Imaging-based detection of anterior chamber inflammation: a comparative diagnostic accuracy study.

PURPOSE: We investigated the impact of operator parameters on the diagnostic performance of danterior segment optical coherence tomography (AS-OCT) in anterior uveitis. DESIGN: Prospective comparative diagnostic analysis. METHODS: Setting: Single site. STUDY POPULATION: Children aged under 18 years with anterior uveitis, recruited consecutively. OBSERVATION PROCEDURES: Index testing: Optovue RTVue80 AS-OCT using 'low-volume' (LV, horizontal and vertical cross-sections) and 'high-volume' (HV, 68 horizontal cross-sections) protocols. Reference testing: slit lamp examination with anterior chamber inflammation graded using standardisation of uveitis nomenclature (SUN). MAIN OUTCOME MEASURE: Index test performance metrics (sensitivity, specificity, likelihood ratios), utility for 'ruling-in' and 'ruling-out' disease (positive / negative predictive values, PPV/NPV), receiver operating characteristic (ROC) curves to explore the impact of different imaging derived metrics, multivariable multilevel regression analyses to quantify correlation of index to reference testing, and repeatability indices across protocols. RESULTS: 40 children (77 eyes: 51 eyes at SUN grade 0, 10 at SUN0.5+, 8 at SUN1+, 8 SUN≥2+ or higher) were included. There was high repeatability across protocols (0.98, p<0.001, 95% CI 0.75-1.0). OCT resulted in strong predictive values for 'ruling-out' (LV-scan NPV 82.9%, 95% CI 71.5 - 90.4%; HV-scan NPV 100%, 95% CI 3% to 100%), and but less predictive value for 'ruling-in' SUN≥0.5+ (LV-scan PPV 52.8% 95% CI 41.5 - 63.7%; HV-scan PPV 34.2%, 95% CI 33.3 to 35.1%). Detection of more than 1 cell within a cross sectional scan was strongly suggestive of clinical activity, with area under the curve of 0.76 (95% CI 0.62 - 0.89) for SUN≥0.5+, and 0.85 (95% CI 0.73- 0.98), for the detection of SUN≥1+. Cell count correlated with SUN grades at higher levels of inflammation (SUN≥2+ both protocols, SUN≥1+ HV-scans). There was an independent positive association between age and AS-OCT cell (adjusted correlation coefficient 0.2 cells for each additional year of age). CONCLUSIONS: Operator dependent factors impact the diagnostic and quantification performance of AS-OCT for anterior chamber inflammation. However, the strong, 'dose-respondent' correlation of low-volume protocols with SUN grading promises clinical utility without the storage and analysis burden of high-volume approaches. Further work will involve exploration of the need for age-specific image metric interpretation.

Effects of Texas State Agency Integration on Mental Health Service Use Among Individuals with Co-occurring Cognitive Disabilities and Mental Health Conditions.

This study uses Texas's 2017 integration of the state disability and mental health agencies as a case study, combining interviews with Texas agency and advocacy organization leaders to examine perceptions of agency integration and augmented synthetic control analyses of 2014-2020 Medical Expenditure Panel Survey to examine impacts on mental health service use among individuals with co-occurring cognitive disabilities (including intellectual and developmental disabilities) and mental health conditions. Interviewees described the intensive process of agency integration and identified primarily positive (e.g., decreased administrative burden) impacts of integration. Quantitative analyses indicated no effects of integration on receipt of mental health-related services among people with co-occurring conditions. While leaders identified some potentially beneficial impacts of state agency integration, the limited impact of integration beyond the agency suggests that interventions at multiple levels of the service system, including those targeting providers, are needed to better meet the mental health service needs for this population.

Barriers and Facilitators to Integrating Acupuncture into the U.S. Health Care System: A Scoping Review.

