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Background: Coaching in academic medicine may help learners develop lifelong learning skills. Studies typically evaluate the impact on coachees and program outcomes. Limited information is available about educating faculty to integrate the role of coaching. We explored a faculty coach training program at an academic medical center in the southern region of the United States. Methods: Twenty faculty members in the college of medicine completed the 34-h training program meeting alternate weeks from May to November 2021. We collected data from reflections during training, a post-training survey, and three post-training focus group discussions making this a qualitatively driven mixed methods research. We used a transcendental phenomenological approach for the qualitative analysis entailing deriving essential meaning of the participants' training experiences and perceptions about coaching. Results: We identified 3 themes (1) perceptions, skills, and understanding of coaching, (2) perceived additional benefits from coach training, and (3) effective instructional practices to teach coaching. Under the first theme, participants expressed improved understanding about the process of coaching in academic medicine, noted the importance of listening to the whole person without judgment, questioning with curiosity, vulnerability, self-awareness, and reflection for building trust. Perceived additional benefits included personal development and illuminating discoveries. Sub-themes for effective instructional practices were learning community encompassing mindfulness, psychological safety, social cohesion, experiential and interactive learning, and suggestions. Faculty experienced internal transformation while learning coaching and felt they had the capacity to influence personal and professional development of learners and colleagues. The concepts reflection, awareness, growth, and relationship were threaded throughout the three themes. Conclusions: The training evoked self-awareness and opportunities for personal growth. The newly trained coaches expressed the beginning of an internal transformation to embody being a coach and demonstrated willingness to influence personal and professional development of learners and colleagues. Effective instructional practices to teach coaching included mindfulness practice, psychological safety, social cohesion, and experiential and interactive learning. Based on these findings, it may be summarized that in the process of training to be a coach, the faculty not only recognized the benefits of coaching for learners but also realized individual personal benefits. [ABSTRACT FROM AUTHOR]

Background: Per- and polyfluoroalkyl substances (PFAS) are fluorinated chemicals linked to adverse pregnancy and birth outcomes. However, the underlying mechanisms, specifically their effects on maternal inflammatory processes, are not well characterized., Objective: We examined associations between prenatal PFAS exposure and repeated measures of inflammatory biomarkers, including C-reactive protein (CRP) and four cytokines [Interleukin-10 (IL-10), IL-1β, IL-6, and tumor necrosis factor-α (TNF-α)]., Methods: We analyzed data from 469 pregnant women in a nested case-control study of preterm birth at Brigham and Women's Hospital in Boston, Massachusetts (2006-2008). We measured nine PFAS in early pregnancy plasma samples (median gestation: 10 weeks), with inflammatory biomarkers measured at median gestations of 10, 18, 26, and 35 weeks. We used linear mixed models for repeated measures and multivariable regression for visit-specific analysis to examine associations between each PFAS and inflammation biomarker, adjusting for maternal demographics, pre-pregnancy BMI, and parity. We examined the effects of PFAS mixture using sum of all PFAS (∑PFAS) and quantile-based g-computation approaches., Results: We observed consistent inverse associations between most PFAS and cytokines, specifically IL-10, IL-6, and TNF-α, in both single pollutant and mixture analyses. For example, an interquartile range increase in perfluorooctanesulfonic acid was associated with -10.87 (95% CI: -19.75, -0.99), -13.91 (95% CI: -24.11, -2.34), and -8.63 (95% CI: -14.51, -2.35) percent change in IL-10, IL-6, and TNF-α levels, respectively. Fetal sex, maternal race, and visit-specific analyses showed associations between most PFAS and cytokines were generally stronger in mid-pregnancy and among women who delivered males or identified as African American., Conclusions: The observed suppression of both regulatory (IL-10) and pro-inflammatory (TNF-α) cytokines suggests that PFAS may alter maternal inflammatory processes or immune functions during pregnancy. Further research is needed to understand the effects of both legacy and newer PFAS on inflammatory pathways and their broader clinical implications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Dead cell sorting is pivotal and plays a very significant role in homeostasis. Apoptosis and ferroptosis are the two major regulatory cell death processes. Apoptosis is a programmed cell death process, while ferroptosis is a regulatory cell death process. Monitoring the dead cells coming out from these processes is extremely important to stop various cellular dysfunctions. Here, we present a single NIR emissive probe that can observe both apoptotic and ferroptosis regulatory cell deaths. We were able to directly visualize the dead cells in both animal and plant cells upon a significant increase in the fluorescence intensity of the probe. During cell death, the increased cytoplasm viscosity restricted the rotor motion and helped in the fluorescence turn-on of the probe. Lysosomal viscosity was found to play a crucial role in the ferroptosis pathway. On the other hand, the probe was not only efficient in mapping the viscosity in various parts of live Caenorhabditis elegans ( C. elegans ) bodies but also able to differentiate between live and dead animals.

Here, we report a modular multicellular system created by mixing and matching discrete engineered bacterial cells. This system can be designed to solve multiple computational decision problems. The modular system is based on a set of engineered bacteria that are modeled as an 'artificial neurosynapse' that, in a coculture, formed a single-layer artificial neural network-type architecture that can perform computational tasks. As a demonstration, we constructed devices that function as a full subtractor and a full adder. The system is also capable of solving problems such as determining if a number between 0 and 9 is a prime number and if a letter between A and L is a vowel. Finally, we built a system that determines the maximum number of pieces of a pie that can be made for a given number of straight cuts. This work may have importance in biocomputer technology development and multicellular synthetic biology., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Wearable ultrasound is emerging as a new paradigm of real-time imaging in freely moving humans and has wide applications from cardiovascular health monitoring to human gesture recognition. However, current wearable ultrasound devices have typically employed pulse-echo imaging which requires high excitation voltages and sampling rates, posing safety risks, and requiring specialized hardware. Our objective was to develop and evaluate a wearable ultrasound system based on time delay spectrometry (TDS) that utilizes low-voltage excitation and significantly simplified instrumentation., Methods: We developed a TDS-based ultrasound system that utilizes continuous, frequency-modulated sweeps at low excitation voltages. By mixing the transmit and receive signals, the system digitizes the ultrasound signal at audio frequency (kHz) sampling rates. Wearable ultrasound transducers were developed, and the system was characterized in terms of imaging performance, acoustic output, thermal characteristics, and applications in musculoskeletal imaging., Results: The prototype TDS system is capable of imaging up to 6 cm of depth with signal-to-noise ratio of up to 42 dB at a spatial resolution of 0.33 mm. Acoustic and thermal radiation measurements were within clinically safe limits for continuous ultrasound imaging. We demonstrated the ability to use a 4-channel wearable system for dynamic imaging of muscle activity., Conclusion: We developed a wearable ultrasound imaging system using TDS to mitigate challenges with pulse echo-based wearable ultrasound imaging systems. Our device is capable of high-resolution, dynamic imaging of deep-seated tissue structures and is safe for long-term use., Significance: This work paves the way for low-voltage wearable ultrasound imaging devices with significantly reduced hardware complexity.

The first step of successful infection by any intracellular pathogen relies on its ability to invade its host cell membrane. However, the detailed structural and molecular understanding underlying lipid membrane modification during pathogenic invasion remains unclear. In this study, we show that a specific Leishmania donovani (LD) protein, KMP-11, forms oligomers that bridge LD and host macrophage (MΦ) membranes. This KMP-11 induced interaction between LD and MΦ depends on the variations in cholesterol (CHOL) and ergosterol (ERG) contents in their respective membranes. These variations are crucial for the subsequent steps of invasion, including (a) the initial attachment, (b) CHOL transport from MΦ to LD, and (c) detachment of LD from the initial point of contact through a liquid ordered (Lo) to liquid disordered (Ld) membrane-phase transition. To validate the importance of KMP-11, we generate KMP-11 depleted LD, which failed to attach and invade host MΦ. Through tryptophan-scanning mutagenesis and synthesized peptides, we develop a generalized mathematical model, which demonstrates that the hydrophobic moment and the symmetry sequence code at the membrane interacting protein domain are key factors in facilitating the membrane phase transition and, consequently, the host cell infection process by Leishmania parasites., (© 2024. The Author(s).)

