Looking after bubba for all our mob: Aboriginal and Torres Strait Islander community experiences and perceptions of stillbirth.

The stillbirth rate among Aboriginal and Torres Strait Islander women and communities in Australia is around double that of non-Indigenous women. While the development of effective prevention strategies during pregnancy and improving care following stillbirth for women and families in communities has become a national priority, there has been limited progress in stillbirth disparities. With community permission, this study aimed to gain a better understanding of community experiences, perceptions, and priorities around stillbirth. We undertook an Indigenous researcher-led, qualitative study, with community consultations guided by a cultural protection protocol and within an unstructured research framework. A total of 18 communities were consulted face-to-face through yarning interviews, focus groups and workshops. This included 54 community member and 159 health professional participants across remote, regional, and urban areas of Queensland, Western Australia, Victoria, South Australia, and Northern Territory. Thematic analysis of consultation data identified common themes across five focus/priority areas to address stillbirth: Stillbirth or Sorry Business Baby care needs to be family-centered; using Indigenous "ways of knowing, being, and doing" to ensure cultural safety; application of Birthing on Country principles to maternal and perinatal care; and yarning approaches to improve communication and learning or education. The results underscore the critical need to co-design evidence-based, culturally appropriate, and community-acceptable resources to help reduce existing disparities in stillbirth rates.

Clinical, Functional, and Quality of Life Outcomes after Computer Assisted Vacuum Thrombectomy for Pulmonary Embolism: Interim Analysis of the STRIKE-PE Study.

PURPOSE: To report 90-day results from the first interim analysis of the STRIKE-PE study, which is evaluating safety, effectiveness, and functional and quality of life (QoL) outcomes of Computer Assisted Vacuum Thrombectomy (CAVT) with the Indigo Aspiration System for the treatment of acute pulmonary embolism (PE). METHODS: STRIKE-PE is a prospective, international, multicenter study that will enroll 600 adult patients with acute PE of ≤14 days and a right ventricle/left ventricle (RV/LV) ratio of ≥0.9 who receive first-line endovascular treatment with CAVT. Primary endpoints are change in RV/LV ratio and incidence of composite major adverse events (MAEs) within 48 hours. Secondary endpoints include functional and QoL assessments. RESULTS: The first 150 consecutive patients were treated with Lightning 12 CAVT. Mean age was 61.3 years, 54.7% were men, 94.7% presented with intermediate-risk PE, and 5.3% presented with high-risk PE. Median thrombectomy and procedure times were 33.5 minutes and 70 minutes, respectively, resulting in a mean reduction in systolic pulmonary artery pressure of 16.3% (P < .001). Mean RV/LV ratio decreased from 1.39 before thrombectomy to 1.01 at 48 hours, a 25.7% reduction (P < .001). Four patients (2.7%) experienced a composite MAE within 48 hours. At 90-day follow-up, patients exhibited statistically significant improvements in the Borg dyspnea scale and QoL measures, and the NYHA class distribution returned to that reported before the index PE. CONCLUSION: These interim results demonstrate a rapid reduction in RV/LV ratio, achieved with a fast thrombectomy time while maintaining safety. This is accompanied by improvements in 90-day functional and QoL outcomes.

Advancing Primary Ciliary Dyskinesia Diagnosis through High-Speed Video Microscopy Analysis.

Primary ciliary dyskinesia (PCD) is an inherited disorder that impairs motile cilia, essential for respiratory health, with a reported prevalence of 1 in 16,309 within Hispanic populations. Despite 70% of Puerto Rican patients having the RSPH4A [c.921+3_921+6del (intronic)] founder mutation, the characterization of the ciliary dysfunction remains unidentified due to the unavailability of advanced diagnostic modalities like High-Speed Video Microscopy Analysis (HSVA). Our study implemented HSVA for the first time on the island as a tool to better diagnose and characterize the RSPH4A [c.921+3_921+6del (intronic)] founder mutation in Puerto Rican patients. By applying HSVA, we analyzed the ciliary beat frequency (CBF) and pattern (CBP) in native Puerto Rican patients with PCD. Our results showed decreased CBF and a rotational CBP linked to the RSPH4A founder mutation in Puerto Ricans, presenting a novel diagnostic marker that could be implemented as an axillary test into the PCD diagnosis algorithm in Puerto Rico. The integration of HSVA technology in Puerto Rico substantially enhances the PCD evaluation and diagnosis framework, facilitating prompt detection and early intervention for improved disease management. This initiative, demonstrating the potential of HSVA as an adjunctive test within the PCD diagnostic algorithm, could serve as a blueprint for analogous developments throughout Latin America.

