Two-color fluorescence-guided surgery for head and neck cancer resections.

Significance: Head and neck squamous cell carcinoma (HNSCC) has the sixth highest incidence worldwide, with > 650,000 cases annually. Surgery is the primary treatment option for HNSCC, during which surgeons balance two main goals: (1) complete cancer resection and (2) preservation of normal tissues to ensure post-surgical quality of life. Unfortunately, these goals are not synergistic, where complete cancer resection is often limited by efforts to preserve normal tissues, particularly nerves, and reduce life-altering comorbidities. Aim: Currently, no clinically validated technology exists to enhance intraoperative cancer and nerve recognition. Fluorescence-guided surgery (FGS) has successfully integrated into clinical medicine, providing surgeons with real-time visualization of important tissues and complex anatomy, where FGS imaging systems operate almost exclusively in the near-infrared (NIR, 650 to 900 nm). Notably, this spectral range permits the detection of two NIR imaging channels for spectrally distinct detection. Approach: Herein, we evaluated the utility of spectrally distinct NIR nerve- and tumor-specific fluorophores for two-color FGS to guide HNSCC surgery. Using a human HNSCC xenograft murine model, we demonstrated that facial nerves and tumors could be readily differentiated using these nerve- and tumor-specific NIR fluorophores. Results: The selected nerve-specific fluorophore showed no significant difference in nerve specificity and off-target tissue fluorescence in the presence of xenograft head and neck tumors. Co-administration of two NIR fluorophores demonstrated successful tissue-specific labeling of nerves and tumors in spectrally distinct NIR imaging channels. Conclusions: We demonstrate a comprehensive FGS tool for cancer resection and nerve sparing during HNSCC procedures for future clinical translation.

Natural sesquiterpene zingiberene exerts ameliorative effects on growth of glioblastoma cells by instigating ROS mediated apoptosis.

Glioblastoma multiforme is the most aggressive and invasive primary brain tumor in adults and its prognosis and survival rate remain poor. Despite substantial improvements in therapy, the 5-year survival rate of glioblastoma patients remains low. Sesquiterpenes have previously been found to be effective in inhibiting the proliferation and growth of breast, gastric and lung cancer cells. Owing to their efficacy, sesquiterpenes have been used in various clinical trials. In the present study, we investigated the anticancer efficacy of a well-known sesquiterpene, Zingiberene, isolated from Zingiber officinale in C6 glioblastoma cells. Zingiberene suppresses the growth and proliferation of C6 cells. Upon treatment of C6 cells with zingiberene, nuclear fragmentation and ROS were qualitatively enhanced compared to untreated control cells. The levels of caspase-3 were also significantly reduced (p<0.01), with a concomitant decline in the mRNA expression of Bax and Bcl-2. On the basis of molecular docking studies, Zingiberene demonstrated good binding energy score of -6.8 and -5.5 Kcal/mol towards Bax and Bcl-2 proteins, respectively. Based on these observations, it was inferred that zingiberene has potential as a plausible therapeutic agent against glioblastoma cells. Detailed mechanistic studies are needed to substantiate and establish the anticancer effects of zingiberene against glioblastoma cells.

Deep learning-derived optimal aviation strategies to control pandemics.

The COVID-19 pandemic affected countries across the globe, demanding drastic public health policies to mitigate the spread of infection, which led to economic crises as a collateral damage. In this work, we investigate the impact of human mobility, described via international commercial flights, on COVID-19 infection dynamics on a global scale. We developed a graph neural network (GNN)-based framework called Dynamic Weighted GraphSAGE (DWSAGE), which operates over spatiotemporal graphs and is well-suited for dynamically changing flight information updated daily. This architecture is designed to be structurally sensitive, capable of learning the relationships between edge features and node features. To gain insights into the influence of air traffic on infection spread, we conducted local sensitivity analysis on our model through perturbation experiments. Our analyses identified Western Europe, the Middle East, and North America as leading regions in fueling the pandemic due to the high volume of air traffic originating or transiting through these areas. We used these observations to propose air traffic reduction strategies that can significantly impact controlling the pandemic with minimal disruption to human mobility. Our work provides a robust deep learning-based tool to study global pandemics and is of key relevance to policymakers for making informed decisions regarding air traffic restrictions during future outbreaks.