Electronic health records (EHRs) are valuable for public health and clinical research but are prone to many sources of bias, including missing data and non-probability selection. Missing data in EHRs is complex due to potential non-recording, fragmentation, or clinically informative absences. This study explores whether polygenic risk score (PRS)-informed multiple imputation for missing traits, combined with sample weighting, can mitigate missing data and selection biases in estimating disease-exposure associations. Simulations were conducted for missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR) conditions under different sampling mechanisms. PRS-informed multiple imputation showed generally lower bias, particularly when combined with sample weighting. For example, in biased samples of 10,000 with exposure and outcome MAR data, PRS-informed imputation had lower percent bias (3.8%) and better coverage rate (0.883) compared to PRS-uninformed (4.5%; 0.877) and complete case analyses (10.3%; 0.784) in covariate-adjusted, weighted, multiple imputation scenarios. In a case study using Michigan Genomics Initiative (n=50,026) data, PRS-informed imputation aligned more closely with a sample-weighted All of Us-derived benchmark than analyses ignoring missing data and selection bias. Researchers should consider leveraging genetic data and sample weighting to address biases from missing data and non-probability sampling in biobanks.

Amyloid accumulation in Alzheimer's disease (AD) is associated with synaptic damage and altered connectivity in brain networks. While measures of amyloid accumulation and biochemical changes in mouse models have utility for translational studies of certain therapeutics, preclinical analysis of altered brain connectivity using clinically relevant fMRI measures has not been well developed for agents intended to improve neural networks. Here, we conduct a longitudinal study in a double knock-in mouse model for AD (App NL-G-F /hMapt), monitoring brain connectivity by means of resting-state fMRI. While the 4-month-old AD mice are indistinguishable from wild-type controls (WT), decreased connectivity in the default-mode network is significant for the AD mice relative to WT mice by 6 months of age and is pronounced by 9 months of age. In a second cohort of 20-month-old mice with persistent functional connectivity deficits for AD relative to WT, we assess the impact of two-months of oral treatment with a silent allosteric modulator of mGluR5 (BMS-984923/ALX001) known to rescue synaptic density. Functional connectivity deficits in the aged AD mice are reversed by the mGluR5-directed treatment. The longitudinal application of fMRI has enabled us to define the preclinical time trajectory of AD-related changes in functional connectivity, and to demonstrate a translatable metric for monitoring disease emergence, progression, and response to synapse-rescuing treatment., (© 2024. The Author(s).)

The GluN3A subunit of N -methyl-D-aspartate receptors (NMDARs) plays an established role in synapse development, but its contribution to neural circuits in the adult brain is less clear. Recent work has demonstrated that in select cell populations, GluN3A assembles with GluN1 to form GluN1/GluN3A receptors that are insensitive to glutamate and instead serve as functional excitatory glycine receptors (eGlyRs). Our understanding of these eGlyRs, and how they contribute to intrinsic excitability and synaptic communication within relevant networks of the developing and the mature brain, is only beginning to be uncovered. Here, using male and female mice, we demonstrate that GluN3A subunits are enriched in the adult ventral hippocampus (VH), where they localize to synaptic and extrasynaptic sites and can assemble as functional eGlyRs on CA1 pyramidal cells. GluN3A expression was barely detectable in the adult dorsal hippocampus (DH). We also observed a high GluN2B content in the adult VH, characterized by slow NMDAR current decay kinetics and a high sensitivity to the GluN2B-containing NMDAR antagonist ifenprodil. Interestingly, the GluN2B enrichment in the adult VH was dependent on GluN3A as GluN3A deletion accelerated NMDAR decay and reduced ifenprodil sensitivity in the VH, suggesting that GluN3A expression can regulate the balance of conventional NMDAR subunit composition at synaptic sites. Lastly, we found that GluN3A knock-out also enhanced both NMDAR-dependent calcium influx and NMDAR-dependent long-term potentiation in the VH. Together, these data reveal a novel role for GluN3A and eGlyRs in the control of ventral hippocampal circuits in the mature brain., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

We report a simulation methodology to quantitatively predict the thermodynamic behaviour (phase diagrams) of polymer mixtures, that exhibit phases with broken orientational symmetry. Our system consists of a binary mixture of short oligomers ( N A = 4) and long rod-like mesogens ( N B = 8). Using coarse-grained molecular dynamics (CGMD) simulations we infer the topology of the temperature-dependent free energy landscape, from the probability distributions of the components for a range of compositions. The mixture exhibits nematic (N) and smectic phases (Sm-A) as a function of two temperature scales, T c , that governs the demixing transition, and T NI the nematic-isotropic temperature. Thus in addition to the isotropic (I), a nematic (N) phases observed in simulations of similar systems earlier we report the formation of a new entropy-stabilized phase separated smectic-A (Sm-A) phase with alternating mesogen-rich and oligomer-rich layers. Using the mean-field free energy for polymer-dispersed liquid crystals (PDLCs), with suitably chosen parameter values, we construct a mean-field phase diagram that matches those obtained from CGMD simulations. Our results are applicable to mixtures of synthetic and biological macromolecules that undergo phase separation and are orientable, thereby giving rise to the liquid crystalline phases. Our proposed methodology has a distinct advantage over other computational techniques in its applicability to systems with complex molecular interactions and in capturing the coarsening dynamics of systems involving multiple order parameters.

