Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants.

The heterogeneity of systemic lupus erythematosus (SLE) can be explained by epigenetic alterations that disrupt transcriptional programs mediating environmental and genetic risk. This study evaluated the epigenetic contribution to SLE heterogeneity considering molecular and serological subtypes, genetics and transcriptional status, followed by drug target discovery. We performed a stratified epigenome-wide association studies of whole blood DNA methylation from 213 SLE patients and 221 controls. Methylation quantitative trait loci analyses, cytokine and transcription factor activity - epigenetic associations and methylation-expression correlations were conducted. New drug targets were searched for based on differentially methylated genes. In a stratified approach, a total of 974 differential methylation CpG sites with dependency on molecular subtypes and autoantibody profiles were found. Mediation analyses suggested that SLE-associated SNPs in the HLA region exert their risk through DNA methylation changes. Novel genetic variants regulating DNAm in disease or in specific molecular contexts were identified. The epigenetic landscapes showed strong association with transcription factor activity and cytokine levels, conditioned by the molecular context. Epigenetic signals were enriched in known and novel drug targets for SLE. This study reveals possible genetic drivers and consequences of epigenetic variability on SLE heterogeneity and disentangles the DNAm mediation role on SLE genetic risk and novel disease-specific meQTLs. Finally, novel targets for drug development were discovered.

Hippo-PKCζ-NFκB signaling axis: A druggable modulator of chondrocyte responses to mechanical stress.

Recent studies have implicated a crucial role of Hippo signaling in cell fate determination by biomechanical signals. Here we show that mechanical loading triggers the activation of a Hippo-PKCζ-NFκB pathway in chondrocytes, resulting in the expression of NFκB target genes associated with inflammation and matrix degradation. Mechanistically, mechanical loading activates an atypical PKC, PKCζ, which phosphorylates NFκB p65 at Serine 536, stimulating its transcriptional activation. This mechanosensitive activation of PKCζ and NFκB p65 is impeded in cells with gene deletion or chemical inhibition of Hippo core kinases LATS1/2, signifying an essential role of Hippo signaling in this mechanotransduction. A PKC inhibitor AEB-071 or PKCζ knockdown prevents p65 Serine 536 phosphorylation. Our study uncovers that the interplay of the Hippo signaling, PKCζ, and NFκB in response to mechanical loading serves as a therapeutic target for knee osteoarthritis and other conditions resulting from mechanical overloading or Hippo signaling deficiencies.

Trophic Nutrition in ICU Patients Undergoing High-Flow Oxygen Therapy and/or Noninvasive Mechanical Ventilation: The Nutri-Trophic Study.

Enteral nutrition (EN) therapy in ICU patients requiring oxygen therapy with high-flow nasal cannula (HFNC) and/or noninvasive mechanical ventilation (NIMV) is controversial. A prospective, cohort, observational, and multicenter study was conducted in 10 ICUs in Spain to analyze the 90-day mortality, tolerance, side effects, and infectious complications of trophic EN in patients requiring HFNC therapy and/or NIVM. A total of 149 patients were enrolled. The mean age, severity scores, tracheobronchitis, bacteremia, and antimicrobial therapy were significantly higher in deceased than in living patients (p < 0.05), and the mortality rate was 14.8%. A total of 110 patients received oral trophic feedings, 36 patients received nasogastric tube feedings (NGFs), and 3 received mixed feedings. Trophic EN was discontinued in only ten (14.9%) patients because of feeding-related complications. The variables selected for the multivariate logistic regression on feeding discontinuation were SOFA upon admission (OR per unit = 1.461) and urea (OR per mg/dL = 1.029). There were no significant differences in the development of new infections according to the route of EN administration. Early trophic feeding administered to patients with acute respiratory failure requiring noninvasive ventilation is safe and feasible, and is associated with few dietary and infectious complications in a mortality, setting comparable to similar studies.

Food Choice Determinants and Changes in Hong Kong During the COVID-19 Pandemic.