Exploring novel natural compound-based therapies for Duchenne muscular dystrophy management: insights from network pharmacology, QSAR modeling, molecular dynamics, and free energy calculations.

Muscular dystrophies encompass a heterogeneous group of rare neuromuscular diseases characterized by progressive muscle degeneration and weakness. Among these, Duchenne muscular dystrophy (DMD) stands out as one of the most severe forms. The present study employs an integrative approach combining network pharmacology, quantitative structure-activity relationship (QSAR) modeling, molecular dynamics (MD) simulations, and free energy calculations to identify potential therapeutic targets and natural compounds for DMD. Upon analyzing the GSE38417 dataset, it was found that individuals with DMD exhibited 290 upregulated differentially expressed genes (DEGs) compared to healthy controls. By utilizing gene ontology (GO) and protein-protein interaction (PPI) network analysis, this study provides insights into the functional roles of the identified DEGs, identifying ten hub genes that play a critical role in the pathology of DMD. These key genes include DMD, TTN, PLEC, DTNA, PKP2, SLC24A, FBXO32, SNTA1, SMAD3, and NOS1. Furthermore, through the use of ligand-based pharmacophore modeling and virtual screening, three natural compounds were identified as potential inhibitors. Among these, compounds 3874518 and 12314417 have demonstrated significant promise as an inhibitor of the SMAD3 protein, a crucial factor in the fibrotic and inflammatory mechanisms associated with DMD. The therapeutic potential of the compounds was further supported by molecular dynamics simulation and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analysis. These findings suggest that the compounds are viable candidates for experimental validation against DMD.

Utility of Video Laryngoscopy in Diagnosing Unanticipated Gastro-Tracheal Fistula Following Intubation for Supratentorial Craniotomy.

Gastro-tracheal fistula (GTF) is a rare but serious complication that can occur after esophagectomy. It involves an abnormal connection between the gastric conduit and the trachea that allows gastric contents to enter the respiratory tract. Although GTF is uncommon, it can lead to severe complications such as aspiration pneumonia, respiratory distress, mediastinitis, and sepsis. This case report details the management of an unexpected air leak in a 55-year-old female with a history of esophagectomy who was scheduled for an urgent supratentorial craniotomy. During anesthesia induction, a significant air leak was detected using a McGrath video laryngoscopy (VDL). This tool helped identify the leak and led to further investigation with fiberoptic bronchoscopy, which uncovered a GTF originating from the right main bronchus. The surgical procedure was postponed for a multidisciplinary assessment, and esophageal stenting was later used to manage the fistula successfully. This case highlights the crucial role of VDL in the early detection and management of complex airway issues, demonstrating its importance in enhancing patient outcomes through improved decision-making and interdisciplinary collaboration.

Subconjunctival injection of anti-VEGF agent bevacizumab as treatment in patients with dry eye disease.

To assess the effect of subconjunctival injection of anti-VEGF bevacizumab in the management of dry eye disease in a tertiary care hospital. In this quasi-experimental trial 150 eyes of 75 patients were selected using non-probability consecutive sampling technique. Detailed clinical examination was performed, the ocular surface disease index (OSDI) questionnaire score, tear film break-up time (TBUT) and Schirmer test 2 were measured and compared pre and post injection. Six patients were excluded and sixty-six patients were included having the mean age was 65.3 (SD=±10.2) years, 50% were aged 66-83 years old, 65.2% were female. Pre injection OSDI score was 30.3 (SD=±2.79), whereas post injection it was 20.2 (SD=±3.01). Pre injection TBUT was 3.0 (SD=±0.30), whereas post injection it was 5.17 (SD=±0.40). Pre injection Schirmer 2 test was 7.97 (SD=±0.51), whereas post injection it was 10.5 (SD=±0.50). Ten patients suffered mild subconjunctival hemorrhage which resolved spontaneously. Three patients were lost to follow up. Subconjunctival injection of anti-VEGF agent bevacizumab can offer a modern and safe solution in patients suffering from dry eye disease nevertheless more trials with large number of patients and longer follow up durations are required for widespread adaptation.

HEART: Learning better representation of EHR data with a heterogeneous relation-aware transformer.