The licensing step of DNA double-strand break repair by homologous recombination entails resection of DNA ends to generate a single-stranded DNA template for assembly of the repair machinery consisting of the RAD51 recombinase and ancillary factors 1 . DNA end resection is mechanistically intricate and reliant on the tumour suppressor complex BRCA1-BARD1 (ref. 2 ). Specifically, three distinct nuclease entities-the 5'-3' exonuclease EXO1 and heterodimeric complexes of the DNA endonuclease DNA2, with either the BLM or WRN helicase-act in synergy to execute the end resection process 3 . A major question concerns whether BRCA1-BARD1 directly regulates end resection. Here, using highly purified protein factors, we provide evidence that BRCA1-BARD1 physically interacts with EXO1, BLM and WRN. Importantly, with reconstituted biochemical systems and a single-molecule analytical tool, we show that BRCA1-BARD1 upregulates the activity of all three resection pathways. We also demonstrate that BRCA1 and BARD1 harbour stand-alone modules that contribute to the overall functionality of BRCA1-BARD1. Moreover, analysis of a BARD1 mutant impaired in DNA binding shows the importance of this BARD1 attribute in end resection, both in vitro and in cells. Thus, BRCA1-BARD1 enhances the efficiency of all three long-range DNA end resection pathways during homologous recombination in human cells., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Objectives: Amyotrophic lateral sclerosis (ALS) causes profound impairments in neurological function, and a cure for this devastating disease remains elusive. This study aimed to identify pre-disposing genetic, phenotypic, and exposure-related factors for amyotrophic lateral sclerosis using multi-modal data and assess their joint predictive potential., Methods: Utilizing data from the UK (United Kingdom) Biobank, we analyzed an unrelated set of 292 ALS cases and 408,831 controls of European descent. Two polygenic risk scores (PRS) are constructed: "GWAS Hits PRS" and "PRS-CS," reflecting oligogenic and polygenic ALS risk profiles, respectively. Time-restricted phenome-wide association studies (PheWAS) were performed to identify pre-existing conditions increasing ALS risk, integrated into phenotypic risk scores (PheRS). A poly-exposure score ("PXS") captures the influence of environmental exposures measured through survey questionnaires. We evaluate the performance of these scores for predicting ALS incidence and stratifying risk, adjusting for baseline demographic covariates., Results: Both PRSs modestly predicted ALS diagnosis but with increased predictive power when combined (covariate-adjusted receiver operating characteristic [AAUC] = 0.584 [0.525, 0.639]). PheRS incorporated diagnoses 1 year before ALS onset (PheRS1) modestly discriminated cases from controls (AAUC = 0.515 [0.472, 0.564]). The "PXS" did not significantly predict ALS. However, a model incorporating PRSs and PheRS1 improved the prediction of ALS (AAUC = 0.604 [0.547, 0.667]), outperforming a model combining all risk scores. This combined risk score identified the top 10% of risk score distribution with a fourfold higher ALS risk (95% CI [2.04, 7.73]) versus those in the 40%-60% range., Discussion: By leveraging UK Biobank data, our study uncovers pre-disposing ALS factors, highlighting the improved effectiveness of multi-factorial prediction models to identify individuals at highest risk for ALS., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: In the context of rural Bihar where few women work outside the home, what scope do adolescent girls and young women have to transition into wage work and careers? While the mobility of girls is still widely restricted to secure their marriageability, the spread of higher schooling and the internet has inflated aspirations and levelled them out across boys, girls and social classes., Methods: The present study drew on 45 focus group discussions and 73 in-depth interviews among adolescent girls and young women and related stakeholders to develop 32 cases of transitioning girls across four districts of rural Bihar in India. The qualitative data were collected in 2022 and analysed using a combination of thematic and comparative narrative analyses., Results: The analysis identified some common features of transitioning girls and their pathways. Many girls had been forced by circumstance-household shocks or chronic poverty-to earn money, thereby building their skills and self-efficacy. Others were from families where progressive values ensured their mobility and exposure. Yet others transitioned "by stealth." But all girls had the backing of at least one parent and all had to learn to navigate public space while safeguarding their reputations. By researching actual pathways (rather than distant dreams), the study identifies a variety of transition outcomes, including "good" jobs as teachers, nurses, and police officers, "low entry" jobs in factories and new services, and full-time businesses built from scratch., Conclusion: The paper suggests that interventions be designed separately for these distinct outcomes and that efforts are best directed towards girls already "self-transitioning" and demonstrating the requisite resolve and self-efficacy., (© 2024 Foundation for Professionals in Services to Adolescents.)

Pulmonary hypertension (PH) in interstitial lung disease (ILD) is relatively common, affecting up to 50% of patients with idiopathic pulmonary fibrosis (IPF). It occurs more frequently in advanced fibrotic ILD, although it may also complicate milder disease and carries significant clinical implications in terms of morbidity and mortality. Key pathological processes driving ILD-PH include hypoxic pulmonary vasoconstriction and pulmonary vascular remodelling. While current understanding of the complex cell signalling pathways and molecular mechanisms underlying ILD-PH remains incomplete, there is evidence for an interplay between the disease pathogenesis of fibrotic ILD and PH, with interest in the role of the pulmonary endothelium in driving pulmonary fibrogenesis more recently. This review examines key clinical trials in ILD-PH therapeutics, including recent research showing promise for the treatment of both ILD-PH and the underlying pulmonary fibrotic process, further supporting the hypothesis of interrelated pathogenesis. Other important management considerations are discussed, including the value of accurate phenotyping in ILD-PH and the success of the "pulmonary vascular" phenotype. This article highlights the close and interconnected nature of fibrotic ILD and PH disease pathogenesis, a perspective likely to improve our understanding and therapeutic approach to this complex condition in the future.

Context: This study aimed to study feto-maternal outcomes in women with preterm prelabor rupture of membranes (PTPROM) on expectant management versus delivery at 34 weeks of gestation and correlate the period of latency and inflammatory markers with delivery outcomes. We have chosen this research topic as there is a paucity of specific guidelines regarding the optimal period of gestation for delivering women with PTPROM., Aim: The study correlated the feto-maternal outcomes in women with PTPROM on expectant management till 37 weeks versus delivery at 34 weeks with a period of latency and maternal inflammatory markers., Methods and Materials: This was a prospective observational study conducted on 262 women with PTPROM from 28-33+6 weeks of gestation. Women were monitored till 37 weeks with biweekly total leukocyte count and weekly C-reactive protein, urine routine microscopy, urine culture, high vaginal culture sensitivity, and ultrasound. Women were monitored expectantly till 37 weeks. However, intervention was done at any time during the feto-maternal compromise. There were 52 women who delivered <34 weeks and 210 women who delivered ≥34 weeks. Feto-maternal outcomes were documented. Group A was assigned to women who delivered before 34 weeks and Group B was assigned to women who delivered after 34 weeks. Statistical analysis was done using SPSS software. A p-value <0.05 was considered significant., Results: Among the study group, 238 (90.8%) women were managed expectantly while 24(9.1%) required intervention. A latency of 3-4 weeks was observed in 131(50%) women. Chorioamnionitis developed in 7 women (4.4%) in group A and 13 women (4.9%) in group B. Neonates developed sepsis in 5.7% in group A and 5.8 % in group B and were comparable in both the groups (p=1.000). Early neonatal death (END) occurred in 10 (3.8%) among which seven died because of low birth weight (LBW), two due to sepsis, and one due to respiratory distress. LBW was significantly associated with END (p<0.001) Conclusion: Expectant management beyond 34 weeks with close monitoring can improve neonatal outcomes without increasing maternal morbidity in women with PTPROM., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Vardhaman Mahavir Medical College and Safdarjung Hospital issued approval IEC/VMMC/SJH/THESIS/2020-11/CC-177. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Jha et al.)

