Multiple Combinations Research Articles

Predictors of Multi‐Vessel Identification, Outcome, and Optimal Surgical Timing for Microvascular Decompression in Hemifacial Spasm

Objectives and BackgroundHemifacial spasm (HFS) is a disabling condition that imposes significant burden upon patients. Microvascular decompression (MVD) surgery is the most effective and long-lasting treatment for HFS, but outcomes following this surgery may vary based on a variety of clinical and operative factors. A more thorough understanding of the variables that impact patient outcome after MVD surgery is needed. MethodsA systematic review and meta-analysis of Medline, Embase, and Central was conducted (n = 2108 screened; n = 86 included) with the goal of determining the impact of the following variables on outcome: duration of disease, geographic location, intraoperative use of an endoscope, and intraoperative finding of single versus multi-vessel neurovascular compression. ResultsMost cases of hemifacial spasm occur on the left side (53.9%, p < 0.001) and are more common in women than men (66.5% versus 33.5%, p < 0.0001). The offending vessel frequencies were: 40.8% anterior inferior cerebellar artery [AICA], 24.9% posterior inferior cerebellar artery [PICA], 17.2% multiple vessels, and 4.7% vertebral artery [VA]. Multiple vessel combinations involved: 26.5% PICA + AICA, 24.6% PICA + VA, 23.1% AICA + VA, and 4.7% AICA + PICA + VA. Relative to the Americas, AICA was less frequent in Europe (p = 0.005), while PICA more frequent in Europe (p = 0.009) and Asia (p < 0.0001). With endoscope assistance, frequency of multiple vessels identified was 31.7% (versus 14.7% with non-endoscopic, p = 0.005), and 27.4% for AICA (43.5% with non-endoscopic, p = 0.003). Spasm improvement was 94.1% near discharge and 96.0% at maximum follow-up. Complications occurred in 16.5% of cases, with spasm recurrence in 2.4%. Greatest frequency of spasm improvement (p < 0.0001) and lowest spasm recurrence rates (p = 0.0005) were reported in series from Asia. For every additional month of pre-operative spasm, the effect size of post-operative improvement decreased (p = 0.04). With every subsequent postoperative month, the effect size of spasm improvement increased (p = 0.0497). The frequency of spasm improvement was significantly higher in series published after 2005 (94.4% versus 97.4%, p = 0.005). ConclusionClinical outcomes following MVD for HFS have improved since 2005. Consideration should be given to earlier operation (shorter disease duration) and use of an endoscope may increase detection of multiple offending vessels. Further studies are needed to understand regional differences in culprit vessel incidence and surgical outcomes in the Americas, Europe, and Asia.

Heterotypic and homotypic continuity in psychopathology: a narrative review.

Psychopathology is a process: it unfolds over time and involves several different factors. To extend our knowledge of such process, it is vital to understand the trajectories that lead to developing and maintaining a specific disorder. The construct of continuity appears very useful to this aim. It refers to the consistency, similarity, and predictability of behaviors or internal states across different developmental phases. This paper aims to present a narrative review of the literature on homotypic and heterotypic continuity of psychopathology across the lifespan. A detailed search of the published literature was conducted using the PsycINFO Record and Medline (PubMed) databases. Articles were included in the review based on the following criteria: (1) publication dates ranging from January 1970 to October 2022; and (2) articles being written in the English language. To ensure a thorough investigation, multiple combinations of keywords such as "continuity," "psychopathology," "infancy," "childhood," "adolescence," "adulthood," "homotypic," and "heterotypic" were used. Articles were excluded if exclusively focused on epidemiologic data and if not specifically addressing the topic of psychopathology continuity. The literature yielded a total of 36 longitudinal studies and an additional 190 articles, spanning the research published between 1970 and 2022. Studies on continuity focus on the etiology of different forms of mental disorders and may represent a fundamental resource from both a theoretical and clinical perspective. Enhancing our understanding of the different trajectories beneath psychopathology may allow clinicians to implement more effective strategies, focusing both on prevention and intervention. Since literature highlights the importance of early detection of clinical signs of psychopathology, future research should focus more on infancy and pre-scholar age.

Development of a Breast Cancer Risk Prediction Model Incorporating Polygenic Risk Scores and Nongenetic Risk Factors for Korean Women.

