Advancing neoadjuvant therapies in resectable non-small cell lung cancer: implications for novel treatment strategies and biomarker discovery.

The delivery of neoadjuvant and perioperative therapies for non-small cell lung cancer has been radically altered by significant advances and by the incorporation of targeted therapies as well as immune checkpoint inhibitors alone or alongside conventional chemotherapy. This evolution has been particularly notable in the incorporation of immunotherapy and targeted therapy into the treatment of resectable NSCLC, where recent FDA approvals of drugs such as nivolumab and pembrolizumab, in combination with platinum doublet chemotherapy, have led to considerable improvements in pathological complete response rates and the potential for enhanced long-term survival outcomes. This review emphasizes the growing importance of biomarkers in optimizing treatment selection and explores the impact of emerging studies that challenge existing treatment paradigms and investigate novel therapeutic combinations poised to redefine standard of care practices. Furthermore, the discussion extends to the unmet needs within perioperative treatment assessment and prognostication, highlighting the prospective value of biomarkers in evaluating treatment responses and prognosis.

The Proton Resonance Enhancement for CEST imaging and Shift Exchange (PRECISE) family of RF pulse shapes for Chemical Exchange Saturation Transfer MRI.

Purpose: To optimize a 100 msec pulse for producing CEST MRI contrast and evaluate in mice. Methods: A gradient ascent algorithm was employed to generate a family of 100 point, 100 msec pulses for use in CEST pulse trains ('PRECISE'). Gradient ascent optimizations were performed for exchange rates (k ca ) = 500 s -1 , 1,500 s -1 , 2,500 s -1 , 3,500 s -1 and 4,500 s -1 and offsets (Δω) = 9.6, 7.8, 4.2 and 2.0 ppm. 7 PRECISE pulse shapes were tested on an 11.7 T scanner using a phantom containing three representative CEST agents with peak saturation B 1 = 4 µT. The pulse producing the most contrast in phantoms was then evaluated for CEST MRI pH mapping of the kidneys in healthy mice after iopamidol administration. Results: The most promising pulse in terms of contrast performance across all three phantoms was the 9.6 ppm, 2500 s -1 optimized pulse with ∼2.7 x improvement over Gaussian and ∼1.3x's over Fermi pulses. This pulse also displayed a large improvement in contrast over the Gaussian pulse after administration of iopamidol in live mice. Conclusion: A new 100 msec pulse was developed based on gradient ascent optimizations which produced better contrast compared to standard Gaussian and Fermi pulses in phantoms. This shape also showed a substantial improvement for CEST MRI pH mapping in live mice over the Gaussian shape and appears promising for a wide range of CEST applications.

Emergency Department Visits And Hospital Capacity In The US: Trends In The Medicare Population During The COVID-19 Pandemic.

Although emergency department (ED) and hospital overcrowding were reported during the later parts of the COVID-19 pandemic, the true extent and potential causes of this overcrowding remain unclear. Using data on the traditional fee-for-service Medicare population, we examined patterns in ED and hospital use during the period 2019-22. We evaluated trends in ED visits, rates of admission from the ED, and thirty-day mortality, as well as measures suggestive of hospital capacity, including hospital Medicare census, length-of-stay, and discharge destination. We found that ED visits remained below baseline throughout the study period, with the standardized number of visits at the end of the study period being approximately 25 percent lower than baseline. Longer length-of-stay persisted through 2022, whereas hospital census was considerably above baseline until stabilizing just above baseline in 2022. Rates of discharge to postacute facilities initially declined and then leveled off at 2 percent below baseline in 2022. These results suggest that widespread reports of overcrowding were not driven by a resurgence in ED visits. Nonetheless, length-of-stay remains higher, presumably related to increased acuity and reduced available bed capacity in the postacute care system.

Microneedle-based sampling of dermal interstitial fluid using a vacuum-assisted skin patch.

Interstitial fluid (ISF) contains a wealth of biomolecules, yet it is underutilized for diagnostic testing due to a lack of rapid and simple techniques for collecting abundant amounts of fluid. Here, we report a simple and minimally invasive technique for rapidly sampling larger quantities of ISF from human skin. A microneedle array is used to generate micropores in skin from which ISF is extracted using a vacuum-assisted skin patch. Using this technique, an average of 20.8 µL of dermal ISF is collected in 25 min, which is an ∼6-fold improvement over existing sampling methods. Proteomic analysis of collected ISF reveals that it has nearly identical protein composition as blood, and >600 medically relevant biomarkers are identified. Toward this end, we demonstrate the detection of SARS-CoV-2 neutralizing antibodies in ISF collected from COVID-19 vaccinees using two commercial immunoassays, showcasing the utility of this technique for diagnostic testing.