Zinc (Zn) based fluorescent metal complexes have gained increasing attention due to their non-toxicity and high brightness with marked fluorescence quantum yield (QY). However, they have rarely been employed in super-resolution microscopy (SRM) to study live cells and in vivo dynamics of lysosomes. Here, we present an NIR emissive highly photostable Zn-complex as a multifaceted fluorescent probe for the long-term dynamical distribution of lysosomes in various cancerous and non-cancerous cells in live condition and in vivo embryogenic evolution in Caenorhabditis elegans ( C. elegans ). Apart from the normal fission, fusion, and kiss & run, the motility and the exact location of lysosomes at each point were mapped precisely. A notable difference in the lysosomal motility in the peripheral region between cancerous and non-cancerous cells was distinctly observed. This is attributed to the difference in viscosity of the cytoplasmic environment. On the other hand, along with the super-resolved structure of the smallest size lysosome (∼77 nm) in live C. elegans , the complete in vivo embryogenic evolution of lysosomes and lysosome-related organelles (LROs) was captured. We were able to capture the images of lysosomes and LROs at different stages of C. elegans , starting from a single cell and extending to a fully matured adult animal., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Post Kala-azar dermal leishmaniasis (PKDL) arises as a significant dermal sequel following Visceral leishmaniasis (VL) caused by protozoan parasite Leishmania donovani (LD). PKDL acts as a significant constrain for VL elimination serving as a crucial reservoir for LD. PKDL patients exhibit depigmented macular and papular lesions on their skin, which results in social discrimination due to loss of natural skin color. Inflammatory reactions, prevalent in both VL and PKDL, potentially lead to tissue damage in areas harboring the parasite. Disruption of the immune-inflammasomal network not only facilitates LD persistence but also leads to the skin hypopigmentation seen in PKDL, impacting social well-being. Activation of inflammasomal markers like STAT1, NLRP1, NLRP3, AIM2, CASP11, and NLRP12 have been identified as a common host-defense mechanism across various Leishmania infections. Conversely, Leishmania modulates inflammasome activation to sustain its presence within the host. Nevertheless, in specific instances of Leishmania infection, inflammasome activation can worsen disease pathology by promoting parasite proliferation and persistence. This study encompasses recent transcriptomic analyses conducted between 2016 and 2023 on human and murine subjects afflicted with VL/PKDL, elucidating significant alterations in inflammasomal markers in both conditions. It offers a comprehensive understanding how these markers contribute in disease progression, drawing upon available literature for logical analysis. Furthermore, our analysis identifies validated miRNA network that could potentially disrupt this crucial immune-inflammasomal network, thereby offering a plausible explanation on how secreted LD-factors could enable membrane-bound LD, isolated from the host cytoplasm, to modulate cytoplasmic inflammasomal markers. Insights from this study could guide the development of host-directed therapeutics to impede transmission and address hypopigmentation, thereby mitigating the social stigma associated with PKDL., Competing Interests: Declaration of competing interest The authors declare that the systematic review was conducted without any conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Electronic health records (EHRs) are increasingly recognized as a cost-effective resource for patient recruitment in clinical research. However, how to optimally select a cohort from millions of individuals to answer a scientific question of interest remains unclear. Consider a study to estimate the mean or mean difference of an expensive outcome. Inexpensive auxiliary covariates predictive of the outcome may often be available in patients' health records, presenting an opportunity to recruit patients selectively, which may improve efficiency in downstream analyses. In this paper we propose a two-phase sampling design that leverages available information on auxiliary covariates in EHR data. A key challenge in using EHR data for multiphase sampling is the potential selection bias, because EHR data are not necessarily representative of the target population. Extending existing literature on two-phase sampling design, we derive an optimal two-phase sampling method that improves efficiency over random sampling while accounting for the potential selection bias in EHR data. We demonstrate the efficiency gain from our sampling design via simulation studies and an application evaluating the prevalence of hypertension among U.S. adults leveraging data from the Michigan Genomics Initiative, a longitudinal biorepository in Michigan Medicine.

Purpose: Our aim was to determine if intraoperative navigation (ION) improved radiographic outcomes in patients undergoing delayed primary/secondary orbital reconstruction for inferomedial defects, as measured by volume restoration, enophthalmos correction, and positional accuracy of implants. Patients and Methods: A prospective quasiexperimental study was performed to compare two groups of patients requiring orbital reconstruction. Use of ION was the exposure evaluated. Outcome measures were (i) intraorbital volume and enophthalmos evaluated radiologically, (ii) implant position accuracy, and (iii) procedural duration. Data were analyzed statistically to compare variance between groups. Results: Forty patients (6 females and 34 males) were recruited into the study with a mean age of 27.3 years. The study group demonstrated a greater reduction of intraorbital volume (0.49 cu.cm; p  = 0.02) and enophthalmos (0.72 mm; p  = 0.001). Implant positioning was more accurate using ION, with less mediolateral ( p  = 0.006) and yaw ( p  = 0.04) deviations. Surgical time for implant positioning was shorter by 17 min, with navigation ( p  < 0.001). Conclusion: The use of ION demonstrated radiographic improvements in volume restoration, enophthalmos correction, as well as accuracy of implant positioning, in patients requiring delayed primary/secondary orbital reconstruction.

Background: Betulinic acid (BA) has been well investigated for its antiproliferative and mitochondrial pathway-mediated apoptosis-inducing effects on various cancers. However, its poor solubility and off-target activity have limited its utility in clinical trials. Additionally, the immune modulatory role of betulinic acid analogue in the tumor microenvironment (TME) is largely unknown. Here, we designed a potential nanotherapy for colorectal cancer (CRC) with a lead betulinic acid analogue, named as 2c, carrying a 1,2,3-triazole-moiety attached to BA through a linker, found more effective than BA for inhibiting CRC cell lines, and was chosen here for this investigation. Epithelial cell adhesion molecule (EpCAM) is highly overexpressed on the CRC cell membrane. A single-stranded short oligonucleotide sequence, aptamer (Apt), that folds into a 3D-defined architecture can be used as a targeting ligand for its specific binding to a target protein. EpCAM targeting aptamer was designed for site-specific homing of aptamer-conjugated-2c-loaded nanoparticles (Apt-2cNP) at the CRC tumor site to enhance therapeutic potential and reduce off-target toxicity in normal cells. We investigated the in vitro and in vivo therapeutic efficacy and anti-tumorigenic immune response of aptamer conjugated nanotherapy in CRC-TME., Methods: After the characterization of nanoengineered aptamer conjugated betulinic acid nanotherapy, we evaluated therapeutic efficacy, tumor targeting efficiency, and anti-tumorigenic immune response using cell-based assays and mouse and rat models., Results: We found that Apt-2cNP improved drug bioavailability, enhanced its biological half-life, improved antiproliferative activity, and minimized off-target cytotoxicity. Importantly, in an in vivo TME, Apt-2cNP showed promising signs of anti-tumorigenic immune response (increased mDC/pDC ratio, enhanced M1 macrophage population, and CD8 T-cells). Furthermore, in vivo upregulation of pro-apoptotic while downregulation of anti-apoptotic genes and significant healing efficacy on cancer tissue histopathology suggest that Apt-2cNP had predominantly greater therapeutic potential than the non-aptamer-conjugated nanoparticles and free drug. Moreover, we observed greater tumor accumulation of the radiolabeled Apt-2cNP by live imaging in the CRC rat model., Conclusions: Enhanced therapeutic efficacy and robust anti-tumorigenic immune response of Apt-2cNP in the CRC-TME are promising indicators of its potential as a prospective therapeutic agent for managing CRC. However, further studies are warranted., (© 2024. The Author(s).)

DSS1, essential for BRCA2-RAD51 dependent homologous recombination (HR), associates with the helical domain (HD) and OB fold 1 (OB1) of the BRCA2 DSS1/DNA-binding domain (DBD) which is frequently targeted by cancer-associated pathogenic variants. Herein, we reveal robust ss/dsDNA binding abilities in HD-OB1 subdomains and find that DSS1 shuts down HD-OB1's DNA binding to enable ssDNA targeting of the BRCA2-RAD51 complex. We show that C-terminal helix mutations of DSS1, including the cancer-associated R57Q mutation, disrupt this DSS1 regulation and permit dsDNA binding of HD-OB1/BRCA2-DBD. Importantly, these DSS1 mutations impair BRCA2/RAD51 ssDNA loading and focus formation and cause decreased HR efficiency, destabilization of stalled forks and R-loop accumulation, and hypersensitize cells to DNA-damaging agents. We propose that DSS1 restrains the intrinsic dsDNA binding of BRCA2-DBD to ensure BRCA2/RAD51 targeting to ssDNA, thereby promoting optimal execution of HR, and potentially replication fork protection and R-loop suppression., (© 2024. The Author(s).)