High energy density in artificial heterostructures through relaxation time modulation.

Electrostatic capacitors are foundational components of advanced electronics and high-power electrical systems owing to their ultrafast charging-discharging capability. Ferroelectric materials offer high maximum polarization, but high remnant polarization has hindered their effective deployment in energy storage applications. Previous methodologies have encountered problems because of the deteriorated crystallinity of the ferroelectric materials. We introduce an approach to control the relaxation time using two-dimensional (2D) materials while minimizing energy loss by using 2D/3D/2D heterostructures and preserving the crystallinity of ferroelectric 3D materials. Using this approach, we were able to achieve an energy density of 191.7 joules per cubic centimeter with an efficiency greater than 90%. This precise control over relaxation time holds promise for a wide array of applications and has the potential to accelerate the development of highly efficient energy storage systems.

VA Providers' Perceptions of Cannabis Use Policies in a Legalized and Nonlegalized State.

Background: Providers in the Department of Veterans Affairs (VA) system are caught between two opposing sets of laws regarding cannabis and cannabidiol (CBD) use by their patients. As VA is a federal agency, it must abide by federal regulations, including that the Food and Drug Administration classifies cannabis as a Schedule 1 drug and therefore cannot recommend or help Veterans obtain it. Meanwhile, 38 states have passed legislation, legalizing medical use of cannabis. Objective: The goal of this project is to examine how VA providers understand state and federal laws, and VA policies about cannabis and CBD use, and to learn more about providers' experiences with patients who use cannabis and CBD within a legalized and nonlegalized state. Materials and Methods: We identified 432 health care providers from two VA facilities in northern Illinois (IL) where medical and recreational cannabis is legal, and two VA facilities in southern Wisconsin (WI) where medical and recreational cannabis is illegal. Participants were invited via e-mail to complete an anonymous online survey, including 31 closed- and open-ended questions about knowledge of state and federal laws and VA policies regarding cannabis and CBD oil, thoughts about the value of cannabis or CBD for treating medical conditions, and behaviors regarding cannabis use by their patients. Results: We received 50 responses (IL N=20, WI N=30). Providers in both states were knowledgeable about cannabis laws in their state but unsure whether they could recommend cannabis. There were more providers who were unclear if they could have a conversation about cannabis with their VA patients in WI compared with IL. Providers were more likely to agree than disagree that cannabis can be beneficial, χ2 (1, 49)=4.74, p=0.030. Providers in both states (81.6%) believe cannabis use is acceptable for end-of-life care, but responses varied for other conditions and symptoms. Discussion: Findings suggest that VA providers could use more guidance on what is allowable within their VA facilities and how state laws affect their practice. Education about safety related to cannabis and other drug interactions would be helpful. There is limited information about possible interactions, warranting future research.

Electrodermal and central measures of the tonic orienting reflex (OR).

Sokolov described both phasic and tonic aspects of the Orienting Reflex (OR), but subsequent research and theory development has focussed primarily on the phasic OR at the expense of the tonic OR. The present study used prestimulus skin conductance level (SCL) during a dishabituation paradigm to model the tonic OR, examining its amplitude patterning over repeated standard stimulus presentations and a change stimulus. We expected sensitisation (increased amplitude) following the initial and change trials, and habituation (decrement) over the intervening trials. Prestimulus EEG alpha level was explored as a potential central measure of the tonic OR (as an inverse correlate), examining its pattern over stimulus repetition and change in relation to the SCL model. We presented a habituation series of innocuous auditory stimuli to two groups (each N = 20) at different ISIs (Long 13-15 s and Short 5-7 s) and recorded electrodermal and EEG data during two counterbalanced conditions; Indifferent: no task requirements; Significant: silent counting. Across groups and conditions, prestimulus SCLs and alpha amplitudes generally showed the expected trials patterns, confirming our main hypotheses. Findings have important implications for including the assessment of Sokolov's tonic OR in modelling central and autonomic nervous system interactions of fundamental attention and learning processes.

Preclinical Characterization of the Anti-Leukemia Activity of the CD33/CD16a/NKG2D Immune-Modulating TriNKET® CC-96191.