To develop a breast cancer prediction model for Korean women using published polygenic risk scores (PRS) combined with nongenetic risk factors (NGRF). Thirteen PRS models generated from single or multiple combinations of the Asian and European PRSs were evaluated among 20,434 Korean women. The AUC and increase in OR per SD were compared for each PRS. The PRSs with the highest predictive power were combined with NGRFs; then, an integrated prediction model was established using the Individualized Coherent Absolute Risk Estimation (iCARE) tool. The absolute breast cancer risk was stratified for 18,142 women with available follow-up data. PRS38_ASN+PRS190_EB, a combination of Asian and European PRSs, had the highest AUC (0.621) among PRSs, with an OR per SD increase of 1.45 (95% confidence interval: 1.31-1.61). Compared with the average risk group (35%-65%), women in the top 5% had a 2.5-fold higher risk of breast cancer. Incorporating NGRFs yielded a modest increase in the AUC of women ages >50 years. For PRS38_ASN+PRS190_EB+NGRF, the average absolute risk was 5.06%. The lifetime absolute risk at age 80 years for women in the top 5% was 9.93%, whereas that of women in the lowest 5% was 2.22%. Women at higher risks were more sensitive to NGRF incorporation. Combined Asian and European PRSs were predictive of breast cancer in Korean women. Our findings support the use of these models for personalized screening and prevention of breast cancer. Our study provides insights into genetic susceptibility and NGRFs for predicting breast cancer in Korean women.

Constitutive Relation Development for Fused Deposition Modeling Three-Dimensional Printing Materials and Simulation of Printing Direction Combination

Abstract Due to the forming or curing process, the materials of three-dimensional (3D) printing have periodic meso-defects, which result in complex constitutive relations and anisotropy. Fused deposition modeling (FDM), which is a typical 3D printing process, inevitably introduces stacking pore defects due to the three-dimensional stacking of materials along the printing direction. At present, research focuses on the mechanical properties of materials printed along only one single direction. To consider the possibility of changing the mechanical properties of materials by adjusting the printing direction, the change in the properties of printing materials along the multiple printing direction combinations was analyzed in this paper. First, based on a continuous medium model, the constitutive model proposed by Garzon-Hernandez et al. was considered, and then to improve the prediction accuracy of the model in the plastic stage, a model describing the porosity change rate of porous materials was introduced to obtain better prediction results. Then, the finite element method (FEM) was developed using the new constitutive relation model implemented by the user defined material subroutine (USERMAT) into ansys software. Second, through the finite element subroutine, the mechanical response of the FDM 3D printing plate with two different printing direction combinations was simulated. The results show that by adjusting the print direction combination of the double-layer FDM 3D printing materials, the materials show a different anisotropy, maximum bearing capacity of tension and shear and buckling resistance.

Hyperkalemia, self-medication, and over-the-counter drug usage in patients with cardiovascular disease in the perspective of polypragmasy

Abstract Cardiovascular disease is a leading cause of death globally. 40 percent of the adult Romanian population is hypertensive, and only three out of seven patients are getting the appropriate treatment. Hyperkalemia is in a close relationship with certain cardiovascular diseases, although the influence of a certain medical treatment on hyperkalemia is not yet established. The aim of our study was to evaluate the pharmacotherapy of a group of patients with cardiovascular disease, representative for the adult population of our are and to analyze the administered drug therapy regarding polypragmasy (the concomitant usage of more than five different classes of substances), over-the-counter drugs and usage of drugs used without medical – physician prescribed - indication, and to evaluate serum potassium levels. The cross-sectional, observational, prospective, pharmaco-epidemiological study targets the observation, recording and analysis of 301 adult patients’ pharmacotherapy and laboratory findings. Based on the demographic data we found that the study group is representative for the adult population of our region. Hypertension was observed in 173 cases, and more than 60 percent of the patients were older than 65 years of age. Other comorbidities, such as ischemic cardiac disease, heart failure, arrhythmias, other cardiovascular diseases as well as chronic kidney failure and diabetes mellitus were positively associated with hypertension. In 50.8 percent of the cases usage of drugs without prescription was present. Likewise, multiple drug combinations were frequent with high rates of polypragmasy. Multiple drug combinations were observed, and self-medication rates were very high, which should be reduced substantially to obtain a more successful pharmacotherapy and a reduced drug interaction-induced side effect.

Phase 2 trial of zolbetuximab in combination with mFOLFOX6 and nivolumab in patients with advanced or metastatic claudin 18.2-positive, HER2-negative gastric or gastroesophageal junction adenocarcinomas.