Background: Polycyclic aromatic hydrocarbons (PAHs) are endocrine disruptors resulting from incomplete combustion. Pregnancy represents a particularly vulnerable period to such exposures, given the significant influence of hormone physiology on fetal growth and pregnancy outcomes. Maternal thyroid hormones play crucial roles in fetal development and pregnancy outcomes. However, limited studies have examined gestational PAH exposure and maternal thyroid hormones during pregnancy., Methods: Our study included 439 women enrolled in the LIFECODES birth cohort in Boston, aiming to explore the relationship between urinary PAH metabolites and thyroid hormones throughout pregnancy. Urine samples for PAH metabolite analysis and plasma samples for thyroid hormone were measured up to four visits throughout gestation. Single pollutant analyses employed linear mixed effect models to investigate individual associations between each PAH metabolite and thyroid hormone concentration. Sensitivity analyses were conducted to assess potential susceptibility windows and fetal-sex-specific effects of PAH exposure. Mixture analyses utilized quantile g-computation to evaluate the collective impact of eight PAH metabolites on thyroid hormone concentrations. Additionally, Bayesian kernel machine regression (BKMR) was employed to explore potential non-linear associations and interactions between PAH metabolites. Subject-specific random intercepts were incorporated to address intra-individual correlation of serial measurements over time in both single pollutant and mixture analyses., Results: Our findings revealed positive trends in associations between PAH metabolites and thyroid hormones, both individually and collectively as a mixture. Sensitivity analyses indicated that these associations were influenced by the study visit and fetal sex. Mixture analyses suggested non-linear relationships and interactions between different PAH exposures., Conclusions: This comprehensive investigation underscores the critical importance of understanding the impact of PAH exposures on thyroid hormone physiology during pregnancy. The findings highlight the intricate interplay between environmental pollutants and human pregnancy physiology, emphasizing the need for targeted interventions and public health policies to mitigate adverse outcomes associated with prenatal PAH exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival and exposure sources., Methods: Participants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. ORs and HRs for each metal were computed using risk and survival models. Environmental risk scores (ERS) were created to evaluate the association between exposure mixtures and ALS risk and survival and exposure source. ALS (ALS-PGS) and metal (metal-PGS) polygenic risk scores were constructed from an independent genome-wide association study and relevant literature-selected single-nucleotide polymorphisms., Results: Plasma and urine samples from 454 ALS and 294 control participants were analysed. Elevated levels of individual metals, including copper, selenium and zinc, significantly associated with ALS risk and survival. ERS representing metal mixtures strongly associated with ALS risk (plasma, OR=2.95, CI=2.38-3.62, p<0.001; urine, OR=3.10, CI=2.43-3.97, p<0.001) and poorer ALS survival (plasma, HR=1.37, CI=1.20-1.58, p<0.001; urine, HR=1.44, CI=1.23-1.67, p<0.001). Addition of the ALS-PGS or metal-PGS did not alter the significance of metals with ALS risk and survival. Occupations with high potential of metal exposure associated with elevated ERS. Additionally, occupational and non-occupational metal exposures were associated with measured plasma and urine metals., Conclusion: Metals in plasma and urine associated with increased ALS risk and reduced survival, independent of genetic risk, and correlated with occupational and non-occupational metal exposures. These data underscore the significance of metal exposure in ALS risk and progression., Competing Interests: Competing interests: ELF: Listed as inventors on a patent, Issue number US10660895, held by University of Michigan titled 'Methods for Treating Amyotrophic Lateral Sclerosis' that targets immune pathways for use in ALS therapeutics. SAG: Listed as inventors on a patent, Issue number US10660895, held by University of Michigan titled 'Methods for Treating Amyotrophic Lateral Sclerosis' that targets immune pathways for use in ALS therapeutics. Scientific consulting for Evidera., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Rhabdomyoma of the orbit is a rare tumor with very few cases reported in the literature. We herein describe a 5-year-old boy who presented to us with a deviation of his left eye. Magnetic Resonance Imaging (MRI) showed a well-defined homogeneous intraconal mass in the superomedial aspect compressing the optic nerve. An excision biopsy was performed and the diagnosis of rhabdomyoma was confirmed on histopathology and immunohistochemistry with a coincidental finding of Trichinella spiralis larvae within the excised specimen. We report this phenomenon in two rare diseases with a predilection for striated muscle occurring simultaneously in a single patient.

Significant progress has been made in augmenting clinical decision-making using artificial intelligence (AI) in the context of secondary and tertiary care at large academic medical centers. For such innovations to have an impact across the spectrum of care, additional challenges must be addressed, including inconsistent use of preventative care and gaps in chronic care management. The integration of additional data, including genomics and data from wearables, could prove critical in addressing these gaps, but technical, legal, and ethical challenges arise. On the technical side, approaches for integrating complex and messy data are needed. Data and design imperfections like selection bias, missing data, and confounding must be addressed. In terms of legal and ethical challenges, while AI has the potential to aid in leveraging patient data to make clinical care decisions, we also risk exacerbating existing disparities. Organizations implementing AI solutions must carefully consider how they can improve care for all and reduce inequities.

Preserving a functional mitochondrial network is crucial for cellular well-being, considering the pivotal role of mitochondria in ensuring cellular survival, especially under stressful conditions. Mitophagy, the selective removal of damaged mitochondria through autophagy, plays a pivotal role in preserving cellular homeostasis by preventing the production of harmful reactive oxygen species from dysfunctional mitochondria. While the involvement of mitophagy in neurodegenerative diseases has been thoroughly investigated, it is becoming increasingly evident that mitophagy plays a significant role in cancer biology. Perturbations in mitophagy pathways lead to suboptimal mitochondrial quality control, catalyzing various aspects of carcinogenesis, including establishing metabolic plasticity, stemness, metabolic reconfiguration of cancer-associated fibroblasts, and immunomodulation. While mitophagy performs a delicate balancing act at the intersection of cell survival and cell death, mounting evidence indicates that, particularly in the context of stress responses induced by cancer therapy, it predominantly promotes cell survival. Here, we showcase an overview of the current understanding of the role of mitophagy in cancer biology and its potential as a target for cancer therapy. Gaining a more comprehensive insight into the interaction between cancer therapy and mitophagy has the potential to reveal novel targets and pathways, paving the way for enhanced treatment strategies for therapy-resistant tumors in the near future., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims/introduction: Deficiency of neurotropic factors is implicated in diabetic neuropathy (DN). Netrin-1 is a neurotropic factor, but its association with DN has not been explored. We have assessed the association between serum netrin-1 levels and early diabetic neuropathy assessed by quantifying corneal nerve fiber loss using corneal confocal microscopy., Materials and Methods: A total of 72 participants with type 2 diabetes, without and with corneal nerve fiber loss (DN- n = 42, DN+ n = 30), and 45 healthy controls were studied. Serum netrin-1 levels were measured by enzyme-linked immunosorbent assay, and corneal nerve morphology was assessed using corneal confocal microscopy., Results: Corneal nerve fiber density, branch density, fiber length and serum netrin-1 levels were significantly lower in the DN- and DN+ groups compared with controls (P < 0.001). Netrin-1 levels correlated with corneal nerve fiber length in the DN+ group (r = 0.51; P < 0.01). A receiver operating characteristic curve analysis showed that a netrin-1 cut-off value of 599.6 (pg/mL) had an area under the curve of 0.85, with a sensitivity of 76% and specificity of 74% (P < 0.001; 95% confidence interval 0.76-0.94) for differentiating patients with and without corneal nerve loss., Conclusions: Serum netrin-1 levels show a progressive decline with increasing severity of small nerve fiber damage in patients with diabetes. Netrin-1 could act as a biomarker for small nerve fiber damage in DN., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Environmental exposures impact amyotrophic lateral sclerosis (ALS) risk and progression, a fatal and progressive neurodegenerative disease. Better characterization of these exposures is needed to decrease disease burden., Objective: To identify exposures in the residential setting that associate with ALS risk, survival, and onset segment., Methods: ALS and control participants recruited from University of Michigan completed a survey that ascertained exposure risks in the residential setting. ALS risk was assessed using logistic regression models followed by latent profile analysis to consider exposure profiles. A case-only analysis considered the contribution of the residential exposure variables via a Cox proportional hazards model for survival outcomes and multinomial logistic regression for onset segment, a polytomous outcome., Results: This study included 367 ALS and 255 control participants. Twelve residential variables were associated with ALS risk after correcting for multiple comparison testing, with storage in an attached garage of chemical products including gasoline or kerosene (odds ratio (OR) = 1.14, p adjusted  < 0.001), gasoline-powered equipment (OR = 1.16, p adjusted  < 0.001), and lawn care products (OR = 1.15, p adjusted  < 0.001) representing the top three risk factors sorted by p adjusted . Latent profile analysis indicated that storage of these chemical products in both attached and detached garages increased ALS risk. Although residential variables were not associated with poorer ALS survival following multiple testing corrections, storing pesticides, lawn care products, and woodworking supplies in the home were associated with shorter ALS survival using nominal p values. No exposures were associated with ALS onset segment., Conclusion: Residential exposures may be important modifiable components of the ALS susceptibility and prognosis exposome.

