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Abstract Background Preterm birth (PTB) is a serious health problem. PTB complications is the main cause of death in infants under five years of age worldwide. The ability to accurately predict risk for PTB during early pregnancy would allow early monitoring and interventions to provide personalized care, and hence improve outcomes for the mother and infant. Objective This study aims to predict the risks of early preterm (

Abstract Understanding the mechanisms of resistance to PARP inhibitors (PARPi) is a clinical priority, especially in breast cancer. We developed a novel mathematical framework accounting for intrinsic resistance to olaparib, identified by fitting the model to tumour growth metrics from breast cancer patient-derived xenograft (PDX) data. Pre-treatment transcriptomic profiles were used with the calculated resistance to identify baseline biomarkers of resistance, including potential combination targets. The model provided both a classification of responses, as well as a continuous description of resistance, allowing for more robust biomarker associations and capturing the observed variability. Thirty-six resistance gene markers were identified, including multiple homologous recombination repair (HRR) pathway genes. High WEE1 expression was also linked to resistance, highlighting an opportunity for combining PARP and WEE1 inhibitors. This framework facilitates a fully automated way of capturing intrinsic resistance, and accounts for the pharmacological response variability captured within PDX studies and hence provides a precision medicine approach.

Abstract The temporal structures of gross primary production (GPP) and ecosystem respiration (ER) vary across time scales in response to complex interactions among dynamic drivers (e.g., flow, light, temperature, organic matter supply). To explore emergent patterns of river metabolic variation, we applied frequency‐domain analysis to multiyear records of metabolism across 87 US rivers. We observed a dominant annual periodicity in metabolic variation and universal fractal scaling (i.e., power spectral density inversely correlated with frequency) at subannual frequencies, suggesting these are foundational temporal structures of river metabolic regimes. Frequency‐domain patterns of river metabolism aligned best with drivers related to energy inputs: benthic light for GPP and GPP for ER. Simple river metabolism models captured frequency‐domain patterns when parameterized with appropriate energy inputs but neglecting temperature controls. These results imply that temporal variation of energy supply imprints directly on metabolic signals and that frequency‐domain patterns provide benchmark properties to predict river metabolic regimes.

Abstract Tauopathies, including Alzheimer’s disease (AD), are a class of neurodegenerative diseases characterized by the presence of insoluble tau inclusions. Tau phosphorylation has traditionally been viewed as the dominant post-translational modification (PTM) controlling tau function and pathogenesis in tauopathies. However, we and others have identified tau acetylation as a primary PTM regulating both normal tau function as well as abnormal pathogenic features including aggregation. Prior work showed robust tau acetylation in aggregation hotspots located within the 2nd and 3rd repeat regions of tau (residues K280 and K311) in tauopathy brains, including AD, compared to non-tauopathy controls. By screening thousands of hybridoma clones, we generated site-specific and modification-specific monoclonal antibodies targeting acetylated tau at residues K280 or K311. To validate these antibodies in a bona fide neuronal system, we targeted the acetyltransferase CBP to the cytoplasm of neurons to promote tau acetylation. Several antibody clones specifically detected CBP-acetylated tau and co-localized with ac-tau in neurons. Additionally, our lead optimal anti-acetylated-tau monoclonal antibodies detected robust tau pathology in tangles and neuritic plaques of human AD brains. Given the now emerging interest in acetylated tau as critical regulator of tau functions, these sensitive and highly specific tools will allow us to further unravel the tau PTM code and, importantly, could be deployed as diagnostic or disease-modifying agents.

Abstract Background The Covid Connected Care Center (C4), a low-barrier telephone nurse hotline, was developed at an academic medical center to increase access to healthcare information and services across the state of Oregon, including to those without a usual source of care. Other studies have demonstrated that telephone triage services can positively influence health behaviors, but it is not known how this effect is maintained across racial/ethnic groups. The objective of this study was to show that the C4 reached throughout the state of Oregon, was valuable to callers, and that recommendations given affected callers’ subsequent health-related behaviors. Methods This mixed-methods study, informed by the RE-AIM (Reach, Effectiveness, Addoption, Implementation and Maintenance) framework, assessed caller demographics and clinical care from March 30 2020 until September 8, 2021. Descriptive statistics, multivariable risk models and Zou’s modified Poisson modeling were applied to electronic health record and call system data; An inductive approach was used for patient and staff experience surveys and semi-structured interviews. Approval was obtained from the OHSU Institutional Review Board (Study 00021413). Results 145,537 telephone calls and 92,100 text-based contacts (61% and 39%, respectively) were included. Callers tended to not have a usual source of primary care and utilized recommended services. Emergency department utilization was minimal (1.5%). Racial or ethnic disparities were not detected in the recommendations, but Black (RR 0.92, CI 0.86–0.98) and Multiracial (RR 0.90 CI 0.81–0.99) callers were less likely than non-Hispanic white callers to receive a COVID-19 test. Participants in the post-call survey (n = 50) would recommend this service to friends or family. Interviews with callers (n = 9) revealed this was because they valued assistance translating general recommendations into a personalized care plan. C4 staff interviewed (n = 9) valued the opportunity to serve the public. The C4 was a trusted resource to the public and reached the intended audiences. However, disparities in access to COVID-19 testing persisted. Conclusions Nursing triage hotlines can guide caller behavior and be an effective part of a robust public health information infrastructure.

Abstract Curved cell shapes are widespread among bacteria and important for cellular motility, virulence and fitness. However, the underlying morphogenetic mechanisms are still incompletely understood. Here, we identify an outer-membrane protein complex that promotes cell curvature in the photosynthetic species Rhodospirillum rubrum. We show that the R. rubrum porins Por39 and Por41 form a helical ribbon-like structure at the outer curve of the cell that recruits the peptidoglycan-binding lipoprotein PapS, with PapS inactivation, porin delocalization or disruption of the porin-PapS interface resulting in cell straightening. We further demonstrate that porin-PapS assemblies act as molecular cages that entrap the cell elongation machinery, thus biasing cell growth towards the outer curve. These findings reveal a mechanistically distinct morphogenetic module mediating bacterial cell shape. Moreover, they uncover an unprecedented role of outer-membrane protein patterning in the spatial control of intracellular processes, adding an important facet to the repertoire of regulatory mechanisms in bacterial cell biology.