The COVID-19 pandemic significantly impacted food behavior choices, including in procurement, preparation, and waste management. Although some of these behavior changes have resulted in positive economic outcomes, such as the growth of employment opportunities for food delivery personnel, others have been deemed environmentally unsustainable, such as the increase in materials used for food packaging. This study examined how the pandemic intensified the negotiations between sustainability and health in food choice behaviors in Hong Kong and demonstrated how contextual and social determinants influenced these behaviors. Public health trumped sustainability drivers during these intense disruptions.

Corrigendum to "Validation of a convolutional neural network that reliably identifies electromyographic compound motor action potentials following train-of-four stimulation: an algorithm development experimental study" [BJA Open 8 (2023) 100236].

[This corrects the article DOI: 10.1016/j.bjao.2023.100236.].

Unlocking the effective alliance of ß-lapachone and hydroxytyrosol against triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is characterised by its aggressiveness and resistance to chemotherapy, demanding the development of effective strategies against its unique characteristics. Derived from lapacho tree bark, ß-lapachone (ß-LP) selectively targets cancer cells with elevated levels of the detoxifying enzyme NQO1. Hydroxytyrosol (HT) is a phenolic compound derived from olive trees with important anticancer properties that include the inhibition of cancer stem cells (CSCs) and metastatic features in TNBC, as well as relevant antioxidant activities by mechanisms such as the induction of NQO1. We aimed to study whether these compounds could have synergistic anticancer activity in TNBC cells and the possible role of NQO1. For this pourpose, we assessed the impact of ß-LP (0.5 or 1.5 µM) and HT (50 and 100 µM) on five TNBC cell lines. We demonstrated that the combination of ß-LP and HT exhibits anti-proliferative, pro-apoptotic, and cell cycle arrest effects in several TNBC cells, including docetaxel-resistant TNBC cells. Additionally, it effectively inhibits the self-renewal and clonogenicity of CSCs, modifying their aggressive phenotype. However, the notable impact of the ß-LP-HT combination does not appear to be solely associated with the levels of the NQO1 protein and ROS. RNA-Seq analysis revealed that the combination's anticancer activity is linked to a strong induction of endoplasmic reticulum stress and apoptosis through the unfolded protein response. In conclusion, in this study, we demonstrated how the combination of ß-LP and HT could offer an affordable, safe, and effective approach against TNBC.

Identifying anatomic landmarks and median nerve characteristics for the analysis of persistent carpal tunnel syndrome using magnetic resonance imaging (MRI).

OBJECTIVE: Carpal tunnel syndrome (CTS) is the most common nerve entrapment neuropathy in the USA. In this study, we define anatomical landmarks to assess symptomatic and asymptomatic cohorts with persistent CTS using MRI imaging. MATERIALS AND METHODS: Distal vs proximal incomplete release was determined using the distal most aspect of the hook of hamate and the distal wrist crease. An incomplete release showed the transverse carpal ligament (TCL) intact at either boundary. Twenty-one patients with persistent CTS were analyzed for incomplete release, median nerve enlargement and T2 signal hyperintensity, and flattening ratio using postoperative wrist MRI. These findings were compared to a ten-patient asymptomatic persistent CTS control group. Fisher's exact and a Student's two-tailed t-tests were used to determine statistical significance. RESULTS: In the symptomatic persistent CTS group, 13 (61.9%) incomplete releases were identified, 5 (38.5%) incomplete distally, and 1 (7.7%) incomplete proximally. There was no statistical significance in the rate of incomplete releases when compared to the asymptomatic group (p = 1.00). T2 signal hyperintensity and enlargement at the site of release showed no statistical significance, (p = 0.319 and p = 0.999, respectively). The mean flattening ratio at the site of release in the symptomatic group (2.45 ± 0.7) was statistically significant compared to the asymptomatic group (1.48 ± 0.46), (p = 0.007). CONCLUSION: Utilizing the established landmarks, the full length of the TCL can be assessed via MRI. Additionally, evaluation of the median nerve flattening ratio at the level of the incomplete release may be utilized as an aid to the clinical management of persistent CTS.

