to gene regulation and triplosensitivity traits. Methods We employed 4C/HiC-seq as a clinical tool to determine the functional impact of incidentally discovered GPR101 duplications on TAD integrity in three families. After defining duplications and breakpoints around GPR101 by clinical-grade and high-density aCGH, we constructed 4C/HiC chromatin contact maps for our study population and compared them with normal and active (X-LAG) controls. Results We showed that duplications involving GPR101 that preserved the centromeric invariant TAD boundary did not generate a pathogenic neo-TAD and that ectopic enhancers were not adopted. This allowed us to discount presumptive/suspected X-LAG diagnoses and GPR101 misexpression, obviating the need for intensive clinical follow-up. Conclusions This study highlights the importance of TAD boundaries and chromatin interactions in determining the functional impact of copy number variants and provides proof-of-concept for using 4C/HiC-seq as a clinical tool to acquire crucial information for genetic counseling and to support clinical decision-making in cases of suspected TADopathies.

Abstract Background Studies have identified individual blood biomarkers associated with chronic obstructive pulmonary disease (COPD) and related phenotypes. However, complex diseases such as COPD typically involve changes in multiple molecules with interconnections that may not be captured when considering single molecular features. Methods Leveraging proteomic data from 3,173 COPDGene Non-Hispanic White (NHW) and African American (AA) participants, we applied sparse multiple canonical correlation network analysis (SmCCNet) to 4,776 proteins assayed on the SomaScan v4.0 platform to derive sparse networks of proteins associated with current vs. former smoking status, airflow obstruction, and emphysema quantitated from high-resolution computed tomography scans. We then used NetSHy, a dimension reduction technique leveraging network topology, to produce summary scores of each proteomic network, referred to as NetSHy scores. We next performed a genome-wide association study (GWAS) to identify variants associated with the NetSHy scores, or network quantitative trait loci (nQTLs). Finally, we evaluated the replicability of the networks in an independent cohort, SPIROMICS. Results We identified networks of 13 to 104 proteins for each phenotype and exposure in NHW and AA, and the derived NetSHy scores significantly associated with the variable of interests. Networks included known (sRAGE, ALPP, MIP1) and novel molecules (CA10, CPB1, HIS3, PXDN) and interactions involved in COPD pathogenesis. We observed 7 nQTL loci associated with NetSHy scores, 4 of which remained after conditional analysis. Networks for smoking status and emphysema, but not airflow obstruction, demonstrated a high degree of replicability across race groups and cohorts. Conclusions In this work, we apply state-of-the-art molecular network generation and summarization approaches to proteomic data from COPDGene participants to uncover protein networks associated with COPD phenotypes. We further identify genetic associations with networks. This work discovers protein networks containing known and novel proteins and protein interactions associated with clinically relevant COPD phenotypes across race groups and cohorts.

Abstract Recent work suggests that AlphaFold (AF)–a deep learning-based model that can accurately infer protein structure from sequence–may discern important features of folded protein energy landscapes, defined by the diversity and frequency of different conformations in the folded state. Here, we test the limits of its predictive power on fold-switching proteins, which assume two structures with regions of distinct secondary and/or tertiary structure. We find that (1) AF is a weak predictor of fold switching and (2) some of its successes result from memorization of training-set structures rather than learned protein energetics. Combining >280,000 models from several implementations of AF2 and AF3, a 35% success rate was achieved for fold switchers likely in AF’s training sets. AF2’s confidence metrics selected against models consistent with experimentally determined fold-switching structures and failed to discriminate between low and high energy conformations. Further, AF captured only one out of seven experimentally confirmed fold switchers outside of its training sets despite extensive sampling of an additional ~280,000 models. Several observations indicate that AF2 has memorized structural information during training, and AF3 misassigns coevolutionary restraints. These limitations constrain the scope of successful predictions, highlighting the need for physically based methods that readily predict multiple protein conformations.

Abstract Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression.

Abstract Background Research demonstrates gaps in medications for opioid use disorder uptake (MOUDs; methadone, buprenorphine, and naltrexone) especially among adolescents. These gaps may be partly attributable to attitudes about and training in MOUDs among youth-serving professionals. We extended prior research by conducting descriptive analyses of attitudes regarding effectiveness and acceptability of MOUDs, as well as training in MOUDs, among youth legal system (YLS) employees and community mental health center (CMHC) personnel who interface professionally with youth. Methods Using survey data from participants (n = 181) recruited from eight Midwest counties, we examined: (1) differences in MOUD attitudes/training by MOUD type and (2) by respondent demographics, and (3) prediction of MOUD attitudes/training by participant-reported initiatives to implement evidence-based practices (EBPs), workplace culture around EBPs, and workplace stress. Attitudes and training were measured in reference to five MOUD types (methadone, oral buprenorphine, injectable buprenorphine, oral naltrexone, injectable naltrexone) on three subscales (effectiveness, acceptability, training). Results Wilcoxon signed-rank tests demonstrated that most outcomes differed significantly by MOUD type (differences observed among 22 of 30 tests). Kruskal-Wallis tests suggested MOUD differences based on demographics. For methadone, CMHC providers endorsed greater perceived effectiveness than YLS providers and age explained significant differences in perceived effectiveness. For buprenorphine, CHMC providers viewed oral or injectable buprenorphine as more effective than YLS employees, respondents from more rural counties viewed oral buprenorphine as more effective than those from less rural counties, and age explained differences in perceived effectiveness. For naltrexone, perceived gender differed by gender. Hierarchical ordinal logistic regression analysis did not find an association between personal initiatives to implement EBPs, workplace culture supporting EBPs, or workplace stress and effectiveness or acceptability of MOUDs. However, personal initiatives to implement EBPs was associated with training in each MOUD. Conclusions These results highlight a few key findings: effectiveness/acceptability of and training in MOUDs largely differ by MOUD type; setting, rurality, age, gender, and education explain group differences in perceived effectiveness of and training in MOUDs; and implementing EBPs is associated with training in MOUDs. Future research would benefit from examining what predicts change in MOUD attitudes longitudinally.