Microfluidic finger-actuated mixer for ultrasensitive electrochemical measurements of protein biomarkers for point-of-care testing.

Current diagnostic tests for high sensitivity detection of protein biomarkers involve long incubation times or require bulky/expensive instrumentation, hindering their use for point-of-care testing. Here, we report a microfluidic electrochemical immunosensor that employs a unique finger-actuated mixer for rapid, ultrasensitive measurements of protein biomarkers. Mixing was implemented during the incubation steps, which accelerated biomolecular transport and promoted immunocomplex formation, leading to enhanced analytical sensitivity and a shortened detection time. Electrochemical measurements were performed using a handheld diagnostic device consisting of a smartphone and miniature potentiostat. Proof of principle was demonstrated by using this platform for quantitative measurements of C-X-C motif chemokine ligand 9 (CXCL9), a serological biomarker for autoimmune and inflammatory diseases, which could be detected in human plasma at concentrations as low as 4.7 pg mL-1 in <25 min. The ability to rapidly detect protein biomarkers with high sensitivity in a point-of-care format makes this device a promising tool for diagnostic testing, particularly in resource-limited settings.

CRISPR/Cas9-mediated Nap knockout affects female reproduction and egg shape in Bombyx mori.

Insect reproductive capacity can affect effective pest control and infertility studies and has become an important focus in recent molecular genetic research. Nucleosome assembly protein (Nap) is highly conserved across multiple species and is involved in forming the sperm nucleus in many species. We used clustered regularly interspaced palindromic repeats/Cas9 technology to knockout BmNap in Bombyx mori and observed that the mutations caused female infertility, whereas male fertility was not affected. BmNap mutants grew and mated normally; however, female mutants laid smaller eggs that could not be fertilised and did not hatch. In addition, female sterility produced by the mutation could be inherited stably via male mutants; therefore, Nap could be used as a potential target for lepidopteran pest control through population regulation. In the current study, we elucidated a new function of BmNap, increased the understanding of the oogenesis regulation network in Lepidoptera and promoted the development of insect sterility technologies.

Deaths with COVID-19 and from all-causes following first-ever SARS-CoV-2 infection in individuals with preexisting mental disorders: A national cohort study from Czechia.