Abstract Global commitments to conservation and sustainable development increasingly demand sensitivity to the rights and territories of Indigenous peoples and local communities. However, existing tenure systems are often overlooked by global actors and their initiatives. Using key informant surveys, literature, and established databases, we describe 62 distinct tenure systems (or place-based, governance relationships between people and coasts) across 24 countries. In all systems, people held rights to access and use aquatic resources to support healthy diets, livelihoods, and culture. The three collective-choice rights (i.e., management, exclusion, transferability) were present in 29% of systems – suggesting conditions sufficient for “self-governance”. People gained or held rights due to their residency (in 63% of systems); through historical use (52%), permits (35%), and/or kinship (29%). Our synthesis provides an opportunity for policy and action to recognize these systems of tenure, and to stimulate further actions that illuminate and recognize the rights of communities toward their sovereignty.

Objective: In March 2020, the emergence of COVID-19 as a pandemic prompted large scale, social lockdowns internationally. Participants/Method: Here, we compared the mental health symptoms and social functioning of pre-pandemic college students collected during the Spring 2020 semester to those of a pandemic group collected during the Fall 2020 semester. Results: Results reveal that students assessed during the pandemic reported more severe symptoms of posttraumatic stress and depression, yet no difference in anxiety symptoms, relative to students assessed before the pandemic. Furthermore, students assessed during the pandemic conceptualized and categorized their emotions with significantly more neutral emotions and significantly fewer positive emotions, yet no difference in negative emotions, relative to students assessed before the pandemic. Despite these mental health effects, we found no difference between the two groups in self-reported social functioning. Conclusion: Overall, these results suggest young adults' mental health was significantly impacted by the pandemic, with the potential for long lasting effects.

Using the backward design model, the author of this article surveys and connects the economic competencies literature evolving from Hansen with the literature on literacy-targeted principles courses. He makes the case why departments should offer LT principles courses--which focus on higher-level mastery of a shorter list of concepts that students can apply throughout their lives--explains what students should be able "to do" after taking LT courses, and differentiates LT principles from existing "intro for non-majors" or "survey" courses. The author intends the article as a starting point for anyone interested in exploring or assessing the LT approach and suggests options for departments thinking about integrating LT principles into their course offerings.

Background Use of pulmonary vein isolation (PVI) to treat atrial fibrillation continues to increase. Despite great interest in leveraging administrative data for real‐world analyses, contemporary procedural codes for identifying PVI have not been evaluated. Methods and Results In this observational retrospective cohort study, inpatient PVIs were identified among US Medicare fee‐for‐service beneficiaries using Current Procedural Terminology (CPT) code 93656 in Carrier Line Files. Each patient was matched with their claims from Medicare Provider Analysis and Review to compare CPT with International Classification of Diseases, Tenth Revision, Procedure Coding System (ICD‐10‐PCS) claims submitted by health care facilities to bill for PVIs. We performed the reverse for commonly matched ICD‐10‐PCS codes, to identify corresponding CPT‐billed procedures. Finally, we reviewed institutional cases for additional comparison of CPT and ICD‐10‐PCS assignation for PVI. We identified 25 617 inpatient PVIs from January 2017 to December 2021, of which 18 165 (71%) were linked to Medicare Provider Analysis and Review. Of these, 16 672 (92%) were billed as ICD‐10‐PCS 02583ZZ: “Destruction of Conduction Mechanism, Percutaneous Approach.” The reverse process yielded heterogeneous results: among 75 003 procedures billed as ICD‐10‐PCS 02583ZZ, only 15 691 (21%) matched with CPT 93656 (PVI), as several other unrelated procedures were billed under this ICD‐10‐PCS code. Institutional case review confirmed the greater specificity of CPT codes. Conclusions The ICD‐10‐PCS code associated with CPT‐billed PVI procedures actually referred to ablation of the atrioventricular junction. Yet this ICD‐10‐PCS code also matched with a wide range of other procedures distinct from PVI. We conclude that ICD‐10‐PCS codes alone are not sensitive nor specific for identifying PVI in claims and cannot be reliably used in isolation for health services research on this important procedure.

Electrons are accelerated to high, nonthermal energies during explosive energy-release events in space, such as magnetic reconnection. However, the properties and acceleration mechanisms of relativistic electrons directly associated with the reconnection X-line are not well understood. This study utilizes Magnetospheric Multiscale (MMS) measurements to analyze the flux and spectral features of subrelativistic to relativistic (∼80–560 keV) electrons during a magnetic reconnection event in Earth’s magnetotail. This event provided a unique opportunity to measure the electrons directly energized by the X-line as MMS stayed in the separatrix layer, where the magnetic field directly connects to the X-line, for approximately half of the observation period. Our analysis revealed that the fluxes of relativistic electrons were clearly enhanced within the separatrix layer, and the highest flux was directed away from the X-line, which suggested that these electrons originated directly from the X-line. Spectral analysis showed that these relativistic electrons deviated from the main plasma sheet population and exhibited an “ankle” feature similar to that observed in galactic cosmic rays. The contribution of “ankle” electrons to the total electron energy density increased from 0.1% to 1% in the separatrix layer though the spectral slopes did not exhibit clear variations. Further analysis indicated that while these relativistic electrons originated from the X-line, they experienced a nonnegligible degree of scattering during transport. These findings provide clear evidence that magnetic reconnection in Earth’s magnetotail can efficiently energize relativistic electrons directly at the X-line, providing new insights into the complex processes governing electron dynamics during magnetic reconnection.

Particle acceleration is a commonly observed phenomenon at dipolarization fronts. Many studies have attempted to determine the acceleration mechanism, with betatron acceleration being a major candidate. In previous work, we attempted to match the observed change in electron energy to the change predicted by betatron acceleration, but found that although this worked in some cases, overall betatron acceleration alone could not describe the observed energy spectrum changes. In this work, we attempted to study whether ion acceleration showed similar behavior and whether a quasi-adiabatic correction would be more accurate. On average the betatron acceleration equation overestimated the observed acceleration and the quasi-adiabatic correction did not account for the difference, although there are limitations to this study due to data fidelity. We then turned to study whether our assumptions about the source population having the same phase space density as the cold pre-existing background population in the plasma sheet are valid. We indirectly studied this by comparing the relative abundances of O+ and He++ as proxies for ionospheric and solar wind populations respectively. We found the betatron acceleration equation method performs slightly better when there is a stronger ionospheric component. This suggests that when more plasma containing O+ is present in the dipolarization front, it indicates that the source population is more local and therefore this method of using betatron acceleration is more valid.