Abstract Type 2 diabetes (T2D) is caused by both genetic and environmental factors and is associated with an increased risk of cardiorenal complications and mortality. Though disproportionately affected by the condition, African Americans (AA) are largely underrepresented in genetic studies of T2D, and few estimates of heritability have been calculated in this race group. Using genome-wide association study (GWAS) data paired with phenotypic data from ~ 19,300 AA participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, Genetics of Hypertension Associated Treatments (GenHAT) study, and the Electronic Medical Records and Genomics (eMERGE) network, we estimated narrow-sense heritability using two methods: Linkage-Disequilibrium Adjusted Kinships (LDAK) and Genome-Wide Complex Trait Analysis (GCTA). Study-level heritability estimates adjusting for age, sex, and genetic ancestry ranged from 18% to 34% across both methods. Overall, the current study narrows the expected range for T2D heritability in this race group compared to prior estimates, while providing new insight into the genetic basis of T2D in AAs for ongoing genetic discovery efforts.

Abstract The scientific community studies tight focusing of radially and azimuthally-polarized vector beams as it is a versatile solution for many applications. We offer a new method to produce tight focusing that ensures a more uniform intensity profile in multiple dimensions, providing a more versatile and stable solution. We manipulate the polarization of the radially and azimuthally polarized vector beams to find an optimal operating point. We examine in detail optical fields whose polarization states lie on the equator of the relevant Poincaré spheres namely, the fundamental Poincaré sphere, the hybrid order Poincaré sphere (HyOPS), and the higher order Poincaré sphere. We find via simulation that the fields falling on these equators have focal plane intensity distributions characterized by a single rotation parameter $$\alpha$$ α determining the individual state of polarization. The strengths of the component field distributions vary with $$\alpha$$ α and can be tuned to achieve equal strengths of longitudinal (z) and transverse (x and y) components at the focal plane. Without control of this parameter (e.g., using $$\alpha =0$$ α = 0 in radially and $$\alpha =\pi$$ α = π in azimuthally-polarized vector beams) intensity in x and y components are at 20% of the z component. In our solution with $$\alpha =\pi /2$$ α = π / 2 , all components are at 80% of the maximum possible intensity of z. In examining the impact of $$\alpha$$ α on a tightly focused beam, we also found that a helicity inversion of HyOPS beams causes a rotation of 180 degree in the axial intensity distribution.

Objective: To evaluate the heterogeneity in treatment effect in posttraumatic stress disorder (PTSD) trials. Patients and Methods: We downloaded data from a publicly available repository that captured PTSD trials published from January 1988 through February 2023. We applied restricted maximum-likelihood random-effect meta-analyses and meta-regression to explore potential moderators of treatment effect including methodologic study features (risk of bias domains and control group response rate), characteristics of the population, and intervention features following the theme, intensity, and platform framework. Results: We included 199 PTSD trials that reported the outcomes of diagnosis resolution (122 trials, 8437 patients) and clinically meaningful improvement (133 trials, 9895 patients). Multiple treatments demonstrated effectiveness but with significant heterogeneity. Statistically significant moderators included risk of bias domains of randomization sequence and outcome measurement, control group response rate reflecting severity of PTSD in the enrolled population, and whether the psychotherapeutic approach was trauma focused (P values

Recent and projected changes in climate over this century pose an unprecedented threat to the health, diversity, and productivity of forest ecosystems. Forests have migrated and adapted to long-term changes in climate over thousands to millions of years; however, natural migration rates and adaptive responses of tree populations cannot match the rapid pace of current climate change. Consequently, more climate-informed approaches to reforestation are needed as current reforestation strategies using local seed sources may no longer be adequate to meet forest management objectives. Assisted migration is a climate change adaptation technique that can help maintain the ecosystem services and economic value that forests provide. Forestry assisted migration (FAM) focusses on the movement of populations of widespread, commercially, or ecologically important forest tree species within or just beyond their current ranges as a way to maintain forest productivity and health in the face of climate change. Although the forestry community recognizes FAM as a reforestation tool, guidance for planning and implementation of FAM is lacking and a framework that provides this guidance can prove useful to land managers with limited time and resources available who want to undertake FAM. We developed a practical framework (the FAM Framework) to provide a structured approach to ensure the most important considerations and best available science are utilized by land managers wanting to implement FAM on their land base. The FAM Framework incorporates multiple factors for the application of FAM in four sequential phases: assessment and analysis, climate-based plant material selection, seed procurement and deployment, and documentation and monitoring. The FAM Framework was tested by developing an assisted migration plan for the Superior National Forest, Minnesota (MN), and lessons learned from the development of this specific plan were used to revise and improve the FAM Framework for suitability across all lands. While originally designed to meet the needs of National Forest System land managers, it is relevant and applicable across the spectrum of land ownership because it incorporates consideration of critical elements in planning and implementing FAM on any landscape while facilitating adaptive management for active learning and future implementation.

