Supramolecular assembly of amphiphilic platinum(ii) Schiff base complexes: diverse spectroscopic changes and nanostructures through rational molecular design and solvent control.

A new class of amphiphilic tetradentate platinum(ii) Schiff base complexes has been designed and synthesized. The self-assembly properties by exploiting the potential Pt⋯Pt interactions of amphiphilic platinum(ii) Schiff base complexes in the solution state have been systematically investigated. The presence of Pt⋯Pt interactions has further been supported by computational studies and non-covalent interaction (NCI) analysis of the dimer of the complex. The extent of the non-covalent Pt⋯Pt and π-π interactions could be regulated by a variation of the solvent compositions and the hydrophobicity of the complexes, which is accompanied by attractive spectroscopic and luminescence changes and leads to diverse morphological transformations. The present work represents a rare example of demonstration of directed cooperative assembly of amphiphilic platinum(ii) Schiff base complexes by intermolecular Pt⋯Pt interactions in solution with an in-depth mechanistic investigation, providing guiding principles for the construction of supramolecular structures with desirable properties using platinum(ii) Schiff base building blocks.

Advancing Breast Cancer Research Through Collaborative Computing: Harnessing Google Colab for Innovation.

This investigation explores the potential efficacy of machine learning algorithms (MLAs), particularly convolutional neural networks (CNNs), in distinguishing between benign and malignant breast cancer tissue through the analysis of 1000 breast cancer images gathered from Kaggle.com, a domain of publicly accessible data. The dataset was meticulously partitioned into training, validation, and testing sets to facilitate model development and evaluation. Our results reveal promising outcomes, with the developed model achieving notable precision (92%), recall (92%), accuracy (92%), sensitivity (89%), specificity (96%), an F1 score of 0.92, and an area under the curve (AUC) of 0.944. These metrics underscore the model's ability to accurately identify malignant breast cancer images. Because of limitations such as sample size and potential variations in image quality, further research, data collection, and integration of theoretical models in a real-world clinical setting are needed to expand the reliability and generalizability of these MLAs. Nonetheless, this study serves to highlight the potential use of artificial intelligence models as supporting tools for physicians to utilize in breast cancer detection.

Nucleosome reorganisation in breast cancer tissues.

BACKGROUND: Nucleosome repositioning in cancer is believed to cause many changes in genome organisation and gene expression. Understanding these changes is important to elucidate fundamental aspects of cancer. It is also important for medical diagnostics based on cell-free DNA (cfDNA), which originates from genomic DNA regions protected from digestion by nucleosomes. RESULTS: We have generated high-resolution nucleosome maps in paired tumour and normal tissues from the same breast cancer patients using MNase-assisted histone H3 ChIP-seq and compared them with the corresponding cfDNA from blood plasma. This analysis has detected single-nucleosome repositioning at key regulatory regions in a patient-specific manner and common cancer-specific patterns across patients. The nucleosomes gained in tumour versus normal tissue were particularly informative of cancer pathways, with ~ 20-fold enrichment at CpG islands, a large fraction of which marked promoters of genes encoding DNA-binding proteins. The tumour tissues were characterised by a 5-10 bp decrease in the average distance between nucleosomes (nucleosome repeat length, NRL), which is qualitatively similar to the differences between pluripotent and differentiated cells. This effect was correlated with gene activity, differential DNA methylation and changes in local occupancy of linker histone variants H1.4 and H1X. CONCLUSIONS: Our study offers a novel resource of high-resolution nucleosome maps in breast cancer patients and reports for the first time the effect of systematic decrease of NRL in paired tumour versus normal breast tissues from the same patient. Our findings provide a new mechanistic understanding of nucleosome repositioning in tumour tissues that can be valuable for patient diagnostics, stratification and monitoring.

A regional approach to reduce postoperative opioid prescribing in Ontario, Canada.

