Neuronal PAS domain 1 identifies a major subpopulation of wakefulness-promoting GABAergic neurons in the basal forebrain.

Here, we describe a group of basal forebrain (BF) neurons expressing neuronal Per-Arnt-Sim (PAS) domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. Immunohistochemical staining in Npas1-cre-2A-TdTomato mice revealed BF Npas1+ neurons are distinct from well-studied parvalbumin or cholinergic neurons. Npas1 staining in GAD67-GFP knock-in mice confirmed that the vast majority of Npas1+ neurons are GABAergic, with minimal colocalization with glutamatergic neurons in vGlut1-cre-tdTomato or vGlut2-cre-tdTomato mice. The density of Npas1+ neurons was high, five to six times that of neighboring cholinergic, parvalbumin, or glutamatergic neurons. Anterograde tracing identified prominent projections of BF Npas1+ neurons to brain regions involved in sleep-wake control, motivated behaviors, and olfaction such as the lateral hypothalamus, lateral habenula, nucleus accumbens shell, ventral tegmental area, and olfactory bulb. Chemogenetic activation of BF Npas1+ neurons in the light period increased the amount of wakefulness and the latency to sleep for 2 to 3 h, due to an increase in long wake bouts and short NREM sleep bouts. NREM slow-wave and sigma power, as well as sleep spindle density, amplitude, and duration, were reduced, reminiscent of findings in several neuropsychiatric disorders. Together with previous findings implicating BF Npas1+ neurons in stress responsiveness, the anatomical projections of BF Npas1+ neurons and the effect of activating them suggest a possible role for BF Npas1+ neurons in motivationally driven wakefulness and stress-induced insomnia. Identification of this major subpopulation of BF GABAergic neurons will facilitate studies of their role in sleep disorders, dementia, and other neuropsychiatric conditions involving BF.

Dense monocular depth estimation for stereoscopic vision based on pyramid transformer and multi-scale feature fusion.

Stereoscopic display technology plays a significant role in industries, such as film, television and autonomous driving. The accuracy of depth estimation is crucial for achieving high-quality and realistic stereoscopic display effects. In addressing the inherent challenges of applying Transformers to depth estimation, the Stereoscopic Pyramid Transformer-Depth (SPT-Depth) is introduced. This method utilizes stepwise downsampling to acquire both shallow and deep semantic information, which are subsequently fused. The training process is divided into fine and coarse convergence stages, employing distinct training strategies and hyperparameters, resulting in a substantial reduction in both training and validation losses. In the training strategy, a shift and scale-invariant mean square error function is employed to compensate for the lack of translational invariance in the Transformers. Additionally, an edge-smoothing function is applied to reduce noise in the depth map, enhancing the model's robustness. The SPT-Depth achieves a global receptive field while effectively reducing time complexity. In comparison with the baseline method, with the New York University Depth V2 (NYU Depth V2) dataset, there is a 10% reduction in Absolute Relative Error (Abs Rel) and a 36% decrease in Root Mean Square Error (RMSE). When compared with the state-of-the-art methods, there is a 17% reduction in RMSE.

First-in-human Phase I Trial of TPST-1120, an Inhibitor of PPARα, as Monotherapy or in Combination with Nivolumab, in Patients with Advanced Solid Tumors.

PURPOSE: TPST-1120 is a first-in-class oral inhibitor of peroxisome proliferator-activated receptor α (PPARα), a fatty acid ligand-activated transcription factor that regulates genes involved in fatty acid oxidation, angiogenesis, and inflammation, and is a novel target for cancer therapy. TPST-1120 displayed antitumor activity in xenograft models and synergistic tumor reduction in syngeneic tumor models when combined with anti-PD-1 agents. EXPERIMENTAL DESIGN: This phase I, open-label, dose-escalation study (NCT03829436) evaluated TPST-1120 as monotherapy in patients with advanced solid tumors and in combination with nivolumab in patients with renal cell carcinoma (RCC), cholangiocarcinoma (CCA), or hepatocellular carcinoma. Objectives included evaluation of safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity (RECIST v1.1). RESULTS: A total of 39 patients enrolled with 38 treated (20 monotherapy, 18 combination; median 3 prior lines of therapy). The most common treatment-related adverse events (TRAE) were grade 1-2 nausea, fatigue, and diarrhea. No grade 4-5 TRAEs or dose-limiting toxicities were reported. In the monotherapy group, 53% (10/19) of evaluable patients had a best objective response of stable disease. In the combination group, 3 patients had partial responses, for an objective response rate of 20% (3/15) across all doses and 30% (3/10) at TPST-1120 ≥400 mg twice daily. Responses occurred in 2 patients with RCC, both of whom had previously progressed on anti-PD-1 therapy, and 1 patient with late-line CCA. CONCLUSIONS: TPST-1120 was well tolerated as monotherapy and in combination with nivolumab and the combination showed preliminary evidence of clinical activity in PD-1 inhibitor refractory and immune compromised cancers. SIGNIFICANCE: TPST-1120 is a first-in-class oral inhibitor of PPARα, whose roles in metabolic and immune regulation are implicated in tumor proliferation/survival and inhibition of anticancer immunity. This first-in-human study of TPST-1120 alone and in combination with nivolumab supports proof-of-concept of PPARα inhibition as a target of therapeutic intervention in solid tumors.