BackgroundElectronic health records (EHRs) commonly contain patient addresses that provide valuable data for geocoding and spatial analysis, enabling more comprehensive descriptions of individual patients for clinical purposes. Despite the widespread use of EHRs in clinical decision support and interventions, no systematic review has examined the extent to which spatial analysis is used to characterize patient phenotypes. ObjectiveThis study reviews advanced spatial analyses that used individual-level health data from EHRs within the United States to characterize patient phenotypes. MethodsWe systematically evaluated English-language, peer-reviewed studies from the PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar databases from inception to August 20, 2023, without imposing constraints on study design or specific health domains. ResultsA substantial proportion of studies (>85%) were limited to geocoding or basic mapping without implementing advanced spatial statistical analysis, leaving only 49 studies that met the eligibility criteria. These studies used diverse spatial methods, with a predominant focus on clustering techniques, while spatiotemporal analysis (frequentist and Bayesian) and modeling were less common. A noteworthy surge (n=42, 86%) in publications was observed after 2017. The publications investigated a variety of adult and pediatric clinical areas, including infectious disease, endocrinology, and cardiology, using phenotypes defined over a range of data domains such as demographics, diagnoses, and visits. The primary health outcomes investigated were asthma, hypertension, and diabetes. Notably, patient phenotypes involving genomics, imaging, and notes were limited. ConclusionsThis review underscores the growing interest in spatial analysis of EHR-derived data and highlights knowledge gaps in clinical health, phenotype domains, and spatial methodologies. We suggest that future research should focus on addressing these gaps and harnessing spatial analysis to enhance individual patient contexts and clinical decision support.

Abstract For the prosthetic retina, a device replacing dysfunctional cones and rods, with the ability to mimic the spectral response properties of these photoreceptors and provide electrical stimulation signals to activate residual visual pathways, can relay sufficient data to the brain for interpretation as color vision. Organic semiconductors including conjugated polymers with four different bandgaps providing wavelength‐specific electrical responses are ideal candidates for potential full‐color vision restoration. Here, conjugated polymer photocapacitor devices immersed in electrolyte are demonstrated to elicit a photovoltage measured by a Ag/AgCl electrode 100 microns from the device of ≈−40 mV for 15–39 µW mm−2 of incident light power density at three wavelengths: 405 nm for blue photoreceptor candidate material, 534 nm for green, 634 nm for red. Photoresponse is substantially improved by introducing polymer donor/acceptor molecules bulk heterojunctions. Devices with bulk heterojunction configurations achieved at least −70 mV for green candidates with the highest at −200 mV for red cone candidates. These findings highlight the potential for organic materials to bridge the gap toward natural vision restoration for retinal dystrophic conditions such as age‐related macular degeneration, Stargardt disease, or retinitis pigmentosa and contribute to the ongoing advancements in visual prosthetic devices.

Abstract High‐frequency measurements obtained at two micrometeorological towers are investigated for a rare northward surging gust front that impacted the Amazon Tall Tower Observatory (ATTO), in central Amazon. The gust front originated from a decaying mesoscale convective system (MCS) during the morning hours of 27 December 2021 near Manaus, Amazonas state, northern Brazil, and surged north‐eastward towards the ATTO site. Large temperature drops and vigorous, persistent winds were observed at the towers which lasted for over 4 h despite the gust front being detached from its parent, decaying MCS. More importantly, the gust front was responsible for drastic increases of CO2 concentrations throughout the tower depths, which suggests that the gust front winds horizontally advected CO2‐rich air from a source upstream from the ATTO site. The CO2‐rich outflow is hypothesized to originate from downward transport and/or biomass burning from forest fires in southeastern Amazon, both ideas that are supported by large increases of aerosol concentrations measured at ATTO following the gust front passage. Our results stress the need for further investigations addressing the role played by mesoscale convective circulations in the redistribution of trace gases and aerosols in the Amazon.

This study addresses the pronounced mental health disparities faced by African American men, characterized by the heightened severity of mental health conditions and their reluctance to seek mental health treatment. Persistent neglect toward the mental health of African American men perpetuates systemic inequities and heightens the stigma surrounding mental well-being within their communities. This study investigates the interaction of masculinity, distrust in doctors, and parental support on attitudes influencing African American men’s reluctance to seek mental health care. A survey administered to 74 African American men revealed a negative correlation between masculinity and attitudes toward seeking mental health treatment. In contrast, no significant correlations were found between distrust in doctors and parental support on attitudes toward seeking mental health treatment. These findings were analyzed using Pearson’s correlation, underscoring the urgent need to address masculine norms in mental health discourse among African American men. Implications of the findings and future directions for masculinity in African American men are discussed.

