Bidirectional activation of stem-like programs between metastatic cancer and alveolar type 2 cells within the niche.

A key step for metastatic outgrowth involves the generation of a deeply altered microenvironment (niche) that supports the malignant behavior of cancer cells. The complexity of the metastatic niche has posed a significant challenge in elucidating the underlying programs driving its origin. Here, by focusing on early stages of breast cancer metastasis to the lung in mice, we describe a cancer-dependent chromatin remodeling and activation of developmental programs in alveolar type 2 (AT2) cells within the niche. We show that metastatic cells can prime AT2 cells into a reprogrammed multilineage state. In turn, this cancer-induced reprogramming of AT2 cells promoted stem-like features in cancer cells and enhanced their initiation capacity. In conclusion, we propose the concept of "reflected stemness" as an early phenomenon during metastatic niche initiation, wherein metastatic cells reprogram the local tissue into a stem-like state that enhances intrinsic cancer-initiating potential, creating a positive feedback loop where tumorigenic programs are amplified.

Evaluation of the effects of the Zika Virus-Immunoglobulin G+ complex on murine microglial cells.

After the Zika virus (ZIKV) epidemic in Brazil, ZIKV infections were linked to damage to the central nervous system (CNS) and congenital anomalies. Due to the virus's ability to cross the placenta and reach brain tissue, its effects become severe, leading to Congenital Zika Syndrome (CZS) and resulting in neuroinflammation, microglial activation, and secretion of neurotoxic factors. The presence of ZIKV triggers an inadequate fetal immune response, as the fetus only has the protection of maternal antibodies of the Immunoglobulin G (IgG) class, which are the only antibodies capable of crossing the placenta. Because of limited understanding regarding the long term consequences of ZIKV infection and the involvement of maternal antibodies, this study sought to assess the impact of the ZIKV + IgG⁺complex on murine microglial cells. The cells were exposed to ZIKV, IgG antibodies, and the ZIKV + IgG⁺complex for 24 and 72 h. Treatment-induced cytotoxic effects were evaluated using the cell viability assay, oxidative stress, and mitochondrial membrane potential. The findings indicated that IgG antibodies exhibit cytotoxic effects on microglia, whether alone or in the presence of ZIKV, leading to compromised cell viability, disrupted mitochondrial membrane potential, and heightened oxidative damage. Our conclusion is that IgG antibodies exert detrimental effects on microglia, triggering their activation and potentially disrupting the creation of a neurotoxic environment. Moreover, the presence of antibodies may correlate with an elevated risk of ZIKV-induced neuroinflammation, contributing to long-term CNS damage.

Milia en plaque on the shoulder as an early manifestations of mycosis fungoides.

Milia en plaque (MEP) is an uncommon skin condition identified as retroauricular confluent milium by Boulzer and Fouqet in 1903 [1]. It can be mistaken for other dermatoses like Favre-Racouchot nodular elastosis, steatocystoma multiplex, and nevus comedonicus. Milia en plaque can either be primary or secondary and is typically benign, often triggered by dermatological procedures like cryotherapy, as reported in this journal. In some cases, MEP can arise as a secondary manifestation of other diseases, including folliculotropic mycosis fungoides (FMF). Despite this association, there are few documented cases in the literature. Herein, we present a patient in whom MEP served as the initial clinical presentation of FMF; the treatment involved oral retinoids and phototherapy. Furthermore, we highlight distinctive features of both conditions. It is important to emphasize that early diagnosis and treatment of FMF are vital for the patient's quality of life. The presence of MEP can serve as a valuable indicator for identifying it.

A forecasting tool for a hospital to plan inbound transfers of COVID-19 patients from other regions.

BACKGROUND: In April 2021, the province of Ontario, Canada, was at the peak of its third wave of the COVID-19 pandemic. Intensive Care Unit (ICU) capacity in the Toronto metropolitan area was insufficient to handle local COVID patients. As a result, some patients from the Toronto metropolitan area were transferred to other regions. METHODS: A spreadsheet-based Monte Carlo simulation tool was built to help a large tertiary hospital plan and make informed decisions about the number of transfer patients it could accept from other hospitals. The model was implemented in Microsoft Excel to enable it to be widely distributed and easily used. The model estimates the probability that each ward will be overcapacity and percentiles of utilization daily for a one-week planning horizon. RESULTS: The model was used from May 2021 to February 2022 to support decisions about the ability to accept transfers from other hospitals. The model was also used to ensure adequate inpatient bed capacity and human resources in response to various COVID-related scenarios, such as changes in hospital admission rates, managing the impact of intra-hospital outbreaks and balancing the COVID response with planned hospital activity. CONCLUSIONS: Coordination between hospitals was necessary due to the high stress on the health care system. A simple planning tool can help to understand the impact of patient transfers on capacity utilization and improve the confidence of hospital leaders when making transfer decisions. The model was also helpful in investigating other operational scenarios and may be helpful when preparing for future outbreaks or public health emergencies.