Carcinoma basocelular de la piel cabelluda tratado con HeberFERON. Seguimiento clínico, ecográfico e histopatológico

Fundamento: El carcinoma basocelular es infrecuente en la piel cabelluda. Es un tumor de invasión local y crecimiento lento, puede ser agresivo, destruir tejidos vecinos, causar ulceración e invadir en profundidad cartílago y hueso. Objetivo: Evaluar los resultados de la aplicación del HeberFERON y el seguimiento con ecografía cutánea en pacientes con carcinoma basocelular en la piel cabelluda. Metodología: Se realizó un estudio observacional, descriptivo y longitudinal en una serie de casos con diagnóstico de carcinoma basocelular de la piel cabelluda en el Policlínico Centro de la ciudad Sancti Spíritus, durante el período de 10 de julio del 2018 a 29 de julio del 2022. Se incluyeron 6 casos. Las variables estudiadas fueron la respuesta al tratamiento mediante la clínica, la ecografía cutánea e histopatología y presencia de eventos adversos. Resultados: Predominó el sexo masculino, subtipo histológico sólido, subtipo clínico nódulo ulcerativo, tamaño del tumor mayor de 30 mm y tiempo de evolución de más de 12 meses; la respuesta al tratamiento en la mayoría de los casos fue parcial. Los eventos adversos fueron dolor y ardor en el sitio de inyección, fiebre, edema y eritema perilesional. Conclusiones: El HeberFERON resultó de utilidad en los pacientes con carcinoma basocelular del cuero cabelludo ya que redujo el tumor en unos casos y en otros lo eliminó. La ecografía permitió la evaluación en tiempo real de la neoplasia; los eventos adversos más frecuentes fueron la fiebre y el dolor en el sitio de inyección, a pesar de ello ningún paciente abandonó el tratamiento.

Background: Basal cell carcinoma is uncommon in the scalp. It is a slow-growing locally invasive tumor, it can be aggressive in destroying neighboring tissues, cause ulceration and invade deep into the cartilage and bone. Objective: To evaluate the results of HeberFERON application and follow-up with cutaneous echographical in patients with scalp basal cell carcinoma. Methodology: An observational, descriptive and longitudinal study was conducted in a series of cases diagnosed with scalp basal cell carcinoma at the Center Polyclinic in Sancti Spíritus city during the period from July 10, 2018 to July 29, 2022. Six clinical cases were included. The studied variables were the answer to the treatment by clinical, cutaneous echographical and histopathology and the presence of adverse events. Results: Male sex predominated, solid histologic subtype, clinical subtype ulcerative nodule, tumor size greater than 30 mm and evolution time of over 12 months; the treatment response in most cases was partial; adverse events were pain and burning at the injection site, fever, edema and perilesional erythema. Conclusion: It was observed that in patients with scalp basal cell carcinoma, the HeberFERON treatment reduced in some cases and eliminated the tumor in others. Echography allowed real-time evaluation of the neoplasm, fever and pain at the injection site were the most frequent adverse events. In spite of this, none of the patients abandoned the therapy.

Validation of a convolutional neural network that reliably identifies electromyographic compound motor action potentials following train-of-four stimulation: an algorithm development experimental study.