Increasing efforts are focusing on natural killer (NK) cell immunotherapies for AML. Here, we characterized CC-96191, a novel CD33/CD16a/NKG2D immune-modulating TriNKET®. CC-96191 simultaneously binds CD33, NKG2D, and CD16a, with NKG2D and CD16a co-engagement increasing the avidity for, and activation of, NK cells. CC-96191 was broadly active against human leukemia cells in a strictly CD33-dependent manner, with maximal efficacy requiring the co-engagement of CD16a and NKG2D. A frequent CD33 single nucleotide polymorphism, R69G, reduced CC-96191 potency but not maximal activity, likely because of reduced CD33 binding. Similarly, the potency, but not the maximal activity, of CC-96191 was reduced by high concentrations of soluble CD33; in contrast, the soluble form of the NKG2D ligand MICA did not impact activity. In the presence of CD33+ AML cells, CC-96191 activated NK cells but not T cells; while maximum anti-AML efficacy was similar, soluble cytokine levels were 10- to >100-fold lower than with a CD33/CD3 bispecific antibody. While CC-96191-mediated cytolysis was not affected by ABC transporter proteins, it was reduced by anti-apoptotic BCL-2 family proteins. Finally, in patient marrow specimens, CC-96191 eliminated AML cells but not normal monocytes, suggesting selectivity of TriNKET-induced cytotoxicity toward neoplastic cells. Together, these findings support the clinical exploration of CC-96191 as in NCT04789655.

Fine tuning of CpG spatial distribution with DNA origami for improved cancer vaccination.

Multivalent presentation of ligands often enhances receptor activation and downstream signalling. DNA origami offers a precise nanoscale spacing of ligands, a potentially useful feature for therapeutic nanoparticles. Here we use a square-block DNA origami platform to explore the importance of the spacing of CpG oligonucleotides. CpG engages Toll-like receptors and therefore acts to activate dendritic cells. Through in vitro cell culture studies and in vivo tumour treatment models, we demonstrate that square blocks induce Th1 immune polarization when CpG is spaced at 3.5 nm. We observe that this DNA origami vaccine enhances DC activation, antigen cross-presentation, CD8 T-cell activation, Th1-polarized CD4 activation and natural-killer-cell activation. The vaccine also effectively synergizes with anti-PD-L1 for improved cancer immunotherapy in melanoma and lymphoma models and induces long-term T-cell memory. Our results suggest that DNA origami may serve as a platform for controlling adjuvant spacing and co-delivering antigens in vaccines.

Controlled formation of three-dimensional cavities during lateral epitaxial growth.

Epitaxial growth is a fundamental step required to create devices for the semiconductor industry, enabling different materials to be combined in layers with precise control of strain and defect structure. Patterning the growth substrate with a mask before performing epitaxial growth offers additional degrees of freedom to engineer the structure and hence function of the semiconductor device. Here, we demonstrate that conditions exist where such epitaxial lateral overgrowth can produce complex, three-dimensional structures that incorporate cavities of deterministic size. We grow germanium on silicon substrates patterned with a dielectric mask and show that fully-enclosed cavities can be created through an unexpected self-assembly process that is controlled by surface diffusion and surface energy minimization. The result is confined cavities enclosed by single crystalline Ge, with size and position tunable through the initial mask pattern. We present a model to account for the observed cavity symmetry, pinch-off and subsequent evolution, reflecting the dominant role of surface energy. Since dielectric mask patterning and epitaxial growth are compatible with conventional device processing steps, we suggest that this mechanism provides a strategy for developing electronic and photonic functionalities.

Improving the Efficiency of Inferences From Hybrid Samples for Effective Health Surveillance Surveys: Comprehensive Review of Quantitative Methods.