Abstract To acquire the ability to fertilize the egg, mammalian spermatozoa must undergo a series of changes occurring within the highly synchronized and specialized environment of the female reproductive tract, collectively known as capacitation. In an attempt to replicate this process in vitro, various culture media for mouse sperm were formulated over the past decades, sharing a similar overall composition but differing mainly in ion concentrations and metabolic substrates. The widespread use of the different media to study the mechanisms of capacitation might hinder a comprehensive understanding of this process, as the medium could become a confounding variable in the analysis. In this context, the present side-by-side study compares the influence of four commonly used culture media (FD, HTF and two TYH versions) on mouse sperm capacitation. We evaluated the induction of protein kinase A phosphorylation pathway, motility, hyperactivation and acrosome reaction. Additionally, in vitro fertilization and embryo development were also assessed. By analyzing these outcomes in two mouse colonies with different reproductive performance, our study provides critical insights to improve the global understanding of sperm function. The results obtained highlight the importance of considering variations in medium composition, and their potential implications for the future interpretation of results.

Objective To identify primary care structures and processes that have the highest and lowest impact on chronic disease management and screening and prevention outcomes as well as to assess the feasibility of implementing these structures and processes into practice.Design A two-round Delphi study was conducted to establish consensus on the impact and feasibility of 258 primary care structures and processes.Participants 29 primary care providers, health system leaders and health services researchers in the USA.Outcomes Primary outcomes were (1) consensus on the impact of each structure and process on chronic disease management and screening and prevention outcomes, separately and (2) consensus on feasibility of implementation by primary care practices.Results Consensus on high impact and feasibility of implementation was reached on four items for chronic disease management: ‘Providers use motivational interviewing to help patients set goals’, ‘Practice has designated staff to manage patient panel’, ‘Practice has onsite providers or staff that speak the most dominant, non-English language spoken by patients’ and ‘Practice includes mental health providers and/or behavioural health specialists in care team’ and seven items for screening and prevention: ‘Practice utilizes standing protocols and orders’, ‘Practice generates reports to alert clinicians to missed targets and to identify gaps in care, such as overdue visits, needed vaccinations, screenings or other preventive services’, ‘Practice has designated staff to manage patient panel’, ‘Practice sets performance goals and uses benchmarking to track quality of care’, ‘Practice uses performance feedback to identify practice-specific areas of improvement’, ‘Practice builds quality improvement activities into practice operations’ and ‘Pre-visit planning data are reviewed during daily huddles’. Only ‘Practice has designated staff to manage patient panel’ appeared on both lists.Conclusion Findings suggest that practices need to focus on implementing mostly distinct, rather than common, structures and processes to optimise chronic disease and preventive care.

ABSTRACT The minimum inhibitory concentration (MIC) of echinocandins against Aspergillus spp. does not represent the actual inhibition threshold of echinocandins. Therefore, the recommended method to evaluate their activity is determining the minimum effective concentration (MEC) in broth microdilution, a method that is less common in clinical settings. This study aimed to assess a user-friendly commercial method, Sensititre YeastOne (SYO), to determine the effectiveness of echinocandins (caspofungin, anidulafungin and micafungin) against Aspergillus spp. Echinocandins MEC was determined against 23 isolates of Aspergillus spp. using SYO and the reference Clinical and Laboratory Standards Institute (CLSI) method. MECs were read with an inverted microscope and a reading mirror. Essential agreement (EA) between the tested methods was defined as a ±twofold dilution difference. There was a high EA (91%–100%) between the reference method and SYO in determining echinocandins MEC against Aspergillus isolates using inverted microscopy. A high EA was also observed between SYO MEC determined by inverted microscopy and a reading mirror, but different incubation times were required. SYO is a reliable, simple method for determining the MEC of echinocandins against Aspergillus isolates, preferably with an inverted microscope, and can be easily used in clinical laboratories when echinocandin susceptibility testing is required.IMPORTANCEUsing a commercial method such as Sensititre YeastOne (SYO) to determine the minimum effective concentration (MEC) of echinocandins against Aspergillus spp. has been shown to be a reliable alternative to the Clinical and Laboratory Standards Institute (CLSI) reference method. This makes it more suitable for high-volume clinical laboratories. SYO provides accurate results comparable to the standard method and could potentially improve patient care by guiding more optimal antifungal treatment choices for patients with Aspergillus infections.

Objective: To test the factor structure, reliability, and validity of the Brazilian version of the Abbreviated Suicidal Narrative Inventory (SNI-38). Methods: We used an anonymous online questionnaire of the SNI-38 and self-report measures administered between November 2020 and October 2021 in the Brazilian community. Participants were recruited through social media advertisements. Confirmatory factor analysis (CFA) was performed to test the factor structure of the SNI-38. In addition, we assessed internal consistency and convergent validity against stressful life events, suicide crisis syndrome, suicidal ideation, and suicide attempts. Results: A total of 2,660 participants were included. The eight-factor model of the SNI-38 had a good model fit (χ2[637] = 7,473.98, p < 0.001, comparative fit index [CFI] = 0.99, Tucker-Lewis index [TLI] = 0.99, root mean squared error of approximation [RMSEA] = 0.07, standardized root mean residual [SRMR] = 0.06). Notably, all items were significantly and positively loaded onto their respective factors (factor loadings ≥ 0.45). The reliability of all subscales except for goal disengagement ranged from good to high. Furthermore, all subscales except goal disengagement showed positive correlations with variables such as suicide crisis syndrome, stressful life events, lifetime/past month suicidal ideation, and lifetime suicide attempts. Conclusion: These findings provide preliminary support for the validity of the Brazilian version of the SNI-38 as an appropriate, valid instrument for measuring suicidal narratives in Brazilian individuals.

This paper applies an Intersectionality Based Policy Analysis Framework to Ontario’s current mental health plan – The Roadmap: A Plan to Build Ontario’s Mental Health and Addictions Services – in order to identify the contextual influences, underlying values and assumptions, which promote or undermine the uptake of human rights and equity as a mental health policy priority in Ontario. We found that dominant framings of the “problem” of mental health (as lack of access, coordination or integration, as a fiscal drain, as an economic burden, and as a clinical or medical problem) served to obscure and ignore the underlying social and structural conditions that impact mental health and the human rights violations that routinely occur in the context of “care.” We discuss the implications of The Roadmap ignoring social and structural determinants of health, and by way of contrast, explore how citizen engagement and activism can support rethinking mental health policy so that it is more just and equitable.