Finite barrier bound state.

A boundary mode localized on one side of a finite-size lattice can tunnel to the opposite side which results in unwanted couplings. Conventional wisdom tells that the tunneling probability decays exponentially with the size of the system which thus requires many lattice sites before eventually becoming negligibly small. Here we show that the tunneling probability for some boundary modes can apparently vanish at specific wavevectors. Thus, similar to bound states in the continuum, a boundary mode can be completely trapped within very few lattice sites where the bulk bandgap is not even well-defined. More intriguingly, the number of trapped states equals the number of lattice sites along the normal direction of the boundary. We provide two configurations and validate the existence of this peculiar finite barrier-bound state experimentally in a dielectric photonic crystal at microwave frequencies. Our work offers extreme flexibility in tuning the coupling between localized states and channels as well as a new mechanism that facilitates unprecedented manipulation of light.

Prediction of hospital mortality among critically ill patients in a single centre in Asia: comparison of artificial neural networks and logistic regression-based model.

INTRODUCTION: This study compared the performance of the artificial neural network (ANN) model with the Acute Physiologic and Chronic Health Evaluation (APACHE) II and IV models for predicting hospital mortality among critically ill patients in Hong Kong. METHODS: This retrospective analysis included all patients admitted to the intensive care unit of Pamela Youde Nethersole Eastern Hospital from January 2010 to December 2019. The ANN model was constructed using parameters identical to the APACHE IV model. Discrimination performance was assessed using area under the receiver operating characteristic curve (AUROC); calibration performance was evaluated using the Brier score and Hosmer-Lemeshow statistic. RESULTS: In total, 14 503 patients were included, with 10% in the validation set and 90% in the ANN model development set. The ANN model (AUROC=0.88, 95% confidence interval [CI]=0.86-0.90, Brier score=0.10; P in Hosmer-Lemeshow test=0.37) outperformed the APACHE II model (AUROC=0.85, 95% CI=0.80-0.85, Brier score=0.14; P<0.001 for both comparisons of AUROCs and Brier scores) but showed performance similar to the APACHE IV model (AUROC=0.87, 95% CI=0.85-0.89, Brier score=0.11; P=0.34 for comparison of AUROCs, and P=0.05 for comparison of Brier scores). The ANN model demonstrated better calibration than the APACHE II and APACHE IV models. CONCLUSION: Our ANN model outperformed the APACHE II model but was similar to the APACHE IV model in terms of predicting hospital mortality in Hong Kong. Artificial neural networks are valuable tools that can enhance real-time prognostic prediction.

Non-Abelian physics in light and sound.

Non-Abelian phenomena arise when the sequence of operations on physical systems influences their behaviors. By possessing internal degrees of freedom such as polarization, light and sound can be subjected to various manipulations, including constituent materials, structured environments, and tailored source conditions. These manipulations enable the creation of a great variety of Hamiltonians, through which rich non-Abelian phenomena can be explored and observed. Recent developments have constituted a versatile testbed for exploring non-Abelian physics at the intersection of atomic, molecular, and optical physics; condensed matter physics; and mathematical physics. These fundamental endeavors could enable photonic and acoustic devices with multiplexing functionalities. Our review aims to provide a timely and comprehensive account of this emerging topic. Starting from the foundation of matrix-valued geometric phases, we address non-Abelian topological charges, non-Abelian gauge fields, non-Abelian braiding, non-Hermitian non-Abelian phenomena, and their realizations with photonics and acoustics and conclude with future prospects.

Doublesex is essential for masculinization but not feminization in Lygus hesperus.

