Evaluation of data imputation strategies in complex, deeply-phenotyped data sets: the case of the EU-AIMS Longitudinal European Autism Project.

An increasing number of large-scale multi-modal research initiatives has been conducted in the typically developing population, e.g. Dev. Cogn. Neur. 32:43-54, 2018; PLoS Med. 12(3):e1001779, 2015; Elam and Van Essen, Enc. Comp. Neur., 2013, as well as in psychiatric cohorts, e.g. Trans. Psych. 10(1):100, 2020; Mol. Psych. 19:659-667, 2014; Mol. Aut. 8:24, 2017; Eur. Child and Adol. Psych. 24(3):265-281, 2015. Missing data is a common problem in such datasets due to the difficulty of assessing multiple measures on a large number of participants. The consequences of missing data accumulate when researchers aim to integrate relationships across multiple measures. Here we aim to evaluate different imputation strategies to fill in missing values in clinical data from a large (total N = 764) and deeply phenotyped (i.e. range of clinical and cognitive instruments administered) sample of N = 453 autistic individuals and N = 311 control individuals recruited as part of the EU-AIMS Longitudinal European Autism Project (LEAP) consortium. In particular, we consider a total of 160 clinical measures divided in 15 overlapping subsets of participants. We use two simple but common univariate strategies-mean and median imputation-as well as a Round Robin regression approach involving four independent multivariate regression models including Bayesian Ridge regression, as well as several non-linear models: Decision Trees (Extra Trees., and Nearest Neighbours regression. We evaluate the models using the traditional mean square error towards removed available data, and also consider the Kullback-Leibler divergence between the observed and the imputed distributions. We show that all of the multivariate approaches tested provide a substantial improvement compared to typical univariate approaches. Further, our analyses reveal that across all 15 data-subsets tested, an Extra Trees regression approach provided the best global results. This not only allows the selection of a unique model to impute missing data for the LEAP project and delivers a fixed set of imputed clinical data to be used by researchers working with the LEAP dataset in the future, but provides more general guidelines for data imputation in large scale epidemiological studies.

PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection.

The energetic burden of continuously concentrating solutes against gradients along the tubule may render the kidney especially vulnerable to ischaemia. Acute kidney injury (AKI) affects 3% of all hospitalized patients. Here we show that the mitochondrial biogenesis regulator, PGC1α, is a pivotal determinant of renal recovery from injury by regulating nicotinamide adenine dinucleotide (NAD) biosynthesis. Following renal ischaemia, Pgc1α(-/-) (also known as Ppargc1a(-/-)) mice develop local deficiency of the NAD precursor niacinamide (NAM, also known as nicotinamide), marked fat accumulation, and failure to re-establish normal function. Notably, exogenous NAM improves local NAD levels, fat accumulation, and renal function in post-ischaemic Pgc1α(-/-) mice. Inducible tubular transgenic mice (iNephPGC1α) recapitulate the effects of NAM supplementation, including more local NAD and less fat accumulation with better renal function after ischaemia. PGC1α coordinately upregulates the enzymes that synthesize NAD de novo from amino acids whereas PGC1α deficiency or AKI attenuates the de novo pathway. NAM enhances NAD via the enzyme NAMPT and augments production of the fat breakdown product ß-hydroxybutyrate, leading to increased production of prostaglandin PGE2 (ref. 5), a secreted autacoid that maintains renal function. NAM treatment reverses established ischaemic AKI and also prevented AKI in an unrelated toxic model. Inhibition of ß-hydroxybutyrate signalling or prostaglandin production similarly abolishes PGC1α-dependent renoprotection. Given the importance of mitochondrial health in ageing and the function of metabolically active organs, the results implicate NAM and NAD as key effectors for achieving PGC1α-dependent stress resistance.

Impact of Endometrial Thickness and Volume Compaction on the Live Birth Rate Following Fresh Embryo Transfer of In Vitro Fertilization.