Colonization has had extremely negative impacts on the mental health and wellness of Indigenous peoples throughout the world. In this paper we take up colonial processes as they relate to Indigenous lives and mental health in three contexts: Canada, Kenya and Australia. This work engages storytelling and the method of storywork (Archibald et al., 2019) as a way to preserve and pass on history and as a way of resisting colonial oppression. This work is grounded in an intersectional approach to social justice and decolonization (Crenshaw, 1990; Hankivsky & Cormier, 2011), and supported sharing, knowledge co-creation and joint thematic narrative analysis of Indigenous experiences of mental health and justice systems across the three contexts. Our writing team represents a collaborative process between Indigenous and non-Indigenous authors where the members of the team most impacted by colonization use stories to reflect on the impact of colonization and its specific ties to psychiatric, justice and child welfare systems. This paper is presented in three main parts beginning with “Emile’s Story,” followed by “Remembering ‘Is That You Ruthie?’” and concluding with “Navigating Kenya’s Colonial Legacy.” This work engages a process of decolonization by challenging these destructive colonial narratives through storytelling. This paper will both document and demonstrate the importance of creating space for different forms of knowledge creation within academia.

In British Columbia (BC), Canada, mental health reforms over the last decade have moved back and forth between calls for practices that restrict human rights and those that are rooted in equity and social justice. In this article, we explore some of these tensions and their implications for human rights and equity in mental health care by critically analyzing three policies guiding mental health reform in BC using an intersectionality-based policy framework. Specifically, we interrogate the effects of a biomedical and individualized framing of mental health and substance use. We argue that such a framing is buttressed by neoliberal ideology and lays the groundwork for public and professional acceptance of coercive practices with particular consequences for Indigenous and racialized populations. This framing is juxtaposed with a holistic wellness and trauma-informed policy framework anchored by an understanding of the impact of colonization. However, what is missing in both policy framings is a full account of the documented ongoing human rights violations experienced by many people accessing BC’s mental health system. Our analysis shows how applying an intersectionality-based policy framework allows for a deeper exploration of the complex, interlocking systems of power and oppression that give rise to these human rights violations. We conclude with a discussion of the important role that decolonizing and intersectional approaches play for capturing the complexities of systemic inequities and advancing mental healthcare that protects and promotes mental wellbeing and human rights.

IntroductionTGFβ is a major immunoinhibitory factor present in the microenvironment of solid tumors. Various cancer types acquire the ability to overexpress TGFβ to escape immune response. Specifically, TGFβ dampens cytotoxic T cell activity, and its presence has been correlated with tumor invasion and poor prognosis.MethodsIn this study, we developed two approaches to counteract the effects of TGFβ and provide a functional advantage to genetically engineered T cells in the immunoinhibitory tumor milieu. We designed a TGFβRI-based co-stimulatory switch receptor (CSRI), comprising the TGFβ receptor I extracellular binding domain and a 4-1BB co-stimulatory signaling moiety. Additionally, we tested the efficacy of a TGFβ-binding scFv trap produced by T cells.ResultsWe demonstrated that both approaches enhanced tumor-specific T cell cytokine secretion, upregulated activation markers, and reduced inhibition markers upon co-culture with melanoma targets. Furthermore, CSRI and the anti-TGFβ trap exhibited improved anti-tumor function in vivo.ConclusionOverall, we show that targeting the TGFβ pathway can enhance cellular immunotherapy.

Background: Artificial urinary sphincter (AUS) placement remains the gold-standard treatment for post-prostatectomy urinary incontinence (PPUI), despite their need for periodic surgical revision. Objective: To understand the experiences of patients who undergo repeat AUS revisions. Design: Mixed design including quantitative surveys and qualitative interviews for thematic analysis. Methods: Men with ⩾2 revisions were collected from a single-institution, retrospective database of AUS patients. Participants were interviewed about their prostatectomy, incontinence, AUS placement, and revisions. A survey was administered utilizing validated tools (e.g., Decision Regret Scale (DRS), Incontinence Impact Questionnaire-7) for quantitative analysis. Interview transcripts were used for qualitative thematic analysis. Results: Of 26 respondents, 20 completed the interview. Twenty-three men completed the survey. The mean DRS score for prostatectomy was 24 (standard deviation (SD) = 27), indicating low regret. Median Incontinence Impact Questionnaire score was 54 (SD = 27), with 70% of participants describing their PPUI as “severe.” Participants experienced a significant decrease in daily pad usage with AUS placement (5.5 pre-AUS vs 1.4 post-AUS, p

Background The treatment of severe aortic stenosis has evolved considerably since the introduction of transcatheter aortic valve replacement (TAVR), yet trends in complications for patients undergoing TAVR or surgical aortic valve replacement (SAVR) at a national level have yet to be evaluated. Methods and Results We performed a retrospective cohort study using Medicare data to evaluate temporal trends in complications among beneficiaries, aged ≥65 years, treated with elective isolated transfemoral TAVR or SAVR between 2012 and 2019. The study end point was the occurrence of a major complication (composite outcome) during index and up to 30 days after. Multivariable logistic regression was used to assess odds of complications for TAVR and SAVR, individually over time, and for TAVR versus SAVR, over time. The cohort included 211 212 patients (mean±SD age, 78.6±7.3 years; 45.0% women). Complication rates during index following elective isolated aortic valve replacement decreased from 49% in 2012 to 22% in 2019. These reductions were more pronounced for TAVR (41% to >19%, Δ=22%) than SAVR (51% to >47%, Δ=4%). After risk adjustment, the risk of any complication with TAVR was 47% (P

Abstract Background Despite Israel’s increased use of prescription opioids, reported deaths resulting or associated with opioids have decreased, in fact dramatically, since 2005. This contrast is unique and difficult to explain. We sought to examine whether higher prescribed opioid dosages among adults without oncologic diagnoses were associated with higher all-cause mortality rates. Methods A historical cohort study in Clalit Health Services, using a data repository including all adult patients prescribed opiates between 2010 and 2020, excluding patients with oncologic diagnoses. Patients were classified into three groups according to opioid use: below 50 Morphine milligram equivalents (MME) per day, 50 to 90 MME per day, and above 90 MME per day. Sex, Charlson comorbidity score, age and socioeconomic status were recorded. Mortality rates were compared between the dosage groups and compared to age-standardized mortality rates in the general population. Results On multivariate analysis, patients receiving 90 or more MME per day were 2.37 (95%CI 2.1 to 2.68) more likely to have died compared to patients receiving below 50 MME per day. The respective hazard ratio among patients receiving between 50 and 90 MME per day was 2.23 (2.01 to 2.46). Among patients aged 18 to 50, standardized mortality ratios (SMRs) compared to the general population ranged between 5.4 to 8.6 among women, receiving between 50 and 90 MME per day, and between 8.07 and 10.7 among women receiving 90 or more MME per day. The respective SMRs among men were 1.2 to 3.8 and 2.7 to 5.4. Conclusion Increased opioid use is independently associated with increased all-cause mortality among non-oncological patients. This result is most notable among young adults with little or no known comorbidities. These findings are consistent with results in other countries and seem more credible than previous Israeli reports. Healthcare regulators and providers should, therefore, act to curtail the increasing opioid prescriptions and devise and enhance controls in the healthcare system, which, until 2020, had very limited mechanisms in place.