Background: Chronic inflammation and DNA methylation are potential mechanisms in dementia etiology. The linkage between inflammation and DNA methylation age acceleration in shaping dementia risk is understudied. We explored the association of inflammatory cytokines with cognitive impairment and whether DNA methylation age acceleration mediates this relationship., Methods: In a subset of the 2016 wave of the Health and Retirement Study (n=3,346, age>50), we employed logistic regression to estimate the associations between each inflammatory cytokine (interleukin-6 (IL-6), C-reactive protein (CRP), and insulin-like growth factor-1 (IGF-1)), and both Langa-Weir classified cognitive impairment non-dementia and dementia, respectively. We calculated DNA methylation age acceleration residuals by regressing GrimAge on chronologic age. We tested if DNA methylation age acceleration mediated the relationship between systemic inflammation and cognitive impairment, adjusting for sociodemographic, behavioral factors, chronic conditions, and cell type proportions., Results: The prevalence of cognitive impairment was 16%. In the fully-adjusted model, participants with a doubling of IL-6 levels had 1.12 (95% CI: 1.02-1.22) times higher odds of cognitive impairment. Similar associations were found for CRP and IGF-1. Participants with a doubling of IL-6 levels had 0.77 (95% CI: 0.64, 0.90) years of GrimAge acceleration. In mediation analyses with each cytokine as predictor separately, 17.7% (95% CI: 7.0%, 50.9%) of the effect of IL-6 on cognitive impairment was mediated through DNA methylation age acceleration. Comparable mediated estimates were found for CRP and IGF-1., Conclusions: Systemic inflammation is associated with cognitive impairment, with suggestive evidence that this relationship is partially mediated through DNA methylation age acceleration.

Purpose: This study quantified the effect of 48 psychosocial constructs on all-cause mortality using data from 7,698 individuals in the U.S. Health and Retirement Study., Methods: Latent class analysis was used to divide participants into mutually exclusive psychosocial wellbeing groups (good, average, or poor) which was subsequently considered as the exposure. Mediation analysis was then conducted to determine the direct effect of the psychosocial wellbeing groups and the indirect (mediating) effects of physical health (functional status and comorbid conditions) and lifestyle factors (physical activity, smoking, and alcohol consumption) on overall survival. We also created a composite health index measure representing the summative effect of the mediators., Results: We observed a strong and statistically significant total effect (TE) between survival time and psychosocial wellbeing group (survival time ratio (SR) = 1.73, 95% confidence interval (CI):1.50,2.01 when comparing good to poor). Mediation analysis revealed that the direct effect via psychosocial wellbeing group accounted for more than half of the TE (SR = 1.46, 95% CI:1.27,1.67). The composite health index measure mediated 36.2% of the TE with the natural indirect effect SR of 1.18 (95% CI:1.13,1.22)., Conclusion: Our findings demonstrate the interconnectedness between psychosocial wellbeing and physical health and lifestyle factors on survival., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Exposure to systemic racism is linked to increased dementia burden. To assess systemic inflammation as a potential pathway linking exposure to racism and dementia disparities, we investigated the mediating role of C-reactive protein (CRP), a systemic inflammation marker, and the moderating role of the racialization process in incident dementia., Methods: In the US Health and Retirement Study (n = 6,908), serum CRP was measured at baseline (2006, 2008 waves). Incident dementia was classified by cognitive tests over a six-year follow-up. Self-reported racialized categories were a proxy for exposure to the racialization process. We decomposed racialized disparities in dementia incidence (non-Hispanic Black and/or Hispanic vs. non-Hispanic white) into 1) the mediated effect of CRP, 2) the moderated portion attributable to the interaction between racialized group membership and CRP, and 3) the controlled direct effect (other pathways through which racism operates)., Results: The 6-year cumulative incidence of dementia is 12%. Among minoritized participants (i.e., non-Hispanic Black and/or Hispanic), high CRP levels ( ≥ 75 th percentile or 4.73μg/mL) are associated with 1.26 (95%CI: 0.98, 1.62) times greater risk of incident dementia than low CRP ( < 4.73μg/mL). Decomposition analysis comparing minoritized versus non-Hispanic white participants shows that the mediating effect of CRP accounts for 3% (95% CI: 0%, 6%) of the racial disparity, while the interaction effect between minoritized group status and high CRP accounts for 14% (95% CI: 1%, 27%) of the disparity. Findings are robust to potential violations of causal mediation assumptions., Conclusions: Minoritized group membership modifies the relationship between systemic inflammation and incident dementia., (© 2024. The Author(s).)

Purpose: To determine the influence of different types of orbital fractures on the radiographic post-treatment outcomes., Methods: The investigation was a retrospective cohort study involving CT data of all patients who underwent delayed primary or secondary surgery for orbital/zygomatico-orbital trauma between 2019 and 2021. The sample was divided into three groups 1, 2, and 3: isolated floor, floor and medial wall, and combined orbit and zygomatic complex fractures. The type of orbital fracture was the exposure, while the outcome measures were reduction in enophthalmos and intraorbital volume and linear relationship between the two variables. Data were analyzed for variance between groups and association. Statistical significance was set at < 0.05., Results: Forty-four patients (3 females and 41 males) with a mean age of 28.6 years were included in the study. Reductions in enophthalmos (P < 0.001) and intraorbital volume (P = 0.003) demonstrated significant variance between the groups. For every cubic centimeter of reduction in volume, the reduction in enophthalmos was 0.78 mm (P < 0.001) in isolated floor fractures, 0.60 mm (P = 0.013) in combined fractures involving the floor and medial walls, and 0.24 mm (P = 0.456) in combined fractures of the orbit and zygoma., Conclusion: Correction of enophthalmos strongly depends on the type of orbital fracture. There exists a significant linear relationship between enophthalmos and intraorbital volume in fractures involving the internal orbit., (Copyright © 2024 Copyright: © 2024 Indian Journal of Ophthalmology.)

