Differential cortical layer engagement during seizure initiation and spread in humans.

Despite decades of research, we still do not understand how spontaneous human seizures start and spread - especially at the level of neuronal microcircuits. In this study, we used laminar arrays of micro-electrodes to simultaneously record the local field potentials and multi-unit neural activities across the six layers of the neocortex during focal seizures in humans. We found that, within the ictal onset zone, the discharges generated during a seizure consisted of current sinks and sources only within the infra-granular and granular layers. Outside of the seizure onset zone, ictal discharges reflected current flow in the supra-granular layers. Interestingly, these patterns of current flow evolved during the course of the seizure - especially outside the seizure onset zone where superficial sinks and sources extended into the deeper layers. Based on these observations, a framework describing cortical-cortical dynamics of seizures is proposed with implications for seizure localization, surgical targeting, and neuromodulation techniques to block the generation and propagation of seizures.

Impact of renal cell carcinoma molecular subtypes on immunotherapy and targeted therapy outcomes.

Saliby et al. show that a machine learning approach can accurately classify clear cell renal cell carcinoma (RCC) into distinct molecular subtypes using transcriptomic data. When applied to tumors biospecimens from the JAVELIN Renal 101 (JR101) trial, a benefit is observed with immune checkpoint inhibitor (ICI)-based therapy across all molecular subtypes.

A study of the relationship between rear-of-wheel particle emissions and close-proximity tire/road noise of a passenger car.

Non-exhaust particulate emissions and road traffic noise will continue to constitute significant threats to the environment and human health during the 21st century. In the EU alone, >60 million adults are subjected to unhealthy levels of vehicle noise, while over 200,000 premature deaths are caused by chronic exposure to excessive concentrations of fine particles, with road traffic being a key source. Although these pollutants share common sources and can affect the same targets, studies have often treated their emissions separately. This study establishes both the phenomenological and mathematical relationships between tire/road noise (TRN) and rear-of-wheel particle (RoWP) emissions. Information from test track measurements, coupled with correlation-based models, enables linking TRN with RoWP emissions through variables such as vehicle speed and pavement properties, including macro-texture scales. A careful examination of the data reveals that pavement macro-texture acts as a crucible in which TRN and RoWP emissions are generated in an interrelated manner. However, at speeds over 70-80 km/h, the depletion of readily mobilizable RoWP fractions, followed by the emergence of refractory (hard-to-mobilize) circum-/super-micron RoWP fractions from resuspension (which accompanies the intensification of air-pumping TRN generation mechanisms), marks a loss of this interdependence. These results, supplemented by valuable insights into the particulate emission performance of pavements, serve to outline future air quality challenges and provide a basis for the simplified monitoring and control (e.g. through acoustic measurements) of RoWP emissions.

Les facteurs de risque du cancer du sein liés à la reproduction étude cas témoins / Reproductive Risk Factors For Breast Cancer: A Case-Control Study

Le cancer du sein est le premier cancer au Mali. L'objectif de ce travail étaitd'étudier les facteurs de risque du cancer du sein associés à la reproduction. Patientes et méthodes : Il s'agit d'une étude cas-témoins(janvier 2017 - septembre 2021) réalisée au CHU Gabriel Touré. L'échantillon était composé de 200 cas et 400 témoins. Un modèle de régression logistique multivarié a été utilisé pour l'identification des facteurs de risque de cancer du sein associés à la reproduction. Des odds ratio ajustés (ORa) ont été produits avec leur intervalle de confiance à 95%. Résultats : L'âge moyen des cas était de 46,1 ans ± 14,6 vs 33,1 ans± 12,1 pour les témoins. Les femmes ménopausées représentaient 37,5%chez les cas contre seulement 4% chez les témoins. La nulliparité, et l'allaitement maternel diminuaient le risque du cancer du sein (p <0,001) tandis que les femmes en postménopause avaient un risque de cancer du sein multiplié par 8,09. Conclusion : L'âge, la nulliparité et la ménopause sont les facteurs de risque du cancer du sein associés à la reproduction au Mali.