Background: International guidelines recommend quantitative neuromuscular monitoring when administering neuromuscular blocking agents. The train-of-four count is important for determining the depth of block and appropriate reversal agents and doses. However, identifying valid compound motor action potentials (cMAPs) during surgery can be challenging because of low-amplitude signals and an inability to observe motor responses. A convolutional neural network (CNN) to classify cMAPs as valid or not might improve the accuracy of such determinations. Methods: We modified a high-accuracy CNN originally developed to identify handwritten numbers. For training, we used digitised electromyograph waveforms (TetraGraph) from a previous study of 29 patients and tuned the model parameters using leave-one-out cross-validation. External validation used a dataset of 19 patients from another study with the same neuromuscular block monitor but with different patient, surgical, and protocol characteristics. All patients underwent ulnar nerve stimulation at the wrist and the surface electromyogram was recorded from the adductor pollicis muscle. Results: The tuned CNN performed highly on the validation dataset, with an accuracy of 0.9997 (99% confidence interval 0.9994-0.9999) and F1 score=0.9998. Performance was equally good for classifying the four individual responses in the train-of-four sequence. The calibration plot showed excellent agreement between the predicted probabilities and the actual prevalence of valid cMAPs. Ten-fold cross-validation using all data showed similar high performance. Conclusions: The CNN distinguished valid cMAPs from artifacts after ulnar nerve stimulation at the wrist with >99.5% accuracy. Incorporation of such a process within quantitative electromyographic neuromuscular block monitors is feasible.

Hippo Signaling Modulates the Inflammatory Response of Chondrocytes to Mechanical Compressive Loading.

Knee osteoarthritis (KOA) is a degenerative disease resulting from mechanical overload, where direct physical impacts on chondrocytes play a crucial role in disease development by inducing inflammation and extracellular matrix degradation. However, the signaling cascades that sense these physical impacts and induce the pathogenic transcriptional programs of KOA remain to be defined, which hinders the identification of novel therapeutic approaches. Recent studies have implicated a crucial role of Hippo signaling in osteoarthritis. Since Hippo signaling senses mechanical cues, we aimed to determine its role in chondrocyte responses to mechanical overload. Here we show that mechanical loading induces the expression of inflammatory and matrix-degrading genes by activating the nuclear factor-kappaB (NFκB) pathway in a Hippo-dependent manner. Applying mechanical compressional force to 3-dimensional cultured chondrocytes activated NFκB and induced the expression of NFκB target genes for inflammation and matrix degradation (i.e., IL1ß and ADAMTS4). Interestingly, deleting the Hippo pathway effector YAP or activating YAP by deleting core Hippo kinases LATS1/2 blocked the NFκB pathway activation induced by mechanical loading. Consistently, treatment with a LATS1/2 kinase inhibitor abolished the upregulation of IL1ß and ADAMTS4 caused by mechanical loading. Mechanistically, mechanical loading activates Protein Kinase C (PKC), which activates NFκB p65 by phosphorylating its Serine 536. Furthermore, the mechano-activation of both PKC and NFκB p65 is blocked in LATS1/2 or YAP knockout cells, indicating that the Hippo pathway is required by this mechanoregulation. Additionally, the mechanical loading-induced phosphorylation of NFκB p65 at Ser536 is blocked by the LATS1/2 inhibitor Lats-In-1 or the PKC inhibitor AEB-071. Our study suggests that the interplay of the Hippo signaling and PKC controls NFκB-mediated inflammation and matrix degradation in response to mechanical loading. Chemical inhibitors targeting Hippo signaling or PKC can prevent the mechanoresponses of chondrocytes associated with inflammation and matrix degradation, providing a novel therapeutic strategy for KOA.

HeberFERON en el tratamiento del carcinoma basoescamoso / HeberFERON in Treating Basosquamous Carcinoma

Introducción: El carcinoma basoescamoso es un subtipo agresivo de carcinoma basocelular compuesto por células basaloides y áreas de células escamosas con una zona de transición intermedia, con tendencia a la recurrencia y metástasis. Objetivo: Describir el caso clínico de una paciente con un carcinoma basoescamoso en región temporal cerca del canto externo del ojo izquierdo. Presentación de caso: Se presentó el caso de una paciente con un carcinoma basoescamoso en región temporal cerca del canto externo del ojo izquierdo de 30 mm de diámetro. Se aplicó HeberFERON con respuesta completa al eliminar el tumor. Conclusiones: El HeberFERON es una opción no quirúrgica de tratamiento que puede ser usada en el carcinoma basoescamoso de localización facial que por su tamaño puede provocar mutilaciones o deformidades en esta zona(AU)