In most holometabolous insects, sex differentiation occurs via a hierarchical cascade of transcription factors, with doublesex (dsx) regulating genes that control sex-specific traits. Although less is known in hemimetabolous insects, early evidence suggests that substantial differences exist from more evolutionarily advanced insects. Here, we identified and characterized dsx in Lygus hesperus (western tarnished plant bug), a hemipteran pest of many agricultural crops in western North America. The full-length transcript for L. hesperus dsx (Lhdsx) and several variants encode proteins with conserved DNA binding and oligomerization domains. Transcript profiling revealed that Lhdsx is ubiquitously expressed, likely undergoes alternative pre-mRNA splicing, and, unlike several model insects, is sex-biased rather than sex-specific. Embryonic RNA interference (RNAi) of Lhdsx only impacted sex development in adult males, which lacked both internal reproductive organs and external genitalia. No discernible impacts on adult female development or reproductivity were observed. RNAi knockdown of Lhdsx in nymphs likewise only affected adult males, which lacked the characteristic dimorphic coloration but had dramatically elevated vitellogenin transcripts. Gene knockout of Lhdsx by CRISPR/Cas9 editing yielded only females in G0 and strongly biased heterozygous G1 offspring to females with the few surviving males showing severely impaired genital development. These results indicate that L. hesperus male development requires Lhdsx, whereas female development proceeds via a basal pathway that functions independently of dsx. A fundamental understanding of sex differentiation in L. hesperus could be important for future gene-based management strategies of this important agricultural pest.

Generation of Spatiotemporal Vortex Pulses by Resonant Diffractive Grating.

Spatiotemporal vortex pulses are wave packets that carry transverse orbital angular momentum, exhibiting exotic structured wave fronts that can twist through space and time. Existing methods to generate these pulses require complex setups like spatial light modulators or computer-optimized structures. Here, we demonstrate a new approach to generate spatiotemporal vortex pulses using just a simple diffractive grating. The key is constructing a phase vortex in frequency-momentum space by leveraging symmetry, resonance, and diffraction. Our approach is applicable to any wave system. We use a liquid surface wave (gravity wave) platform to directly demonstrate and observe the real-time generation and evolution of spatiotemporal vortex pulses. This straightforward technique provides opportunities to explore pulse dynamics and potential applications across different disciplines.

Exploiting Topological Darkness in Photonic Crystal Slabs for Spatiotemporal Vortex Generation.

Spatiotemporal optical vortices (STOVs) with swirling phase singularities in space and time hold great promise for a wide range of applications across diverse fields. However, current approaches to generate STOVs lack integrability and rely on bulky free-space optical components. Here, we demonstrate routine STOV generation by harnessing the topological darkness phenomenon of a photonic crystal slab. Complete polarization conversion enforced by symmetry enables topological darkness to arise from photonic bands of guided resonances, imprinting vortex singularities onto an ultrashort reflected pulse. Utilizing time-resolved spatial mapping, we provide the first observation of STOV generation using a photonic crystal slab, revealing the imprinted STOV structure manifested as a curved vortex line in the pulse profile in space and time. Our work establishes photonic crystal slabs as a versatile and accessible platform for engineering STOVs and harnessing the topological darkness in nanophotonics.

Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio on postoperative day three as a biochemical predictor of clinically significant pancreatic fistula in patients undergoing distal pancreatectomy.

INTRODUCTION AND AIMS: Distal pancreatectomy is a frequent procedure and postoperative fistula, its most common complication, has an incidence of 30 to 60%. The aim of the present work was to study the role of the neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio, as indicators of inflammatory response in the setting of pancreatic fistula. METHODS: A retrospective observational study was conducted on patients that underwent distal pancreatectomy. The diagnosis of postoperative pancreatic fistula was made according to the definition proposed by the International Study Group on Pancreatic Fistula. The relation of postoperative pancreatic fistula to the neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio was determined in the postoperative evaluation. SPSS v.21 software was utilized for the statistical analysis and a P<.05 was considered statistically significant. RESULTS: A total of 12 patients (27.2%) developed grade B or grade C postoperative pancreatic fistula. ROC curves were constructed and a threshold of 8.3 (PPV 0.40, NPV 0.86) was established for the neutrophil-to-lymphocyte ratio, with an area under the curve of 0.71, sensitivity of 0.81, and specificity of 0.62, whereas a threshold of 33.2 (PPV 0.50, NPV 0.84) was established for the platelet-to-lymphocyte ratio, with an area under the curve of 0.72, sensitivity of 0.72, and specificity of 0.71. CONCLUSION: The neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio are serologic markers that can aid in identifying patients that will present with grade B or grade C postoperative pancreatic fistula, thus helping to provide an opportune focus on care and resources.