OBJECTIVE: Pretrained language models have recently demonstrated their effectiveness in modeling Electronic Health Record (EHR) data by modeling the encounters of patients as sentences. However, existing methods fall short of utilizing the inherent heterogeneous correlations between medical entities-which include diagnoses, medications, procedures, and lab tests. Existing studies either focus merely on diagnosis entities or encode different entities in a homogeneous space, leading to suboptimal performance. Motivated by this, we aim to develop a foundational language model pre-trained on EHR data with explicitly incorporating the heterogeneous correlations among these entities. METHODS: In this study, we propose HEART, a heterogeneous relation-aware transformer for EHR. Our model includes a range of heterogeneous entities within each input sequence and represents pairwise relationships between entities as a relation embedding. Such a higher-order representation allows the model to perform complex reasoning and derive attention weights in the heterogeneous context. Additionally, a multi-level attention scheme is employed to exploit the connection between different encounters while alleviating the high computational costs. For pretraining, HEART engages with two tasks, missing entity prediction and anomaly detection, which both effectively enhance the model's performance on various downstream tasks. RESULTS: Extensive experiments on two EHR datasets and five downstream tasks demonstrate HEART's superior performance compared to four SOTA foundation models. For instance, HEART achieves improvements of 12.1% and 4.1% over Med-BERT in death and readmission prediction, respectively. Additionally, case studies show that HEART offers interpretable insights into the relationships between entities through the learned relation embeddings. CONCLUSION: We study the problem of EHR representation learning and propose HEART, a model that leverages the heterogeneous relationships between medical entities. Our approach includes a multi-level encoding scheme and two specialized pretrained objectives, designed to boost both the efficiency and effectiveness of the model. We have comprehensively evaluated HEART across five clinically significant downstream tasks using two EHR datasets. The experimental results verify the model's great performance and validate its practical utility in healthcare applications.

Spermidine protects cellular redox status and ionic homeostasis in D-galactose induced senescence and natural aging rat models.

Impaired redox homeostasis is an important hallmark of aging. Among various anti-aging interventions, caloric restriction mimetics (CRMs) are the most effective in promoting health and longevity. The potential role of spermidine (SPD) as a CRM in modulating oxidative stress and redox homeostasis during aging remains unclear. This study aimed to investigate the protective effect of SPD in D-galactose (D-gal) accelerated induced senescence model and naturally aged rats. Young male rats (4 months), D-gal induced (500 mg/kg b. w., subcutaneously) aging model and naturally aged (22 months) rats were supplemented with SPD (10 mg/kg b. w., orally) for 6 weeks. The results showed that SPD supplementation suppresses the age induced increase in reactive oxygen species, lipid peroxidation and protein oxidation. Additionally, it increases the level of antioxidants, plasma membrane redox system in erythrocytes and membrane. These results also indicate that membrane transporter activity is correlated with the susceptibility of the erythrocyte towards oxidative damage. We therefore present evidence that SPD improves redox status and membrane impairments in erythrocytes in experimental and naturally aging rat models, however, more research is required to recommend a potential therapeutic role for SPD as an anti-aging intervention strategy.

Demographic trends and disparities in mortality related to coexisting heart failure and diabetes mellitus among older adults in the United States between 1999 and 2020: A retrospective population-based cohort study from the CDC WONDER database.

Background: Heart Failure (HF) and Diabetes Mellitus (DM) often coexist, and each condition independently increases the likelihood of developing the other. While there has been concern regarding the increasing burden of disease for both conditions individually over the last decade, a comprehensive examination of mortality trends and demographic and regional disparities needs to be thoroughly explored in the United States (US). Methods: This study analyzed death certificates from the CDC WONDER database, focusing on mortality caused by the co-occurrence of HF and DM in adults aged 75 and older from 1999 to 2020. Age-adjusted mortality rates (AAMRs) and annual percent changes (APCs) were computed and categorized by year, gender, race, census region, state, and metropolitan status. Results: A total of 663,016 deaths were reported in patients with coexisting HF and DM. Overall, AAMR increased from 154.1 to 186.1 per 100,000 population between 1999 and 2020, with a notable significant increase from 2018 to 2020 (APC: 11.30). Older men had consistently higher AAMRs than older women (185 vs. 135.4). Furthermore, we found that AAMRs were highest among non-Hispanic (NH) American Indian or Alaskan natives and lowest in NH Asian or Pacific Islanders (214.4 vs. 104.1). Similarly, AAMRs were highest in the Midwestern region and among those dwelling in non-metropolitan areas. Conclusions: Mortality from HF and DM has risen significantly in recent years, especially among older men, NH American Indian or Alaska Natives, and those in non-metropolitan areas. Urgent policies need to be developed to address these disparities and promote equitable healthcare access.