BACKGROUND: Opioid-related morbidity and mortality continue to rise in the province of Ontario. We implemented a provincial campaign to reduce the number of opioid pills prescribed at discharge after surgery in the Ontario Surgical Quality Improvement Network (ON-SQIN). METHODS: Activities related to the provincial campaign were implemented between April 2019 and March 2020 and between October 2020 and March 2021. Self-reported data from participating hospitals were used to determine changes in postoperative opioid prescribing patterns across participating hospitals. RESULTS: A total of 33 and 26 hospitals participated in the provincial campaign in the first and second year, respectively. During the first year of the campaign, the median morphine equivalent (MEQ) from opioid prescriptions decreased significantly in a number of surgical specialties, including General Surgery (from 105 [75-130] to 75 [55-107], P < 0.001) (median, interquartile range) and Orthopedic Surgery (from 450 [239-600] to 334 [167-435], P < 0.001). The median number of opioid pills prescribed at discharge per surgery also decreased significantly, from 25 (15-53) to 15 (11-38) for 1 mg hydromorphone (P < 0.001) and 25 (20-51) to 20 (15-30) for oxycodone (P < 0.001). The decrease in opioid prescriptions continued in the second year of the campaign. CONCLUSIONS: Our approach resulted in a significant reduction in the number of postoperative opioids prescribed across a number of surgical specialties. Our findings indicate that evidence-based strategies derived from a regional collaborative network can be leveraged to promote and sustain quality improvement activities.

Microheater Integrated Nanotube Array Gas Sensor for Parts-Per-Trillion Level Gas Detection and Single Sensor-Based Gas Discrimination.

Real-time monitoring of health threatening gases for chemical safety and human health protection requires detection and discrimination of trace gases with proper gas sensors. In many applications, costly, bulky, and power-hungry devices, normally employing optical gas sensors and electrochemical gas sensors, are used for this purpose. Using a single miniature low-power semiconductor gas sensor to achieve this goal is hardly possible, mostly due to its selectivity issue. Herein, we report a dual-mode microheater integrated nanotube array gas sensor (MINA sensor). The MINA sensor can detect hydrogen, acetone, toluene, and formaldehyde with the lowest measured limits of detection (LODs) as 40 parts-per-trillion (ppt) and the theoretical LODs of ∼7 ppt, under the continuous heating (CH) mode, owing to the nanotubular architecture with large sensing area and excellent surface catalytic activity. Intriguingly, unlike the conventional electronic noses that use arrays of gas sensors for gas discrimination, we discovered that when driven by the pulse heating (PH) mode, a single MINA sensor possesses discrimination capability of multiple gases through a transient feature extraction method. These above features of our MINA sensors make them highly attractive for distributed low-power sensor networks and battery-powered mobile sensing systems for chemical/environmental safety and healthcare applications.

Scoping Review of Studies Evaluating Frailty and Its Association with Medication Harm.

INTRODUCTION: Frailty is associated with an increased risk of death and morbid events. Frail individuals are known to have multiple comorbidities which are often associated with polypharmacy. Whilst a relationship between polypharmacy and frailty has been demonstrated, it is not clear if there is an independent relationship between frailty and medication harm. AIMS: This scoping review aimed to identify and critically appraise studies evaluating medication harm in patients with frailty. METHODS: PubMed, EMBASE, CINAHL and Cochrane databases were searched from inception until 1 February 2021 using key search terms that are synonymous with frailty (such as frail and frail elderly) and medication harm (such as adverse drug events and adverse drug reactions). To be included, studies must have identified medication harm as a primary or secondary outcome measure, and used a frailty assessment tool to determine frailty, or clearly defined how frailty was assessed. Data were narratively synthesised and presented in tables. The checklist from the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies from the National Heart, Lung, and Blood Institute was used to assess the quality and risk of bias of studies that met the inclusion criteria. RESULTS: Of 2685 retrieved abstracts, 24 underwent full-text review and nine studies met the inclusion criteria. Three studies were retrospective cohort studies, and six were prospective observational studies. Six studies comprised two distinct groups of frail and non-frail individuals, and the remaining three studies evaluated medication harm in an entirely frail population. Seven studies used validated frailty tools such as the Clinical Frailty Scale, Fried Frailty Index, and Fried Frailty Phenotype. Two studies measured frailty using self-defined criteria. Overall, frail individuals were at risk of medication harm with rates ranging between 18.7 and 77% across the nine studies. However, whether frailty is an independent predictor of medication harm remains uncertain, as this was only evaluated in one study. The risk of bias assessment identified limitations in methods and reporting with all nine studies. CONCLUSION: This scoping review identified nine studies evaluating medication harm in frail patients. However, all were limited by the methodological quality and inadequate reporting of study factors. There are few high-quality studies that described a relationship between medication harm and frailty. More robust studies are required that examine the independent relationship between frailty and medication harm, after adjusting for all possible confounders and in particular polypharmacy.

Cryopreservation and post-thaw characterization of dissociated human islet cells.

