Repurposing the Open Global Health Library for the discovery of novel Mpro destabilizers with scope as broad-spectrum antivirals.

The SARS coronavirus 2 (SARS-CoV-2) epidemic remains globally active. The emergence of new variants of interest and variants of concern (VoCs), which are potentially more vaccine-resistant and less sensitive to existing treatments, is evident due to their high prevalence. The prospective spread of such variants and other coronaviruses with epidemic potential demands preparedness that can be met by developing fast-track workflows to find new candidates that target viral proteins with a clear in vitro and in vivo phenotype. Mpro (or 3CLpro) is directly involved in the viral replication cycle and the production and function of viral polyproteins, which makes it an ideal target. The biological relevance of Mpro is highly conserved among betacoronaviruses like HCoV-OC43 and SARS-CoV-2, which makes the identification of new chemical scaffolds targeting them a good starting point for designing broad-spectrum antivirals. We report an optimized methodology based on orthogonal cell-free assays to identify small molecules that inhibit the binding pockets of both SARS-CoV-2-Mpro and HCoV-OC43-Mpro; this blockade correlates with antiviral activities in HCoV-OC43 cellular models. By using such a fast-tracking approach against the Open Global Health Library (Merck KGaA), we have found evidence of the antiviral activity of compound OGHL98. In silico studies dissecting intermolecular interactions between OGHL98 and both proteases and comprising docking and molecular dynamics simulations (MDSs) concluded that the binding mode was primarily governed by conserved H-bonds with their C-terminal amino acids and that the rational design of OGHL98 has potential against VoCs proteases resistant to current therapeutics.

Enzymatic Metabolic Switches of Astrocyte Response to Lipotoxicity as Potential Therapeutic Targets for Nervous System Diseases.

Astrocytes play a pivotal role in maintaining brain homeostasis. Recent research has highlighted the significance of palmitic acid (PA) in triggering pro-inflammatory pathways contributing to neurotoxicity. Furthermore, Genomic-scale metabolic models and control theory have revealed that metabolic switches (MSs) are metabolic pathway regulators by potentially exacerbating neurotoxicity, thereby offering promising therapeutic targets. Herein, we characterized these enzymatic MSs in silico as potential therapeutic targets, employing protein-protein and drug-protein interaction networks alongside structural characterization techniques. Our findings indicate that five MSs (P00558, P04406, Q08426, P09110, and O76062) were functionally linked to nervous system drug targets and may be indirectly regulated by specific neurological drugs, some of which exhibit polypharmacological potential (e.g., Trifluperidol, Trifluoperazine, Disulfiram, and Haloperidol). Furthermore, four MSs (P00558, P04406, Q08426, and P09110) feature ligand-binding or allosteric cavities with druggable potential. Our results advocate for a focused exploration of P00558 (phosphoglycerate kinase 1), P04406 (glyceraldehyde-3-phosphate dehydrogenase), Q08426 (peroxisomal bifunctional enzyme, enoyl-CoA hydratase, and 3-hydroxyacyl CoA dehydrogenase), P09110 (peroxisomal 3-ketoacyl-CoA thiolase), and O76062 (Delta(14)-sterol reductase) as promising targets for the development or repurposing of pharmacological compounds, which could have the potential to modulate lipotoxic-altered metabolic pathways, offering new avenues for the treatment of related human diseases such as neurological diseases.

Maintenance Pembrolizumab Therapy in Patients with Metastatic HER2-negative Breast Cancer with Prior Response to Chemotherapy.

PURPOSE: Accumulating toxicities hinder indefinite chemotherapy for many patients with metastatic/recurrent HER2-negative breast cancer. We conducted a phase II trial of pembrolizumab monotherapy following induction chemotherapy to determine the efficacy of maintenance immunotherapy in patients with metastatic HER2-negative inflammatory breast cancer (IBC) and non-IBC triple-negative breast cancer (TNBC) and a biomarker study. PATIENTS AND METHODS: Patients with a complete response, partial response, or stable disease (SD) after at least three cycles of chemotherapy for HER2-negative breast cancer received pembrolizumab, regardless of programmed death-ligand 1 expression. Pembrolizumab (200 mg) was administered every 3 weeks until disease progression, intolerable toxicity, or 2 years of pembrolizumab exposure. The endpoints included the 4-month disease control rate (DCR), progression-free survival (PFS), overall survival, and response biomarkers in the blood. RESULTS: Of 43 treated patients, 11 had metastatic IBC and 32 non-IBC TNBC. The 4-month DCR was 58.1% [95% confidence interval (CI), 43.4-72.9]. For all patients, the median PFS was 4.8 months (95% CI, 3.0-7.1 months). The toxicity profile was similar to the previous pembrolizumab monotherapy study. Patients with high T-cell clonality at baseline had a longer PFS with pembrolizumab treatment than did those with low T-cell clonality (10.4 vs. 3.6 months, P = 0.04). Patients who achieved SD also demonstrated a significant increase in T-cell clonality during therapy compared with those who did not achieve SD (20% vs. 5.9% mean increase, respectively; P = 0.04). CONCLUSIONS: Pembrolizumab monotherapy achieved durable treatment responses. Patients with a high baseline T-cell clonality had prolonged disease control with pembrolizumab.