OBJECTIVES: The aim of our study was to compare the live birth rate following fresh embryo transfer (ET) during in vitro fertilization (IVF) in women with or without endometrial compaction in thickness and volume between the day of human chorionic gonadotrophin (hCG) and the ET day. METHODS: This is a retrospective analysis of infertile women undergoing the first IVF cycle with fresh ET. A single operator performed all the ultrasound measurements for endometrial thickness and endometrial volume using three-dimensional ultrasound. Endometrial compaction was calculated as the difference of the measurement between the hCG day and ET day. The predictive values of age of women, number of embryos transferred, and endometrial compaction in thickness and volume on live birth were studied. RESULTS: A total of 268 women who underwent the first IVF cycle with fresh ET between June 2005 and August 2006 were included in this retrospective analysis. Endometrial thickness was significantly higher on the ET day than the hCG day while endometrial volume was significantly smaller on the ET day than the hCG day. Women with a live birth were younger, had a higher serum estradiol level on the hCG day, and similar absolute or percentage change of endometrial thickness and volume when compared to those without a live birth. CONCLUSION: Endometrial thickness and volume compaction was not a significant predictor of live birth in the multivariate logistic regression model. Endometrial thickness and volume compaction did not affect the live birth rate in the fresh IVF cycle.

PGC1α in the kidney.

Acute kidney injury (AKI) arising from diverse etiologies is characterized by mitochondrial dysfunction. The peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC1α), a master regulator of mitochondrial biogenesis, has been shown to be protective in AKI. Interestingly, reduction of PGC1α has also been implicated in the development of diabetic kidney disease and renal fibrosis. The beneficial renal effects of PGC1α make it a prime target for therapeutics aimed at ameliorating AKI, forms of chronic kidney disease (CKD), and their intersection. This review summarizes the current literature on the relationship between renal health and PGC1α and proposes areas of future interest.

[Genetic Polymorphisms of 30 InDel Loci in Ewenki Ethnic Group from Inner Mongolia].

OBJECTIVES: To study the genetic polymorphisms of 30 insertion/deletion （InDel） loci and evaluate their forensic application in Ewenki ethnic group from Inner Mongolia. METHODS: Peripheral blood samples were collected from 87 unrelated healthy individuals in Ewenki ethnic group. Genomic DNA were extracted, and 30 InDel loci of the samples were multiplex amplified and genotyped. Hardy-Weinberg balance tests were preformed for all loci and genetic parameters were calculated by modified PowerStats v1.2 software. The linkage disequilibrium between loci were tested by SNPAnalyzer v2.0 software. Based on the allele frequencies of 30 InDel loci, the genetic relationships between Ewenki ethnic group and other populations were evaluated by analysis of molecular variance, principal component analysis and phylogenetic reconstruction. RESULTS: After correction, 30 InDel loci conformed to Hardy-Weinberg equilibrium. It was found that the pairwise InDel loci were in linkage equilibrium after Bonferroni correction. The results of population genetics indicated that Ewenki ethnic group had close genetic relationships with Henan Han and Beijing Han populations; whereas it was significantly different from several populations in Europe and Mexico. CONCLUSIONS: There are relatively high genetic polymorphisms on 30 InDel loci of Ewenki ethnic group from Inner Mongolia, which can be used as a helpful supplement application for STR detection system.

Comparison of the Efficacy and Safety of Perioperative Immunochemotherapeutic Strategies for Resectable Non-small Cell Lung Cancer: a Systematic Review and Network Meta-analysis.

AIMS: The aim of this network meta-analysis was to elucidate the efficacy and safety of various immune checkpoint inhibitors (ICIs) used in combination with chemotherapy for the treatment of non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Data from randomised controlled trials comparing perioperative ICI-chemotherapy and chemotherapy alone were acquired from the EMBASE, Web of Science, Cochrane Library databases, PubMed, and meeting abstracts from inception until August 2023. The endpoints for this analysis were pathological complete response, event-free survival and treatment-related adverse events of any grade or adverse events of grade 3 or higher. RESULTS: In total, six randomised controlled trials with 2538 NSCLC patients were selected for this network meta-analysis. Compared with other ICIs, toripalimab + chemotherapy demonstrated increased pathological complete response rates and prolonged event-free survival in NSCLC. In patients with negative/low PD-L1 expression or squamous cell pathology, toripalimab + chemotherapy was the most effective regimen. In contrast, nivolumab + chemotherapy was preferable for patients with high PD-L1 expression or non-squamous cell pathology. Among the analysed regimens, toripalimab + chemotherapy presented the highest risk of adverse events of any grade, whereas nivolumab + chemotherapy showed the highest risk of grade 3-4 adverse events. Conversely, durvalumab + chemotherapy exhibited the lowest risk of grade 3-4 adverse events. CONCLUSIONS: Among the evaluated perioperative immunochemotherapy regimens, toripalimab + chemotherapy indicated a significantly increased survival benefit for most resectable NSCLC patients. However, for high PD-L1 expression and non-squamous NSCLC patients, nivolumab + chemotherapy provided the most potent outcomes. Perioperative durvalumab + chemotherapy is a relatively safe treatment. The findings of this investigation are expected to assist clinicians in making informed decisions among promising treatment options.