Accuracy of an artificial intelligence algorithm for detecting moderate-to-severe vertebral compression fractures on abdominal and thoracic computed tomography scans / Acurácia de um algoritmo de inteligência artificial na detecção de fraturas compressivas moderadas a graves na tomografia computadorizada abdominal e torácica

Abstract Objective: To describe the accuracy of HealthVCF, a software product that uses artificial intelligence, in the detection of incidental moderate-to-severe vertebral compression fractures (VCFs) on chest and abdominal computed tomography scans. Materials and Methods: We included a consecutive sample of 899 chest and abdominal computed tomography scans of patients 51-99 years of age. Scans were retrospectively evaluated by the software and by two specialists in musculoskeletal imaging for the presence of VCFs with vertebral body height loss > 25%. We compared the software analysis with that of a general radiologist, using the evaluation of the two specialists as the reference. Results: The software showed a diagnostic accuracy of 89.6% (95% CI: 87.4-91.5%) for moderate-to-severe VCFs, with a sensitivity of 73.8%, a specificity of 92.7%, and a negative predictive value of 94.8%. Among the 145 positive scans detected by the software, the general radiologist failed to report the fractures in 62 (42.8%), and the algorithm detected additional fractures in 38 of those scans. Conclusion: The software has good accuracy for the detection of moderate-to-severe VCFs, with high specificity, and can increase the opportunistic detection rate of VCFs by radiologists who do not specialize in musculoskeletal imaging.

Resumo Objetivo: Descrever a acurácia do software HealthVCF na detecção incidental de fraturas compressivas de corpos vertebrais moderadas a graves em exames de tomografia computadorizada do tórax e abdome. Materiais e Métodos: Foram incluídos 899 exames consecutivos de pacientes com idades entre 51 e 99 anos. As imagens foram retrospectivamente avaliadas pelo software e por dois radiologistas especializados em musculoesquelético que investigaram fraturas compressivas de corpos vertebrais com perda da altura somática > 25%. A análise comparativa foi realizada entre o software e um radiologista geral, usando a avaliação do especialista como referência. Resultados: O software apresentou uma acurácia de 89,6% (IC 95%: 87,4-91,5%) para fraturas compressivas moderadas a graves, com sensibilidade de 73,8%, especificidade de 92,7% e valor preditivo negativo de 94,8%. Entre as 145 tomografias positivas detectadas pelo software, o radiologista geral deixou de relatar as fraturas em 62 (42,8%) e o algoritmo detectou fraturas adicionais em 38 dessas tomografias. Conclusão: O software possui boa acurácia na detecção de fraturas compressivas moderadas a graves, com alta especificidade, podendo aumentar a taxa de detecção oportunística dessas fraturas por radiologistas não especializados em musculoesquelético.

Metformin inhibits paclitaxel-induced mechanical allodynia by activating opioidergic pathways and reducing cytokines production in the dorsal root ganglia and thalamus.

It has been shown that AMP-activated protein kinase (AMPK) is involved in the nociceptive processing. This observation has prompted us to investigate the effects of the AMPK activator metformin on the paclitaxel-induced mechanical allodynia, a well-established model of neuropathic pain. Mechanical allodynia was induced by four intraperitoneal (i.p) injections of paclitaxel (2 mg/kg.day) in mice. Metformin was administered per os (p.o.). Naltrexoneandglibenclamide were used to investigate mechanisms mediating metformin activity. Concentrations of cytokines in the dorsal root ganglia (DRG) and thalamus were determined. After a single p.o. administration, the two highest doses of metformin (500 and 1000 mg/kg) attenuated the mechanical allodynia. This response was attenuated by all doses of metformin (250, 500 and 1000 mg/kg) when two administrations, 2 h apart, were carried out. Naltrexone (5 and 10 mg/kg, i.p.), but not glibenclamide (20 and 40 mg/kg, p.o.), attenuated metformin activity. Concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and CXCL-1 in the DRG were increased after administration of paclitaxel. Metformin (1000 mg/kg) reduced concentrations of TNF-α, IL-1ß and CXCL-1 in the DRG. Concentration of IL-6, but not TNF-α, in the thalamus was increased after administration of paclitaxel. Metformin (1000 mg/kg) reduced concentration of IL-6 in the thalamus. In summary, metformin exhibits activity in the model of neuropathic pain induced by paclitaxel. This activity may be mediated by activation of opioidergic pathways and reduced production of TNF-α, IL-1ß and CXCL-1 in the DRG and IL-6 in the thalamus.