ß-tubulin functions in spermatogenesis in Lygus hesperus Knight.

Lygus hesperus Knight is an important insect pest of crops across western North America, with field management heavily reliant on the use of chemical insecticides. Because of the evolution of resistance to these insecticides, effective and environmentally benign pest management strategies are needed. Traditional sterile insect technique (SIT) has been successfully employed to manage or eradicate some insect pests but involves introducing irradiated insects with random mutations into field populations. New genetically-driven SIT techniques are a safer alternative, causing fixed mutations that manipulate individual genes in target pests to produce sterile individuals for release. Here, we identified seven ß-tubulin coding genes from L. hesperus and show that Lhßtub2 is critical in male sperm production and fertility. Lhßtub2 is expressed primarily in the male testes and targeting of this gene by RNA interference or gene editing leads to male sterility.

Novice learners' perspectives on obstetric airway crisis decision-making training using virtual reality simulation.

BACKGROUND: Current training on managing an obstetric difficult airway crisis is likely inadequate, as real-life opportunities to practice are rare. Frequent simulation training sessions could be helpful but are resource intensive. Virtual reality (VR) simulation training may be a potential tool to complement existing simulation curricula. METHODS: In this pilot qualitative study, a VR simulation scenario of an obstetric airway crisis was designed to test the decision-making of novice learners rotating through obstetric anesthesia training. Individual interviews were conducted pre-VR to assess learning needs and post-VR to assess perspectives on utilizing the VR teaching tool. The interviews were transcribed and thematically analyzed. RESULTS: Twenty-one residents were recruited and participated in the study. Analysis of pre-VR interviews identified three major themes, including gaps in the current curriculum, lack of confidence in managing obstetric difficult airway crises, and recognition that simulation is resource intensive. Post-VR interview themes revealed that VR could be helpful in learning decision-making under stress. Suggested improvements included better video and audio quality, and adding haptic feedback and potential multiplayer features in the future. CONCLUSION: We identified the advantages of VR simulation and its potential as an intervention to address gaps in our curriculum. Areas of improvement were identified for more effective future implementation.

Constrained tandem neural network assisted inverse design of metasurfaces for microwave absorption.

Designing microwave absorbers with customized spectrums is an attractive topic in both scientific and engineering communities. However, due to the massive number of design parameters involved, the design process is typically time-consuming and computationally expensive. To address this challenge, machine learning has emerged as a powerful tool for optimizing design parameters. In this work, we present an analytical model for an absorber composed of a multi-layered metasurface and propose a novel inverse design method based on a constrained tandem neural network. The network can provide structural and material parameters optimized for a given absorption spectrum, without requiring professional knowledge. Furthermore, additional physical attributes, such as absorber thickness, can be optimized when soft constraints are applied. As an illustrative example, we use the neural network to design broadband microwave absorbers with a thickness close to the causality limit imposed by the Kramers-Kronig relation. Our approach provides new insights into the reverse engineering of physical devices.

Experimental Realization of Stable Exceptional Chains Protected by Non-Hermitian Latent Symmetries Unique to Mechanical Systems.

Lines of exceptional points are robust in the three-dimensional non-Hermitian parameter space without requiring any symmetry. However, when more elaborate exceptional structures are considered, the role of symmetry becomes critical. One such case is the exceptional chain (EC), which is formed by the intersection or osculation of multiple exceptional lines (ELs). In this Letter, we investigate a non-Hermitian classical mechanical system and reveal that a symmetry intrinsic to second-order dynamical equations, in combination with the source-free principle of ELs, guarantees the emergence of ECs. This symmetry can be understood as a non-Hermitian generalized latent symmetry, which is absent in prevailing formalisms rooted in first-order Schrödinger-like equations and has largely been overlooked so far. We experimentally confirm and characterize the ECs using an active mechanical oscillator system. Moreover, by measuring eigenvalue braiding around the ELs meeting at a chain point, we demonstrate the source-free principle of directed ELs that underlies the mechanism for EC formation. Our Letter not only enriches the diversity of non-Hermitian exceptional point configurations, but also highlights the new potential for non-Hermitian physics in second-order dynamical systems.

Neuronal PAS domain 1 identifies a major subpopulation of wakefulness-promoting GABAergic neurons in basal forebrain.