ABSTRACT Archaea are widespread in the environment and play fundamental roles in diverse ecosystems; however, characterization of their unique biology requires advanced tools. This is particularly challenging when characterizing gene function. Here, we generate randomly barcoded transposon libraries in the model methanogenic archaeon Methanococcus maripaludis and use high-throughput growth methods to conduct fitness assays (RB-TnSeq) across over 100 unique growth conditions. Using our approach, we identified new genes involved in nutrient utilization and response to oxidative stress. We identified novel genes for the usage of diverse nitrogen sources in M. maripaludis including a putative regulator of alanine deamination and molybdate transporters important for nitrogen fixation. Furthermore, leveraging the fitness data, we inferred that M. maripaludis can utilize additional nitrogen sources including ʟ-glutamine, ᴅ-glucuronamide, and adenosine. Under autotrophic growth conditions, we identified a gene encoding a domain of unknown function (DUF166) that is important for fitness and hypothesize that it has an accessory role in carbon dioxide assimilation. Finally, comparing fitness costs of oxygen versus sulfite stress, we identified a previously uncharacterized class of dissimilatory sulfite reductase-like proteins (Dsr-LP; group IIId) that is important during growth in the presence of sulfite. When overexpressed, Dsr-LP conferred sulfite resistance and enabled use of sulfite as the sole sulfur source. The high-throughput approach employed here allowed for generation of a large-scale data set that can be used as a resource to further understand gene function and metabolism in the archaeal domain.IMPORTANCEArchaea are widespread in the environment, yet basic aspects of their biology remain underexplored. To address this, we apply randomly barcoded transposon libraries (RB-TnSeq) to the model archaeon Methanococcus maripaludis. RB-TnSeq coupled with high-throughput growth assays across over 100 unique conditions identified roles for previously uncharacterized genes, including several encoding proteins with domains of unknown function (DUFs). We also expand on our understanding of carbon and nitrogen metabolism and characterize a group IIId dissimilatory sulfite reductase-like protein as a functional sulfite reductase. This data set encompasses a wide range of additional conditions including stress, nitrogen fixation, amino acid supplementation, and autotrophy, thus providing an extensive data set for the archaeal community to mine for characterizing additional genes of unknown function.

Background Cognitive impairment is common among adults with heart failure (HF) and associated with poor outcomes. However, less is known about the trajectory of cognitive decline after a first HF hospitalization. We examined the rate of cognitive decline among adults with incident HF hospitalization compared with those without HF hospitalization. Methods and Results The REGARDS (Reasons for Geographic and Racial Differences in Stroke) study is a prospective longitudinal study of 23 894 participants aged ≥45 years free of HF at baseline. HF hospitalization was expert adjudicated. Changes in global cognitive function (primary outcome) were assessed with the Six‐Item Screener (range, 0–6). Secondary outcomes included change in Word List Learning (range, 0–30), Word List Delayed Recall (WLD; range, 0–10), and Animal Fluency Test (range, 0+). Segmented linear mixed‐effects regression models were used. Over 5 years, mean scores across all 4 cognitive tests declined for all participants regardless of HF status. Those with incident HF hospitalization experienced faster declines in the Six‐Item Screener versus those who were HF free (difference, −0.031 [95% CI, −0.047 to −0.016]; P

Abstract Introduction Rates of substance use are high among youth involved in the legal system (YILS); however, YILS are less likely to initiate and complete substance use treatment compared to their non legally-involved peers. There are multiple steps involved in connecting youth to needed services, from screening and referral within the juvenile legal system to treatment initiation and completion within the behavioral health system. Understanding potential gaps in the care continuum requires data and decision-making from these two systems. The current study reports on the development of data dashboards that integrate these systems’ data to help guide decisions to improve substance use screening and treatment for YILS, focusing on end-user feedback regarding dashboard utility. Methods Three focus groups were conducted with n = 21 end-users from juvenile legal systems and community mental health centers in front-line positions and in decision-making roles across 8 counties to gather feedback on an early version of the data dashboards; dashboards were then modified based on feedback. Results Qualitative analysis revealed topics related to (1) important aesthetic features of the dashboard, (2) user features such as filtering options and benchmarking to compare local data with other counties, and (3) the centrality of consistent terminology for data dashboard elements. Results also revealed the use of dashboards to facilitate collaboration between legal and behavioral health systems. Conclusions Feedback from end-users highlight important design elements and dashboard utility as well as the challenges of working with cross-system and cross-jurisdiction data.

Introduction: Ferric derisomaltose is the newest available parenteral iron formulation. Studies have demonstrated a good safety profile with improved tolerability compared to alternative parenteral iron formulations. To date there have been no reported acute, life-threatening cardiac events associated with ferric derisomaltose. Case Report: An 86-year-old male who had previously tolerated routine iron infusions received a first dose of ferric derisomaltose at an outpatient infusion clinic. Six minutes into the infusion the patient became unresponsive with no palpable pulse. Return of spontaneous circulation was achieved after two minutes of chest compressions. Electrocardiogram showed complete heart block requiring transcutaneous pacing and vasopressor administration. The patient was transferred to the emergency department for stabilization and then admitted to the cardiac intensive care unit. During admission, the patient received a dual-chamber, permanent pacemaker without complication and was ultimately discharged. Conclusion: It may be reasonable to consider parenteral iron as a toxicological etiology for patients presenting with complete heart block temporally associated with parenteral iron administration, particularly in patients with underlying conduction abnormalities.

Abstract The fishing cat, Prionailurus viverrinus, faces a population decline, increasing the importance of maintaining healthy zoo populations. Unfortunately, zoo-managed individuals currently face a high prevalence of transitional cell carcinoma (TCC), a form of bladder cancer. To investigate the genetics of inherited diseases among captive fishing cats, we present a chromosome-scale assembly, generate the pedigree of the zoo-managed population, reaffirm the close genetic relationship with the Asian leopard cat (Prionailurus bengalensis), and identify 7.4 million single nucleotide variants (SNVs) and 23,432 structural variants (SVs) from whole genome sequencing (WGS) data of healthy and TCC cats. Only BRCA2 was found to have a high recurrent number of missense mutations in fishing cats diagnosed with TCC when compared to inherited human cancer risk variants. These new fishing cat genomic resources will aid conservation efforts to improve their genetic fitness and enhance the comparative study of feline genomes.