Abstract Epithelial tissues sheath organs and electro-mechanically regulate ion and water transport to regulate development, homeostasis, and hydrostatic organ pressure. Here, we demonstrate how external electrical stimulation allows us to control these processes in living tissues. Specifically, we electrically stimulate hollow, 3D kidneyoids and gut organoids and find that physiological-strength electrical stimulation of ∼ 5 - 10 V/cm powerfully inflates hollow tissues; a process we call electro-inflation. Electro-inflation is mediated by increased ion flux through ion channels/transporters and triggers subsequent osmotic water flow into the lumen, generating hydrostatic pressure that competes against cytoskeletal tension. Our computational studies suggest that electro-inflation is strongly driven by field-induced ion crowding on the outer surface of the tissue. Electrically stimulated tissues also break symmetry in 3D resulting from electrotaxis and affecting tissue shape. The ability of electrical cues to regulate tissue size and shape emphasizes the role and importance of the electrical micro-environment for living tissues.

Abstract Background Depression is prevalent among Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) Veterans, yet rates of Veteran mental health care utilization remain modest. The current study examined: factors in electronic health records (EHR) associated with lack of treatment initiation and treatment delay; the accuracy of regression and machine learning models to predict initiation of treatment. Methods We obtained data from the VA Corporate Data Warehouse (CDW). EHR data were extracted for 127,423 Veterans who deployed to Iraq/Afghanistan after 9/11 with a positive depression screen and a first depression diagnosis between 2001 and 2021. We also obtained 12-month pre-diagnosis and post-diagnosis patient data. Retrospective cohort analysis was employed to test if predictors can reliably differentiate patients who initiated, delayed, or received no mental health treatment associated with their depression diagnosis. Results 108,457 Veterans with depression, initiated depression-related care (55,492 Veterans delayed treatment beyond one month). Those who were male, without VA disability benefits, with a mild depression diagnosis, and had a history of psychotherapy were less likely to initiate treatment. Among those who initiated care, those with single and mild depression episodes at baseline, with either PTSD or who lacked comorbidities were more likely to delay treatment for depression. A history of mental health treatment, of an anxiety disorder, and a positive depression screen were each related to faster treatment initiation. Classification of patients was modest (ROC AUC = 0.59 95%CI = 0.586–0.602; machine learning F-measure = 0.46). Conclusions Having VA disability benefits was the strongest predictor of treatment initiation after a depression diagnosis and a history of mental health treatment was the strongest predictor of delayed initiation of treatment. The complexity of the relationship between VA benefits and history of mental health care with treatment initiation after a depression diagnosis is further discussed. Modest classification accuracy with currently known predictors suggests the need to identify additional predictors of successful depression management.

The surface topography and chemistry of titanium–aluminum–vanadium (Ti6Al4V) implants play critical roles in the osteoblast differentiation of human bone marrow stromal cells (MSCs) and the creation of an osteogenic microenvironment. To assess the effects of a microscale/nanoscale (MN) topography, this study compared the effects of MN-modified, anodized, and smooth Ti6Al4V surfaces on MSC response, and for the first time, directly contrasted MN-induced osteoblast differentiation with culture on tissue culture polystyrene (TCPS) in osteogenic medium (OM). Surface characterization revealed distinct differences in microroughness, composition, and topography among the Ti6Al4V substrates. MSCs on MN surfaces exhibited enhanced osteoblastic differentiation, evidenced by increased expression of RUNX2, SP7, BGLAP, BMP2, and BMPR1A (fold increases: 3.2, 1.8, 1.4, 1.3, and 1.2). The MN surface also induced a pro-healing inflammasome with upregulation of anti-inflammatory mediators (170–200% increase) and downregulation of pro-inflammatory factors (40–82% reduction). Integrin expression shifted towards osteoblast-associated integrins on MN surfaces. RNA-seq analysis revealed distinct gene expression profiles between MSCs on MN surfaces and those in OM, with only 199 shared genes out of over 1000 differentially expressed genes. Pathway analysis showed that MN surfaces promoted bone formation, maturation, and remodeling through non-canonical Wnt signaling, while OM stimulated endochondral bone development and mineralization via canonical Wnt3a signaling. These findings highlight the importance of Ti6Al4V surface properties in directing MSC differentiation and indicate that MN-modified surfaces act via signaling pathways that differ from OM culture methods, more accurately mimicking peri-implant osteogenesis in vivo.

Background: Spatial-temporal control of mRNA translation in dendrites is important for synaptic plasticity. In response to pre-synaptic stimuli, local mRNA translation can be rapidly triggered near stimulated synapses to supply the necessary proteins for synapse maturation or elimination, and 3′ untranslated regions (UTRs) are responsible for proper localization of mRNAs in dendrites. Although FISH is a robust technique for analyzing RNA localization in fixed neurons, live-cell imaging of RNA dynamics remains challenging. Methods: In this study, we optimized existing RNA visualization techniques (MS2-tagging and microinjection of fluorescently-labeled mRNAs) to observe novel behaviors of dendritic mRNAs. Results: We found that the signal-to-noise ratio (SNR) of MS2-tagged mRNAs was greatly improved by maximizing the ratio of the MS2-RNA to MS2 coat protein-fluorescent protein (MCP-FP) constructs, as well as by the choice of promoter. Our observations also showed that directly fluorescently labeled mRNAs result in brighter granules compared to other methods. Importantly, we visualized the dynamic movement of co-labeled mRNA/protein complexes in dendrites and within dendritic spines. In addition, we observed the simultaneous movement of three distinct mRNAs within a single neuron. Surprisingly, we observed splitting of these complexes within dendritic spines. Conclusions: Using highly optimized RNA-labeling methods for live-cell imaging, one can now visualize the dynamics of multiple RNA / protein complexes within the context of diverse cellular events. Newly observed RNA movements in dendrites and synapses may shed light on the complexities of spatio-temporal control of gene expression in neurons.