Relationship between SGLT2 inhibitor use and specific cancer types: a systematic review and meta-analysis.

Aim: The study aimed to explore the incidence of cancer as an adverse event to SGLT2 inhibitors (SGLT2i) use in Type 2 diabetes.Materials & methods: The study followed PRISMA guidelines to pool RCTs conforming the inclusion criteria. Random effects model was used to pool risk ratios.Results & conclusion: After reviewing 19 studies, the analysis suggested a possible increased risk of reproductive, breast, thyroid, hematologic/lymphatic, urinary, skin and skeletal cancers with SGLT2i use. Conversely, lower incidences of respiratory and cardiovascular cancers were noted. However, these associations lacked statistical significance. Caution is advised in using SGLT2i due to potential cancer risks, especially in diabetic patients prone to cancer. More RCTs are essential due to limited research in this area.

SGLT2 inhibitors, widely used to manage Type 2 diabetes, provide benefits for blood sugar control, cardiovascular health and kidney function. However, their impact on cancer risk remains unclear. This review and meta-analysis examined randomized controlled trials to evaluate cancer outcomes in adults using SGLT2 inhibitors. Findings indicated mixed effects on various cancer types, with some inhibitors potentially increasing risk while others showed no significant impact. Further research is essential to clarify the relationship between SGLT2 inhibitors and cancer.

Orally self-disintegrating milk protein puffs enriched with food by-products for the elderly.

Supercritical fluid extrusion (SCFX) processing was used to develop milk protein-based orally self-disintegrating puffs enriched with fruit and dairy by-products, designed specifically to cater to the needs of elderly population having swallowing issues and lactose intolerance. Lactose hydrolyzed skim milk powder (LHSMP) was also added in the formulation to mitigate lactose intolerance while LHSMP was also exploited as a precursor for the polymerization of galactose and lactose to generate galacto-oligosaccharides (GOS) in the puffs. This study for the first time took advantage of the unique features of SCFX processing for in-process GOS formation and enrichment of puffs, achieving GOS contents up to 0.48 g/30 g serving of puffs, thereby making them nutritionally superior and functionally attractive snacks. The estimated nutritional profile revealed that SCFX puffs contained higher levels of protein (16.3 g/30 g), fiber (1.6 g/30 g), phenolics and other valuable nutrients compared to the starch-rich, disintegrating Market Baby puffs.

Orbital malignant peripheral nerve sheath tumor: A case report and review.

Malignant peripheral nerve sheath tumor of the orbit is an exceedingly rare entity. These tumors exhibit locally aggressive behavior, recurrences, distant metastasis, and poor response to existing treatment protocols. Orbital nerve sheath tumors are often associated with neurofibromatosis 1, and malignant transformation of neurofibroma into malignant nerve sheath tumor has also been seen. The recommended treatment for localized disease is radical or wide surgical excision to achieve negative margins followed by chemoradiation. For extensive disease, chemotherapy and radiotherapy can be utilized to stabilize the disease. Due to poor response and outcomes with current regimens, the focus has been shifted to approaches utilizing molecular targets and immunological agents. Despite all the advancements, the outcomes still remain discouraging for moderate- to high-grade lesions and thus necessitate studies to design promising treatment modalities.

Exploring perceptions of pilot licensing and training standards: a survey of Canadian student and licensed pilots.