Evaluation of the healing potential of Nile tilapia skin collagen in traumatic oral ulcers in male rats.

OBJECTIVE: To evaluate the healing potential of Nile tilapia skin collagen using a rat model with experimentally induced traumatic oral ulcers. DESIGN: Male Wistar rats were segregated into three experimental groups (n = 8/group/euthanasia day). Ulcers were induced using a dermatological punch on the left buccal mucosa. The rats were then euthanized on days 1, 5, 10, 15, and 20 (ntotal=120 rats). Each group received topical treatment, 2x/day, with 1 % Nile tilapia skin collagen orabase (experimental group), only orabase (negative control), or Oncilom-A® orabase (positive control). Ulcer area, closure percentage, and body mass variation were measured. Slides were prepared for histological analysis, which included Picrosirius red staining (collagen analysis), and immunohistochemistry (platelet endothelial cell adhesion molecule, alpha-smooth muscle actin, and transforming growth factor-beta). RESULTS: On day 15, the experimental and positive control groups displayed smaller ulcer areas, a higher percentage of closure, complete re-epithelialization, superior histological repair scores, and a reduced count of polymorphonuclear cells in comparison to the negative control group (p < 0.05). Additionally, the experimental group exhibited an increased number of blood vessels, total collagen (types I and III) and expression of platelet endothelial cell adhesion molecule, alpha-smooth muscle actin, and transforming growth factor-beta relative to the negative and positive control groups (p < 0.05). By day 20, the experimental group showed a more significant weight gain compared to the other groups (p < 0.0001). CONCLUSIONS: Nile tilapia skin collagen orabase optimizes the healing of traumatic ulcers by stimulating re-epithelialization, angiogenesis, and collagenesis. Transforming growth factor-beta plays a significant role in this process.

Outcomes of Apert Syndrome Hand Reconstruction With Tilapia Skin: A Prospective Study.

BACKGROUND: Tilapia skin has already been used in various medical scenarios, but there are no studies showing the use of tilapia skin for hand reconstruction in Apert syndrome. The objective of this study is to determine whether the use of tilapia skin during graft bed preparation for children with Apert syndrome can shorten wound reepithelialization intervals, reduce the number of dressing changes, and decrease patient discomfort. METHODS: This is a prospective study on consecutive patients with Apert syndrome who underwent hand reconstruction at our Hospital. Patients were divided into 2 groups: (1) a control group consisting of patients who underwent conventional digit separation hand reconstruction surgery (2) an experimental group consisting of patients who underwent similar digit separation hand reconstruction surgery that commenced with the placement of a thin layer of tilapia skin at the raw commissures during a first operation, which was subsequently replaced by an autologous skin graft during a second operation staged 10 days postoperatively. Pain assessment was performed using the Visual Analog Scale. The number of dressing changes was also assessed. A T test compared the total number of dressings changes and pain data. RESULTS: Experimental group patients (n = 8) required an average of 9.4 days of daily dressing changes, and control group patients (n = 5) required an average of 20.8 days of daily dressing changes ( P < 0.05) and tended to experience significantly less pain when compared with patients in the control group ( P = 0.079). CONCLUSION: Tilapia skin can shorten wound reepithelialization intervals by reducing the total number of dressing changes.

A clindamycin acetylated derivative with reduced antibacterial activity inhibits articular hyperalgesia and edema by attenuating neutrophil recruitment, NF-κB activation and tumor necrosis factor-α production.

We recently demonstrated that clindamycin exhibits activities in acute and chronic models of pain and inflammation. In the present study, we investigated the effects of clindamycin and a clindamycin acetylated derivative (CAD) in models of acute joint inflammation and in a microbiological assay. Joint inflammation was induced in mice by intraarticular (i.a.) injection of zymosan or lipopolysaccharide (LPS). Clindamycin or CAD were administered via the intraperitoneal route 1 h before zymosan or LPS. Paw withdrawal threshold, joint diameter, histological changes, neutrophil recruitment, tumor necrosis factor-α (TNF-α) production and phosphorylation of the IκBα and NF-κB/p65 were evaluated. In vitro assays were used to measure the antibacterial activity of clindamycin and CAD and also their effects on zymosan-induced TNF-α production by RAW264.7 macrophages. Clindamycin exhibited activity against Staphylococcus aureus and Salmonella Typhimurium ATCC® strains at much lower concentrations than CAD. Intraarticular injection of zymosan or LPS induced articular hyperalgesia, edema and neutrophil infiltration in the joints. Zymosan also induced histological changes, NF-κB activation and TNF-α production. Responses induced by zymosan and LPS were inhibited by clindamycin (200 and 400 mg/kg) or CAD (436 mg/kg). Both clindamycin and CAD inhibited in vitro TNF-α production by macrophages. In summary, we provided additional insights of the clindamycin immunomodulatory effects, whose mechanism was associated with NF-κB inhibition and reduced TNF-α production. Such effects were extended to a clindamycin derivative with reduced antibacterial activity, indicating that clindamycin derivatives should be investigated as candidates to drugs that could be useful in the management of inflammatory and painful conditions.