Objective: To describe telemedicine use patterns and understand clinic’s approaches to shifting care delivery during the COVID-19 pandemic. Methods: We used electronic health record data from 203 community health centers across 13 states between 01/01/2019 and 6/31/2021 to describe trends in telemedicine visit rates over time. Qualitative data were collected from 13 of those community health centers to understand factors influencing adoption and implementation of telemedicine. Results: Most clinics in our sample were in urban areas (n = 176) and served a majority of uninsured and publicly insured patients (12.8% and 44.4%, respectively) across racial and ethnic minority groups (16.6% Black and 29.3% Hispanic). During our analysis period there was a 791% increase in telemedicine visits from before the pandemic (.06% pre- vs 47.5% during). A latent class growth analysis was used to examine differences in patterns of adoption of telemedicine across the 203 CHCs. The model resulted in 6 clusters representing various levels of telemedicine adoption. A mixed methods approach streamlined these clusters into 4 final groups. Clinics that reported rapid adoption of telemedicine attributed this change to leadership prioritization of telemedicine, robust quality improvement processes (eg, using PDSA processes), and emphasis on training and technology support. Conclusions: In response to the COVID-19 pandemic, telemedicine adoption rates varied across clinics. Our study highlight that organizational factors contributed to the clinic’s ability to rapidly uptake and use telemedicine services throughout the pandemic. These approaches could inform future non-pandemic practice change and care delivery.

Background Right‐sided heart failure (HF) due to severe tricuspid regurgitation (TR) is associated with reduced quality of life (QoL). Here, we analyzed the impact of TR on specific QoL dimensions and the effect of transcatheter tricuspid valve intervention (TTVI) on individual QoL items. Methods and Results In this study, we included 174 patients with HF (49% women; median age, 79 years; 97% New York Heart Association ≥3) with baseline QoL assessment undergoing TTVI by transcatheter edge‐to‐edge‐repair at our center between April 2016 and March 2022. QoL was assessed by the standardized Minnesota Living With HF Questionnaire. QoL change after TTVI and correlation to functional end points were analyzed. In addition, all QoL domains and the 21 individual items of the Minnesota Living With HF Questionnaire were analyzed. TTVI significantly reduced TR (TR ≥3: baseline 95%, 1‐year‐follow‐up 7%; P

Background T cells play a central role in the antitumor response. However, they often face numerous hurdles in the tumor microenvironment, including the scarcity of available essential metabolites such as glucose and amino acids. Moreover, cancer cells can monopolize these resources to thrive and proliferate by upregulating metabolite transporters and maintaining a high metabolic rate, thereby outcompeting T cells.Methods Herein, we sought to improve T-cell antitumor function in the tumor vicinity by enhancing their glycolytic capacity to better compete with tumor cells. To achieve this, we engineered human T cells to express a key glycolysis enzyme, phosphofructokinase, in conjunction with Glucose transporter 3, a glucose transporter. We co-expressed these, along with tumor-specific chimeric antigen or T-cell receptors.Results Engineered cells demonstrated an increased cytokine secretion and upregulation of T-cell activation markers compared with control cells. Moreover, they displayed superior glycolytic capacity, which translated into an improved in vivo therapeutic potential in a xenograft model of human tumors.Conclusion In summary, these findings support the implementation of T-cell metabolic engineering to enhance the efficacy of cellular immunotherapies for cancer.

Abstract Cybermedical systems that regulate patient clotting in real time with personalized blood product delivery will improve treatment outcomes. These systems will harness popular viscoelastic assays of clot strength such as thromboelastography (TEG), which help evaluate coagulation status in numerous conditions: major surgery (e.g., heart, vascular, hip fracture, and trauma); liver cirrhosis and transplants; COVID-19; ICU stays; sepsis; obstetrics; diabetes; and coagulopathies like hemophilia. But these measurements are time-consuming, and thus impractical for urgent care and automated coagulation control. Because protein concentrations in a blood sample can be measured in about five minutes, we develop personalized, phenomenological, quick, control-oriented models that predict TEG curve outputs from input blood protein concentrations, to facilitate treatment decisions based on TEG curves. Here, we accurately predict, experimentally validate, and mechanistically justify curves and parameters for common TEG assays (Functional Fibrinogen, Citrated Native, Platelet Mapping, and Rapid TEG), and verify results with trauma patient clotting data.

Abstract Long-standing interpretations of the Last Glacial Maximum (21,000 ± 2000 years ago) in Australia suggest that the period was extremely cold and arid, during which the Indo-Australian summer monsoon system collapsed, and human populations declined and retreated to ecological refuges to survive. Here, we use transient iTRACE simulations, combined with palaeoclimate proxy records and archaeological data to re-interpret the late Last Glacial Maximum and terminal Pleistocene (21,000 – 11,000 years) in Australia. The model suggests climates during the peak Last Glacial Maximum were cooler than present (−4 to −11 °C), but there is no evidence of monsoon collapse or substantial decreases in moisture balance across Australia. Kernel Density Estimates of archaeological ages show relatively stable and persistent human activity across most regions throughout the late Last Glacial Maximum and terminal Pleistocene, consistent with genetic evidence. Spatial coverage of archaeological sites steadily increased across the terminal Pleistocene; however, substantial population change is not evident.