BACKGROUND: Evidence suggests reduced survival rates following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in people with preexisting mental disorders, especially psychotic disorders, before the broad introduction of vaccines. It remains unknown whether this elevated mortality risk persisted at later phases of the pandemic and when accounting for the confounding effect of vaccination uptake and clinically recorded physical comorbidities. METHODS AND FINDINGS: We used data from Czech national health registers to identify first-ever serologically confirmed SARS-CoV-2 infections in 5 epochs related to different phases of the pandemic: 1st March 2020 to 30th September 2020, 1st October 2020 to 26th December 2020, 27th December 2020 to 31st March 2021, 1st April 2021 to 31st October 2021, and 1st November 2021 to 29th February 2022. In these people, we ascertained cases of mental disorders using 2 approaches: (1) per the International Classification of Diseases 10th Revision (ICD-10) diagnostic codes for substance use, psychotic, affective, and anxiety disorders; and (2) per ICD-10 diagnostic codes for the above mental disorders coupled with a prescription for anxiolytics/hypnotics/sedatives, antidepressants, antipsychotics, or stimulants per the Anatomical Therapeutic Chemical (ATC) classification codes. We matched individuals with preexisting mental disorders with counterparts who had no recorded mental disorders on age, sex, month and year of infection, vaccination status, and the Charlson Comorbidity Index (CCI). We assessed deaths with Coronavirus Disease 2019 (COVID-19) and from all-causes in the time period of 28 and 60 days following the infection using stratified Cox proportional hazards models, adjusting for matching variables and additional confounders. The number of individuals in matched-cohorts ranged from 1,328 in epoch 1 to 854,079 in epoch 5. The proportion of females ranged from 34.98% in people diagnosed with substance use disorders in epoch 3 to 71.16% in individuals diagnosed and treated with anxiety disorders in epoch 5. The mean age ranged from 40.97 years (standard deviation [SD] = 15.69 years) in individuals with substance use disorders in epoch 5 to 56.04 years (SD = 18.37 years) in people with psychotic disorders in epoch 2. People diagnosed with or diagnosed and treated for psychotic disorders had a consistently elevated risk of dying with COVID-19 in epochs 2, 3, 4, and 5, with adjusted hazard ratios (aHRs) ranging from 1.46 [95% confidence intervals (CIs), 1.18, 1.79] to 1.93 [95% CIs, 1.12, 3.32]. This patient group demonstrated also a consistently elevated risk of all-cause mortality in epochs 2, 3, 4, and 5 (aHR from 1.43 [95% CIs, 1.23, 1.66] to 1.99 [95% CIs, 1.25, 3.16]). The models could not be reliably fit for psychotic disorders in epoch 1. People diagnosed with substance use disorders had an increased risk of all-cause mortality 28 days postinfection in epoch 3, 4, and 5 (aHR from 1.30 [95% CIs, 1.14, 1.47] to 1.59 [95% CIs, 1.19, 2.12]) and 60 days postinfection in epoch 2, 3, 4, and 5 (aHR from 1.22 [95% CIs, 1.08, 1.38] to 1.52 [95% CIs, 1.16, 1.98]). Cases ascertained based on diagnosis of substance use disorders and treatment had increased risk of all-cause mortality in epoch 2, 3, 4, and 5 (aHR from 1.22 [95% CIs, 1.03, 1.43] to 1.91 [95% CIs, 1.25, 2.91]). The models could not be reliably fit for substance use disorders in epoch 1. In contrast to these, people diagnosed with anxiety disorders had a decreased risk of death with COVID-19 in epoch 2, 3, and 5 (aHR from 0.78 [95% CIs, 0.69, 0.88] to 0.89 [95% CIs, 0.81, 0.98]) and all-cause mortality in epoch 2, 3, 4, and 5 (aHR from 0.83 [95% CIs, 0.77, 0.90] to 0.88 [95% CIs, 0.83, 0.93]). People diagnosed and treated for affective disorders had a decreased risk of both death with COVID-19 and from all-causes in epoch 3 (aHR from 0.87 [95% CIs, 0.79, 0.96] to 0.90 [95% CIs, 0.83, 0.99]), but demonstrated broadly null effects in other epochs. Given the unavailability of data on a number of potentially influential confounders, particularly body mass index, tobacco smoking status, and socioeconomic status, part of the detected associations might be due to residual confounding. CONCLUSIONS: People with preexisting psychotic, and, less robustly, substance use disorders demonstrated a persistently elevated risk of death following SARS-CoV-2 infection throughout the pandemic. While it cannot be ruled out that part of the detected associations is due to residual confounding, this excess mortality cannot be fully explained by lower vaccination uptake and more clinically recorded physical comorbidities in these patient groups.

Single-cell atlas of the human brain vasculature across development, adulthood and disease.

A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood1. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell-cell interaction analyses predict substantial endothelial-to-perivascular cell ligand-receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.

MRS2 missense variation at Asp216 abrogates inhibitory Mg2+ binding, potentiating cell migration and apoptosis resistance.

Mitochondrial magnesium (Mg2+) is a crucial modulator of protein stability, enzymatic activity, ATP synthesis, and cell death. Mitochondrial RNA splicing protein 2 (MRS2) is the main Mg2+ channel in the inner mitochondrial membrane that mediates influx into the matrix. Recent cryo-electron microscopy (cryo-EM) human MRS2 structures exhibit minimal conformational changes at high and low Mg2+, yet the regulation of human MRS2 and orthologues by Mg2+ binding to analogous matrix domains has been well established. Further, a missense variation at D216 has been identified associated with malignant melanoma and MRS2 expression and activity is implicated in gastric cancer. Thus, to gain more mechanistic and functional insight into Mg2+ sensing by the human MRS2 matrix domain and the association with proliferative disease, we assessed the structural, biophysical, and functional effects of a D216Q mutant. We show that the D216Q mutation is sufficient to abrogate Mg2+-binding and associated conformational changes including increased α-helicity, stability, and monomerization. Further, we reveal that the MRS2 matrix domains interact with ~µM affinity, which is weakened by up to two orders of magnitude in the presence of Mg2+ for wild-type but unaffected for D216Q. Finally, we demonstrate the importance of Mg2+ sensing by MRS2 to prevent matrix Mg2+ overload as HeLa cells overexpressing MRS2 show enhanced Mg2+ uptake, cell migration, and resistance to apoptosis while MRS2 D216Q robustly potentiates these cancer phenotypes. Collectively, our findings further define the MRS2 matrix domain as a critical Mg2+ sensor that undergoes conformational and assembly changes upon Mg2+ interactions dependent on D216 to temper matrix Mg2+ overload.