Nano-scaled surfaces and sustainable-antibiotic-release from polymeric coating for application on intra-osseous implants and trans-mucosal abutments.

Multifunctional surfaces may display the potential to accelerate and promote the healing process around dental implants. However, the initial cellular biocompatibility, molecular activity, and the release of functionalized molecules from these novel surfaces require extensive investigation for clinical use. Aiming to develop and compare innovative surfaces for application in dental implants, the present study utilized titanium disks, which were treated and divided into four groups: machined (Macro); acid-etched (Micro); anodized-hydrophilic surface (TNTs); and anodized surface coated with a rifampicin-loaded polymeric layer (poly(lactide-co-glycolide), PLGA) (TNTsRIMP). The samples were characterized regarding their physicochemical properties and the cumulative release of rifampicin (RIMP), investigated at different pH values. Additionally, differentiated osteoblasts from mesenchymal cells were used for cell viability and qRT-PCR analysis. Antibacterial properties of each surface treatment were investigated against Staphylococcus epidermidis. TNTsRIMP demonstrated controlled drug release for up to 7 days in neutral pH environments. Osteogenic cell cultures indicated that all the evaluated surfaces showed biocompatibility. The TNTs group revealed up-regulated values for bone-related gene quantification in 7 days, followed by the TNTsRIMP group. Furthermore, the antibiotic-functionalized surface revealed effectiveness to inhibit S. epidermidis and stimulate promising conditions for osteogenic cell behavior. Characteristics such as nanomorphology and hydrophilicity were determinants for the up-regulated quantification of osteogenic biomarkers related to early bone maturation, encouraging application in intra-osseous implant surfaces; in addition, antibiotic-functionalized surfaces demonstrated significant higher antibacterial properties compared to the other groups. Our findings suggest that polymeric-antibiotic-loaded coating might be applied for the prevention of early infections, favoring its application in multifunctional surfaces for intra- and/or trans-mucosal components of dental implants, while, hydrophilic nanotextured surfaces promoted optimistic properties to stimulate early bone-related cell responses, favoring its application in bone-anchored surfaces.

Forecasting ICU Census by Combining Time Series and Survival Models.

Capacity planning of ICUs is essential for effective management of health safety, quality of patient care, and the allocation of ICU resources. Whereas ICU length of stay (LOS) may be estimated using patient information such as severity of illness scoring systems, ICU census is impacted by both patient LOS and arrival patterns. We set out to develop and evaluate an ICU census forecasting algorithm using the Multiple Organ Dysfunction Score (MODS) and the Nine Equivalents of Nursing Manpower Use Score (NEMS) for capacity planning purposes. DESIGN: Retrospective observational study. SETTING: We developed the algorithm using data from the Medical-Surgical ICU (MSICU) at University Hospital, London, Canada and validated using data from the Critical Care Trauma Centre (CCTC) at Victoria Hospital, London, Canada. PATIENTS: Adult patient admissions (7,434) to the MSICU and (9,075) to the CCTC from 2015 to 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We developed an Autoregressive integrated moving average time series model that forecasts patients arriving in the ICU and a survival model using MODS, NEMS, and other factors to estimate patient LOS. The models were combined to create an algorithm that forecasts ICU census for planning horizons ranging from 1 to 7 days. We evaluated the algorithm quality using several fit metrics. The root mean squared error ranged from 2.055 to 2.890 beds/d and the mean absolute percentage error from 9.4% to 13.2%. We show that this forecasting algorithm provides a better fit when compared with a moving average or a time series model that directly forecasts ICU census. Additionally, we evaluated the performance of the algorithm using data during the global COVID-19 pandemic and found that the error of the forecasts increased proportionally with the number of COVID-19 patients in the ICU. CONCLUSIONS: It is possible to develop accurate tools to forecast ICU census. This type of algorithm may be important to clinicians and managers when planning ICU capacity as well as staffing and surgical demand planning over a short time horizon.

Lung adenocarcinoma promotion by air pollutants.