TPS4173 Background: Zolbetuximab, a chimeric immunoglobulin G1 monoclonal antibody, binds to claudin 18.2 (CLDN18.2) and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In the pivotal phase 3 SPOTLIGHT study, zolbetuximab with modified FOLFOX6 (mFOLFOX6; leucovorin [folinic acid], fluorouracil [5-FU], and oxaliplatin) significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with CLDN18.2-positive, HER2-negative gastric and gastroesophageal junction (G/GEJ) adenocarcinomas. The phase 2 ILUSTRO trial is investigating the efficacy and safety of zolbetuximab, alone and in multiple combinations, in patients with CLDN18.2-positive, HER2-negative advanced/metastatic G/GEJ adenocarcinomas. Methods: The ILUSTRO trial is enrolling two new cohorts, 4A (safety cohort) and 4B, with approximately 12 and 50 patients planned, respectively, to assess safety and efficacy of the first-line combination of zolbetuximab, mFOLFOX6, and nivolumab in G/GEJ adenocarcinomas. Both cohorts are enrolling patients whose tumors are HER2-negative with high or intermediate CLDN18.2 positivity (moderate to strong immunohistochemistry staining intensity in ≥75% of tumor cells [high] or ≥50% but &lt;75% of tumor cells [intermediate]). In Cohort 4A, patients will receive a loading dose of 800 mg/m2 of zolbetuximab with 240 mg of nivolumab and mFOLFOX6 on cycle 1 day 1, followed by 400 mg/m2 of zolbetuximab with 240 mg of nivolumab and mFOLFOX6 every 2 weeks (on days 15 and 29 of each 42-day cycle). Up to 12 mFOLFOX6 treatments (4 cycles) will be administered; patients may continue to receive folinic acid and 5-FU alongside zolbetuximab and nivolumab. Tolerability and safety of the combination of zolbetuximab, mFOLFOX6, and nivolumab will be evaluated during a 2-week dose-limiting toxicity assessment period. If the 800 mg/m2 loading dose of zolbetuximab was assessed as not tolerable, patients were to be de-escalated to 600 mg/m2 as their loading dose but received the same subsequent 400 mg/m2 doses of zolbetuximab every 2 weeks. Cohort 4B will receive this combination at the dose level determined in Cohort 4A. Efficacy endpoints include objective response rate, disease control rate, duration of response, PFS, and OS. Safety and tolerability, pharmacokinetics, immunogenicity, and health-related quality of life will also be evaluated. Currently, 20+ sites are recruiting in 6 countries (France, Italy, Japan, Korea, Taiwan, United States); more US sites are planned. Clinical trial information: NCT03505320 .

CRI-CCTG-0003/IND.240: An immunotherapy platform study in platinum-resistant high grade serous ovarian cancer (IPROC).

TPS5617 Background: Identifying new treatments for patients with platinum-resistant high grade serous ovarian cancer (HGSC) is a priority. Although several biological features of HGSC suggest inherent immunogenicity, immunotherapy has had limited efficacy to date. IPROC is an adaptive platform trial designed to evaluate multiple immunotherapy combinations selected and informed by an expert panel. IPROC accommodates both biomarker-agnostic and biomarker-directed combinations. Protocol and sub study specific translational studies are conducted on archived diagnostic tissue and serial prospective blood and tumor sample collection. Methods: IPROC is an open-label, multi center, phase II platform trial. Eligibility includes HGSC histology; progression within 6 months of the last platinum regimen; &lt;1 prior line of chemotherapy for platinum resistant disease (unlimited prior lines for platinum sensitive); prior treatment with immunotherapy allowed (provided not discontinued for toxicity), ECOG 0/1. Patients must be willing and able to undergo study procedures. The primary endpoint is ORR (RECIST1.1). Secondary endpoints include iRECIST ORR, RECIST/iRECIST progression free and overall survival and safety. Exploratory objectives include whole exome sequencing and immune profiling of tumor and blood samples to identify biomarkers and new immunotherapy strategies/combinations for future evaluation. Tumor biopsy occurs at baseline, cycle 2 and progression (voluntary) with blood and plasma collected at each cycle and on progression. All sub studies use Simon 2-stage design with 10 patients (pts) enrolled in each stage. At the end of stage 1, in the absence of response, a modified cohort based on biomarker selection may be created through protocol amendment. In each substudy a null hypothesis that the objective response rate (ORR) is ≤5% is tested against a one-sided alternative that the ORR is ≥ 25%. A combination would be accepted as active if ≥4/20 pts respond with α=0.02 and power of 0.76. As of January 19, 2023, 2 sub studies are open and 12 patients have accrued. Sub study A is evaluating the combination of durvalumab and BA3011, a conditionally active anti-AXL humanized monoclonal antibody (IgG1) conjugated to monomethyl auristatin E (MMAE) in AXL overexpressing HGSC. Sub study B is evaluating durvalumab plus BA3021, a CAB anti-receptor tyrosine kinase orphan receptor 2 (ROR2) humanized monoclonal antibody (IgG1) conjugated to MMAE in ROR2 overexpressing HGSC. Further sub studies are planned (NCT04918186). Clinical trial information: NCT04918186 .