Background: Acupuncture is a widely practiced complementary and integrative health modality that has multiple clinical applications. The use of acupuncture in the United States is rapidly increasing. Although studies have shown the efficacy and effectiveness of acupuncture for various ailments, the integration of acupuncture into the U.S. health care system remains a challenge. Little is known about the factors affecting this integration. Objective: To provide a systematic review of the barriers and facilitators affecting the integration of acupuncture into the U.S. health care system. Methods: Four electronic databases were searched. Three independent reviewers were involved in the screening and data charting processes. Findings were synthesized and categorized into four levels based on the Social Ecological Model. Results: A total of 22 studies were included in the final review. The barriers and facilitators affecting the integration of acupuncture were mapped into four levels (individual, interpersonal, organizational, and policy). The most frequently reported barriers and facilitators were mapped into the Social Ecological Model constructs within the "Individual" level (i.e., beliefs and attitudes of acupuncture, and practical issues) and the "Organizational" level (i.e., credentialing, space and facility, referral system). Conclusion: This review has identified and synthesized the breadth of evidence on the barriers and facilitators to the integration of acupuncture into the U.S. health care system. Results of this review will guide future implementation studies to develop and test implementation strategies to integrate acupuncture into the U.S. health care system.

Unleashing anti-tumour immunity: dietary restriction and exercise interventions adjunct to chemotherapy for cancer patients.

Conventional chemotherapies can stimulate the immune system by increasing tumour antigenicity (e.g., neoantigen exposure to immune cells) and altering adjuvanticity in the tumour (e.g., danger associated molecular patterns and cytokines). These molecules promote the recruitment, activation, and maturation of dendritic cells, which in turn, prime and activate cytotoxic T cells against tumour cells. However, several factors can decrease the immunostimulatory efficacy of chemotherapeutic agents. These include reduced tumour cell antigenicity and adjuvanticity and compromised immune function at a local and systemic level. Findings from preclinical studies show that dietary restriction and exercise promote systemic changes that may help to restore immune system function through several mechanisms, including an enhanced infiltration and function of antitumoral immune cells and a decrease in immunosuppressive cells, leading to a reduction in tumour volume. In addition, dietary restriction and exercise training in mice have been shown to enhance the efficacy of chemotherapy. In human studies there is also emerging evidence that dietary restriction and exercise can impact the immune system towards a more antitumoral profile. In this review, we discuss the immunostimulatory effects of dietary restriction (caloric restriction and fasting) and exercise training in preclinical cancer models, and potential synergies with chemotherapy. We then review clinical studies assessing the effects of these interventions on immune-related endpoints and tumour responses. Finally, we propose that combining dietary restriction with exercise could be a promising strategy to increase chemotherapy efficacy.

Prescription of Nicotine Replacement Therapy for Hospitalized Tobacco Users.

OBJECTIVES: In hospitalized patients, cigarette smoking is linked to increased readmission rates, emergency department visits, and overall mortality. Smoking cessation reduces these risks, but many patients who smoke are unsuccessful in quitting. Nicotine replacement therapy (NRT) is an effective tool that assists patients who smoke with quitting. This study evaluates NRT prescriptions during and after hospitalization at a large health system for patients who smoke. METHODS: A retrospective cohort study was conducted to determine the number of patients who were prescribed NRT during an inpatient admission and at time of discharge from a network of nine hospitals across South Carolina between January 1, 2019 and January 1, 2023. RESULTS: This study included 20,757 patients identified as actively smoking with at least one hospitalization during the study period. Of the cohort, 34.9% were prescribed at least one prescription for NRT during their admission to the hospital. Of the patients identified, 12.6% were prescribed NRT upon discharge from the hospital. CONCLUSIONS: This study identified significantly low rates of NRT prescribed to smokers during hospitalization and at discharge. Although the management of chronic conditions is typically addressed in the outpatient setting, hospitalization may provide an opportunity for patients to initiate health behavior changes. The low rates of prescriptions for NRT present an opportunity to improve tobacco treatment during hospitalization and beyond.

Utility of serial troponin testing for emergency department patients with syncope.