BACKGROUND: Increasingly, survey researchers rely on hybrid samples to improve coverage and increase the number of respondents by combining independent samples. For instance, it is possible to combine 2 probability samples with one relying on telephone and another on mail. More commonly, however, researchers are now supplementing probability samples with those from online panels that are less costly. Setting aside ad hoc approaches that are void of rigor, traditionally, the method of composite estimation has been used to blend results from different sample surveys. This means individual point estimates from different surveys are pooled together, 1 estimate at a time. Given that for a typical study many estimates must be produced, this piecemeal approach is computationally burdensome and subject to the inferential limitations of the individual surveys that are used in this process. OBJECTIVE: In this paper, we will provide a comprehensive review of the traditional method of composite estimation. Subsequently, the method of composite weighting is introduced, which is significantly more efficient, both computationally and inferentially when pooling data from multiple surveys. With the growing interest in hybrid sampling alternatives, we hope to offer an accessible methodology for improving the efficiency of inferences from such sample surveys without sacrificing rigor. METHODS: Specifically, we will illustrate why the many ad hoc procedures for blending survey data from multiple surveys are void of scientific integrity and subject to misleading inferences. Moreover, we will demonstrate how the traditional approach of composite estimation fails to offer a pragmatic and scalable solution in practice. By relying on theoretical and empirical justifications, in contrast, we will show how our proposed methodology of composite weighting is both scientifically sound and inferentially and computationally superior to the old method of composite estimation. RESULTS: Using data from 3 large surveys that have relied on hybrid samples composed of probability-based and supplemental sample components from online panels, we illustrate that our proposed method of composite weighting is superior to the traditional method of composite estimation in 2 distinct ways. Computationally, it is vastly less demanding and hence more accessible for practitioners. Inferentially, it produces more efficient estimates with higher levels of external validity when pooling data from multiple surveys. CONCLUSIONS: The new realities of the digital age have brought about a number of resilient challenges for survey researchers, which in turn have exposed some of the inefficiencies associated with the traditional methods this community has relied upon for decades. The resilience of such challenges suggests that piecemeal approaches that may have limited applicability or restricted accessibility will prove to be inadequate and transient. It is from this perspective that our proposed method of composite weighting has aimed to introduce a durable and accessible solution for hybrid sample surveys.

Salt-Assisted Vapor-Liquid-Solid Growth of 1D van der Waals Materials.

The method of salt-assisted vapor-liquid-solid (VLS) growth is introduced to synthesize 1D nanostructures of trichalcogenide van der Waals (vdW) materials, exemplified by niobium trisulfide (NbS3 ). The method uses a unique catalyst consisting of an alloy of Au and an alkali metal halide (NaCl) to enable rapid and directional growth. High yields of two types of NbS3 1D nanostructures, nanowires and nanoribbons, each with sub-ten nanometer diameter, tens of micrometers length, and distinct 1D morphology and growth orientation are demonstrated. Strategies to control the location, size, and morphology of growth, and extend the growth method to synthesize other transition metal trichalcogenides, NbSe3 and TiS3 , as nanowires are demonstrated. Finally, the role of the Au-NaCl alloy catalyst in guiding VLS synthesis is described and the growth mechanism based on the relationships measured between structure (growth orientation, morphology, and dimensions) and growth conditions (catalyst volume and growth time) is discussed. These results introduce opportunities to expand the library of emerging 1D vdW materials to make use of their unique properties through controlled growth at nanoscale dimensions.

No evidence of association between either Modic change or disc degeneration and five circulating inflammatory proteins.

Introduction: Intervertebral disc degeneration and Modic change are the main spinal structural changes associated with chronic low back pain (LBP). Both conditions are thought to manifest local inflammation and if inflammatory proteins translocate to the blood circulation could be detected systemically. The work here assesses whether the presence of disc degeneration is associated with detectable blood level changes of five inflammatory markers and whether chronic LBP is associated with these changes. Materials and Methods: Two hundred and forty TwinsUK cohort participants with both MRI disc degeneration grade and Modic change extent, and IL-6, IL-8, IL-8 TNF, and CX3CL1 protein blood concentration measurements were included in this work. Linear mixed effects models were used to test the association of blood cytokine concentration with disc degeneration score and Modic change volumetric score. Association of chronic LBP status from questionnaires with disc degeneration, Modic change, and cytokine blood concentration was also tested. Results: No statistically significant association between disc degeneration or Modic change with cytokine blood concentration was found. Instead, regression analysis pointed strong association between cytokine blood concentration with body mass index for IL-6 and with age for IL-6 and TNF. Mild association was found between IL-8 blood concentration and body mass index. Additionally, LBP status was associated with Modic change volumetric score but not associated with any cytokine concentration. Conclusions: We found no evidence that Modic change and disc degeneration are able to produce changes in tested blood cytokine concentration. However, age and body mass index have strong influence on cytokine concentration and both are associated with the conditions studied which may confound associations found in the literature. It is then unlikely that cytokines produced in the disc or vertebral bone marrow induce chronic LBP.

Diagnostic accuracy of prehospital lung ultrasound for acute decompensated heart failure: A systematic review and Meta-analysis.