Somatic hereditary gene panel analysis: A pilot study from Uzbekistan.

e15044 Background: Molecular diagnostics is gaining importance in routine clinical practice. Availability of actionable genetic changes in hereditary panel of genes has acquired even larger interest. This study is an attempt evaluate the limited somatic genetic alterations in small population of Uzbek patients. Methods: Somatic tumor sample material was analyzed using FOUNDATIONONER CDx (F1CDx) - the NGS based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations(indels), and copy numbers alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures. Our focus of hereditary panel included following genes-TP53, CDH1, PTEN, STK11, PALB2, CHEK2, ATM, NBN, BARD1, BRCA1 and BRCA2. Results: Out of 76 patients analyzed 50 were found have at list one abnormal gene from the above hereditary panel. TP53 was frequent pathogenic mutation in 50 of 76 patients. Commonest hereditary gene alterations were seen in ATM gene -12/50(6%). BRCA2 mutations existed in 7 of 50(3,5%), PTEN – 6/50(3%), PALB-2 – 4/50(2%), CHEK-2 – 5/50(2,5%), NBN – 5/50(2,5%), STK11 – 3/50(1,5%), CDH1 – 2/50(1%), BRCA1-2(1%), BARD1 – 1/50(0,5%). Some patients had multiple gene combinations. One of the patients had four gene abnormality-PTEN, PALB2, CHEK2, and BRCA2.Three patients have 3(1,5%) somatic hereditary mutations, 23(11,5%) patients have two abnormal hereditary genes and 38(19%) patients had changes in single gene only. Important actionable mutations (BRCA, PALB2 and CHEK2 were found in 15(11,4%) patients. Conclusions: This is the first exploratory analysis of somatic hereditary multi-gene panel. About 11% of the patients were found to have actionable gene mutations.

COMPARISON OF FIRST RESULTS OF RADIOFREQUENCY RENAL DENERVATIONS WITH FIRST AND SECOND GENERATION TECHNIQUES

Objective: A form of renal denervation, when using radiofrequency technique, thermal energy destroys the nerve-fibres around the renal artery. The Symplicity FlexTM was the first such catheter, an improved new generation version of it is the Symplicity SpyralTM catheter. In the Albert Szent-Györgyi Health Center of the University of Szeged, renal denervations were performed with both devices in hypertensive patients whose blood pressure could not be reduced to the goal range with multiple antihypertensive combinations. Design and method: With the first generation catheter, only the main branch was ablated at 4-5 points per side, and with the Symplicity SpyralTM catheter, even the segmental small branches together with the main branches were ablated at a total of at least 16-18 points per side. Results: With the old method after RDN, SBP decreased by 40 mmHg and DBP by 20 mmHg. The reduction was greatest 1 month after the intervention, 45 and 35 mm Hg. But did not reach the goal values. With new method after RDN, SBP decreased by 38 mmHg and DBP by 27 mmHg. The reduction was greatest 1 month after the intervention, 49 and 37 mm Hg. With the new the SBP was already in the target range after the intervention and remained there for 6 months. In addition, the number of antihypertensives could be significantly reduced. With the old method the goal BP value could not be achieved. Vascular complications did not occur in either case of interventions. Conclusions: Our first result with the Symplicity SpyralTM catheter according to the new concepts supports the view that more accurate ablation and preferably distal ablation can lead to more effective blood pressure reduction.

Distributed Computation for Marginal Likelihood based Model Choice

We propose a general method for distributed Bayesian model choice, using the marginal likelihood, where a data set is split in non-overlapping subsets. These subsets are only accessed locally by individual workers and no data is shared between the workers. We approximate the model evidence for the full data set through Monte Carlo sampling from the posterior on every subset generating a model evidence per subset. The results are combined using a novel approach which corrects for the splitting using summary statistics of the generated samples. Our divide-and-conquer approach enables Bayesian model choice in the large data setting, exploiting all available information but limiting communication between workers. We derive theoretical error bounds that quantify the resulting trade-off between computational gain and loss in precision. The embarrassingly parallel nature yields important speed-ups when used on massive data sets as illustrated by our real world experiments. In addition, we show how the suggested approach can be extended to model choice within a reversible jump setting that explores multiple feature combinations within one run.