BACKGROUND: For emergency department (ED) patients with syncope, cardiac troponin can identify acute coronary syndrome (ACS) and prognosticate for 30-day serious adverse events. However, it is unclear if serial testing improves diagnostic yield and prognostication. METHODS: This was a secondary analysis of data from two prospective studies conducted to develop the Canadian Syncope Risk Score. Adults (age ≥ 16 years) with syncope were enrolled, and patient characteristics, vital signs, physician diagnostic impression, electrocardiogram and troponin results, and adjudicated 30-day serious adverse event were collected. The primary outcome was the detection of a serious adverse event within 30 days of ED disposition. The secondary outcome was comparison of ED length of stay among patients with single versus serial troponin measurements. RESULTS: 4996 patients [mean age 64.5 (SD 18.8) years, 52.2% male] were included: 4397 (89.8%) with single troponin [232 (5.3%) with serious adverse event in the ED and 203 (4.6%) after ED disposition]; 499 (10.2%) patients with > 1 troponin measurement [39 (7.8%) with serious adverse event in ED and 60 (12.0%) after ED disposition]. Among those with serial measurements, 10 patients (2.0%) had a rise from below to above the 99th percentile threshold, of whom 4 patients (0.8%) suffered serious adverse event: two with arrhythmias diagnosed on electrocardiogram, one with ACS and one suffered respiratory failure. Nine patients (1.8%) had Canadian Syncope Risk Score risk reclassification based on serial measurement, and none suffered 30-day serious adverse event. Median ED length of stay was significantly longer for patients with serial testing (5.6 vs. 3.8 h, p < 0.001). CONCLUSIONS: The initial troponin measurement was sufficient for serious adverse event detection and in-ED risk stratification. Serial troponin testing does not improve the diagnostic yield or prognostication and should be reserved for patients with ongoing symptoms or electrocardiogram findings suggestive of cardiac ischemia.

ABSTRAIT: CONTEXTE: Pour les patients du service des urgences (DE) atteints de syncope, la troponine cardiaque peut identifier le syndrome coronarien aigu (SCA) et le pronostic pour les événements indésirables graves de 30 jours. Cependant, il n'est pas clair si les tests en série améliorent le rendement diagnostique et le pronostic. MéTHODES: Il s'agissait d'une analyse secondaire des données de deux études prospectives menées pour élaborer le Canadian Syncope Risk Score. Des adultes (âgés de 16 ans) atteints de syncope ont été recrutés, et les caractéristiques du patient, les signes vitaux, l'empreinte diagnostique du médecin, les résultats de l'électrocardiogramme et de la troponine, ainsi que les événements indésirables graves évalués à 30 jours ont été recueillis. Le critère de jugement principal était la détection d'un événement indésirable grave dans les 30 jours suivant la décision de l'urgence. Le critère de jugement secondaire était la comparaison de la durée de séjour à l'urgence chez les patients ayant une seule mesure de troponine par rapport à la mesure en série. RéSULTATS: 4 996 patients [âge moyen 64,5 (ET 18,8) ans, 52,2 % d'hommes] ont été inclus : 4 397 (89,8 %) avec une seule troponine [232 (5,3 %) avec un événement indésirable grave à l'urgence et 203 (4,6 %) après l'urgence]; 499 (10,2 %) patients avec > 1 mesure de la troponine [39 (7,8 %) avec événement indésirable grave à l'urgence et 60 (12,0 %) après la décision à l'urgence]. Parmi les patients ayant fait l'objet de mesures en série, 10 (2,0 %) présentaient une augmentation du seuil inférieur à supérieur au seuil du 99e percentile, dont 4 (0,8 %) ont subi un événement indésirable grave : deux avec arythmies diagnostiquées par électrocardiogramme, un avec SCA et un avec insuffisance respiratoire. Neuf patients (1,8 %) ont présenté une reclassification du risque selon le score canadien de risque de syncope en fonction de la mesure en série, et aucun n'a subi d'événement indésirable grave de 30 jours. La durée médiane de séjour aux urgences était significativement plus longue pour les patients ayant subi des tests en série (5,6 vs. 3,8 heures, p < 0,001). CONCLUSIONS: La mesure initiale de la troponine était suffisante pour la détection des effets indésirables graves et la stratification des risques aux urgences. Les tests de troponine en série n'améliorent pas le rendement diagnostique ou le pronostic et doivent être réservés aux patients présentant des symptômes continus ou des résultats d'électrocardiogramme suggérant une ischémie cardiaque.

Semi-field evaluation of aquatic predators for the control of Anopheles funestus in rural south-eastern Tanzania.