Endoscopic Spine Surgery on Instagram: Analysis of Content and Engagement.

Introduction Social media platforms have changed the way society communicates and collaborates. Prior research in healthcare discusses how social media can empower patients, dispel health-related misinformation, and help maintain a patient-centered practice. The goal of this study was to evaluate the use of #endoscopicspinesurgery on Instagram and create a blueprint for creating engaging posts on the social media platform. Methodology Public Instagram posts (n = 171) that utilized #endoscopicspinesurgery were collected over three months in 2022. Each post was assessed for photo and caption content, likes, comments, number of followers, and hashtag information. Engagement rates were calculated for each post to assess the active interaction of post characteristics and content. Results The majority of posts were published by medical professionals (72/171, 42.1%) and industry-related user accounts (55/171, 32.2%). Content related to training, conferences, and the operating room garnered the highest average engagement. Post characteristics (number of hashtags and number of post photos) were significantly associated with engagement. Conclusions Results highlighted general trends in creating engaging social media posts, such as using hashtags intentionally to increase searchability and visibility, having higher numbers of photos in a post and using high-quality photos, and understanding the dynamic social media algorithms that may affect post viewership. When structuring social media posts, users should be aware of the audience they want to attract and construct their content accordingly.

Recent Trends in Concomitant Distal Clavicle Excision During Rotator Cuff Repair.

The purpose of this study is to evaluate trends in distal clavicle excision (DCE) in association with arthroscopic rotator cuff repair (RCR) from 2010 to 2019. The National Surgical Quality Improvement Program database was queried to identify all patients who underwent arthroscopic RCR from January 1, 2010 to December 31, 2019, and was further subdivided into procedure type: (1) isolated RCR; and (2) RCR with arthroscopic or open DCE. The proportion of each surgery type, by year and within groups, was calculated. The Cochran-Armitage test for trend was used to analyze yearly proportions of RCR with concomitant DCE. In a sample size of 19,163 patients, the proportion of RCR with DCE decreased from 51.2% to 40.8% (r = -0.830; p = 0.003). Although the results of this study suggest that surgeons are performing fewer DCEs in the setting of RCR, many DCEs are still being done. (Journal of Surgical Orthopaedic Advances 33(2):077-079, 2024).

Integrated cryoEM structure of a spumaretrovirus reveals cross-kingdom evolutionary relationships and the molecular basis for assembly and virus entry.

Foamy viruses (FVs) are an ancient lineage of retroviruses, with an evolutionary history spanning over 450 million years. Vector systems based on Prototype Foamy Virus (PFV) are promising candidates for gene and oncolytic therapies. Structural studies of PFV contribute to the understanding of the mechanisms of FV replication, cell entry and infection, and retroviral evolution. Here we combine cryoEM and cryoET to determine high-resolution in situ structures of the PFV icosahedral capsid (CA) and envelope glycoprotein (Env), including its type III transmembrane anchor and membrane-proximal external region (MPER), and show how they are organized in an integrated structure of assembled PFV particles. The atomic models reveal an ancient retroviral capsid architecture and an unexpected relationship between Env and other class 1 fusion proteins of the Mononegavirales. Our results represent the de novo structure determination of an assembled retrovirus particle.

Actinium chelation and crystallization in a macromolecular scaffold.

Targeted alpha therapy (TAT) pairs the specificity of antigen targeting with the lethality of alpha particles to eradicate cancerous cells. Actinium-225 [225Ac; t1/2 = 9.920(3) days] is an alpha-emitting radioisotope driving the next generation of TAT radiopharmaceuticals. Despite promising clinical results, a fundamental understanding of Ac coordination chemistry lags behind the rest of the Periodic Table due to its limited availability, lack of stable isotopes, and inadequate systems poised to probe the chemical behavior of this radionuclide. In this work, we demonstrate a platform that combines an 8-coordinate synthetic ligand and a mammalian protein to characterize the solution and solid-state behavior of the longest-lived Ac isotope, 227Ac [t1/2 = 21.772(3) years]. We expect these results to direct renewed efforts for 225Ac-TAT development, aid in understanding Ac coordination behavior relative to other +3 lanthanides and actinides, and more broadly inform this element's position on the Periodic Table.