Comparison of long-acting injectable antipsychotics with oral antipsychotics and hospital readmission rates in pediatric patients.

Introduction: Studies indicate that long-acting injectable antipsychotics (LAIAs) reduce the risk of relapse and hospitalization compared with oral antipsychotics (APs) in adults. Oral formulations of APs are well-studied in the pediatric population, but little is known regarding the off-label use of LAIAs in this population. Methods: This retrospective chart review evaluated readmission rates for pediatric patients admitted to a psychiatric ward in a large academic hospital between January 1, 2015, and December 1, 2022, requiring AP therapy. The experimental group included patients initiated on LAIA therapy, and the control group included patients initiated on a new oral AP. Patients were matched by several clinical factors. Results: Each group consisted of 38 patients. For the primary outcome, hospital readmission rates at 3 months, the LAIA group had a 13.2% readmission rate compared with 26.3% in the comparator group (p = .153). In months 4 through 6, there was a 5.3% versus 15.8% readmission rate, respectively (p = .139). In months 7 through 12, it was 7.9% versus 18.4% (p = .179). There were significantly fewer cumulative readmissions at the 1-year mark in the LAIA group (N = 9, 23.7%) compared with the oral AP group (N = 18, 47.4%) (p = .031). No statistically significant differences were seen in hospital length of stay although results numerically favored LAIA. Discussion: In a pediatric population, the administration of an LAIA when compared with the oral equivalent resulted in numerically fewer hospital readmissions, decreased length of stay, and fewer adverse effects, but these effects were not statistically significant except for cumulative readmissions at 1 year.

Dynamic equilibrium between cancer stem cells and non-stem cancer cells in human SW620 and MCF-7 cancer cell populations.

BACKGROUND: Cancer stem cells (CSCs) paradigm suggests that CSCs might have important clinical implications in cancer therapy. Previously, we reported that accumulation efficiency of CSCs is different post low- and high-LET irradiation in 48 h. METHODS: Cancer stem cells and non-stem cancer cells (NSCCs) were sorted and functionally identified through a variety of assays such as antigen profiles and sphere formation. Inter-conversion between CSCs and NSCCs were in situ visualised. Cancer stem cells proportions were assayed over multiple generations under normal and irradiation surroundings. Supplement and inhibition of TGF-ß1, as well as immunofluorescence assay of E-cadherin and Vimentin, were performed. RESULTS: Surface antigen markers of CSCs and NSCCs exist in an intrinsic homoeostasis state with spontaneous and in situ visualisable inter-conversions, irrespective of prior radiations. Supplement with TGF-ß1 accelerates the equilibrium, whereas inhibition of TGF-ß signalling disturbs the equilibrium and significantly decreases CSC proportion. Epithelial mesenchymal transition (EMT) might be activated during the process. CONCLUSION: Our results indicate that the intrinsic inter-conversion and dynamic equilibrium between CSCs and NSCCs exist under normal and irradiation surroundings, and TGF-ß might have important roles in the equilibrium through activating EMT.

Analysis of an ultra-compact wavelength filter based on hybrid plasmonic waveguide structure.

In this letter, we propose and analyze an ultra-compact wavelength filter on silicon-based hybrid plasmonic waveguides, which confines light in a nanometeric silica dioxide layer between the silicon substrate and metal cap. The filter consists of a stub structure coupled to a straight waveguide. The three-dimensional finite-difference time-domain (FDTD) method is applied to calculate the spectral responses of such devices. Similar resonant behaviors are obtained since those devices are based on two-dimensional Metal-Insulator-Metal waveguide structure. Results also show that by adding stubs and tuning the distance between stubs can further improve the device's performance and shape the spectral response to some extent.

Evaluation of Interprofessional Education on Effective Communication Between Pharmacy and Physician Assistant Students.