BACKGROUND: Lung ultrasound (LUS) reduces time to diagnosis and treatment of acute decompensated heart failure (ADHF) in emergency department (ED) patients with undifferentiated dyspnea. We conducted a systematic review to evaluate the diagnostic accuracy and clinical impact of LUS for ADHF in the prehospital setting. METHODS: We performed a keyword search of multiple databases from inception through June 1, 2023. Included studies were those enrolling prehospital patients with undifferentiated dyspnea or suspected ADHF, and specifically diagnostic studies comparing prehospital LUS to a gold standard and intervention studies with a non-US comparator group. Title and abstract screening, full text review, risk of bias (ROB) assessments, and data extraction were performed by multiple authors. and adjudicated. The primary outcome was pooled sensitivity, specificity, and diagnostic likelihood ratios (LR) for prehospital LUS. A test-treatment threshold of 0.7 was applied based on prior ADHF literature in the ED. Intervention outcomes included mortality, mechanical ventilation, and time to HF specific treatment. RESULTS: Eight diagnostic studies (n = 691) and two intervention studies (n = 70) met inclusion criteria. No diagnostic studies were low-ROB. Both intervention studies were critical-ROB, and not pooled. Pooled sensitivity and specificity of prehospital LUS for ADHF were 86.7% (95%CI:70.8%-94.6%) and 87.5% (78.2%-93.2%), respectively, with similar performance by physician vs. paramedic LUS and number of lung zones evaluated. Pooled LR+ and LR- were 7.27 (95% CI: 3.69-13.10) and 0.17 (95% CI: 0.06-0.34), respectively. Area under the summary receiver operating characteristic curve was 0.922. At the observed 42.4% ADHF prevalence (pre-test probability), positive pre-hospital LUS exceeded the 70% threshold to initiate treatment (post-test probability 84%, 80-88%). CONCLUSIONS: LUS had similar diagnostic test characteristics for ADHF diagnosis in the prehospital setting as in the ED. A positive prehospital LUS may be sufficient to initiate early ADHF treatment based on published test-treatment thresholds. More studies are needed to determine the clinical impact of prehospital LUS.

Discovery of circulating blood biomarkers in patients with and without Modic changes of the lumbar spine: a preliminary analysis.

PURPOSE: The following study aimed to determine the existence of blood biomarkers in symptomatic patients with or without lumbar Modic changes (MC). METHODS: A cross-sectional sub-analyses of a prospective cohort was performed. Fasting blood samples were collected from patients with and without lumbar MC who had undergone spinal fusion or microdiscectomy. An 80-plex panel and CCL5/RANTES were used to assess preoperative plasma cytokine concentrations. Patient demographics and imaging phenotypes were also assessed. RESULTS: Thirty-one subjects were analysed (n = 18 no MC; n = 13 MC). No significant differences were found in age, sex, body mass index, smoking and alcohol history, and surgical procedure (i.e. fusion, decompression) between the two groups (p > 0.05). Several statistically significant blood biomarkers in MC patients were identified, including elevated levels of C-C Motif Chemokine Ligand 5 (CCL5, p = 0.0006), while Macrophage Migration Inhibitory Factor (MIF) was significantly lower (p = 0.009). Additionally, C-X-C Motif Chemokine Ligand 5 (CXCL5, p = 0.052), Pentraxin 3 (PTX3, p = 0.06) and Galectin-3 (Gal-3, p = 0.07) showed potential relevance. Moreover, MC patients exhibited significantly higher levels of disc degeneration (p = 0.0001) and displacement severity (p = 0.020). Based on multivariate analyses and controlling for disc degeneration/displacement, CCL5 (OR 1.02; 95% CI 1.002-1.033; p = 0.028) and MIF (OR 0.60; 95% CI 0.382-0.951; p = 0.030) were independently associated with MC patients. CONCLUSION: This "proof-of-concept" study is the first to identify specific and significantly circulating blood biomarkers associated with symptomatic patients with lumbar MC, independent of disc alterations of degeneration and/or bulges/herniations. Specifically, differences in CCL5 and MIF protein levels were significantly noted in MC patients compared to those without MC.

Knowledge, perceptions, and beliefs about urinary tract infections in persons with neurogenic bladder and impacts on interventions to promote person-centered care.