The objective of this study is to optimize the cryopreservation of dissociated islet cells and obtain functional cells that can be used in single-cell transcriptome studies on the pathology and treatment of diabetes. Using an iterative graded freezing approach we obtained viable cells after cooling in 10% dimethyl sulfoxide and 6% hydroxyethyl starch at 1°C/min to -40°C, storage in liquid nitrogen, rapid thaw, and removal of cryoprotectants by serial dilution. The expression of epithelial cell adhesion molecule declined immediately after thaw, but recovered after overnight incubation, while that of an endocrine cell marker (HPi2) remained high after cryopreservation. Patch-clamp electrophysiology revealed differences in channel activities and exocytosis of various islet cell types; however, exocytotic responses, and the biophysical properties of voltage-gated Na+ and Ca2+ channels, are sustained after cryopreservation. Single-cell RNA sequencing indicates that overall transcriptome and crucial exocytosis genes are comparable between fresh and cryopreserved dispersed human islet cells. Thus, we report an optimized procedure for cryopreserving dispersed islet cells that maintained their membrane integrity, along with their molecular and functional phenotypes. Our findings will not only provide a ready source of cells for investigating cellular mechanisms in diabetes but also for bio-engineering pseudo-islets and islet sheets for modeling studies and potential transplant applications.

In Vivo Comparison of Radiation Exposure in Third-Generation vs Second-Generation Dual-Source Dual-Energy CT for Imaging Urinary Calculi.

Purpose: To investigate the potential for decreasing radiation dose when utilizing a third-generation vs second-generation dual-source dual-energy CT (dsDECT) scanner, while maintaining diagnostic image quality and acceptable image noise. Materials and Methods: Retrospective analysis of patients who underwent dsDECT for clinical suspicion of urolithiasis from October 2, 2017, to September 5, 2018. Patient demographics, body mass index, abdominal diameter, scanning parameters, and CT dose index volume (CTDIvol) were recorded. Image quality was assessed by measuring the attenuation and standard deviation (SD) regions of interest in the aorta and in the bladder. Image noise was determined by averaging the SD at both levels. Patients were excluded if they had not undergone both third- and second-generation dual-energy CT (DECT), time between DECT was more than 2 years, or scan parameters were outside the standard protocol. Results: A total of 117 patients met the inclusion criteria. Examinations performed on a third-generation DECT had an average CTDIvol 12.3 mGy, while examinations performed on a second-generation DECT had an average CTDIvol 13.3 mGy (p < 0.001). Average image noise was significantly lower for the third-generation DECT (SD = 10.3) compared with the second-generation DECT (SD = 13.9) (p < 0.001). Conclusions: The third-generation dsDECT scanners can simultaneously decrease patient radiation dose and decrease image noise compared with second-generation DECT. These reductions in radiation exposure can be particularly important in patients with urinary stone disease who often require repeated imaging to evaluate for stone development and recurrence as well as treatment assessment.

Conjunctival Stromal Tumor: Report of 2 New Cases and Review of the Literature.

Conjunctival stromal tumor (COST) is an emerging entity with only a limited number of cases reported in the literature. In this report, we describe 2 additional cases, review the accumulative clinical and histopathological features and expand on the immunophenotypic property of this entity. COST appears to have a sporadic presentation, affecting both sexes and patients of variable ethnicity and age group and predominantly occurring on the bulbar conjunctiva as a slow-growing asymptomatic or slightly tender mass-like lesion. Histopathologically, COST is characterized by singly dispersed spindle to round cells, often with some degree of degenerative nuclear atypia, within a myxomatous to collagenous stroma. Lesional cells are characteristically positive for CD34 and vimentin, negative for S100, SOX10 and STAT6 and show a normal pattern of staining with RB1 by immunohistochemistry. The reported cases to date have shown an indolent biological behavior, reliably treated by a complete surgical excision.

Subgaleal haematoma as a cause of periorbital necrotising fasciitis: a case report.

Subgaleal haematoma in adulthood and periorbital necrotising fasciitis are unusual occurrences that have not been reported together. We discuss the first observed case of a 35-year-old female with periorbital necrotising fasciitis postulated to be caused by subgaleal haematoma following head trauma that was successfully managed with antibiotics and surgery.

Health Insurance Portability and Accountability Act Noncompliance in Patient Photograph Management in Plastic Surgery.