ABSTRACTAnemia is common in older adults, but often unexplained. Previously, we conducted a randomized, controlled trial of intravenous (IV) iron sucrose to study its impact on the 6-minute walk test and hemoglobin in older adults with unexplained anemia and ferritin levels of 20–200 ng/mL. In this report, we present for the first time the response of hemoglobin, as well as the dynamic response of biomarkers of erythropoiesis and iron indices, in a pooled analysis of the initially IV iron-treated group of 9 subjects and the subsequently IV iron treated 10 subjects from the delayed treatment group. We hypothesized that there would be a reproducible hemoglobin response from IV iron, and that iron indices and erythropoietic markers would reflect appropriate iron loading and reduced erythropoietic stress. To investigate the biochemical response of anemia to IV iron, we studied the dynamics of soluble transferrin receptor (STfR), hepcidin, erythropoietin (EPO), and iron indices over 12 weeks after treatment. In total, all 19 treated subjects were evaluable: 9 from initial treatment and 10 after cross-over. Hemoglobin rose from 11.0 to 11.7 g/dL, 12 weeks after initiating IV iron treatment of 1000 mg divided weekly over 5 weeks. We found early changes of iron loading after 1–2 IV iron dose: serum iron increased by 184 mcg/dL from a baseline of 66 mcg/dL, ferritin by 184 ng/mL from 68 ng/mL, and hepcidin by 7.49 ng/mL from 19.2 ng/mL, while STfR and serum EPO declined by 0.55 mg/L and 3.5 mU/mL from 19.2 ng/mL and 14 mU/mL, respectively. The erythroid response and evidence of enhanced iron trafficking are consistent with the hypothesis that IV iron overcomes iron deficient or iron-restricted erythropoiesis. These data provide new insight that iron-restricted erythropoiesis is a potential and targetable mechanism for patients diagnosed with unexplained anemia of the elderly and offers support for larger prospective trials of IV iron among anemic older adults of low to normal ferritin.

Translational strategies to characterize and monitor extracellular vesicles such as exosome (EX) shedding and the clinical impact of this data within hepatocellular carcinoma (HCC) remains unclear. In this study, EX shedding was assessed in early-stage HCC and evaluated as a stratification factor for time to progression (TTP) following first-cycle liver-directed therapy (LDT). Plasma EXs were isolated from HCC patients undergoing LDT using ultracentrifugation. Purified EXs were stained using markers CD9 and CD63 and quantified using an ImageStreamX flow cytometer. Circulating EXs expressing CD9 were isolated at 10-fold higher levels compared to CD63. The intensity of CD9+ EX shedding following LDT was positively correlated with treatment response. High post-LDT CD9+ EX shedding stratified TTP risk with a 30% lower frequency of disease progression at 1 year following LDT. Post-LDT high CD9+ EX shedding was observed in 100% (10/10) of patients successfully bridged to liver transplantation while only 22% (2/9) of patients with tumor progression had high CD9+ EX shedding post-LDT. CD9+ EX shedding also stratified TTP risk within the first cycle objective response rate (ORR) group, identifying patients still at higher disease progression. EX shedding was concordant with imaging response rate, stratified TTP in early-stage HCC, and may have important implications for assessing post-LDT viable, biologically aggressive HCC.

Abstract Background Prescription opioids are widely used for pain control and palliative care but have been associated with a variety of untoward effects, including opioid use disorder, addiction, and increased mortality. Patterns of opioid use in Israel are to date poorly described. Methods Using a community-based database, the authors performed a retrospective analysis of filled opioid prescriptions of Israeli HMO members 18 years of age or older during the years of 2010–2020 that filled at least one opioid prescription. Morphine milligram equivalent (MME) calculations were stratified by presence or absence of oncology diagnosis and by specific opioid medication. Results The percentage of HMO members who filled at least one opioid prescription increased every year from 2.1% in 2010 to 4.2% in 2020. There was an increase in the MME per prescription (44.2%), daily MME per capita (142.1%) and MME per prescription-filling patient (39%) from 2010 to 2020. Increased prescription opioid use is driven by a small group of non-oncological patients, which is less than 1.5% of opioid-prescribed patients and 0.1% of the adult population, primarily owing to fentanyl use. Conclusion Supervision and control of opioid prescriptions in Israel should be a focused effort directed at patients prescribed uniquely high dosages rather than a population-wide strategy that focuses on all patients prescribed opioids. This should be complemented by improved physician training and access to non-opioid therapies, as well as improved data collection and analysis.

Abstract Congenital heart disease (CHD) represents a significant contributor to both morbidity and mortality in neonates and children. There’s currently no analogous dried blood spot (DBS) screening for CHD immediately after birth. This study was set to assess the feasibility of using DBS to identify reliable metabolite biomarkers with clinical relevance, with the aim to screen and classify CHD utilizing the DBS. We assembled a cohort of DBS datasets from the California Department of Public Health (CDPH) Biobank, encompassing both normal controls and three pre-defined CHD categories. A DBS-based quantitative metabolomics method was developed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). We conducted a correlation analysis comparing the absolute quantitated metabolite concentration in DBS against the CDPH NBS records to verify the reliability of metabolic profiling. For hydrophilic and hydrophobic metabolites, we executed significant pathway and metabolite analyses respectively. Logistic and LightGBM models were established to aid in CHD discrimination and classification. Consistent and reliable quantification of metabolites were demonstrated in DBS samples stored for up to 15 years. We discerned dysregulated metabolic pathways in CHD patients, including deviations in lipid and energy metabolism, as well as oxidative stress pathways. Furthermore, we identified three metabolites and twelve metabolites as potential biomarkers for CHD assessment and subtypes classifying. This study is the first to confirm the feasibility of validating metabolite profiling results using long-term stored DBS samples. Our findings highlight the potential clinical applications of our DBS-based methods for CHD screening and subtype classification.

Abstract African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.

Abstract Background Prior studies have reported conflicting results regarding the association of prenatal maternal depression with offspring cortisol levels. We examined associations of high levels of prenatal depressive symptoms with child cortisol biomarkers. Methods In Project Viva (n = 925, Massachusetts USA), mothers reported their depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) during pregnancy, cord blood glucocorticoids were measured at delivery, and child hair cortisol levels were measured in mid-childhood (mean (SD) age: 7.8 (0.8) years) and early adolescence (mean (SD) age: 13.2 (0.9) years). In the Generation R Study (n = 1644, Rotterdam, The Netherlands), mothers reported depressive symptoms using the Brief Symptom Inventory (BSI) during pregnancy, and child hair cortisol was measured at a mean (SD) age of 6.0 (0.5) years. We used cutoffs of ≥ 13 for the EPDS and > 0.75 for the BSI to indicate high levels of prenatal depressive symptoms. We used multivariable linear regression models adjusted for child sex and age (at outcome), and maternal pre-pregnancy BMI, education, social support from friends/family, pregnancy smoking status, marital status, and household income to assess associations separately in each cohort. We also meta-analyzed childhood hair cortisol results from both cohorts. Results 8.0% and 5.1% of women respectively experienced high levels of prenatal depressive symptoms in Project Viva and the Generation R Study. We found no associations between high levels of maternal depressive symptoms during pregnancy and child cortisol biomarkers in either cohort. Conclusions The present study does not find support for the direct link between high levels of maternal depressive symptoms and offspring cortisol levels.