CheMo4METPANC: A phase 2 study with combination chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) Motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) in metastatic treatment-naïve pancreas adenocarcinoma.

TPS4200 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a uniformly fatal disease for which treatments result in limited benefit. Failure of immune checkpoint blockade is attributed to multiple immunosuppressive pathways within the tumor microenvironment. The C-X-C motif chemokine receptor 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis results in exclusion of anti-tumor immune cells. Preclinical studies demonstrated that simultaneous CXCR4 inhibition (CXCR4i) and anti-programmed cell death 1 (aPD1) resulted in tumor stabilization. We extended these findings by testing multiple combinations of CXCR4i, aPD1, and gemcitabine in the KPC mouse model of PDAC. Mice treated with gemcitabine, CXCR4i, and aPD1 (triple therapy) experienced a survival benefit compared to mice treated with either gemcitabine alone, or with CXCR4i/aPD1. Tumors from mice treated with triple therapy demonstrated increased apoptosis and a favorable tumor immune microenvironment (TIME). Motixafortide with pembrolizumab, fluorouracil, and nanoliposomal irinotecan has shown encouraging results in the second-line setting in mPDAC with a confirmed ORR of 13.2% and progression free survival (PFS) of 3.8 months (m). The goal of this first-in-man trial is to test preliminary safety and efficacy of Motixafortide (CXCR4i), Cemiplimab (aPD1), Gemcitabine, and Nab-paclitaxel (MCGN) in treatment naïve mPDAC. Methods: This is an open label, multicenter, investigator-initiated simon-2-stage phase 2 clinical trial in mPDAC testing MCGN. The study includes a six-patient safety run-in cohort and an additional 4 patients comprising a pilot efficacy signal seeking study (N=10). If ≥3 of the 10 patients within the pilot stage were to experience a partial response (PR) by RECIST criteria within 16 weeks, the combination would be considered promising and an expansion cohort of an additional 30 patients was planned. On 09/21/22, we amended the study to forego the planned open-label expansion cohort (N=30) and transition directly to a randomized phase 2 trial testing MCGN compared toGemcitabine and Nab-paclitaxel (GN) alone (N=102), after completion of the pilot phase of the study. The primary endpoint is PFS. The study has 80% power to detect an improvement in PFS from 6 to 9.2 m (HR 0.65) with a one-sided alpha of 0.20. One interim analysis for futility is planned when 50% of the PFS events are observed. Secondary objectives include ORR, disease control rate, duration of clinical benefit and OS. Required (pilot portion) and optional (randomized portion) paired tumor biopsies will undergo exploratory analysis including interrogation of the TIME. This trial was started in September 2020 and has enrolled 10 patients to the pilot stage as of 02/2023. Clinical trial information: NCT04543071 .

Sustainable decision-making game for the next generation of smart citizens

Cities are increasingly facing the consequences of climate change, it is therefore urgent to take actions to reach the targets set by the UN Sustainable Development Goals. By 2050, 70% of the world population will live in cities, engaging citizens in the sustainable transformation of the built environment is crucial. Moreover, children and youth require specific attention to secure their active participation in the process. ByMaker is a serious game developed to facilitate the participation of children and youth in sustainable urban transformation. The objective of ByMaker is to improve the knowledge about sustainability and raise awareness on the importance of making balanced decisions. While the environmental dimension is already well covered and assimilated by children and youth, the social and economic ones remain more challenging to understand. The method uses a 3D map of the concrete city, interactive elements of popular landmarks and friendly characters of local historical figures. The players are invited to experiment multiple combination of choices corresponding to different scenarios of urban development such as road and transportation, urban nature, residential buildings and public space. The impact of their decisions on the overall sustainability of their city is presented as visual feedback. Scenarios in the game focus on the realization of SDGs’ ambitions and objectives. The vision is both mid-term oriented, addressing the climate urgency and long-term focused to anticipate future needs. Furthermore, ByMaker presents innovative technological solutions to play with. The game was tested in three classes in primary schools in Trondheim, Norway. The feedback guided the further development and improvements such as better visualization, interaction features and simplified scenario descriptions. By playing with ByMaker, children succeeded to learn, experiment, and create their sustainable city.

System Identification and Hybrid Model Predictive Control in Personalized mHealth Interventions for Physical Activity.