BACKGROUND: Biological control is a promising alternative or complementary approach for controlling vector populations in response to the spread of insecticide resistance in malaria vectors. This study evaluated the efficacy of three selected potential predators on the density and fitness parameters of Anopheles funestus larvae in rural Tanzania. METHODS: Common predator families Aeshnidae (dragonflies), Coenagrionidae (damselflies), and Notonectidae (backswimmers) and An. funestus group larvae were collected from natural aquatic habitats in rural south-eastern Tanzania. Predators were starved for 12-h while An. funestus larvae were given fish food before starting the experiment. Anopheles funestus larvae were placed into artificial habitats containing predators, exposing them to potential predation. The number of surviving An. funestus larvae were counted every 24-h. An emergence traps were placed at the top of artificial habitats to capture emerging mosquitoes. Emerged mosquitoes were monitored until they died. Female wings were measured and used as a proxy for body size. Generalized linear mixed models (GLMM) with binomial variates at 95% CI and Cox proportional hazard models were used to assess the proportion of dead mosquitoes and the daily survival determined. RESULTS: There were significant differences in the number of emerged mosquitoes between the treatment and control groups (P < 0.001). Thus, all predator species played a significant role in reducing the density of An. funestus mosquitoes (P < 0.001). Furthermore, these predators had notable effects on the fitness parameters and survival of emerged mosquitoes (P < 0.001). Among the three predators studied, Coenagrionidae (damselflies) were most efficient followed by Notonectidae (backswimmers), with Aeshnidae (dragonflies) being the least efficient. CONCLUSION: Selected aquatic predators have the potential to reduce the survival and density of An. funestus larvae. They might eventually be included within an integrated malaria vector control strategy, ultimately leading to a reduction in malaria transmission.

Whole-genome sequencing of Western Canadian Borrelia spp. collected from diverse tick and animal hosts reveals short-lived local genotypes interspersed with longer-lived continental genotypes.

Changing climates are allowing the geographic expansion of ticks and their animal hosts, increasing the risk of Borrelia-caused zoonoses in Canada. However, little is known about the genomic diversity of Borrelia from the west of the Canadian Rockies and from the tick vectors Ixodes pacificus, Ixodes auritulus and Ixodes angustus. Here, we report the whole-genome shotgun sequences of 51 Borrelia isolates from multiple tick species collected on a range of animal hosts between 1993 and 2016, located primarily in coastal British Columbia. The bacterial isolates represented three different species from the Lyme disease-causing Borrelia burgdorferi sensu lato genospecies complex [Borrelia burgdorferi sensu stricto (n=47), Borrelia americana (n=3) and Borrelia bissettiae (n=1)]. The traditional eight-gene multi-locus sequence typing (MLST) strategy was applied to facilitate comparisons across studies. This identified 13 known Borrelia sequence types (STs), established 6 new STs, and assigned 5 novel types to the nearest sequence types. B. burgdorferi s. s. isolates were further differentiated into ten ospC types, plus one novel ospC with less than 92 % nucleotide identity to all previously defined ospC types. The MLST types resampled over extended time periods belonged to previously described STs that are distributed across North America. The most geographically widespread ST, ST.12, was isolated from all three tick species. Conversely, new B. burgdorferi s. s. STs from Vancouver Island and the Vancouver region were only detected for short periods, revealing a surprising transience in space, time and host tick species, possibly due to displacement by longer-lived genotypes that expanded across North America.This article contains data hosted by Microreact.

Concurrent Validity of the Anxiety Disorders Section of the Anxiety Disorder Interview Schedule- Autism Spectrum Addendum (ADIS-ASA) in Autistic Youth.

PURPOSE: Examine the concurrent validity of specific Anxiety Disorders Section of the Anxiety Disorder Interview Schedule for DSM-IV-Autism Spectrum Addendum (ADIS-ASA)-Parent Interview in a sample of 167 autistic youth who met diagnostic criteria for an anxiety-related disorder (Mage = 9.91; 78.4% male; 82% non-Hispanic; 77.67% White). METHODS: Concurrent validity of Diagnostic and Statistical Manual (DSM)-defined ADIS-ASA anxiety disorder diagnostic caseness was examined via relations with (a) parent-reported dimensions of youth anxiety symptomology and (b) dimensional measures of youth anxiety-related functional impairment, respectively, using logistic regression models and point-biserial correlations. RESULTS: Significant relations were found between separation anxiety disorder and social anxiety disorder (but not generalized anxiety disorder nor obsessive-compulsive disorder) caseness, respectively, and theoretically consistent facets of dimensional youth anxiety symptomology. Relations between ADIS-ASA diagnostic caseness and youth functional impairment-related variables revealed that only separation anxiety disorder demonstrated robust evidence of convergent validity. CONCLUSION: Despite mixed findings concerning relations between ADIS-ASA anxiety disorder diagnostic caseness and dimensional measures of anxiety severity and anxiety-related impairment, the present findings provide further support for the status of the ADIS-ASA as a gold standard for assessment of anxiety in autistic youth. This work also highlights the importance of continuing to improve precision in measurement of anxiety symptomology in autistic youth, with implications for clinical assessment.