PURPOSE: The purpose of this study was to assess the effect of Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) on student self-perceived competencies and perceptions of interprofessional (IP) communication and teamwork in a clinical case review activity. TeamSTEPPS is an evidence-based curriculum that is used to enhance and support IP healthcare communication. METHODS: A repeated-measures, pretest/posttest study evaluated physician assistant students' and student pharmacists' perceptions of TeamSTEPPS. Students completed Performance Assessment for Communication and Teamwork (PACT) surveys, evaluating teamwork, knowledge, attitudes, and skills perceptions before and after a TeamSTEPPS lecture and associated activity with peer feedback. RESULTS: Overall, 87.4% (n = 429) completed pre- and post-PACT surveys. Apart from the Mutual Support domain (p = .898), all changes were significantly positive (p < .004), with the greatest improvements occurring in the Attitudes and Perceived Skills domains. CONCLUSION: TeamSTEPPS IP education, application, and peer feedback improved students' perceptions of multiple domains, including effective communication. Using TeamSTEPPS tools in IP formats enabled the students to safely practice and collaborate in preparation for clinical practice.

Pharmacotherapy treatment of stimulant use disorder.

Stimulant use disorder (SUD) is a public health problem in the United States that is associated with increased morbidity and mortality. Psychosocial interventions, such as cognitive behavioral therapy and contingency management, are the main treatment modality for SUDs and no pharmacotherapy is currently FDA approved for this indication. Although some medications show promising data for the treatment of SUD, the evidence remains inconsistent, and the clinical application is limited due to the heterogenicity of the population and the lack of studies in patients with various comorbidities. Selection of pharmacotherapy treatment for methamphetamine intoxication, persistent methamphetamine-associated psychosis with methamphetamine use disorder, and cocaine use disorder in patients with co-occurring OUD are discussed in 3 patient cases.

Pure angular momentum generator using a ring resonator.

This paper reports a pure angular momentum generator using a ring resonator surrounded by a group of nano-rods. The evanescent waves of the circulating light in the ring are scattered by the nano-rods and generate a rotating electromagnetic field, which has only angular momentum but no linear momentum along the axis of rotation. The angular order is determined by the difference between the order of Whispering Gallery mode and the number of the rods, the rotating frequency is equal to the light frequency divided by the angular order. The maximum amplitude of the rotating electromagnetic fields can be 10 times higher than the amplitude of the input field when there are 36 rods (R(rod) = 120 nm, nr = 1.6). The pure angular momentum generator provides a new platform for trapping and rotation of small particles.

Coupling-induced phase shift in a microring-coupled Mach-Zehnder interferometer.

We experimentally study the effects of the coupling-induced phase shift (CIPS) in silicon-on-insulator microring-coupled Mach-Zehnder interferometer (MZI) devices for the flat-top filter application. Excellent agreement is obtained between the theoretical modeling and the experiment. It is demonstrated that width offset of the uncoupled MZI arm can compensate the CIPS and approximate a box-like filter with only 0.02% deviation from its ideal requirement.

Current and emerging therapies for insomnia.

Up to 10% of the US adult population will experience chronic insomnia, with women and elderly individuals at particularly high risk. Cognitive behavioral therapy is the core treatment for insomnia. When cognitive behavioral therapy is not enough, medications can help patients overcome the barriers and learned behaviors that prevent a good night's sleep. Benzodiazepines and nonbenzodiazepine GABA-A receptor agonists are the traditional medications used to treat insomnia. More recently, orexin inhibitors have been introduced that may have fewer adverse effects, including the development of dependence. To date, only suvorexant and lemborexant have been approved for the treatment of insomnia. However, several other agents are in later stages of development. This article will review the available pharmacotherapeutic options for treating insomnia.

Mitochondrial dysfunction resulting from loss of cytochrome c impairs radiation-induced bystander effect.

Cytochrome c is a pivotal protein that resides in mitochondria as component of mitochondria respiration and apoptosis initiator. Using murine cells lacking cytochrome c, we showed here that cytochrome c-deficient cells had attenuated reactive oxygen species/nitric oxide and micronuclei induction to radiation-induced bystander signals, indicating cytochrome c is essential for the bystander effect.

Surface plasmon converging and diverging properties modulated by polymer refractive structures on metal films.

Polymer refractive microstructures are fabricated on metallic thin films and employed to modulate surface plasmons (SPs) propagations in a refractive manner. SP waves converging with different focal lengths and diverging effects are realized by the refractive structures. Authors investigated the modulation effect on SP waves as a function of different thicknesses and different shapes of the polymer micro-structures based on the effective refractive index model, where imaging properties of the SPs are observed experimentally by detecting the leaky radiation intensity of the SPs.