Quercetin is an important antioxidant with high bioactivity and it has been used as SARS-CoV-2 inhibitor significantly. Quercetin, one of the most abundant flavonoids in nature, has been in the spot of numerous experimental and theoretical studies in the past decade due to its great biological and medicinal importance. But there have been limited instances of employing quercetin and its derivatives as a fluorescent framework for specific detection of various cations and anions in the chemosensing field. Therefore, we have developed a novel chemosensor based on quercetin coupled benzyl ethers (QBE) for selective detection of Hg 2+ with "naked-eye" colorimetric and "turn-on" fluorometric response. Initially QBE itself exhibited very weak fluorescence with low quantum yield (Φ = 0.009) due to operating photoinduced electron transfer (PET) and inhibition of excited state intramolecular proton transfer (ESIPT) as well as intramolecular charge transfer (ICT) within the molecule. But in presence of Hg 2+ , QBE showed a sharp increase in fluorescence intensity by 18-fold at wavelength 444 nm with high quantum yield (Φ = 0.159) for the chelation-enhanced fluorescence (CHEF) with coordination of Hg 2+ , which hampers PET within the molecule. The strong binding affinity of QBE towards Hg 2+ has been proved by lower detection limit at 8.47 µM and high binding constant value as 2 × 10 4 M -1 . The binding mechanism has been verified by DFT study, Cyclic voltammograms and Jobs plot analysis. For the practical application, the binding selectivity of QBE with Hg 2+ has been capitalized in physiological medium to detect intracellular Hg 2+ levels in living plant tissue by using green gram seeds. Thus, employing QBE as a fluorescent chemosensor for the specific identification of Hg 2+ will pave the way for a novel approach to simplifying the creation of various chemosensors based on quercetin backbone for the precise detection of various biologically significant analytes., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals linked to adverse pregnancy outcomes. Although their underlying biological mechanisms are not fully understood, evidence suggests PFAS may disrupt endocrine functions and contribute to oxidative stress (OS) and inflammation., Objective: We examined associations between early pregnancy PFAS exposure and OS biomarkers, exploring potential effect modifications by fetal sex and maternal race., Methods: We used data from 469 LIFECODES participants with measured plasma PFAS (median 10 weeks gestation) and repeated measures (median 10, 18, 26, and 35 weeks gestation) of urinary OS biomarkers [8-iso-prostaglandin-F2α (8-isoprostane) and 8-hydroxydeoxyguanosine (8-OHdG)]. Protein damage biomarkers (chlorotyrosine, dityrosine, and nitrotyrosine) were additionally measured in plasma from a subset (N = 167) during the third visit. Associations between each PFAS and OS biomarkers were examined using linear mixed-effects models and multivariable linear regressions, adjusting for potential confounders, including maternal age, race, education level, pre-pregnancy BMI, insurance status, and parity. Effect modifications were evaluated by including an interaction term between each PFAS and fetal sex or maternal race in the models., Results: We observed significant positive associations between PFOS and 8-isoprostane, with a 9.68% increase in 8-isoprostane levels (95% CI: 0.10%, 20.18%) per interquartile range increase in PFOS. In contrast, PFUA was negatively associated [9.32% (95% CI: -17.68%, -0.11%)], while there were suggestive positive associations for MPAH and PFOA with 8-isoprostane. The associations of several PFAS with 8-OHdG varied by fetal sex, showing generally positive trends in women who delivered females, but negative or null in those who delivered males. No significant effect modification by maternal race was observed., Conclusions: This study provides evidence linking PFAS exposure to OS during pregnancy, with potential sex-specific effects of certain PFAS on 8-OHdG. Further research should explore additional OS/inflammatory biomarkers and assess the modifying effects of dietary and behavioral patterns across diverse populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

We consider the setting where (1) an internal study builds a linear regression model for prediction based on individual-level data, (2) some external studies have fitted similar linear regression models that use only subsets of the covariates and provide coefficient estimates for the reduced models without individual-level data, and (3) there is heterogeneity across these study populations. The goal is to integrate the external model summary information into fitting the internal model to improve prediction accuracy. We adapt the James-Stein shrinkage method to propose estimators that are no worse and are oftentimes better in the prediction mean squared error after information integration, regardless of the degree of study population heterogeneity. We conduct comprehensive simulation studies to investigate the numerical performance of the proposed estimators. We also apply the method to enhance a prediction model for patella bone lead level in terms of blood lead level and other covariates by integrating summary information from published literature., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Biometric Society.)

RNA profiling studies have revealed that ∼75% of the human genome is transcribed to RNA but only a meagre fraction of it is translated to proteins. Majority of transcribed RNA constitute a specialized pool of non-coding RNAs. Human genome contains approximately 506 genes encoding a set of 51 different tRNAs, constituting a unique class of non-coding RNAs that not only have essential housekeeping functions as translator molecules during protein synthesis, but have numerous uncharted regulatory functions. Intriguing findings regarding a variety of non-canonical functions of tRNAs, tRNA derived fragments (tRFs), esoteric epitranscriptomic modifications of tRNAs, along with aminoacyl-tRNA synthetases (AARSs) and ARS-interacting multifunctional proteins (AIMPs), envision a 'peripheral dogma' controlling the flow of genetic information in the backdrop of qualitative information wrung out of the long-live central dogma of molecular biology, to drive cells towards either proliferation or differentiation programs. Our review will substantiate intriguing peculiarities of tRNA gene clusters, atypical tRNA-transcription from internal promoters catalysed by another distinct RNA polymerase enzyme, dynamically diverse tRNA epitranscriptome, intricate mechanism of tRNA-charging by AARSs governing translation fidelity, epigenetic regulation of gene expression by tRNA fragments, and the role of tRNAs and tRNA derived/associated molecules as quantitative determinants of the functional proteome, covertly orchestrating the process of tumorigenesis, through a deregulated tRNA-ome mediating selective codon-biased translation of cancer related gene transcripts., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Background: Text messages may enhance physical activity levels in patients with cardiovascular disease, including those enrolled in cardiac rehabilitation. However, the independent and long-term effects of text messages remain uncertain., Methods: The VALENTINE study (Virtual Application-supported Environment to Increase Exercise) was a micro-randomized trial that delivered text messages through a smartwatch (Apple Watch or Fitbit Versa) to participants initiating cardiac rehabilitation. Participants were randomized 4× per day over 6-months to receive no text message or a message encouraging low-level physical activity. Text messages were tailored on contextual factors (eg, weather). Our primary outcome was step count 60 minutes following a text message, and we used a centered and weighted least squares mean method to estimate causal effects. Given potential measurement differences between devices determined a priori, data were assessed separately for Apple Watch and Fitbit Versa users over 3 time periods corresponding to the initiation (0-30 days), maintenance (31-120 days), and completion (121-182 days) of cardiac rehabilitation., Results: One hundred eight participants were included with 70 552 randomizations over 6 months; mean age was 59.5 (SD, 10.7) years with 36 (32.4%) female and 68 (63.0%) Apple Watch participants. For Apple Watch participants, text messages led to a trend in increased step count by 10% in the 60-minutes following a message during days 1 to 30 (95% CI, -1% to +20%), with no effect from days 31 to 120 (+1% [95% CI, -4% to +5%]), and a significant 6% increase during days 121 to 182 (95% CI, +0% to +11%). For Fitbit users, text messages significantly increased step count by 17% (95% CI, +7% to +28%) in the 60-minutes following a message in the first 30 days of the study with no effect subsequently., Conclusions: In patients undergoing cardiac rehabilitation, contextually tailored text messages may increase physical activity, but this effect varies over time and by device., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04587882., Competing Interests: Dr Golbus receives funding from the National Institutes of Health (NIH; L30HL143700, 1K23HL168220) and PCORI. Dr Nallamothu is a principal investigator or coinvestigator on research grants from the NIH, VA HSR&D and the American Heart Association. He also receives compensation as Editor-in-Chief of Circulation: Cardiovascular Quality and Outcomes, a journal of the American Heart Association. Finally, he is a coinventor on US Utility Patent Number US15/356 012 (US20170148158A1) entitled Automated Analysis of Vasculature in Coronary Angiograms that uses software technology with signal processing and machine learning to automate the reading of coronary angiograms, held by the University of Michigan. The patent is licensed to AngioInsight Inc, in which Dr Nallamothu holds ownership shares and receives consultancy fees. Dr SachinKheterpal is a principal investigator or coinvestigator on research grants from the US NIH, Blue Cross Blue Shield of Michigan, the American Heart Association, Apple, Merck & Co, and Becton Dickinson & Company; and is a coinventor on US patent number 62/791 257 entitled Automated System To Medical Procedures, which is held by the University of Michigan. Dr Klasnja is a principal investigator or a coinvestigator on research grants from NIH. Dr Murphy is a principal investigator or a coinvestigator on research grants from NIH. Dr Vik Kheterpal is a Principal and employee of CareEvolution. V. Taralunga is a Software Architect employed by CareEvolution. The other authors report no conflicts.