STUDY DESIGN: Qualitative study. OBJECTIVES: To explore how knowledge, perceptions, and beliefs about urinary tract infections (UTIs) among persons with neurogenic bladder (NB) may impact health behaviors and provider management and enhance person-centeredness of interventions to improve UTI management. SETTING: Three Veterans Affairs (VA) medical centers. METHODS: Adults with NB due to spinal cord injury/disorder (SCI/D) or multiple sclerosis (MS) with UTI diagnoses in the prior year participated in focus groups. Transcripts were coded using deductive codes linked to the Health Belief Model and inductive codes informed by grounded theory. RESULTS: Twenty-three Veterans (SCI/D, 78%; MS: 18.5%) participated in discussions. Three themes emerged: (1) UTI knowledge; (2) factors affecting the intervention environment; and (3) factors affecting modes of delivery. Knowledge gaps included UTI prevention, specific symptoms most indicative of UTI, and antibiotic side effects. Poor perceptions of providers lacking knowledge about NB and ineffective patient-provider communication were common in the Emergency Department and non-VA facilities, whereas participants had positive perceptions of home-based care. Participants perceived lower severity and frequency of antibiotic risks compared to UTI risks. Participant preferences for education included caregiver involvement, verbal and written materials, and diverse settings like peer groups. CONCLUSIONS: Identifying patient perspectives enhances person-centeredness and allows for novel interventions improving patient knowledge and behaviors about UTIs. Partnering with trusted providers and home-based caregivers and improving NB knowledge and communication in certain care settings were important. Patient education should address mental risk representations and incorporate preferences for content delivery to optimize self-efficacy and strengthen cues to action.

Association of Calcium and Vitamin D Supplements with Fractures in Persons with a Traumatic SCI.

Background: Osteoporotic fractures occur in almost half of patients with a spinal cord injury (SCI) and are associated with significant morbidity and excess mortality. Paralyzed Veterans Administration (PVA) guidelines suggest that adequate calcium and vitamin D intake is important for skeletal health, however, the association of these supplements with osteoporotic fracture risk is unclear. Objectives: To determine the association of filled prescriptions for calcium and vitamin D with fracture risk in Veterans with an SCI. Methods: The 5897 persons with a traumatic SCI of at least 2 years' duration (96% male; 4% female) included in the VSSC SCI/D Registry in FY2014 were followed from FY2014 to FY2020 for incident upper and lower extremity fractures. Filled daily prescriptions for calcium or vitamin D supplements for ≥6 months with an adherence ≥80% were examined. Results: Filled prescriptions for calcium (hazard ratio [HR] 0.65; 95% CI, 0.54-0.78) and vitamin D (HR 0.33; 95% CI, 0.29-0.38) supplements were associated with a significantly decreased risk for incident fractures. Conclusion: Calcium and vitamin D supplements are associated with decreased risk of fracture, supporting PVA guidelines that calcium and vitamin D intake are important for skeletal health in persons with an SCI.

Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM.

RNA sequencing and genetic data support spleen tyrosine kinase (SYK) and high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) as putative targets to be modulated for Alzheimer's disease (AD) therapy. FCER1G is a component of Fc receptor complexes that contain an immunoreceptor tyrosine-based activation motif (ITAM). SYK interacts with the Fc receptor by binding to doubly phosphorylated ITAM (p-ITAM) via its two tandem SH2 domains (SYK-tSH2). Interaction of the FCER1G p-ITAM with SYK-tSH2 enables SYK activation via phosphorylation. Since SYK activation is reported to exacerbate AD pathology, we hypothesized that disruption of this interaction would be beneficial for AD patients. Herein, we developed biochemical and biophysical assays to enable the discovery of small molecules that perturb the interaction between the FCER1G p-ITAM and SYK-tSH2. We identified two distinct chemotypes using a high-throughput screen (HTS) and orthogonally assessed their binding. Both chemotypes covalently modify SYK-tSH2 and inhibit its interaction with FCER1G p-ITAM, however, these compounds lack selectivity and this limits their utility as chemical tools.