Flubromazolam overdose: A review of a new designer benzodiazepine and the role of flumazenil.

Designer products, a term referring to analogs of known chemical compounds with no established medical use, represent an easily accessible alternative to prescription-only products. During the past decade, designer benzodiazepines have become widely available on the online forums. Although these agents offer individuals an inexpensive and accessible alternative to prescription-only products, they are not without risk. Because of the lack of federally enforced quality standards, these designer products come with an intrinsic risk of unpredictable and potentially toxic adverse effects. This article presents a 36-year-old male with prolonged bradycardia resulting from the use of flubromazolam, a designer benzodiazepine purchased from the Internet. A PubMed search was conducted for flubromazolam, designer benzodiazepine, and flumazenil. This article will summarize the available literature regarding flubromazolam and the role of flumazenil in managing these overdoses.

[Preliminary evaluation of endoscopic selective varices devascularization in children].

Objective: To investigate the effect of the endoscopic selective varices devascularization (ESVD) for the esophageal gastric varices bleeding (EGVB) in children. Methods: The clinical data of the patients diagnosed with EGVB and treated with ESVD from January 2018 to March 2018 were retrospectively analyzed. The effects, safety and complications of ESVD were evaluated. Results: There were five patients (including 2 males and 3 females, age ranged from 4 to 7 years) in the study. No rebleeding was found at the first follow-up on one week post operation. Three patients were treated with the endo-therapy at the twice follow-up (3 months after surgery): 2 patients had ESVD again and 1 patient had resection under endoscopy due to stenosis caused by surgical scar. After the second procedure, there was no rebleeding but one patient had abdominal pain caused by mesenteric thrombosis, cured with low molecular weight heparin. Conclusion: The ESVD for EGVB is safe and effective, but the long-term curative effect should be further studied.

An Evolutionarily Conserved uORF Regulates PGC1α and Oxidative Metabolism in Mice, Flies, and Bluefin Tuna.

Mitochondrial abundance and function are tightly controlled during metabolic adaptation but dysregulated in pathological states such as diabetes, neurodegeneration, cancer, and kidney disease. We show here that translation of PGC1α, a key governor of mitochondrial biogenesis and oxidative metabolism, is negatively regulated by an upstream open reading frame (uORF) in the 5' untranslated region of its gene (PPARGC1A). We find that uORF-mediated translational repression is a feature of PPARGC1A orthologs from human to fly. Strikingly, whereas multiple inhibitory uORFs are broadly present in fish PPARGC1A orthologs, they are completely absent in the Atlantic bluefin tuna, an animal with exceptionally high mitochondrial content. In mice, an engineered mutation disrupting the PPARGC1A uORF increases PGC1α protein levels and oxidative metabolism and confers protection from acute kidney injury. These studies identify a translational regulatory element governing oxidative metabolism and highlight its potential contribution to the evolution of organismal mitochondrial function.

TFEB-driven lysosomal biogenesis is pivotal for PGC1α-dependent renal stress resistance.

Because injured mitochondria can accelerate cell death through the elaboration of oxidative free radicals and other mediators, it is striking that proliferator gamma coactivator 1-alpha (PGC1α), a stimulator of increased mitochondrial abundance, protects stressed renal cells instead of potentiating injury. Here we report that PGC1α's induction of lysosomes via transcription factor EB (TFEB) may be pivotal for kidney protection. CRISPR and stable gene transfer showed that PGC1α knockout tubular cells were sensitized to the genotoxic stressor cisplatin whereas transgenic cells were protected. The biosensor mtKeima unexpectedly revealed that cisplatin blunts mitophagy both in cells and mice. PGC1α not only counteracted this effect but also raised basal mitophagy, as did the downstream mediator nicotinamide adenine dinucleotide (NAD+). PGC1α did not consistently affect known autophagy pathways modulated by cisplatin. Instead RNA sequencing identified coordinated regulation of lysosomal biogenesis via TFEB. This effector pathway was sufficiently important that inhibition of TFEB or lysosomes unveiled a striking harmful effect of excess PGC1α in cells and conditional mice. These results uncover an unexpected effect of cisplatin on mitophagy and PGC1α's exquisite reliance on lysosomes for kidney protection. Finally, the data illuminate TFEB as a novel target for renal tubular stress resistance.