Breast cancer is the leading cancer in Mali. The objective of this study was to evaluate the risk factors of breast cancer associated with reproduction. Patients and methods: We conducted a case-control study (January 2017 - September 2021) at the Gabriel Touré Teaching Hospital. The sample consisted of 200 cases and 400 controls. A multivariable logistic regression model was used to identify reproductive factors associated with breast cancer. Adjusted odds ratios (AOR) were produced withn their 95% confidence intervals. Results: The mean age of cases was 46.1 years ± 14.6 vs 33.1 years ± 12.1 for controls. Menopausal women constituted 37.5 % of cases vs only 4% in the controls group. Nulliparity and breastfeeding were negatively associated with breast cancer (p <0,001) while postmenopausal women had a8.09-fold increase in the risk of breast cancer. Conclusion: Nulliparity, breastfeeding and menopause were the reproductive factors associated with breast cancer in Mali.

Evaluation de la qualité de vie après mastectomie pour cancer du sein au CHU Gabriel Touré / Evaluation of the quality of life after mastectomy for breast cancer at the Gabriel Touré university hospital

Les thérapeutiques oncologiques entraînent des répercussions sur la qualité de vie des patientes. Cette qualité de vie constitue un élément cardinal dans le parcours de soins de malades. Nous avons initié ce travail pour évaluer la qualité de vie après mastectomie. Matériel et méthode : Nous avons réalisé une étude transversale descriptive sur une période de 5ans allant de janvier 2016 à décembre 2020 au service de chirurgie générale au CHU Gabriel Touré. Nous avons inclus tous les patients opérés pour cancer du sein avec preuve histologique et ayant subi une mastectomie et acceptant de répondre au questionnaire. Résultat : Le questionnaire QLQC3O est une échelle spécifique au cancer utilisée pour établir le score sur la qualité de vie comme beaucoup d'autres mais à la différence d'être plus simple, facile d'utilisation et plus utilisé. Nous avons enregistré 79 cas de mastectomie pour cancer du sein. La prévalence de la mastectomie était de 5,8%. L'âge médian était de 58 ans. Les patientes avaient au moins un enfant dans 92,38%. Le carcinome canalaire de type non spécifique était le type histologique le plus fréquent avec 87,33%.Les effets secondaires de la mastectomie affectent le domaine des symptômes ont constitué l'étape la plus difficile à supporter avec p value non significatif. Ces situations ont sérieusement affecté l'estime de soi. Parmi les effets secondaires affectant la qualité de vie (52 cas), les troubles digestifs (22 cas) étaient au 1er plan suivis de dyspnée (7 cas) et des difficultés financières (8 cas) qui ont abouti à la vente de biens. Conclusion : La place de la qualité de vie reste incontestable dans la stratégie thérapeutique et son évaluation améliore quant au choix thérapeutique.

Oncology therapies have repercussions on the quality of life of patients. This quality of life is a cardinal element in the care pathway of patients. We initiated this work to assess the quality of life after mastectomy. Material and method: We carried out a descriptive cross-sectional study over a period of 5 years from January 2016 to December 2020 in the General Surgery Department of the Gabriel Touré University Hospital. We included all patients who had undergone surgery for breast cancer with histological evidence and who had undergone a mastectomy and agreed to answer the questionnaire. Results: The QLQC3O questionnaire is a cancer-specific scale used to establish the quality of life score like many others, but with the difference that it is simpler, easier to use and more widely used. We have recorded 79 cases of mastectomy for breast cancer. The prevalence of mastectomy was 5.8%. The median age was 58 years. Patients had at least one child 92.38%. Non-specific ductal carcinoma was the most common histological type with 87.33%.The side effects of mastectomy affect the area of symptoms were the most difficult stage to bear with p value not significant. These situations have seriously affected self-esteem. Among the side effects affecting quality of life (52 cases), digestive disorders (22 cases) were in the first place, followed by dyspnea (7 cases) and financial difficulties (8 cases) which resulted in the sale of goods. Conclusion: The place of quality of life remains undeniable in the therapeutic strategy and its evaluation improves the therapeutic choice

Circulating and Intratumoral Immune Determinants of Response to Atezolizumab plus Bevacizumab in Patients with Variant Histology or Sarcomatoid Renal Cell Carcinoma.