This study investigates the perspectives of Canadian student and licenced pilots on general aviation pilot training and licencing practices. Employing a mixed-methods approach, this research critiques the reliance on flight hours as the sole competence metric and examines the alignment of existing practices with modern aviation's complexities. Findings reveal a divergence in opinions between novice and experienced pilots on flight hours' importance, with a consensus towards a competency-based evaluation model. The study identifies critical shortcomings in existing training practices, such as the challenge of integrating technology, fostering advanced skills, and efficiently utilising instructional resources. It suggests recommendations for regulatory enhancements, aiming to ensure training practices evolve in line with the changing requirements of aviation safety and technology. The conclusion calls for urgent reform, underlining the imperative for training adaptations that can prepare pilots to proficiently manage the complexities of contemporary airspace, thus safeguarding their proficiency and safety.

A survey conducted among Canadian student and licenced pilots to examine perspectives on general aviation pilot training and licencing practices uncovered critical shortcomings. The findings advocate for a strong preference for competency-based evaluations, urging reforms and regulatory improvements to ensure alignment with the evolving landscape of aviation safety and technological advancements.

Kharadar spontaneous quintuplets reached their adolescence life: A case report.

Quintuplet pregnancies are associated with significant perinatal morbidity and mortality. The spontaneous quintuplets are a rare occurrence, and the survival is extremely rare. The first quintuplets known to survive infancy to adulthood were the Dionne Quintuplets, born in 1934. Kharadar quintuplets born in 2006, in Karachi Pakistan, were the first set of quintuplets who were born alive and reached their adolescence. A 30-year old women, presented at Kharadar General Hospital (KGH) during the 28th week of gestation for pregnancy evaluation. She was diagnosed with a quintuplet pregnancy with no gross foetal abnormality on ultrasound abdomen. The patient had premature rupture of membrane at 30th week of gestation, and emergency caesarean section was performed. All five quints were born alive, had normal APGAR scores, were premature, and had low birth weight. After birth, all quints were immediately shifted to the neonatal intensive care unit. After a 10 day hospital stay, all quints were discharged. In 2023, all quints celebrated their 17th Birthday.

Insecticidal Activities of Securidaca longepedunculata Fresen Extracts and Feeding Behavior of Schizaphis graminum Rondani: Electropenetrography Approach.

The aphid, Schizaphis graminum Rondani (Hemiptera: Aphididae), is one of the most destructive pests of wheat. It is responsible for significant economic losses in the agricultural sector, with an estimated 45% of wheat fields affected. Plant-based insecticides have seen a rapid increase in popularity in recent years due to their efficacy, cost-effectiveness, biodegradability, and lower toxicity compared to synthetic pesticides. The study aimed to evaluate the toxic potential of S. longipedunculata extracts against S. graminum and investigate the insect's feeding behavior on wheat. Initially macerated in methanol, the different extracts of S. longipedunculata organs were fractionated using n-hexane, chloroform, ethyl acetate, and butanol. The feeding behavior was analyzed by comparing the waveforms generated by the EPG with the control. After 72 h of treatment, the ethyl acetate fraction extracted from root had the highest toxicity against aphids, with mean 26 mortality of S. graminum at LC50 of 330 ppm; 25 mortality S. graminum at LC50 of 400 ppm for leaves; and mean 24.5 mortality S. graminum at LC50 of 540 ppm in stem bark. EPG analysis indicated that the extract fractions enhanced plant tissue resistance by significantly preventing aphid access to the phloem. The toxic effect of the botanical extracts significantly enhanced the chemical composition of the leaf medium, resulting in a drastic reduction in the number of tissue attacks by S. graminum. In summary, besides their toxicity to S. graminum, extracts of S. longipedunculata reinforce the plant's defense mechanisms, significantly reducing the S. graminum population. They also reinforce wheat's defense mechanisms. S. longipedunculata can, therefore, be used as a promising agent in the biological control of S. graminum.

Did the exposure of coacervate droplets to rain make them the first stable protocells?

Membraneless coacervate microdroplets have long been proposed as model protocells as they can grow, divide, and concentrate RNA by natural partitioning. However, the rapid exchange of RNA between these compartments, along with their rapid fusion, both within minutes, means that individual droplets would be unable to maintain their separate genetic identities. Hence, Darwinian evolution would not be possible, and the population would be vulnerable to collapse due to the rapid spread of parasitic RNAs. In this study, we show that distilled water, mimicking rain/freshwater, leads to the formation of electrostatic crosslinks on the interface of coacervate droplets that not only suppress droplet fusion indefinitely but also allow the spatiotemporal compartmentalization of RNA on a timescale of days depending on the length and structure of RNA. We suggest that these nonfusing membraneless droplets could potentially act as protocells with the capacity to evolve compartmentalized ribozymes in prebiotic environments.