Iohexol Plasma Clearance Measurement Protocol Standardization for Adults - a Consensus Paper of the European Kidney Function Consortium.

International consensus supports the development of standardized protocols for measured glomerular filtration rate (mGFR) to facilitate the integration of mGFR testing in both clinical and research settings. To this end, the European Kidney Function Consortium convened an international group of experts with relevant experience in mGFR. The working group performed an extensive literature search to inform the development of recommendations for mGFR determination using one-compartment plasma clearance models and iohexol as the exogenous filtration marker. Iohexol was selected as it is non-radio labeled, inexpensive, safe, can be assayed at a central laboratory, and the other commonly used non-radio labeled tracers have been (inulin) or are soon to be (iothalamate) discontinued. A plasma clearance model was selected over urine clearance as it requires no urine collection. A one-compartment was preferred to two compartments as it requires fewer samples. The recommendations are based on published evidence complemented by expert opinion. The consensus paper covers practical advice for patients and health professionals, preparation, administration and safety aspects of iohexol, laboratory analysis, blood sample collection and sampling times using both multiple and single sample protocols, description of the mGFR mathematical calculations as well as implementation strategies. Supplementary materials include patient and provider information sheets, standard operating procedures, a study protocol template, and support for mGFR calculation.

SERPINA3 is a marker of cartilage differentiation and is essential for the expression of extracellular matrix genes during early chondrogenesis.

Serine proteinase inhibitors (serpins) are a family of structurally similar proteins which regulate many diverse biological processes from blood coagulation to extracellular matrix (ECM) remodelling. Chondrogenesis involves the condensation and differentiation of mesenchymal stem cells (MSCs) into chondrocytes which occurs during early development. Here, and for the first time, we demonstrate that one serpin, SERPINA3 (gene name SERPINA3, protein also known as alpha-1 antichymotrypsin), plays a critical role in chondrogenic differentiation. We observed that SERPINA3 expression was markedly induced at early time points during in vitro chondrogenesis. We examined the expression of SERPINA3 in human cartilage development, identifying significant enrichment of SERPINA3 in developing foetal cartilage compared to total limb, which correlated with well-described markers of cartilage differentiation. When SERPINA3 was silenced using siRNA, cartilage pellets were smaller and contained lower proteoglycan as determined by dimethyl methylene blue assay (DMMB) and safranin-O staining. Consistent with this, RNA sequencing revealed significant downregulation of genes associated with cartilage ECM formation perturbing chondrogenesis. Conversely, SERPINA3 silencing had a negligible effect on the gene expression profile during osteogenesis suggesting the role of SERPINA3 is specific to chondrocyte differentiation. The global effect on cartilage formation led us to investigate the effect of SERPINA3 silencing on the master transcriptional regulator of chondrogenesis, SOX9. Indeed, we observed that SOX9 protein levels were markedly reduced at early time points suggesting a role for SERPINA3 in regulating SOX9 expression and activity. In summary, our data support a non-redundant role for SERPINA3 in enabling chondrogenesis via regulation of SOX9 levels.

Therapeutic DBS for OCD Suppresses the Default Mode Network.