BACKGROUND: Today, plastic surgeons have largely transitioned to digital photography. This shift has introduced new risks to daily workflows, notably data theft and Health Insurance Portability and Accountability Act (HIPAA) violations. METHODS: We performed a national survey of digital photograph management patterns among members of the American Society of Plastic Surgery and trainees in Accreditation Council for Graduate Medical Education-accredited plastic surgery programs. RESULTS: Our findings showed that attendings preferred the use of stand-alone digital cameras (91.4%), whereas trainees preferred the use of smartphones (96.1%) for capturing patient photographs. The rate of noncompliance was nearly identical; 82.8% of attendings were HIPAA noncompliant when using stand-alone digital cameras compared with 90.2% of trainees using smartphones. Both groups also breached HIPAA rules when using other photographic management modalities. CONCLUSIONS: This is the first study to quantify the prevalence of noncompliance with regard to an entire digital photograph management workflow. These findings were consistent with previous studies that reported that younger physicians tend to embrace newer technologies, whereas older attendings are more reluctant. The findings also suggest that HIPAA noncompliance in digital photograph security and management is a significant problem within the plastic surgery community.

Assessing Age as a Risk Factor for Complications in Autologous Breast Reconstruction.

BACKGROUND: Breast cancer is primarily a diagnosis of older women. Many patients seeking breast reconstruction are elderly women (aged 65 years or older). However, many surgeons anecdotally believe that surgery in elderly patients is inherently dangerous, or at least prone to more complications. METHODS: The authors conducted a retrospective cohort study composed of chart review of all deep inferior epigastric perforator flap breast reconstruction patients at a single institution divided into an elderly cohort (65 years or older) and a nonelderly cohort (younger than 65 years). Cohort was the primary predictor variable. Demographic and comorbidity data were secondary predictor variables. Primary outcomes were complete flap loss, partial flap loss, or need for flap reexploration. Secondary outcomes such as wound healing problems, seroma, and others were also assessed. RESULTS: There were 285 flaps in the nonelderly cohort and 54 flaps in the elderly cohort. The elderly cohort had higher rates of diabetes, hypertension, and hyperlipidemia. Chi-square analysis showed no significant differences in primary outcomes between the two cohorts. Breast wound dehiscence was significantly higher in the elderly cohort (p < 0.01). On logistic regression, being elderly was seen as a significant risk factor for complete flap loss (OR, 10.92; 95 percent CI, 0.97 to 122.67; p = 0.05). The overall success rate for the nonelderly cohort was 99.6 percent, whereas the success rate for the nonelderly cohort was 96.3 percent. CONCLUSIONS: Elderly women desire breast reconstruction. Free flap breast reconstruction is a viable and safe procedure in these patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells.

BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we conducted whole-genome CRISPR-Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, 'Shieldin' (SHLD1/2), with FAM35A interacting with single-stranded DNA through its C-terminal oligonucleotide/oligosaccharide-binding fold region. We establish that Shieldin acts as the downstream effector of 53BP1/RIF1/MAD2L2 to promote DNA double-strand break (DSB) end-joining by restricting DSB resection and to counteract homologous recombination by antagonizing BRCA2/RAD51 loading in BRCA1-deficient cells. Notably, Shieldin inactivation further sensitizes BRCA1-deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1-deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 expression in human breast cancers displaying intrinsic or acquired PARP-inhibitor resistance.

Periumbilical Perforator-Sparing Abdominoplasty in Patients With Abdominal Scars.

Abdominoplasty is one of the most common cosmetic surgical procedures. Patients who undergo abdominoplasties with abdominal scars are at an increased risk for skin necrosis and wound breakdown. To prevent further disruption of vascularity, the dissection and mobilization is often limited resulting in a suboptimal esthetic result. The periumbilical perforator-sparing technique allows for vascular preservation and adequate mobilization to produce excellent esthetic results in patients with abdominal scars.

Host cell perforation by listeriolysin O (LLO) activates a Ca2+-dependent cPKC/Rac1/Arp2/3 signaling pathway that promotes Listeria monocytogenes internalization independently of membrane resealing.