The application of control systems principles in behavioral medicine includes developing interventions that can be individualized to promote healthy behaviors, such as sustained engagement in adequate levels of physical activity (PA). This paper presents the use of system identification and control engineering methods in the design of behavioral interventions through the novel formalism of a control-optimization trial (COT). The multiple stages of a COT, from experimental design in system identification through controller implementation, are illustrated using participant data from Just Walk, an intervention to promote walking behavior in sedentary adults. ARX models for individual participants are estimated using multiple estimation and validation data combinations, with the model leading to the best performance over a weighted norm being selected. This model serves as the internal model in a hybrid MPC controller formulated with three degree-of-freedom (3DoF) tuning that properly balances the requirements of physical activity interventions. Its performance in a realistic closed-loop setting is evaluated via simulation. These results serve as proof of concept for the COT approach, which is currently being evaluated with human participants in the clinical trial YourMove.

The dynamic response of quorum sensing to density is robust to signal supplementation and individual signal synthase knockouts.

Quorum sensing (QS) is a widespread mechanism of environment sensing and behavioural coordination in bacteria. At its core, QS is based on the production, sensing and response to small signalling molecules. Previous work with Pseudomonas aeruginosa shows that QS can be used to achieve quantitative resolution and deliver a dosed response to the bacteria's density environment, implying a sophisticated mechanism of control. To shed light on how the mechanistic signal components contribute to graded responses to density, we assess the impact of genetic (AHL signal synthase deletion) and/or signal supplementation (exogenous AHL addition) perturbations on lasB reaction-norms to changes in density. Our approach condenses data from 2000 timeseries (over 74 000 individual observations) into a comprehensive view of QS-controlled gene expression across variation in genetic, environmental and signal determinants of lasB expression. We first confirm that deleting either (∆lasI, ∆rhlI) or both (∆lasIrhlI) AHL signal synthase gene attenuates QS response to density. In the ∆rhlI background we show persistent yet attenuated density-dependent lasB expression due to native 3-oxo-C12-HSL signalling. We then test if density-independent quantities of AHL signal (3-oxo-C12-HSL, C4-HSL) added to the WT either flatten or increase responsiveness to density and find that the WT response is robust to all tested concentrations of signal, alone or in combination. We then move to progressively supplementing the genetic knockouts and find that cognate signal supplementation of a single AHL signal (∆lasI +3-oxo-C12-HSL, ∆rhlI +C4HSL) is sufficient to restore the ability to respond in a density-dependent manner to increasing density. We also find that dual signal supplementation of the double AHL synthase knockout restores the ability to produce a graded response to increasing density, despite adding a density-independent amount of signal. Only the addition of high concentrations of both AHLs and PQS can force maximal lasB expression and ablate responsiveness to density. Our results show that density-dependent control of lasB expression is robust to multiple combinations of QS gene deletion and density-independent signal supplementation. Our work develops a modular approach to query the robustness and mechanistic bases of the central environmental sensing phenotype of quorum sensing.

Interaction between atrial-ventricular and ventricular-ventricular delay in CRT

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): United Hospital Medical Education and Research Committee, United Hospital Foundation. Background Appropriate programming of atrial-ventricular delay (AVD) and ventricular-ventricular delay (VVD) is critical for delivery of optimal cardiac resynchronization therapy (CRT). However, there is debate over how to determine optimal programming for a given patient. This is complicated by the use of 2 distinct methods of defining the activation timing at a given AVD and VVD used by different device manufacturers. Purpose To describe how electrical dyssynchrony is affected by changes in AVD, VVD and the method used to program AVD and VVD. Methods We measured electrical synchrony at multiple combinations of AVD/VVD in 41 patients with underlying left bundle branch block (LBBB) using a novel methodology called electrical dyssynchrony mapping (EDM). Electrical dyssynchrony was quantified by cardiac resynchronization index (CRI), calculated as % change in area under the curve between combinations of 9 anterior and 9 posterior surface electrograms. Results EDM (Figure 1) shows CRI at multiple combinations of atrial-to-RV-paced, (A-RVp, y-axis) and atrial-to-LV-paced (A-LVp, x-axis) intervals. VVD changes to produce LV preactivation are shown at short and long AVDs using the methods of 2 different CRT device manufacturers: Method 1: fixing A-RVp and shortening A-LVp; and Method 2: fixing A-LVp and lengthening A-RVp. During simultaneous BiV pacing, CRI at short AVD (61.7±20.9) was significantly (p&amp;lt;0.001) greater than at long AVD (46.9±14.0). On average, CRI was significantly greater at short AVD than at long AVD during LV preactivation of 20 or 40 ms (Figure 2). At short AVD, Method 2 resulted in slightly but significantly better CRI at VVD 20 and 40 ms. At long AVD, Method 1 resulted in large and significantly better CRI at VVD 20 and 40 ms. Conclusions The interaction between AVD and VVD is complex, and the electrical resynchronization achieved when programming depends on both the AVD at which VVD is programmed, and the programming algorithm used by the device manufacturer. At longer AVDs, Method 1 yields significantly better resynchronization than Method 2 when programming VVD. Studies assessing effects of AVD and VVD programming that involve patients with CRT devices from different manufacturers need to modify programming parameters appropriately in order to accurately interpret results. Methods For programming VVD and EDM