Coronary artery calcium as a marker of healthy and unhealthy aging in adults aged 75 and older: The Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND AND AIMS: Coronary artery calcium (CAC) is validated for risk prediction among middle-aged adults, but there is limited research exploring implications of CAC among older adults. We used data from the Atherosclerosis Risk in Communities (ARIC) study to evaluate the association of CAC with domains of healthy and unhealthy aging in adults aged ≥75 years. METHODS: We included 2,290 participants aged ≥75 years free of known coronary heart disease who underwent CAC scoring at study visit 7. We examined the cross-sectional association of CAC = 0, 1-999 (reference), and ≥1000 with seven domains of aging: cognitive function, hearing, ankle-brachial index (ABI), pulse-wave velocity (PWV), forced vital capacity (FVC), physical functioning, and grip strength. RESULTS: The mean age was 80.5 ± 4.3 years, 38.6% male, and 77.7% White. 10.3% had CAC = 0 and 19.2% had CAC≥1000. Individuals with CAC = 0 had the lowest while those with CAC≥1000 had the highest proportion with dementia (2% vs 8%), hearing impairment (46% vs 67%), low ABI (3% vs 18%), high PWV (27% vs 41%), reduced FVC (34% vs 42%), impaired grip strength (66% vs 74%), and mean composite abnormal aging score (2.6 vs 3.7). Participants with CAC = 0 were less likely to have abnormal ABI (aOR:0.15, 95%CI:0.07-0.34), high PWV (aOR:0.57, 95%CI:0.41-0.80), and reduced FVC (aOR:0.69, 95%CI:0.50-0.96). Conversely, participants with CAC≥1000 were more likely to have low ABI (aOR:1.74, 95%CI:1.27-2.39), high PWV (aOR:1.52, 95%CI:1.15-2.00), impaired physical functioning (aOR:1.35, 95%CI:1.05-1.73), and impaired grip strength (aOR:1.46, 95%CI:1.08-1.99). CONCLUSIONS: Our findings highlight CAC as a simple measure broadly associated with biological aging, with clinical and research implications for estimating the physical and physiological aging trajectory of older individuals.

Kinome-Wide Synthetic Lethal Screen Identifies PANK4 as a Modulator of Temozolomide Resistance in Glioblastoma.

Temozolomide (TMZ) represents the cornerstone of therapy for glioblastoma (GBM). However, acquisition of resistance limits its therapeutic potential. The human kinome is an undisputable source of druggable targets, still, current knowledge remains confined to a limited fraction of it, with a multitude of under-investigated proteins yet to be characterized. Here, following a kinome-wide RNAi screen, pantothenate kinase 4 (PANK4) isuncovered as a modulator of TMZ resistance in GBM. Validation of PANK4 across various TMZ-resistant GBM cell models, patient-derived GBM cell lines, tissue samples, as well as in vivo studies, corroborates the potential translational significance of these findings. Moreover, PANK4 expression is induced during TMZ treatment, and its expression is associated with a worse clinical outcome. Furthermore, a Tandem Mass Tag (TMT)-based quantitative proteomic approach, reveals that PANK4 abrogation leads to a significant downregulation of a host of proteins with central roles in cellular detoxification and cellular response to oxidative stress. More specifically, as cells undergo genotoxic stress during TMZ exposure, PANK4 depletion represents a crucial event that can lead to accumulation of intracellular reactive oxygen species (ROS) and subsequent cell death. Collectively, a previously unreported role for PANK4 in mediating therapeutic resistance to TMZ in GBM is unveiled.

Using artificial odors to optimize attractiveness of host decoy traps to malaria vectors.

Malaria vector surveillance tools often incorporate features of hosts that are attractive to blood-seeking females. The recently developed host decoy trap (HDT) combines visual, thermal, and olfactory stimuli associated with human hosts and has shown great efficacy in terms of collecting malaria vectors. Synthetic odors and yeast-produced carbon dioxide (CO2) could prove useful by mimicking the human odors currently used in HDTs and provide standardized and easy-to-use olfactory attractants. The objective of this study was to test the attractiveness of various olfactory attractant cues in HDTs to capture malaria vectors. We compared 4 different odor treatments in outdoor field settings in southern Benin and western Burkina Faso: the standard HDT using a human, HDT with yeast-produced CO2, HDT with an artificial odor blend, and HDT with yeast-produced CO2 plus artificial odor blend. In both experimental sites, the standard HDT that incorporated a real human produced the greatest catch of Anopheles gambiae s.l (Diptera: Culicidae). The alternatives tested were still effective at collecting target vector species, although the most effective included CO2, either alone (Benin) or in combination with synthetic odor (Burkina Faso). The trap using synthetic human odor alone caught the fewest An. gambiae s.l. compared to the other baited traps. Both Anopheles coluzzii and Anopheles gambiae were caught by each trap, with a predominance of An. coluzzii. Synthetic baits could, therefore, represent a more standardized and easier-to-deploy approach than using real human odor baits for a robust vector monitoring strategy.