Host cell invasion is an indispensable step for a successful infection by intracellular pathogens. Recent studies identified pathogen-induced host cell plasma membrane perforation as a novel mechanism used by diverse pathogens (Trypanosoma cruzi, Listeria monocytogenes, and adenovirus) to promote their internalization into target cells. It was concluded that T. cruzi and adenovirus damage the host cell plasma membrane to hijack the endocytic-dependent membrane resealing machinery, thereby invading the host cell. We studied L. monocytogenes and its secreted pore-forming toxin listeriolysin O (LLO) to identify key signaling events activated upon plasma membrane perforation that lead to bacterial internalization. Using various approaches, including fluorescence resonance energy transfer imaging, we found that the influx of extracellular Ca2+ subsequent to LLO-mediated plasma membrane perforation is required for the activation of a conventional protein kinase C (cPKC). cPKC is positioned upstream of Rac1 and the Arp2/3 complex, which activation leads to F-actin--dependent bacterial internalization. Inhibition of this pathway did not prevent membrane resealing, revealing that perforation-dependent L. monocytogenes endocytosis is distinct from the resealing machinery. These studies identified the LLO-dependent endocytic pathway of L. monocytogenes and support a novel model for pathogen uptake promoted by plasma membrane injury that is independent of membrane resealing.

High-Throughput Microplate-Based Assay to Monitor Plasma Membrane Wounding and Repair.

The plasma membrane of mammalian cells is susceptible to disruption by mechanical and biochemical damages that frequently occur within tissues. Therefore, efficient and rapid repair of the plasma membrane is essential for maintaining cellular homeostasis and survival. Excessive damage of the plasma membrane and defects in its repair are associated with pathological conditions such as infections, muscular dystrophy, heart failure, diabetes, and lung and neurodegenerative diseases. The molecular events that remodel the plasma membrane during its repair remain poorly understood. In the present work, we report the development of a quantitative high-throughput assay that monitors the efficiency of the plasma membrane repair in real time using a sensitive microplate reader. In this assay, the plasma membrane of living cells is perforated by the bacterial pore-forming toxin listeriolysin O and the integrity and recovery of the membrane are monitored at 37°C by measuring the fluorescence intensity of the membrane impermeant dye propidium iodide. We demonstrate that listeriolysin O causes dose-dependent plasma membrane wounding and activation of the cell repair machinery. This assay was successfully applied to cell types from different origins including epithelial and muscle cells. In conclusion, this high-throughput assay provides a novel opportunity for the discovery of membrane repair effectors and the development of new therapeutic compounds that could target membrane repair in various pathological processes, from degenerative to infectious diseases.

Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis.

Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world's working adult population and affects those with type 1 and type 2 diabetes. We identified Runt-related transcription factor 1 (RUNX1) as a gene upregulated in CD31+ vascular endothelial cells obtained from human PDR fibrovascular membranes (FVMs) via transcriptomic analysis. In vitro studies using human retinal microvascular endothelial cells (HRMECs) showed increased RUNX1 RNA and protein expression in response to high glucose, whereas RUNX1 inhibition reduced HRMEC migration, proliferation, and tube formation. Immunohistochemical staining for RUNX1 showed reactivity in vessels of patient-derived FVMs and angiogenic tufts in the retina of mice with oxygen-induced retinopathy, suggesting that RUNX1 upregulation is a hallmark of aberrant retinal angiogenesis. Inhibition of RUNX1 activity with the Ro5-3335 small molecule resulted in a significant reduction of neovascular tufts in oxygen-induced retinopathy, supporting the feasibility of targeting RUNX1 in aberrant retinal angiogenesis.

Lower omental t-regulatory cell count is associated with higher fasting glucose and lower ß-cell function in adults with obesity.

OBJECTIVE: T-lymphocytes are potential initiators and regulators of adipose tissue (AT) inflammation, but there is limited human data on omental AT. The aim of this study was to assess the relationship between T cells, particularly Foxp3+ regulatory T (Treg) cells, in human subcutaneous (subQ) and omental AT and type 2 diabetes risk. METHODS: SubQ and deep subQ (DsubQ) abdominal and omental AT biopsies were collected from 44 patients (body mass index, BMI ≥25) undergoing elective abdominal surgery. Flow cytometry was used to quantify CD4+ T cell (T effector and Treg) and macrophages (M1 and M2), and systemic inflammation was measured in fasting blood. RESULTS: Tregs were significantly lower in omental versus subQ and DsubQ AT, and M1 cell counts were significantly higher in the omental and DsubQ depot relative to the subQ. Only omental AT Tregs were negatively associated with fasting glucose and MCP-1 and positively associated with homeostasis model assessment (HOMA)-ß. M1 and M2 cell counts across multiple depots had significant relationships with HOMA-insulin resistance, tumor necrosis factor-α, insulin, and HOMA-ß. All relationships were consistent across ethnicities. CONCLUSIONS: Tregs were significantly lower in omental versus both subQ adipose depots. Fewer omental Tregs may have metabolic implications based on depot-specific relationships with higher fasting glucose and lower ß-cell function.