Introduction: Basal squamous cell carcinoma is an aggressive subtype of basal cell carcinoma composed of basaloid cells and areas of squamous cells with an intermediate transition zone, with a tendency to recur and metastasize. Objective: To describe the clinical case of a patient with a basal squamous cell carcinoma in the temporal region near the external canthus of the left eye. Case report: This paper reports a case of a female patient with a basal squamous cell carcinoma in the temporal region near the external canthus of her left eye with 30 mm diameter. HeberFERON was used with complete response when eliminating the tumor. Conclusions: HeberFERON is a non-surgical treatment option that can be used in facial basal squamous cell carcinoma that, due to its size, can cause mutilations or deformities in this area(AU)

Fibrin Glue is a Viable Alternative to Fat Graft for Interposition After Tarsal Coalition Resection.

BACKGROUND: Tarsal coalition is one of the most common foot and ankle pathologies in children, yet there is no consensus regarding what to interpose after resection. Fibrin glue could be considered, but the literature comparing fibrin glue to other interposition types is sparse. The purpose of this study was to evaluate the effectiveness of fibrin glue for interposition compared with fat graft by analyzing the rate of coalition recurrence and wound complications. We hypothesized that fibrin glue would have similar rates of coalition recurrence and fewer wound complications compared with fat graft interposition. METHODS: A retrospective cohort study was performed examining all patients who underwent a tarsal coalition resection at a free-standing children's hospital in the United States from 2000 to 2021. Only patients undergoing isolated primary tarsal coalition resection with interposition of fibrin glue or fat graft were included. Wound complications were defined as any concern for an incision site that prompted the use of antibiotics. Comparative analyses were conducted using χ 2 and Fisher exact test to examine relationships among interposition type, coalition recurrence, and wound complications. RESULTS: One hundred twenty-two tarsal coalition resections met our inclusion criteria. Fibrin glue was used for interposition in 29 cases and fat graft was used in 93 cases. The difference in the coalition recurrence rate between fibrin glue and fat graft interposition was not statistically significant (6.9% vs. 4.3%, P =0.627). The difference in wound complication rate between fibrin glue and fat graft interposition was not statistically significant (3.4% vs 7.5%, P = 0.679). CONCLUSION: Fibrin glue interposition after tarsal coalition resection is a viable alternative to fat graft interposition. Fibrin glue has similar rates of coalition recurrence and wound complications when compared with fat grafts. Given our results and the lack of tissue harvesting required with fibrin glue, fibrin glue may be superior to fat grafts for interposition after tarsal coalition resection. LEVEL OF EVIDENCE: Level III, a retrospective comparative study between treatment groups.

The most influential studies concerning revision shoulder arthroplasty research.

Background: Bibliometric analysis is a unique tool that can be used to study the characteristics and trends of a given topic. This study aimed to report on the most influential studies concerning revision shoulder arthroplasty research. Methods: On July 4th, 2022, the Institute of Scientific Information (ISI) Web of Knowledge Database was used to identify articles concerning revision shoulder arthroplasty research. The top 50 most cited articles were selected and analyzed. Results: The mean number of citations was 142 (median: 97; range 599-70). Most articles were published in the 2010s (56%), followed by the 2000s (38%), and 1990s (6%). The most common level of evidence (LOE) was LOE II (42%) followed by LOE IV (38%), LOE I and III each had 10%. The greatest number of papers were published in the Journal of Shoulder and Elbow Surgery (46%), followed by the Journal of Bone and Joint Surgery- American Version (14%). Conclusion: This review can serve as a useful tool to study the most influential articles concerning revision shoulder arthroplasty research. Most of the articles were classified as clinical outcomes (62%), followed by natural history/epidemiology (12%), and surgical technique (10%). Our findings suggest that high-quality studies (LOE I) are lacking and other areas of research besides clinical outcomes are not as well studied.

Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature.

Primary Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.