Disease heterogeneity and molecular classification of inflammatory palmoplantar diseases.

BACKGROUND: Palmoplantar pustulosis (PPP) is an inflammatory disease characterized by relapsing eruptions of neutrophil-filled, sterile pustules on the palms and soles that can be clinically difficult to differentiate from non-pustular palmoplantar psoriasis (palmPP) and dyshidrotic palmoplantar eczema (DPE). OBJECTIVE: We sought to identify overlapping and unique PPP, palmPP, and DPE drivers to provide molecular insight into their pathogenesis. METHODS: We performed bulk RNA sequencing of lesional PPP (n = 33), palmPP (n = 5), and DPE (n = 28) samples, as well as 5 healthy nonacral and 10 healthy acral skin samples. RESULTS: Acral skin showed a unique immune environment, likely contributing to a unique niche for palmoplantar inflammatory diseases. Compared to healthy acral skin, PPP, palmPP, and DPE displayed a broad overlapping transcriptomic signature characterized by shared upregulation of proinflammatory cytokines (TNF, IL-36), chemokines, and T-cell-associated genes, along with unique disease features of each disease state, including enriched neutrophil processes in PPP and to a lesser extent in palmPP, and lipid antigen processing in DPE. Strikingly, unsupervised clustering and trajectory analyses demonstrated divergent inflammatory profiles within the 3 disease states. These identified putative key upstream immunologic switches, including eicosanoids, interferon responses, and neutrophil degranulation, contributing to disease heterogeneity. CONCLUSION: A molecular overlap exists between different inflammatory palmoplantar diseases that supersedes clinical and histologic assessment. This highlights the heterogeneity within each condition, suggesting limitations of current disease classification and the need to move toward a molecular classification of inflammatory acral diseases.

Patient-Centered Outcomes of a Lymphedema Pump in Patients with Symptomatic Lower Extremity Edema.

BACKGROUND: Phlebolymphedema is a challenging condition to manage, with limited options for effective treatment. For patients, this may be debilitating and lead to infection, loss of independence and affect quality of life. This study aims to evaluate patient-reported outcomes of an advanced pneumatic compression device (APCD) in the treatment of lower extremity phlebolymphedema. METHODS: Patients with diagnosis of lower extremity phlebolymphedema at an acute care facility within the New York City Health and Hospitals Cooperation treated with the Flexitouch (FLX) (Tactile Systems Technology, Inc, Minneapolis, Minnesota) APCD from December 2021 to March 2023 were evaluated. Patient-perceived subjective outcomes were assessed via a short questionnaire, with subsequent analysis using chi-squared test. Primary end points were subjective improvements in 1) swelling, 2) pain, and 3) ease of use of device as surrogates for patient satisfaction. Secondary end point was subjective patient-reported compliance, obtained by investigating 1) if patients were trained to use device, and 2) if patients were using the device. RESULTS: A total of 52 participants were included in this study, consisting of 30.8% male and 69.2% female patients with a mean age of 71.7 years. While selection criteria did not exclude unilateral disease or alternative etiologies, we note that the entire study population had been diagnosed with bilateral lower extremity lymphedema in the setting of chronic venous insufficiency. Other patient characteristics including race, comorbidities and smoking status were documented in Table 1. Table 2 demonstrates the results of chi-squared analysis. This study noted significant patient-perceived improvement in swelling and pain (91.4% with P < 0.00001; 85.7% with P = 0.00002 respectively) and patient-reported ease of use of the FLX device (85.7% with P = 0.00002). Additional secondary findings included a majority of patients reporting being trained on how to use FLX and also maintaining compliance with the device (69.2% with P = 0.005; 67.3% with P = 0.012 respectively). CONCLUSIONS: FLX APCD use has been found to demonstrate desirable patient-reported outcomes as a general trend. The participants in this study noted statistically significant subjective improvement in swelling and pain, ease of use of device and adherence to training and compliance with device. FLX appears to be positively received by patients, and the authors recommend its consideration for management of bilateral lower extremity phlebolymphedema.