The forests of Great Britain (GB) are an important resource, which are under threat from climate change and exotic pests and diseases. The forest sector has been proactive in launching initiatives and supporting activities to improve the resistance and resilience of forests in GB. These interventions can be directed at forests at a range of scales, from genetic to national. This article describes the range of potential and actual actions focused on adapting Britain’s forests to climate change and damage from pests and diseases. However, there are also barriers to improving the resilience of forests in GB and these are also discussed.

Abstract Introduction Transthyretin amyloidosis (ATTR) is a progressive, heterogeneous rare disease manifesting as ATTR polyneuropathy (ATTR-PN), ATTR cardiomyopathy (ATTR-CM), or a mixed phenotype. Tafamidis meglumine (20 mg po qd) is approved in some markets to delay neurologic progression in ATTR-PN, while high-dose tafamidis (80/61 mg po qd) is approved worldwide to reduce cardiovascular mortality and cardiovascular-related hospitalization in ATTR-CM. The objective of this study was to assess the real-world benefit of high-dose tafamidis for delaying neurologic progression in patients with mixed-phenotype variant ATTR-CM (ATTRv-CM). Methods This exploratory, retrospective, observational cohort study evaluated anonymized electronic medical records and included adult patients with mixed-phenotype ATTRv-CM treated with high-dose tafamidis for at least 6 months. Neurologic assessments included the Medical Research Council (MRC) Scale for Muscle Strength, Neuropathy Impairment Score (NIS) muscle weakness subscale, and Polyneuropathy Disability (PND) instrument. Modified body mass index (mBMI) was also assessed. Results Patients (N = 10) started tafamidis treatment an average of 3.8 months after diagnosis, with an average treatment duration of 20.8 months. Seven of 10 patients demonstrated normal muscle strength on the MRC scale throughout the study, and 9 of 10 patients had no decline in muscle strength during the post-treatment period. The NIS muscle weakness subscale score was ≤ 60 for all patients in the study at all time points, suggesting normal function to mild impairment. Six of 10 patients had no change in walking capacity as measured by the PND instrument at pre- and post-assessments, while one-third of patients had a decrease in PND stage (signaling improvement) from pre- to post-assessment. mBMI remained relatively stable throughout the study. Conclusion This is the first real-world study to demonstrate the potential value of high-dose tafamidis for delaying neurologic disease progression in patients with mixed-phenotype ATTRv-CM. The findings underscore the importance of multidisciplinary assessment for patients with ATTR amyloidosis. Trial registration ClinicalTrials.gov: NCT05139680.

Abstract X‐linked muscular dystrophy in cats (FXMD) is an uncommon disease, with few reports describing its pathogenic genetic variants. A 9‐year‐old castrated male domestic shorthair cat was presented with persistent muscle swelling and breathing difficulty from 3 years of age. Serum activity of alanine aminotransferase, aspartate transaminase, and creatine kinase were abnormally high. Physical and neurological examinations showed muscle swelling in the neck and proximal limb, slow gait, and occasional breathing difficulties. Electromyography showed pseudomyotonic discharges and complex repetitive discharges with a “dive‐bomber” sound. Histopathology revealed muscle necrosis and regeneration. Whole‐genome sequencing identified a novel and unique hemizygous nonsense genetic variant, c.8333G > A in dystrophin (DMD), potentially causing a premature termination codon (p.Trp2778Ter). Based on a combination of clinical and histological findings and the presence of the DMD nonsense genetic variant, this case was considered FXMD, which showed mild clinical signs and long‐term survival, even though immunohistochemical characterization was lacking.

Abstract. Introduction:. The phase 2 chronic pain master protocol (CPMP) presented here provides a construct to accelerate the investigation of novel analgesics, broadly referred to here as mechanisms. Designed to address historical challenges in analgesic research and development, such as the choice of indication, this protocol enables the efficient evaluation of potential therapeutics with different mechanisms of action in 3 pain types: nociceptive pain (osteoarthritis), neuropathic pain (diabetic peripheral neuropathic pain), and mixed pain (chronic low back pain). Methods:. The study design was determined before the identification of any specific molecule. Statistical simulations were conducted to optimize the methodology and design, the culmination of which were submitted to and accepted by the Complex Innovative Trial Design Pilot Meeting Program, a unique collaboration with the United States Food and Drug Administration. Benefits of the CPMP include limiting the number of study participants exposed to placebo and reducing the total sample size over time by leveraging placebo data across studies within a pain type and efficacy data across pain types for a specific molecule. The CPMP design enables: (1) efficient evaluation of multiple novel mechanisms of action; (2) the study of multiple molecules simultaneously or serially; (3) direct statistical comparison of molecules within a pain type; and (4) efficient planning and conduct of clinical studies. ClinicalTrials.gov ID NCT05986292. Perspective:. By evaluating novel mechanisms across different pain types, therapeutic potential can be assessed more efficiently compared with traditional individual clinical studies.

Background: Warm autoimmune haemolytic anaemia (wAIHA) is an acquired haemolytic disorder most commonly treated with a combination of corticosteroids, rituximab and/or splenectomy. Third-line therapies for refractory cases include immunosuppressive agents. Mycophenolate mofetil is frequently used in these scenarios, although its use is supported by small studies and anecdotal evidence rather than large-scale data. Case description: We describe three cases of refractory warm autoimmune haemolytic anaemia successfully treated with mycophenolate mofetil. Case 1: A persistent case of autoimmune haemolytic anaemia in a 56-year-old was ultimately managed with mycophenolate mofetil, leading to successful steroid tapering and stable haemoglobin levels without relapse. Case 2: A woman with a complex oncological history, including lymphoma and breast cancer, achieved remission with mycophenolate therapy, maintaining stability post-steroid treatment. Case 3: Mycophenolate proved effective for a 63-year-old with cirrhosis after recurrent autoimmune anaemia and deep vein thrombosis, enabling cessation of steroids and maintaining remission. Conclusion: Management of this condition can be challenging and balancing the available treatments is crucial to reduce potential complications from long-term therapies that appear to be ineffective. Our case series demonstrates anecdotal experience on successful use of mycophenolate mofetil for complex refractory cases of wAIHA.