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 µm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1ß. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for  PM2.5 air pollutants  and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.

Chemical characterization, antinociceptive and anti-inflammatory effect of Lippia lacunosa, a species used by the Bandeirantes.

ETHNOPHARMACOLOGICAL RELEVANCE: Lippia lacunosa Mart. & Schauer is an endemic plant from the Serra do Espinhaço mountain range located on the Atlantic plateau, Brazil. It is known as "chá de pedestre" and "rosmaninho" in folk medicine. This species has a characteristic mango aroma and is widely used by the population for flu, colds, sinus infections, coughing, relaxing baths, and foot baths after long walks. It is often confused with and, therefore, used interchangeably with L. rotundifolia and L. pseudothea. AIM OF THE STUDY: This study aimed to increase scientific knowledge on the ethnopharmacological use of Lippia lacunosa through the evaluation of the micromolecular composition and anti-inflammatory and antinociceptive activities of the hexane and ethanolic extracts, essential oil, and fractions in mice. MATERIALS AND METHODS: The chemical profile of L. lacunosa extracts and fractions were obtained by chromatographic methods such as Ultra-Performance Liquid Chromatography (UPLC), Gas Chromatography (GC), Column Chromatography (CC), and Thin Layer Chromatography (TLC). Carrageenan-induced paw edema was used to investigate the anti-inflammatory activity in mice. Mechanical allodynia induced by carrageenan and hot plate tests were employed to evaluate the antinociceptive activity. RESULTS: The main constituents found in the essential oil were the monoterpenes myrcene (13.81%), linalool (6.84%), ipsenone (21.2%), and myrcenone (25.44%); and sesquiterpenes elemol (7.30%) and spathulenol (3.15%). The chromatograph fractionation of essential oil yielded a fraction rich in the main compounds (F33), ipsenone and mircenone. In experimental models of paw edema and mechanical allodynia induced by carrageenan (600 µg, 30 µL, i.pl.), the administration of hexane extract, essential oil (50 or 100 mg/kg, p.o.) or majority fraction (10 mg/kg, p.o.) reduced paw edema. The ethanolic extract (100 mg/kg) reduced mechanical allodynia only in the 2 nd h of evaluation. On the other hand, the hexane extract (50 or 100 mg/kg) and essential oil (100 mg/kg), as well as the majority fraction (10 mg/kg), reduced mechanical allodynia throughout the evaluation period. The hexane extract, essential oil, and majority fraction F33 also reduced the heat-induced nociceptive response. Also, majority fraction F33 did not affect the time mice spent in the rota-rod apparatus. CONCLUSIONS: The elucidation of the composition of the essential oil and the demonstration of the activity of L. lacunosa in experimental models of acute inflammation and also in models of nociceptive and inflammatory pain can help to increase knowledge on the ancient ethnopharmacological use by the Bandeirantes, aiming at the evaluation of the species as a candidate for herbal medicine or phytopharmaceutical in the treatment of patients with inflammatory and painful conditions.

Traumatic Spinal Injury: Preliminary Results of Respiratory Function, Voice and Quality of Life.

OBJECTIVES: Assess respiratory muscle strength, voice and the quality of life of patients with traumatic cervical and thoracic spinal cord injury. METHODS: Preliminary analytical case control study of 28 adult men, aged between 18 and 65 years, divided into two groups: a research group consisting of 14 patients with cervical and thoracic spinal cord injury, and control group (CG) with 14 noninjured individuals. The subjects had their maximum inspiratory and expiratory pressures measured, underwent voice handicap index-10 assessment, had their voices recorded for auditory perception analysis, using the voice deviation and GRBASI scales, and for acoustic analysis, based on extraction of the parameters selected and completed a quality-of-life questionnaire (WHOQOL-bref protocol). RESULTS: Intergroup comparison indicated that the research group exhibited lower respiratory muscle strength in relation to the CG, MIP and MEP P-values < 0.001 and < 0.001, respectively; and in relation to the device's reference value, MIP and MEP P-values < 0.001 and < 0.001, respectively; the patients reported no voice handicaps according to the voice handicap index; overall vocal deviation severity on the voice deviation was higher in the CG, P = 0.040; there was greater occurrence of roughness and instability on the GRBASI scale, P= 0.040; there was greater difficulty in modulating vocal frequency (P= 0.002) and resonance, with a laryngopharyngeal focus; the acoustic parameters were normal; and lower scores were obtained in the physical domain of quality of life (P< 0.001). CONCLUSION: The individuals with traumatic spinal cord and thoracic injury exhibited changes in respiratory measures, vocal deviation and dissatisfaction in the physical domain of the WHOQOL-bref protocol.