Omics analyses in citrus reveal a possible role of RNA translation pathways and Unfolded Protein Response regulators in the tolerance to combined drought, high irradiance, and heat stress.

Environmental changes derived from global warming and human activities increase the intensity and frequency of stressful conditions for plants. Multiple abiotic factors acting simultaneously enhance stress pressure and drastically reduce plant growth, yield, and survival. Stress combination causes a specific stress situation that induces a particular plant response different to the sum of responses to the individual stresses. Here, by comparing transcriptomic and proteomic profiles to different abiotic stress combinations in two citrus genotypes, Carrizo citrange (Citrus sinensis×Poncirus trifoliata) and Cleopatra mandarin (Citrus reshni), with contrasting tolerance to different abiotic stresses, we revealed key responses to the triple combination of heat stress, high irradiance and drought. The specific transcriptomic response to this stress combination in Carrizo was directed to regulate RNA metabolic pathways and translation processes, potentially conferring an advantage with respect to Cleopatra. In addition, we found endoplasmic reticulum stress response as common to all individual and combined stress conditions in both genotypes and identified the accumulation of specific groups of heat shock proteins (HSPs), such as small HSPs and HSP70s, and regulators of the unfolded protein response, BiP2 and PDIL2-2, as possible factors involved in citrus tolerance to triple stress combination. Taken together, our findings provide new insights into the acclimation process of citrus plants to multiple stress combination, necessary for increasing crop tolerance to the changing climatic conditions.

Efficient Charge Transfer in Narrowband Organic Photodiodes Based on Self‐Assembled Heterojunction for Spectrally Selective Photodetection and Imaging

AbstractSpectrally selective photodetection has been used in many areas where only band‐specific optical signals are aimed to be detected. Organic photodiodes (OPDs) based on internal light depletion mechanisms have been utilized to realize narrowband photodetection. However, the fabrication of the photoactive layers by conventional solution methods can result in the deterioration of the underneath organic depletion layers and cause high‐density defect states at their interface. Herein, a new approach is presented to realize efficient charge transfer by adopting a self‐assembly strategy to prepare donor/acceptor bulk heterojunctions as the photoactive layers for narrowband OPDs. This method is able to prepare highly smooth, phase‐uniform, and low‐defect‐density thin films with controlled thickness. With this strategy, a narrowband near‐infrared OPD centered at 760 nm with a full‐width‐at‐half‐maximum of around 60 nm, peak external quantum efficiency of 49%, and peak specific detectivity of over 1013 Jones under −5 V is achieved. Multiple material combinations for the depletion and photoactive layers are examined, and the results show the effectiveness to realize the spectrally selective photodetection (from 740 to 900 nm) in general. More importantly, the narrowband OPDs can be integrated into a matrix for imaging, which demonstrates the mass‐scale fabrication feasibility of these OPDs.

Transnasal targeted delivery of therapeutics in central nervous system diseases: a narrative review.