Dual-source photon-counting CT: impact of residual cross-scatter on quantitative spectral results.

Dual-source photon-counting CT combines the high temporal resolution and high pitch of dual-source CT with the material quantification capabilities of photon-counting CT. It, however, results in cross-scatter that increases in severity with increased patient size and collimation. This cross-scatter must be corrected to ensure the removal of scatter artifacts and improve quantitative accuracy. To evaluate residual cross-scatter of a first-generation dual-source photon-counting CT and the effect of phantom size, collimation, and radiation dose, a phantom was scanned in single- and dual-source modes with and without its extension ring at three collimations and three radiation doses. Virtual monoenergetic images (VMI) at 50 keV, VMI 150 keV, and iodine density maps were reconstructed to determine variation between acquisition parameters in single- and dual-source modes. Additionally, differences relative to single-source acquisitions and to single-source and small collimation acquisitions were calculated to reflect residual cross-scatter with and without matched collimation. At VMI 50 keV, inserts exhibited accuracy and similar variation between single- and dual-source modes, averaging 5.4 ± 2.6 and 6.2 ± 2.5 HU, respectively, across phantom size, collimation, and radiation dose. Differences relative to single-source measured 5.1 ± 8.5 and 0.4 ± 4.2 HU while differences relative to single-source and small collimation acquisitions were 6.4 ± 10.8 HU and -0.5 ± 3.9 HU for VMI 50 and 150 keV, respectively. This minimal residual cross-scatter increases confidence in the quantitative accuracy of spectral results necessary for clinical applications of dual-source photon-counting CT with motion, such as cardiac imaging.

PixelPrint: Generating Patient-Specific Phantoms for Spectral CT using Dual Filament 3D Printing.

In recent years, the importance of spectral CT scanners in clinical settings has significantly increased, necessitating the development of phantoms with spectral capabilities. This study introduces a dual-filament 3D printing technique for the fabrication of multi-material phantoms suitable for spectral CT, focusing particularly on creating realistic phantoms with orthopedic implants to mimic metal artifacts. Previously, we developed PixelPrint for creating patient-specific lung phantoms that accurately replicate lung properties through precise attenuation profiles and textures. This research extends PixelPrint's utility by incorporating a dual-filament printing approach, which merges materials such as calcium-doped Polylactic Acid (PLA) and metal-doped PLA, to emulate both soft tissue and bone, as well as orthopedic implants. The PixelPrint dual-filament technique utilizes an interleaved approach for material usage, whereby alternating lines of calcium-doped and metal-doped PLA are laid down. The development of specialized filament extruders and deposition mechanisms in this study allows for controlled layering of materials. The effectiveness of this technique was evaluated using various phantom types, including one with a dual filament orthopedic implant and another based on a human knee CT scan with a medical implant. Spectral CT scanner results demonstrated a high degree of similarity between the phantoms and the original patient scans in terms of texture, density, and the creation of realistic metal artifacts. The PixelPrint technology's ability to produce multi-material, lifelike phantoms present new opportunities for evaluating and developing metal artifact reduction (MAR) algorithms and strategies.

Automated, IMU-based spine angle estimation and IMU location identification for telerehabilitation.

BACKGROUND: Telerehabilitation is a promising avenue for improving patient outcomes and expanding accessibility. However, there is currently no spine-related assessment for telerehabilitation that covers multiple exercises. METHODS: We propose a wearable system with two inertial measurement units (IMUs) to identify IMU locations and estimate spine angles for ten commonly prescribed spinal degeneration rehabilitation exercises (supine chin tuck head lift rotation, dead bug unilateral isometric hold, pilates saw, catcow full spine, wall angel, quadruped neck flexion/extension, adductor open book, side plank hip dip, bird dog hip spinal flexion, and windmill single leg). Twelve healthy subjects performed these spine-related exercises, and wearable IMU data were collected for spine angle estimation and IMU location identification. RESULTS: Results demonstrated average mean absolute spinal angle estimation errors of 2.59 ∘ and average classification accuracy of 92.97%. The proposed system effectively identified IMU locations and assessed spine-related rehabilitation exercises while demonstrating robustness to individual differences and exercise variations. CONCLUSION: This inexpensive, convenient, and user-friendly approach to spine degeneration rehabilitation could potentially be implemented at home or provide remote assessment, offering a promising avenue to enhance patient outcomes and improve accessibility for spine-related rehabilitation. TRIAL REGISTRATION:  No. E2021013P in Shanghai Jiao Tong University.