BACKGROUND: Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) is an emerging treatment for severe, refractory obsessive-compulsive disorder (OCD). The therapeutic effects of DBS are hypothesized to be mediated by direct modulation of a distributed cortico-striato-thalmo-cortical network underlying OCD symptoms. However, the exact underlying mechanism by which DBS exerts its therapeutic effects still remains unclear. METHOD: In five participants receiving DBS for severe, refractory OCD (3 responders, 2 non-responders), we conducted a DBS On/Off cycling paradigm during the acquisition of functional MRI to determine the network effects of stimulation across a variety of bipolar configurations. We also performed tractography using diffusion-weighted imaging (DWI) to relate the functional impact of DBS to the underlying structural connectivity between active stimulation contacts and functional brain networks. RESULTS: We found that therapeutic DBS had a distributed effect, suppressing BOLD activity within regions such as the orbitofrontal cortex, dorsomedial prefrontal cortex, and subthalamic nuclei compared to non-therapeutic configurations. Many of the regions suppressed by therapeutic DBS were components of the default mode network (DMN). Moreover, the estimated stimulation field from the therapeutic configurations exhibited significant structural connectivity to core nodes of the DMN. CONCLUSIONS: Therapeutic DBS for OCD suppresses BOLD activity within a distributed set of regions within the DMN relative to non-therapeutic configurations. We propose that these effects may be mediated by interruption of communication through structural white matter connections surrounding the DBS active contacts.

Population genetics meets ecology: a guide to individual-based simulations in continuous landscapes.

Individual-based simulation has become an increasingly crucial tool for many fields of population biology. However, implementing realistic and stable simulations in continuous space presents a variety of difficulties, from modeling choices to computational efficiency. This paper aims to be a practical guide to spatial simulation, helping researchers to implement realistic and efficient spatial, individual-based simulations and avoid common pitfalls. To do this, we delve into mechanisms of mating, reproduction, density-dependent feedback, and dispersal, all of which may vary across the landscape, discuss how these affect population dynamics, and describe how to parameterize simulations in convenient ways (for instance, to achieve a desired population density). We also demonstrate how to implement these models using the current version of the individual-based simulator, SLiM. Since SLiM has the capacity to simulate genomes, we also discuss natural selection---in particular, how genetic variation can affect demographic processes. Finally, we provide four short vignettes: simulations of pikas that shift their range up a mountain as temperatures rise; mosquitoes that live in rivers as juveniles and experience seasonally changing habitat; cane toads that expand across Australia, reaching 120 million individuals; and monarch butterflies whose populations are regulated by an explicitly modeled resource (milkweed).

Mechanistic insights into steroid hormone-mediated regulation of the androgen receptor gene.

Expression of the androgen receptor is key to the response of cells and tissues to androgenic steroids, such as testosterone or dihydrotestosterone, as well as impacting the benefit of hormone-dependent therapies for endocrine diseases and hormone-dependent cancers. However, the mechanisms controlling androgen receptor expression are not fully understood, limiting our ability to effectively promote or inhibit androgenic signalling therapeutically. An autoregulatory loop has been described in which androgen receptor may repress its own expression in the presence of hormone, although the molecular mechanisms are not fully understood. In this work, we elucidate the mechanisms of autoregulation and demonstrate, for the first time, that a similar repression of the AR gene is facilitated by the progesterone receptor. We show that the progesterone receptor, like the androgen receptor binds to response elements within the AR gene to effect transcriptional repression in response to hormone treatment. Mechanistically, this repression involves hormone-dependent histone deacetylation within the AR 5'UTR region and looping between sequences in intron 2 and the transcription start site (TSS). This novel pathway controlling AR expression in response to hormone stimulation may have important implications for understanding cell or tissue selective receptor signalling.

A novel Nav1.5-dependent feedback mechanism driving glycolytic acidification in breast cancer metastasis.

Solid tumours have abnormally high intracellular [Na+]. The activity of various Na+ channels may underlie this Na+ accumulation. Voltage-gated Na+ channels (VGSCs) have been shown to be functionally active in cancer cell lines, where they promote invasion. However, the mechanisms involved, and clinical relevance, are incompletely understood. Here, we show that protein expression of the Nav1.5 VGSC subtype strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. In addition, VGSCs are functionally active in patient-derived breast tumour cells, cell lines, and cancer-associated fibroblasts. Knockdown of Nav1.5 in a mouse model of breast cancer suppresses expression of invasion-regulating genes. Nav1.5 activity increases ATP demand and glycolysis in breast cancer cells, likely by upregulating activity of the Na+/K+ ATPase, thus promoting H+ production and extracellular acidification. The pH of murine xenograft tumours is lower at the periphery than in the core, in regions of higher proliferation and lower apoptosis. In turn, acidic extracellular pH elevates persistent Na+ influx through Nav1.5 into breast cancer cells. Together, these findings show positive feedback between extracellular acidification and the movement of Na+ into cancer cells which can facilitate invasion. These results highlight the clinical significance of Nav1.5 activity as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment.