Aims: Hepatocellular carcinoma (HCC) is still a leading cause of cancer-related death worldwide. But its chemotherapeutic options are far from expectation. We here compared H-ras targeted genetic therapy to a commercial docetaxel formulation (DXT) in inhibiting HCC in rats., Main Methods: After the physicochemical characterization of phosphorothioate-antisense oligomer (PS-ASO) against H-ras mutated gene, the PS-ASO-mediated in vitro hemolysis, in vivo hepatic uptake, its pharmacokinetic profile, tissue distribution in some highly perfused organs, its effect in normal rats, antineoplastic efficacy in carcinogen-induced HCC in rats were evaluated and compared against DXT treatment. Mutated H-ras expression by in situ hybridization, hep-par-I, CK-7, CD-15, p53 expression patterns by immunohistochemical methods, scanning electron microscopic evaluation of hepatic architecture, various hepatic marker enzyme levels and caspase-3/9 apoptotic enzyme activities were also carried out in the experimental rats., Key Findings: PS-ASO showed low in vitro hemolysis (<3 %), and had a sustained PS-ASO blood residence time in vivo compared to DTX, with a time-dependent hepatic uptake. It showed no toxic manifestations in normal rats. PS-ASO distribution was although initially less in the lung than liver and kidney, but at 8 h it accumulated more in lung than kidney. Antineoplastic potential of PS-ASO (treated for 6 weeks) excelled in inhibiting chemically induced tumorigenesis compared to DTX in rats, by inhibiting H-ras gene expression, some immonohistochemical modulations, and inducing caspase-3/9-mediated apoptosis. It prevented HCC-mediated lung metastatic tumor in the experimental rats., Significance: PS-ASO genetic therapy showed potential to inhibit HCC far more effectively than DXT in rats., Competing Interests: Declaration of competing interest The authors declare no potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

ZnO/layered carbon nanocomposites with varied sizes of ZnO nanoparticles (NPs) were synthesized by mechanical milling of mixture of ZnO NPs and carbon NPs. The NP size of ZnO was controlled with average particle sizes about 19.33, 21.87, 24.21, and 27.89 nm by varying the concentrations of carbon NPs viz 0, 2, 5, and 10 weight percent, respectively, in the mixture. Presence of carbon with ZnO in the form of composite also resulted in the enhanced shift of the band gap of ZnO due to the optical transitions in the impurity states or presence of carbon as compared to the ZnO size change alone. Additionally, the enhancement of absorbance in the visible region with an increase in carbon content was observed. Such an increase in absorbance can enhance the photocatalytic activity of ZnO NPs. Raman bands for ZnO NPs also were found to shift faster in the presence of layered carbon. The quenching of visible photoluminescence emission of ZnO NPs with an increase in concentration of carbon NPs in the composite indicated the phenomenon associated with transfer of electrons from ZnO to layered carbon helping the separation of photo-generated electrons and holes in ZnO and can lead to enhancement of the photocatalytic activity of ZnO NPs. In the photocatalytic studies, it was observed that the degradation of methylene blue (MB) dye was significantly enhanced by the increase of content of layered carbon in the nanocomposite. The sample containing 10% carbon showed the highest adsorption in dark conditions which was up to 60% of the starting strength and this was further enhanced to 88% in the presence of UV radiation. Enhanced adsorption of MB dye and the effective separation of electron-hole pairs due to charge transfer were believed to be the main causes behind such kind of improvement in the photocatalytic effects., (© 2024 IOP Publishing Ltd.)

Objectives: To develop recommendations regarding the use of weights to reduce selection bias for commonly performed analyses using electronic health record (EHR)-linked biobank data., Materials and Methods: We mapped diagnosis (ICD code) data to standardized phecodes from 3 EHR-linked biobanks with varying recruitment strategies: All of Us (AOU; n = 244 071), Michigan Genomics Initiative (MGI; n = 81 243), and UK Biobank (UKB; n = 401 167). Using 2019 National Health Interview Survey data, we constructed selection weights for AOU and MGI to represent the US adult population more. We used weights previously developed for UKB to represent the UKB-eligible population. We conducted 4 common analyses comparing unweighted and weighted results., Results: For AOU and MGI, estimated phecode prevalences decreased after weighting (weighted-unweighted median phecode prevalence ratio [MPR]: 0.82 and 0.61), while UKB estimates increased (MPR: 1.06). Weighting minimally impacted latent phenome dimensionality estimation. Comparing weighted versus unweighted phenome-wide association study for colorectal cancer, the strongest associations remained unaltered, with considerable overlap in significant hits. Weighting affected the estimated log-odds ratio for sex and colorectal cancer to align more closely with national registry-based estimates., Discussion: Weighting had a limited impact on dimensionality estimation and large-scale hypothesis testing but impacted prevalence and association estimation. When interested in estimating effect size, specific signals from untargeted association analyses should be followed up by weighted analysis., Conclusion: EHR-linked biobanks should report recruitment and selection mechanisms and provide selection weights with defined target populations. Researchers should consider their intended estimands, specify source and target populations, and weight EHR-linked biobank analyses accordingly., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: The objective is to analyze the radiological diagnosis of orbital lesions and their correlation with the final histopathological findings. We compared the initial reports by extramural radiologists and an in-house radiologist specialized in orbital imaging to evaluate the diagnostic accuracy in the interpretation of orbital imaging., Methods: This was a retrospective chart review of forty patients referred to a Tertiary Eye Care Center in South India over a period of 7 years. These patients already had their imaging done elsewhere. The imaging was re-evaluated by an in-house radiologist. The radiological findings were correlated with the histopathological diagnosis. The diagnostic accuracy between the two radiologists was compared. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value in differentiating malignant from benign lesions were calculated in both groups. The sensitivity and PPV of the radiological diagnosis for neoplastic and inflammatory lesions in both groups were analyzed., Results: The accuracy in differentiating malignant from benign and inflammatory lesions by our in-house radiologist and extramural radiologists was 95% (κ = 0.9 [0.764, 0.997]) and 50% (κ = 0.036 [-0.160, 0.232]), respectively. The sensitivity and PPV of the radiological diagnosis by our in-house radiologist were 93.31% and 100% for benign lesions and 95.24% and 95.24% for malignant lesions. On the contrary, reports from the extramural radiologists showed a sensitivity and PPV of 76.92% and 66.67% for benign lesions and 14.28% and 60% for malignant lesions., Conclusion: A high radiological diagnostic accuracy is possible when analyzed by radiologists experienced in orbital imaging., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Middle East African Journal of Ophthalmology.)