Renal cell carcinoma (RCC) of variant histology comprises approximately 20% of kidney cancer diagnoses, yet the optimal therapy for these patients and the factors that impact immunotherapy response remain largely unknown. To better understand the determinants of immunotherapy response in this population, we characterized blood- and tissue-based immune markers for patients with variant histology RCC, or any RCC histology with sarcomatoid differentiation, enrolled in a phase II clinical trial of atezolizumab and bevacizumab. Baseline circulating (plasma) inflammatory cytokines were highly correlated with one another, forming an "inflammatory module" that was increased in International Metastatic RCC Database Consortium poor-risk patients and was associated with worse progression-free survival (PFS; P = 0.028). At baseline, an elevated circulating vascular endothelial growth factor A (VEGF-A) level was associated with a lack of response (P = 0.03) and worse PFS (P = 0.021). However, a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit (P = 0.01) and improved overall survival (P = 0.0058). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes, with a reduction in CD4+PD-L1+ [HR, 0.62; 95% confidence interval (CI), 0.49-0.91; P = 0.016] and CD8+PD-L1+ T cells (HR, 0.59; 95% CI, 0.39-0.87; P = 0.009) correlated with improved PFS. Within the tumor itself, a higher percentage of terminally exhausted (PD-1+ and either TIM-3+ or LAG-3+) CD8+ T cells was associated with worse PFS (P = 0.028). Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab and provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations.

Workflow enabling deepscale immunopeptidome, proteome, ubiquitylome, phosphoproteome, and acetylome analyses of sample-limited tissues.

Serial multi-omic analysis of proteome, phosphoproteome, and acetylome provides insights into changes in protein expression, cell signaling, cross-talk and epigenetic pathways involved in disease pathology and treatment. However, ubiquitylome and HLA peptidome data collection used to understand protein degradation and antigen presentation have not together been serialized, and instead require separate samples for parallel processing using distinct protocols. Here we present MONTE, a highly sensitive multi-omic native tissue enrichment workflow, that enables serial, deep-scale analysis of HLA-I and HLA-II immunopeptidome, ubiquitylome, proteome, phosphoproteome, and acetylome from the same tissue sample. We demonstrate that the depth of coverage and quantitative precision of each 'ome is not compromised by serialization, and the addition of HLA immunopeptidomics enables the identification of peptides derived from cancer/testis antigens and patient specific neoantigens. We evaluate the technical feasibility of the MONTE workflow using a small cohort of patient lung adenocarcinoma tumors.

Conservative management of intravesical erosion of a synthetic mid-urethral sling for the treatment of stress urinary incontinence, based on patient preference: A case report.

BACKGROUND: Intravesical mesh erosion is an uncommon late complication of placement of a synthetic mid-urethral sling (MUS) for the treatment of stress urinary incontinence, and only a few cases have been reported. Optimal management remains controversial, though there is a tendency toward surgical removal through a variety of routes. However, surgical removal comes with its own risks and is not necessarily associated with an improvement in symptoms. We, herein present the first case of a conservatively managed intravesical mesh erosion following MUS placement. CASE: Nine years after insertion of a tension-free vaginal tape (TVT), a patient presented with persistent lower abdominal pain and dysuria. Flexible cystoscopy demonstrated an erosion of the tape through the bladder wall. The patient declined surgical intervention at the time. Therefore, she was commenced on regular methenamine hippurate and vaginal oestrogen, and kept under surveillance with regular cystoscopies. Her symptoms responded to this treatment and 6 years later remained well controlled on this regime. CONCLUSION: This case demonstrates that conservative management may be a safe and appropriate option for patients who decline surgical excision of mesh erosion.

A proteogenomic portrait of lung squamous cell carcinoma.

Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.

An atypical distribution of acute calcific periarthritis in the setting of trauma.

Case report of an atypical location of ACP. ACP should be considered even in small joints with characteristic imaging even with trauma involvement.

Psychosocial burden and out-of-pocket costs in patients with atopic dermatitis in Ireland.

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases in the developed world, affecting 1-3% of the adult population in Europe. This inflammatory disease can have a marked impact on affected individuals, leading to significant impairment in physical wellbeing and quality of life (QoL). The aim of this study was to investigate the psychosocial impact and financial burden of AD on patients in Ireland. To increase our understanding of the psychosocial and financial aspects of AD disease burden in the Irish population, an online survey was designed. The survey was launched by the Irish Skin Foundation, and included questions focusing on disease severity, disease control, psychosocial impact, interrupted sleep, missed work and school days, and financial cost. The survey showed that the impact of AD on QoL was profound. The survey demonstrated that 85% of adults described interrupted sleep, 70% reported social anxiety, 65% avoid exercise and sports, 52% avoid social activities, 52% avoid sexual intimacy and 43% feel they are depressed as a result of their AD. Approximately one-quarter of those surveyed can spend up to €2300 annually on over-the-counter, prescription and alternative treatments. This study has shown the significant impact AD has on patients living in Ireland. It also highlights that out-of-pocket costs for patients is higher compared with previous studies across European countries.