Background: Wild-type transthyretin amyloidosis (ATTRwt amyloidosis) is primarily diagnosed in elderly men but diagnoses in younger patients and women have recently increased. Objectives: The purpose of this study was to examine age- and sex-related differences in patients with ATTRwt amyloidosis enrolled in the THAOS (Transthyretin Amyloidosis Outcomes Survey). Methods: THAOS was a global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic transthyretin gene variants. Patient characteristics at enrollment were analyzed by age at enrollment and sex (data cutoff date: August 1, 2022). Results: Of 1,251 patients with ATTRwt amyloidosis, 13.7%, 49.1%, 34.5%, and 2.8% were aged

ContextFrench Guiana is a French overseas department where very different linguistic, cultural and societal populations live together in a small area. Health issues and their specific epidemiological profiles call for research projects crossing several cultures. In this context, health mediators have a role to play in research. The aim of this study was to describe the perceptions, attitudes and opinions on research of mediators and researchers collaborating on research projects, and to describe the strengths and difficulties encountered during this cooperation.MethodsThe Inter-med project was conducted in French Guiana between February 2022 and April 2023 on the base of semi-directive interviews with mediators, or researchers, all working in health research in the intercultural context of French Guiana. The socio-demographic characteristics of the participants were described. An inductive thematic analysis was carried out on all the interviews, and word occurrence analysis on certain themes. The information was triangulated with field coordination notebooks from two epidemiological surveys conducted in French Guiana between 2021 and 2022.ResultsA total of 26 semi-structured interviews were conducted and 1,328 notebook pages analyzed. Mediation was described as an indispensable interface between the world of research and that of the population targeted by a survey. Mediators have a role to play at different stages of projects, in respect of good clinical practice, ethics and legislation. They act as interfaces between languages, concepts and representations. Their profession remains under-defined and under-dimensioned. The jobs offered are often precarious. Mediation work is emotionally costly, calls on soft skills and requires a combination of rigor and flexibility. All these aspects are implemented in the specific world of research, where there are common concepts and divergent perceptions. Researchers and mediators converge on a common goal: improving health.ConclusionThis study covers several aspects of the development and implementation of research projects. Respect for good clinical practice and people, transparency and data quality are redundant concerns, and this study touches on ethnocentrism, stigmatization and cultural representations. This study points out that the integration and recognition of mediators could be beneficial in research conducted in a cross-cultural context.

Introducción: La gestión de la calidad tiene importancia estratégica para la competitividad y sostenibilidad de las organizaciones. Objetivo: Analizar el comportamiento de la producción científica en gestión de la calidad para el período 2011-2022. Metodología: Estudio bibliométrico y cienciométrico de 998 artículos obtenidos de la base de datos Scopus. Para el análisis se utilizaron indicadores de producción, concentración, colaboración, impacto y relacionales. Resultados: Entre los hallazgos se destaca que la producción científica refleja una línea de tendencia exponencial con valor de ajuste de R2 = 0.80. Los autores con mayor producción de artículos son Bäckström, I., Gremyr, I. y Tari J.J. Se identificaron 14 revistas que conforman el núcleo, sobresaliendo la revista Total Quality Management and Business Excellence por la cantidad de artículos publicados, número de citas y emparejamiento bibliográfico. Conclusiones: Las tendencias de investigación contemporáneas y emergentes de investigación son la Gestión de la Calidad Total, el modelo de la Fundación Europea para la Gestión de la Calidad, ventajas competitivas, gestión de la cadena de suministro, seis sigma, excelencia empresarial y sostenibilidad.

Abstract Dung beetles are economically important beneficial insects that process dung. To locate this source, they use volatile organic compounds (VOCs). The objectives of the study were to evaluate the attractiveness of ten electrophysiologically-active dung volatiles (phenol, skatole, indole, p-cresol, butanone, butyric acid, eucalyptol, dimethyl sulphide, dimethyl disulphide, and toluene) to dung beetles in the field and to investigate how the composition of volatile blends influences efficacy as lures for use in traps. Six combinations of the compounds were compared with field collected cattle dung bait and a negative control, across three seasons. Both dung and synthetic baits captured all exotic dung beetle species present in the study area. A six-compound mix (M1), comprising major dung volatiles, served as an attractive chemical mixture. The addition of dimethyl sulphide, dimethyl disulphide (M2) and toluene (M4) enhanced attractancy of M1 for dung beetles, while eucalyptol (M3) decreased the attractancy. The degree of attraction by various dung beetle species to synthetic baits varied, but baits proved to be effective, especially for summer trapping. The trap design used in this study presented a convenient and practical way to sample dung beetle and other associated scarabs from open pastures. The attraction of introduced dung beetle species to synthetic baits is documented here for the first time in Australia. In addition, necrophagous Omorgus sp. is reported here for the first time to be attracted to synthetic baits. They showed a significant attraction to the mixture containing dimethyl sulphide and dimethyl disulphide (M2). The current study represents a promising first step towards formulating a synthetic chemical lure for dung beetles, offering a consistent, standardised, and bio-secure trapping method compared to use of naturally occurring dung baits, especially as a multi-species lure.