A safety and feasibility analysis on the use of cold-stored platelets in combat trauma.

BACKGROUND: Damage-control resuscitation has come full circle, with the use of whole blood and balanced components. Lack of platelet availability may limit effective damage-control resuscitation. Platelets are typically stored and transfused at room temperature and have a short shelf-life, while cold-stored platelets (CSPs) have the advantage of a longer shelf-life. The US military introduced CSPs into the battlefield surgical environment in 2016. This study is a safety analysis for the use of CSPs in battlefield trauma. METHODS: The Department of Defense Trauma Registry and Armed Services Blood Program databases were queried to identify casualties who received room-temperature-stored platelets (RSPs) or both RSPs and CSPs between January 1, 2016, and February 29, 2020. Characteristics of recipients of RSPs and RSPs-CSPs were compared and analyzed. RESULTS: A total of 274 patients were identified; 131 (47.8%) received RSPs and 143 (52.2%) received RSPs-CSPs. The casualties were mostly male (97.1%), similar in age (31.7 years), with a median Injury Severity Score of 22. There was no difference in survival for recipients of RSPs (88.5%) versus RSPs-CSPs (86.7%; p = 0.645). Adverse events were similar between the two cohorts. Blood products received were higher in the RSPs-CSPs cohort compared with the RSPs cohort. The RSPs-CSPs cohort had more massive transfusion (53.5% vs. 33.5%, p = 0.001). A logistic regression model demonstrated that use of RSPs-CSPs was not associated with mortality, with an adjusted odds ratio of 0.96 (p > 0.9; 95% confidence interval, 0.41-2.25). CONCLUSION: In this safety analysis of RSPs-CSPs compared with RSPs in a combat setting, survival was similar between the two groups. Given the safety and logistical feasibility, the results support continued use of CSPs in military environments and further research into how to optimize resuscitation strategies. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Structural basis for the inhibition of ßFXIIa by garadacimab.

Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of hereditary angioedema (HAE). Here, we describe a high-resolution cryoelectron microscopy (cryo-EM) structure of the beta-chain from FXIIa (ßFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to ßFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This structural mechanism is likely the primary contributor to the inhibition of activated FXIIa proteolytic activity in HAE. Garadacimab Fab-ßFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXIIa. Structural analysis with other bona fide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a surprisingly similar mechanism of ßFXIIa inhibition by garadacimab. In summary, the garadacimab Fab-ßFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes.

Expanding Access to Contraceptive Services in a Family Medicine Residency Clinic: The Rapid Access to Contraception Clinic Model.

BACKGROUND AND OBJECTIVES: Learning to provide long-acting reversible contraception (LARC) during family medicine residency is an important step in building capacity for the primary care workforce to meet the reproductive health care needs of communities. We aimed to measure the impact of adding a contraceptive visit type (CVT) allowing for rapid access to contraception (RAC) on family medicine resident LARC procedure numbers. METHODS: Our program created a CVT in which patients were seen only for contraceptive services. We added the CVT to third-year family medicine resident continuity clinic schedules and a block of CVTs (the RAC clinic) to the third-year gynecology rotation. Residents self-reported LARC procedure numbers performed throughout residency, and the totals were compared for graduating residents from 2023 (post-RAC cohort) to 2022 graduates and 2018-2022 graduates (pre-RAC cohort). RESULTS: Post-RAC cohort residents reported a statistically significant increase in intrauterine device (IUD; P=.015) and contraceptive implant (P=.010) removals compared to the 2022 pre-RAC cohort. Insertions of IUDs and contraceptive implants were unchanged when compared to the pre-RAC cohort. IUD removals (P=.004) and insertions (P=.034), and contraceptive implant removals (P=.028) were significantly increased for post-RAC compared to 2022 graduates, with no difference in contraceptive implant insertions (P=.211). CONCLUSIONS: The addition of the CVT and RAC clinic contributed to an increase in LARC removals in both comparisons, and IUD insertions between 2022 and 2023. This clinic model offers an opportunity for other family medicine residency programs to improve access to contraceptive services and increase resident training in LARC management.