Here we describe a novel group of basal forebrain (BF) neurons expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. Immunohistochemical staining in Npas1-cre-2A-TdTomato mice revealed BF Npas1 + neurons are distinct from well-studied parvalbumin or cholinergic neurons. Npas1 staining in GAD67-GFP knock-in mice confirmed that the vast majority of Npas1 + neurons are GABAergic, with minimal colocalization with glutamatergic neurons in vGlut1-cre-tdTomato or vGlut2-cre-tdTomato mice. The density of Npas1 + neurons was high, 5-6 times that of neighboring cholinergic, parvalbumin or glutamatergic neurons. Anterograde tracing identified prominent projections of BF Npas1 + neurons to brain regions involved in sleep-wake control, motivated behaviors and olfaction such as the lateral hypothalamus, lateral habenula, nucleus accumbens shell, ventral tegmental area and olfactory bulb. Chemogenetic activation of BF Npas1 + neurons in the light (inactive) period increased the amount of wakefulness and the latency to sleep for 2-3 hr, due to an increase in long wake bouts and short NREM sleep bouts. Non-REM slow-wave (0-1.5 Hz) and sigma (9-15 Hz) power, as well as sleep spindle density, amplitude and duration, were reduced, reminiscent of findings in several neuropsychiatric disorders. Together with previous findings implicating BF Npas1 + neurons in stress responsiveness, the anatomical projections of BF Npas1 + neurons and the effect of activating them suggest a possible role for BF Npas1 + neurons in motivationally-driven wakefulness and stress-induced insomnia. Identification of this major subpopulation of BF GABAergic neurons will facilitate studies of their role in sleep disorders, dementia and other neuropsychiatric conditions involving BF. SIGNIFICANCE STATEMENT: We characterize a group of basal forebrain (BF) neurons in the mouse expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. BF Npas1 + neurons are a major subset of GABAergic neurons distinct and more numerous than cholinergic, parvalbumin or glutamate neurons. BF Npas1 + neurons target brain areas involved in arousal, motivation and olfaction. Activation of BF Npas1 + neurons in the light (inactive) period increased wakefulness and the latency to sleep due to increased long wake bouts. Non-REM sleep slow waves and spindles were reduced reminiscent of findings in several neuropsychiatric disorders. Identification of this major subpopulation of BF GABAergic wake-promoting neurons will allow studies of their role in insomnia, dementia and other conditions involving BF.

A non-canonical striatopallidal Go pathway that supports motor control.

In the classical model of the basal ganglia, direct pathway striatal projection neurons (dSPNs) send projections to the substantia nigra (SNr) and entopeduncular nucleus to regulate motor function. Recent studies have re-established that dSPNs also possess axon collaterals within the globus pallidus (GPe) (bridging collaterals), yet the significance of these collaterals for behavior is unknown. Here we use in vivo optical and chemogenetic tools combined with deep learning approaches in mice to dissect the roles of dSPN GPe collaterals in motor function. We find that dSPNs projecting to the SNr send synchronous motor-related information to the GPe via axon collaterals. Inhibition of native activity in dSPN GPe terminals impairs motor activity and function via regulation of Npas1 neurons. We propose a model by which dSPN GPe axon collaterals (striatopallidal Go pathway) act in concert with the canonical terminals in the SNr to support motor control by inhibiting Npas1 neurons.

The Effects of Human Papillomavirus Status and Treatment on the Positive Predictive Value of Post-radiotherapy 18F-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography in Advanced Head and Neck Squamous Cell Carcinoma.

AIMS: The high negative predictive value of post-chemoradiation (CRT) positron emission tomography-computed tomography (PET-CT) is well established in head and neck squamous cell cancers (HNSCC). The positive predictive value (PPV) remains under scrutiny, with increasing evidence that it is affected by several factors. The aim of this study was to assess the PPV of post-treatment PET-CT for residual nodal disease when stratified by treatment modality and tumour human papillomavirus (HPV) status. MATERIALS AND METHODS: This was a retrospective cohort study in a tertiary oncology centre carried out between January 2013 and December 2019. Patients were radically treated with radiotherapy only/CRT for node-positive HNSCC. PET-CT nodal responses were categorised as complete, equivocal (EQR) or incomplete (ICR), and outcomes extracted from electronic records. RESULTS: In total, 480 patients were evaluated, all had a minimum potential follow-up of 2 years, with a median of 39.2 months. The PPV of 12-week PET-CT was significantly different between HPV-positive (22.5%) and HPV-unrelated (52.7%) disease, P < 0.001. It was also significantly different between the CRT (24.8%) and radiotherapy-only (51.1%) groups, P = 0.001. The PPV of an EQR was significantly less than an ICR, irrespective of HPV status and primary treatment modality. In HPV-positive disease, the PPV of an EQR was 9.0% for the CRT group compared with 21.4% for radiotherapy only, P = 0.278. The PPV in those who achieved an ICR was 34.2% in the CRT group, significantly lower than 70.0% in the radiotherapy-only group, P = 0.03. CONCLUSION: The PPV of 12-week PET-CT is significantly lower for HPV-positive compared with HPV-unrelated HNSCC. It is poorer in patients with HPV-positive disease treated with CRT compared with radiotherapy alone.

Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors.

While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well established, how to optimally block the activity of PGE2 signaling remains to be demonstrated. Clinical trials with prostaglandin pathway targeted agents have shown activity but without sufficient significance or dose-limiting toxicities that have prevented approval. PGE2 signals through four receptors (EP1-4) to modulate tumor progression. EP2 and EP4 signaling exacerbates tumor pathology and is immunosuppressive through potentiating cAMP production. EP1 and EP3 signaling has the opposite effect through increasing IP3 and decreasing cAMP. Using available small-molecule antagonists of single EP receptors, the cyclooxygenase-2 (COX-2) inhibitor celecoxib, or a novel dual EP2/EP4 antagonist generated in this investigation, we tested which approach to block PGE2 signaling optimally restored immunologic activity in mouse and human immune cells and antitumor activity in syngeneic, spontaneous, and xenograft tumor models. We found that dual antagonism of EP2 and EP4 together significantly enhanced the activation of PGE2-suppressed mouse and human monocytes and CD8+ T cells in vitro as compared with single EP antagonists. CD8+ T-cell activation was dampened by single EP1 and EP3 antagonists. Dual EP2/EP4 PGE2 receptor antagonists increased tumor microenvironment lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC)min+/- spontaneous colorectal tumor model, compared with celecoxib. These results support a hypothesis that redundancy of EP2 and EP4 receptor signaling necessitates a therapeutic strategy of dual blockade of EP2 and EP4. Here we describe TPST-1495, a first-in-class orally available small-molecule dual EP2/EP4 antagonist. Significance: Prostaglandin (PGE2) drives tumor progression but the pathway has not been effectively drugged. We demonstrate significantly enhanced immunologic potency and antitumor activity through blockade of EP2 and EP4 PGE2 receptor signaling together with a single molecule.

Cross-cultural translation into Chinese and psychometric evaluation of a screening tool for nocturia: the Targeting the individual's Aetiology of Nocturia to Guide Outcomes (TANGO) questionnaire.

INTRODUCTION: We conducted translation and psychometric validation of a self-administered, 22-item dichotomous response-based questionnaire to identify nocturia aetiologies and co-morbidities in adult patients. METHODS: The Targeting the individual's Aetiology of Nocturia to Guide Outcomes (TANGO) questionnaire was forward- and backward-translated, then finalised using a standardised methodology. The resulting version, a Chinese version of the TANGO [TANGO (CV)], was evaluated for internal consistency, test-retest reliability, content validity, convergent validity, criterion validity, and discriminant validity via responses from 65 participants (46 men and 19 women; mean age, 67 years, range, 50-88), in comparison with other validated questionnaires and a 4-day bladder/sleep diary. RESULTS: Only 0.4% of responses were missing; 3% of participants required assistance with comprehension. The Kuder-Richardson Formula 20 (KR-20) coefficient for the whole tool was 0.711. Kappa values for individual domains and the whole tool varied from 0.871 to 0.866, indicating satisfactory test-retest reliability. There was strong agreement between the sum of positive responses to each domain and the whole tool (intra-class correlation coefficient=0.878-1.000). Modest correlations (ρ=0.4-0.6) were detected between the tool and bladder/sleep diary-based parameters for convergent validity. Criterion validity was confirmed for each domain and the whole tool [ρ=0.287-0.687]. In receiver operating characteristic analysis, the tool could distinguish patients (≥2 nocturia episodes/night) from controls (≤1 nocturia episode/night) [Youden's J statistic=0.453, area under the curve=0.818, 95% confidence interval (CI)=0.683-0.953] and patients with significant nocturia distress from patients with mild nocturia distress (Youden's J statistic=0.398, area under the curve=0.729, 95% CI=0.581-0.878). CONCLUSION: The TANGO (CV) was formally crossculturally adapted and translated. Its psychometric properties (except sensitivity to change) were validated.