Abstract Ambient fine particulate matter (PM2.5) is the world’s leading environmental health risk factor. Quantification is needed of regional contributions to changes in global PM2.5 exposure. Here we interpret satellite-derived PM2.5 estimates over 1998-2019 and find a reversal of previous growth in global PM2.5 air pollution, which is quantitatively attributed to contributions from 13 regions. Global population-weighted (PW) PM2.5 exposure, related to both pollution levels and population size, increased from 1998 (28.3 μg/m3) to a peak in 2011 (38.9 μg/m3) and decreased steadily afterwards (34.7 μg/m3 in 2019). Post-2011 change was related to exposure reduction in China and slowed exposure growth in other regions (especially South Asia, the Middle East and Africa). The post-2011 exposure reduction contributes to stagnation of growth in global PM2.5-attributable mortality and increasing health benefits per µg/m3 marginal reduction in exposure, implying increasing urgency and benefits of PM2.5 mitigation with aging population and cleaner air.

Abstract Motivation Ovarian cancer (OC) is a highly lethal gynecological malignancy. Extensive research has shown that OC cells undergo significant metabolic alterations during tumorigenesis. In this study, we aim to leverage these metabolic changes as potential biomarkers for assessing ovarian cancer. Methods A functional module-based approach was utilized to identify key gene expression pathways that distinguish different stages of ovarian cancer (OC) within a tissue biopsy cohort. This cohort consisted of control samples (n = 79), stage I/II samples (n = 280), and stage III/IV samples (n = 1016). To further explore these altered molecular pathways, minimal spanning tree (MST) analysis was applied, leading to the formulation of metabolic biomarker hypotheses for OC liquid biopsy. To validate, a multiple reaction monitoring (MRM) based quantitative LCMS/MS method was developed. This method allowed for the precise quantification of targeted metabolite biomarkers using an OC blood cohort comprising control samples (n = 464), benign samples (n = 3), and OC samples (n = 13). Results Eleven functional modules were identified as significant differentiators (false discovery rate, FDR

Introduction and Objectives: Intrahepatic cholestasis of pregnancy (ICP) is often accompanied by fetal and maternal complications. Materials and Methods: Retrospective review of the clinical course of women with ICP and their neonates treated at our medical center over a 10-year period. Special attention was paid to the maternal and neonatal response to 2 different modes of ursodeoxycholic acid (UDCA) administration. Results: Neonates of mothers with high total bile acid levels had a poorer composite neonatal outcome. Twenty-seven women who presented at an advanced stage of their pregnancies did not receive UDCA. UDCA was administered in 2 modes: either a full dose at admission (76 women) or a gradually increasing dose until the desired dosage was reached (25 women). The mean gestational age at delivery for the 94 neonates that were exposed to full UDCA dose was the lowest (36±2.3 weeks for the full dose, 37±1.4 weeks for the 30 neonates from the gradually increasing dose, 38±1.6 weeks for the 29 neonates from the no treatment group, p

Abstract The mechanisms driving catchment nitrogen storage and release operate at multiple spatiotemporal scales. Consequently, analyses grounded in different observational timescales can yield discrepant interpretations of underlying mechanisms. To assess the consistency of nitrate export patterns between event‐ and inter‐annual scales, we evaluated multiple years of high‐frequency observations of nitrate concentrations (C) and discharge (Q) including 3,480 discrete discharge events from 28 dominantly agricultural catchments. We observed consistent and often drastic divergence between long‐term and median event‐specific C‐Q patterns. Most catchments showed long‐term enrichment patterns (positive C‐Q slope), but events were, on average, more chemostatic (close‐to‐zero C‐Q slopes). C‐Q slope variability was high for small events but decreased with event magnitude, approaching chemostatic patterns during the largest storms, yielding compelling evidence against nitrate source limitation. We conclude that nitrate export patterns observed at different temporal scales and event magnitudes are controlled by different processes, therefore embedding complementary information.

The magnetospheric systems of ice giants, as the ideal and the unique template of a typical class of exoplanets, have not been sufficiently studied in the past decade. The complexity of these asymmetric and extremely dynamic magnetospheres provides us a great chance to systematically investigate the general mechanism of driving the magnetospheres of such common exoplanets in the Universe, and the key factors of influencing the global and local magnetospheric structures of this type of planets. In this paper, we discuss the science return of probing magnetospheric systems of ice giants for the future missions, throughout different magnetospheric regions, across from the interaction with upstream solar wind to the downstream region of the magnetotail. We emphasize the importance of detecting the magnetospheric systems of ice giants in the next decades, which enables us to deeply understand the space enviroNMent and habitability of not only the ice giants themselves but also the analogous exoplanets which are widely distributed in the Universe.

Abstract Plaques identified by Coronary CT angiography (CCTA) are important in clinical diagnosis and primary prevention. High-risk plaque features by CCTA have been extensively validated using optical coherence tomography (OCT). However, since their general diagnostic performance and limitations have not been fully investigated, we sought to compare CCTA with OCT among consecutive vessel sections. We retrospectively compared 188 consecutive plaques and 84 normal sections in 41 vessels from 40 consecutive patients referred for chest pain evaluation who had both CCTA and OCT with a median time lapse of 1 day. The distance to reference points were used to co-register between the modalities and the diagnostic performance of CCTA was evaluated against OCT. Plaque categories evaluated by CT were calcified, non-calcified and mixed. The diagnostic performance of CCTA was excellent for detecting any plaque identified by OCT with the sensitivity, specificity, negative and positive predictive values and accuracy of 92%, 98%, 99%, 84% and 93%, respectively. The lower than expected negative predictive value was due to failure of detecting sub-millimeter calcified (≤ 0.25 mm2) (N = 12) and non-calcified plaques (N = 4). Misclassification of plaque type accounted for majority of false negative findings (25/41, 61%) which was most prevalent among the mixed plaque (19/41, 46%). There was calcification within mixed plaques (N = 5) seen by CCTA but missed by OCT. Our findings suggest that CCTA is excellent at identifying coronary plaques except those sub-millimeter in size which likely represent very early atherosclerosis, although the clinical implication of very mild atherosclerosis is yet to be determined.

Abstract Hypoxia in coastal waters and lakes is widely recognized as a detrimental environmental issue, yet we lack a comparable understanding of hypoxia in rivers. We investigated controls on hypoxia using 118 million paired observations of dissolved oxygen (DO) concentration and water temperature in over 125,000 locations in rivers from 93 countries. We found hypoxia (DO