Abstract X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Abstract Background Muscular dystrophies (MDs) are a large, heterogeneous group of degenerative muscle diseases. X‐linked dystrophin‐deficient MD in cats is the first genetically characterized cat model for a human disease and a few novel forms have been identified. Hypothesis/Objectives Muscular dystrophy was suspected in a young male domestic shorthair cat. Clinical, molecular, and genetic techniques could provide a definitive diagnosis. Animals A 1‐year‐old male domestic shorthair cat presented for progressive difficulty walking, macroglossia and dysphagia beginning at 6 months of age. The tongue was thickened, protruded with constant ptyalism, and thickening and rigidity of the neck and shoulders were observed. Methods A complete neurological examination, baseline laboratory evaluation and biopsies of the trapezius muscle were performed with owner consent. Indirect immunofluorescence staining of muscle cryosections was performed using several monoclonal and polyclonal antibodies against dystrophy‐associated proteins. DNA was isolated for genomic analyses by whole genome sequencing and comparison to DNA variants in the 99 Lives Cat Genome Sequencing dataset. Results and Clinical Importance Aspartate aminotransferase (687 IU/L) and creatine kinase (24 830 IU/L) activities were increased and mild hypokalemia (3.7 mmol/L) was present. Biopsy samples from the trapezius muscle confirmed a degenerative and regenerative myopathy and protein alterations identified by immunohistochemistry resulted in a diagnosis of a in dystrophin‐deficient form of X‐linked MD. A stop gain variant (c.4849C>T; p.Gln1617Ter) dystrophin was identified by genome sequencing. Precision/genomic medicine efforts for the domestic cat and in veterinary medicine support disease variant and animal model discovery and provide opportunities for targeted treatments for companion animals.

Abstract Background Granulomatous hepatitis (GH) is a form of chronic hepatitis (CH) in dogs for which limited information is published. Hypothesis Describe the clinical presentation, clinical pathology, ultrasound, and hepatic histopathology findings and to report survival times in dogs with GH. Animals Twenty‐nine client‐owned dogs with GH. Methods Retrospective observational study. Pathology records were searched. Inclusion criteria included a histopathologic diagnosis of GH, absence of an identified etiology or evidence of extrahepatic granulomatous disease, and a medical record available for review. Clinical presentation, clinical pathologic findings, treatment protocols, and survival times were recorded. Available hepatic biopsy material was graded and scored, and ultrasound evaluations reviewed. Results The median age was 7 years (range, 0.66‐12 years). Nineteen breeds were represented. Decreased appetite (19/29), lethargy (16/29), and fever (13/29) were seen most commonly. All dogs had increased serum transaminase activities, whereas 21/29 and 12/24 had hyperbilirubinemia and neutrophilia, respectively. Ultrasonographic findings included hepatomegaly (12/22), nodular parenchymal lesions (9/22), and hyperechoic parenchymal bands (8/22). Histopathologic necroinflammatory scores were moderate to severe in 16/19 dogs, and fibrosis scores were mild in 14/19 dogs. Treatments varied and included antibiotics, immunosuppressive drugs, and hepatoprotectants. Overall median survival was 635 days (range, 1‐2482 days). Conclusion and Clinical Importance Granulomatous hepatitis in dogs is associated with high histopathologic grade, fever, neutrophilia, and a high incidence of hepatomegaly and focal parenchymal lesions on ultrasound examination. Despite disease severity on presentation, dogs with GH can have a good outcome with prolonged survival.

Abstract Objective The relationship between multiple sclerosis and the gut microbiome has been supported by animal models in which commensal microbes are required for the development of experimental autoimmune encephalomyelitis. However, observational study findings in humans have only occasionally converged when comparing multiple sclerosis cases and controls which may in part reflect confounding by comorbidities and disease duration. The study of microbiome in pediatric‐onset multiple sclerosis offers unique opportunities as it is closer to biological disease onset and minimizes confounding by comorbidities and environmental exposures. Methods A multicenter case–control study in which 35 pediatric‐onset multiple sclerosis cases were 1:1 matched to healthy controls on age, sex, self‐reported race, ethnicity, and recruiting site. Linear mixed effects models, weighted correlation network analyses, and PICRUSt2 were used to identify microbial co‐occurrence networks and for predicting functional abundances based on marker gene sequences. Results Two microbial co‐occurrence networks (one reaching significance after adjustment for multiple comparisons; q

Abstract The ability to obtain dynamic movement assessments using force plate technology holds the promise of providing more detailed knowledge of the strength, balance and forces generated by active-duty military personnel. To date, there are not well-defined use cases for implementation of force plate assessments in military training environments. We sought to determine if force plate technology assessments could provide additional insights, related to the likelihood of graduation, beyond that provided by traditional physical fitness tests (PFT’s), in an elite Marine training school. Serial force plate measures were also obtained on those Marines successfully completing training to determine if consistent measures reflecting the effects of training on muscle skeletal load-over-time could be accurately measured. A pre-training force plate assessment performed in 112 Marines did not predict graduation rates. For Marines who successfully completed the course, serial measures obtained throughout training were highly variable for each individual and no firm conclusions could be drawn related to load imposed or the fitness attained during training.