EF Bart's Disease with Coinheritance of Gγ-XmnI and Aγ-Globin Polymorphisms: A Case of Nontransfusion-Dependant Thalassemia.

EF Bart's disease is a rare form of nontransfusion-dependant thalassemia (NTDT) due to the coinheritance of homozygous hemoglobin E (ß E/ß E) genotype with hemoglobin H disease. These individuals are routinely found to have thalassemia intermedia with moderate anemia, increased hemoglobin Bart's and hemoglobin F on electrophoresis. The contribution of hemoglobin F-inducing polymorphisms in this disease has not been described previously. Here, we describe the hematological profile in a young child with coinheritance of Gγ-XmnI and Aγ-globin gene polymorphisms in EF Bart's disease. Interestingly, in this rare form of NTDT, normal HbF and elevated HbA2 were noted.

Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma.

To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas.

Chitosan-Polycaprolactone Core-Shell Microparticles for Sustained Delivery of Bevacizumab.

The current therapy for treating neovascular age-related macular degeneration requires monthly intravitreal injection of angiogenesis inhibitors such as bevacizumab or ranibizumab via a 31-gauge needle to inhibit choroidal neovascularization. However, repeated intravitreal injections are associated with poor patient compliance and potential side effects. Microparticle-based injectable devices have shown great promise to address this issue by sustained delivery of protein therapeutics, but critical barriers remain, including limited loading capacity and steady long-term release without compromising the anti-angiogenic activity of drugs. Addressing these challenges, we developed a unique method for synthesizing biodegradable polymer-based core-shell microparticles with sizes around 10 µm, high physical integrity, and uniform size. Subsequent electrostatic and physical interactions to control protein diffusion were designed for the core-shell microparticles to effectively increase the capacity of drug loading to 25%, reduce burst release by almost 30%, and extend the period of drug release from 3 to 6 months. Remarkably, the microparticles enabled a longer-term drug administration and maintained high drug potency up to 6 months in vitro, representing significant advancement compared to conventional microparticle-based delivery platforms or currently commercialized devices. Additionally, the microparticles presented minimal toxicity to human retinal cells in vitro with over 90% cell viability, and they also exhibited good injection feasibility through 31-gauge needles in an ex vivo porcine eye model. These results warrant further studies to evaluate the clinical potential for treating posterior ophthalmic diseases as well as other conditions or injuries requiring long-term local drug administration.

Accommodative tissues influence the shape of the cornea and potentially drive corneal morphogenesis.

This study investigates whether the presence of accommodative tissues biomechanically influences the shape of the cornea and potentially drives corneal morphogenesis during embryonic ocular development. Porcine eyes were subjected to an internal pressure simulating intraocular pressure. Ocular geometry was evaluated using a corneal topographer and digital cameras before and after dissection of the accommodative tissues. A computational model of the porcine eye was constructed and loaded by an internal pressure representing intraocular pressure. Eye shape was evaluated in models with and without the ciliary body. The porcine model was generalized to the human model, simplified model, or embryonic model with different ocular tissue shapes, sizes, and stiffnesses. Experimental data showed that, even in the six-month-old pig eye, the average corneal radius of curvature increased after the removal of accommodative tissues compared to sham controls (p = 0.002). Computational results agreed with the experimental data and further suggested that the change in corneal radius is greater when the tissue stiffness is low and the intraocular pressure is high, regardless of the geometry and size of the eye components. Using a combined in vitro and in silico approach, this study explores the biomechanical influence of the accommodative tissues and related loads on the cornea and offers additional factors that might influence the shape of the cornea.

Big Data and diabetes: the applications of Big Data for diabetes care now and in the future.

We review current applications of Big Data in diabetes care and consider the future potential by carrying out a scoping study of the academic literature on Big Data and diabetes care. Healthcare data are being produced at ever-increasing rates, and this information has the potential to transform the provision of diabetes care. Big Data is beginning to have an impact on diabetes care through data research. The use of Big Data for routine clinical care is still a future application. Vast amounts of healthcare data are already being produced, and the key is harnessing these to produce actionable insights. Considerable development work is required to achieve these goals.