Currently, neurointervention, surgery, medication, and central nervous system (CNS) stimulation are the main treatments used in CNS diseases. These approaches are used to overcome the blood brain barrier (BBB), but they have limitations that necessitate the development of targeted delivery methods. Thus, recent research has focused on spatiotemporally direct and indirect targeted delivery methods because they decrease the effect on nontarget cells, thus minimizing side effects and increasing the patient's quality of life. Methods that enable therapeutics to be directly passed through the BBB to facilitate delivery to target cells include the use of nanomedicine (nanoparticles and extracellular vesicles), and magnetic field-mediated delivery. Nanoparticles are divided into organic, inorganic types depending on their outer shell composition. Extracellular vesicles consist of apoptotic bodies, microvesicles, and exosomes. Magnetic field-mediated delivery methods include magnetic field-mediated passive/actively-assisted navigation, magnetotactic bacteria, magnetic resonance navigation, and magnetic nanobots-in developmental chronological order of when they were developed. Indirect methods increase the BBB permeability, allowing therapeutics to reach the CNS, and include chemical delivery and mechanical delivery (focused ultrasound and LASER therapy). Chemical methods (chemical permeation enhancers) include mannitol, a prevalent BBB permeabilizer, and other chemicals-bradykinin and 1-O-pentylglycerol-to resolve the limitations of mannitol. Focused ultrasound is in either high intensity or low intensity. LASER therapies includes three types: laser interstitial therapy, photodynamic therapy, and photobiomodulation therapy. The combination of direct and indirect methods is not as common as their individual use but represents an area for further research in the field. This review aims to analyze the advantages and disadvantages of these methods, describe the combined use of direct and indirect deliveries, and provide the future prospects of each targeted delivery method. We conclude that the most promising method is the nose-to-CNS delivery of hybrid nanomedicine, multiple combination of organic, inorganic nanoparticles and exosomes, via magnetic resonance navigation following preconditioning treatment with photobiomodulation therapy or focused ultrasound in low intensity as a strategy for differentiating this review from others on targeted CNS delivery; however, additional studies are needed to demonstrate the application of this approach in more complex in vivo pathways.

Plasma proteomic profiles of pain subtypes in adolescents and young adults with endometriosis.

What are the similarities and differences in the systemic proteomic profiles by endometriosis-associated pain subtypes among adolescents and young adults with endometriosis? Endometriosis-associated pain subtypes exhibited distinct plasma proteomic profiles. Endometriosis patients, especially those diagnosed in adolescents and young adults, are often plagued by various pain symptoms. However, it is not clear what biological processes underlie this heterogeneity. We conducted a cross-sectional analysis using data and plasma samples from 142 adolescent or young adult participants of the Women's Health Study: From Adolescence to Adulthood cohort with laparoscopically confirmed endometriosis. We measured 1305 plasma protein levels by SomaScan. We classified self-reported endometriosis-associated pain into subtypes of dysmenorrhea, acyclic pelvic pain, life impacting pelvic pain, bladder pain, bowel pain, and widespread pain phenotype. We used logistic regression to calculate the odds ratios and 95% confidence intervals for differentially expressed proteins, adjusting for age, BMI, fasting status, and hormone use at blood draw. Ingenuity Pathway Analysis identified enriched biological pathways. Our study population consisted mainly of adolescents and young adults (mean age at blood draw = 18 years), with nearly all (97%) scored as rASRM stage I/II at laparoscopic diagnosis of endometriosis, which is a common clinical presentation of endometriosis diagnosed at a younger age. Pain subtypes exhibited distinct plasma proteomic profiles. Multiple cell movement pathways were downregulated in cases with severe dysmenorrhea and life impacting pelvic pain compared to those without (P < 7.5×10-15). Endometriosis cases with acyclic pelvic pain had upregulation of immune cell adhesion pathways (P < 9.0×10-9), while those with bladder pain had upregulation of immune cell migration (P < 3.7×10-8) and those with bowel pain had downregulation (P < 6.5×10-7) of the immune cell migration pathways compared to those without. Having a wide-spread pain phenotype involved downregulation of multiple immune pathways (P < 8.0×10-10). Our study was limited by the lack of an independent validation cohort. We were also only able to explore any presence of a pain subtype and could not evaluate multiple combinations by pain subtypes. Further mechanistic studies are warranted to elucidate the differences in pathophysiology by endometriosis-pain subtype. The observed variation in plasma protein profiles by pain subtypes suggests different underlying molecular mechanisms, highlighting the need for potential consideration of pain subtypes for effectively treating endometriosis patients presenting with various pain symptoms. This study was supported by the Department of Defense W81XWH1910318 and the 2017 Boston Center for Endometriosis Trainee Award. Financial support for establishment of and data collection within the A2A cohort were provided by the J. Willard and Alice S. Marriott Foundation. N.S., A.F.V., S.A.M., and K.L.T. have received funding from the Marriott Family Foundation. C.B.S. is funded by an R35 MIRA Award from NIGMS (5R35GM142676). S.A.M. and K.L.T. are supported by NICHD R01HD094842. S.A.M. reports serving as an advisory board member for AbbVie and Roche, Field Chief Editor for Frontiers in Reproductive Health, personal fees from Abbott for roundtable participation; none of these are related to this study. Other authors report no conflict of interest. N/A.

Clinical usefulness of reintubation criteria in extremely preterm infants: a cohort study

ObjectiveTo describe the thresholds of instability used by clinicians at reintubation and evaluate the accuracy of different combinations of criteria in predicting reintubation decisions.DesignSecondary analysis using data obtained from the...