Abstract Pulmonary arterial hypertension (PAH) is characterized by endothelial cell (EC) dysfunction. There are no data from living patients to inform whether differential gene expression of pulmonary artery ECs (PAECs) can discern disease subtypes, progression and pathogenesis. We aimed to further validate our previously described method to propagate ECs from right heart catheter (RHC) balloon tips and to perform additional PAEC phenotyping. We performed bulk RNA sequencing of PAECs from RHC balloons. Using unsupervised dimensionality reduction and clustering we compared transcriptional signatures from PAH to controls and other forms of pulmonary hypertension. Select PAEC samples underwent single cell and population growth characterization and anoikis quantification. Fifty-four specimens were analyzed from 49 subjects. The transcriptome appeared stable over limited passages. Six genes involved in sex steroid signaling, metabolism, and oncogenesis were significantly upregulated in PAH subjects as compared to controls. Genes regulating BMP and Wnt signaling, oxidative stress and cellular metabolism were differentially expressed in PAH subjects. Changes in gene expression tracked with clinical events in PAH subjects with serial samples over time. Functional assays demonstrated enhanced replication competency and anoikis resistance. Our findings recapitulate fundamental biological processes of PAH and provide new evidence of a cancer-like phenotype in ECs from the central vasculature of PAH patients. This “cell biopsy” method may provide insight into patient and lung EC heterogeneity to advance precision medicine approaches in PAH.

Abstract Introduction Transthyretin amyloidosis (ATTR amyloidosis) is primarily associated with a cardiac or neurologic phenotype, but a mixed phenotype is increasingly described. Methods This study describes the mixed phenotype cohort in the Transthyretin Amyloidosis Outcomes Survey (THAOS). THAOS is an ongoing, longitudinal, observational survey of patients with ATTR amyloidosis, including both hereditary (ATTRv) and wild-type disease, and asymptomatic carriers of pathogenic transthyretin variants. Baseline characteristics of patients with a mixed phenotype (at enrollment or reclassified during follow-up) are described (data cutoff: January 4, 2022). Results Approximately one-third of symptomatic patients (n = 1185/3542; 33.5%) were classified at enrollment or follow-up as mixed phenotype (median age, 66.5 years). Of those, 344 (29.0%) were reclassified to mixed phenotype within a median 1–2 years of follow-up. Most patients with mixed phenotype had ATTRv amyloidosis (75.7%). The most frequent genotypes were V30M (38.9%) and wild type (24.3%). Conclusions These THAOS data represent the largest analysis of a real-world mixed phenotype ATTR amyloidosis population to date and suggest that a mixed phenotype may be more prevalent than previously thought. Patients may also migrate from a primarily neurologic or cardiologic presentation to a mixed phenotype over time. These data reinforce the need for multidisciplinary evaluation at initial assessment and follow-up of all patients with ATTR amyloidosis. Trial Registration ClinicalTrials.gov: NCT00628745.

Case summary This report describes the diagnostic findings, natural history and genetic analysis of the candidate gene Forkhead Box F1 ( FOXF1 ) in a young cat with developmental lung disease and high probability of pulmonary hypertension. A 1-year-old male entire Chartreux cat was referred for cardiac murmur investigation and exercise intolerance. Echocardiography identified a high-velocity tricuspid regurgitant jet with right-sided cardiac changes, supporting a high probability of pulmonary hypertension. No congenital cardiac shunts or left-sided cardiac changes were found to support a primary cardiac cause of pulmonary hypertension. Extensive laboratory work, thoracic radiographs and CT were performed. Histopathological characterisation (lung biopsy and later post mortem) was necessary to reach the final diagnosis. Eight months after diagnosis, the cat developed right-sided congestive heart failure, eventually leading to euthanasia. Survival from diagnosis to death was 12 months. Relevance and novel information Developmental lung disease belongs to a group of diffuse lung diseases in humans associated with pulmonary hypertension. The veterinary literature describing lung growth disorders in cats is sparse, and the present report provides information on clinical presentation and progression alongside a thorough diagnostic workup, which may aid clinicians in identifying this condition. Lung biopsy was pivotal in reaching the final diagnosis. No causal variants in FOXF1 were identified.

IntroductionIn French Guiana, a European territory in Guiana shield in the Amazon area, close to 40% of the current population was born abroad. In this context, it is important to listen to the experiences of migrants to better understand the difficulties encountered within the healthcare pathways. This is the aim of ANRS Parcours d’Haïti project, an epidemiological, biographical and socio-anthropological study conducted on a representative sample of the Haitian community in French Guiana and focusing on the social determinants of health.MethodologyWithin the framework of this study, the Infectious and Tropical Diseases clinical team of Cayenne Hospital has established close collaboration with health mediators and the ethnobotanist anthropologist of the study. To illustrate the contribution of a personalized approach to health mediation, we report the case of a migrant woman of Haitian origin admitted to the Infectious and Tropical Diseases Unit. We highlight the different socio-cultural aspects addressed and their place in the care process through a thematic discussion and socio-anthropological analysis of the care relationship, based on participatory ethnography and inductive analysis of an in-depth interview with the patient.ResultThis example illustrates the need for a multidisciplinary approach to ensure culturally adapted care for patients. Personal interviews are important because they allow to better take into account the cultural specificities of patients’ experiences and the socio-cultural environment in which they live (and especially, in the case of Haitian patients, their religious affiliation). By allowing them to speak and express themselves freely, they integrate not only their own cultural baggage, but also their own expectations and representations of the disease they suffer from and how it should be treated. Ultimately, this tripartite collaboration between patient, caregiver, and anthropologist or health mediator leads to a better therapeutic alliance.ConclusionThe analysis of this health care relationship is emblematic of the issue of cultural competence and pre-conceptualizes what intercultural mediation in health care could be, as close as possible to the caregiver and the individual.