Druggable cavities and allosteric modulators of the cell division cycle 7 (CDC7) kinase.

Cell division cycle 7 kinase (CDC7) has been found overexpressed in many cancer cell lines being also one of the kinases involved in the nuclear protein TDP-43 phosphorylation in vivo. Thus, inhibitors of CDC7 are emerging drug candidates for the treatment of oncological and neurodegenerative unmet diseases. All the known CDC7 inhibitors are ATP-competitives, lacking of selectivity enough for success in clinical trials. As allosteric sites are less conserved among kinase proteins, discovery of allosteric modulators of CDC7 is a great challenge and opportunity in this field.Using different computational approaches, we have here identified new druggable cavities on the human CDC7 structure and subsequently selective CDC7 inhibitors with allosteric modulation mainly targeting the pockets where the interaction between this kinase and its activator DBF4 takes place.

Cartografías artísticas: jóvenes autores de la construcción del pasado reciente / Artistic cartographies: Young people who are authors of the recent past

(analítico) Se presentan los resultados de una investigación que buscó conocer las maneras como los jóvenes construyen sus ideas e imaginarios sobre el pasado reciente en Colombia. El proyecto fue desarrollado en la ciudad de Manizales y contó con la participación de 24 jóvenes entre los 12 y 18 años de edad. El estudio se desarrolló por medio de cartografías de experiencias que se vinculan al pasado reciente y la reconstrucción de la memoria colectiva. Se encontró que los jóvenes emplean signos que se han utilizado tradicionalmente para representar la paz y la memoria, además, que los procesos dialógicos y creativos favorecen los espacios de reflexión en los cuales se trascienden estos signos y se construyen significados más amplios que a su vez les permiten narrar experiencias de vida.

(analytical) This article presents the results of a research project that sought to understand the ways in which young people construct their ideas and imaginaries about the recent past in Colombia. The research was conducted in the city of Manizales with the participation of 24 young people between 12 and 18 years of age. The research was carried out using cartographies of experiences from the recent past and the reconstruction of collective memory. It was identified that young people use signs that have been traditionally used to represent peace and memory. Dialogue and creative processes generate reflection spaces in which these signs are transcended and broader meanings are constructed, which in turn allow them to narrate their life experiences.

(analítico) Este artigo apresenta os resultados de um projeto de pesquisa que procurou compreender as formas pelas quais os jovens constroem suas idéias e imaginários sobre o passado recente na Colômbia. O projeto foi desenvolvido na cidade de Manizales, com a participação de 24 jovens entre 12 e 18 anos de idade. A pesquisa foi desenvolvida por meio de experiências de mapeamento ligadas ao passado recente e à reconstrução da memória coletiva. Constatou-se que os jovens utilizam sinais que tradicionalmente são usados para representar a paz e a memória, e que os processos dialógicos e criativos favorecem espaços de reflexão nos quais esses sinais são transcendidos e significados mais amplos são construídos, o que por sua vez lhes permite narrar experiências de vida.

European consensus-based interdisciplinary guideline for invasive cutaneous squamous cell carcinoma: Part 2. Treatment-Update 2023.

In order to update recommendations on treatment, supportive care, education, and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary panel of experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), the European Society for Radiotherapy and Oncology (ESTRO), the European Union of Medical Specialists (UEMS), the European Academy of Dermatology and Venereology (EADV), and the European Organisation of Research and Treatment of Cancer (EORTC) was formed. Recommendations were based on an evidence-based literature review, guidelines, and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable), and distant metastatic cSCC. For common primary cSCC, the first-line treatment is surgical excision with postoperative margin assessment or micrographically controlled surgery. Achieving clear surgical margins is the most important treatment consideration for patients with cSCCs amenable to surgery. Regarding adjuvant radiotherapy for patients with high-risk localised cSCC with clear surgical margins, current evidence has not shown significant benefit for those with at least one high-risk factor. Radiotherapy should be considered as the primary treatment for non-surgical candidates/tumours. For cSCC with cytologically or histologically confirmed regional nodal metastasis, lymph node dissection is recommended. For patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiotherapy, anti-PD-1 agents are the first-line systemic treatment, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drugs Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC, include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiotherapy. Multidisciplinary board decisions are mandatory for all patients with advanced cSCC, considering the risks of toxicity, the age and frailty of patients, and co-morbidities, including immunosuppression. Patients should be engaged in informed, shared decision-making on management and be provided with the best supportive care to improve symptom management and quality of life. The frequency of follow-up visits and investigations for subsequent new cSCC depends on underlying risk characteristics.

European consensus-based interdisciplinary guideline for invasive cutaneous squamous cell carcinoma. Part 1: Diagnostics and prevention-Update 2023.

Invasive cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in white populations, accounting for 20% of all cutaneous malignancies. Overall, cSCC mostly has very good prognosis after treatment, with 5-year cure rates greater than 90%. Despite the overall favourable prognosis and the proportionally rare deaths, cSCC is associated with a high total number of deaths due to its high incidence. A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), the European Society for Radiotherapy and Oncology (ESTRO), the European Union of Medical Specialists (UEMS), the European Academy of Dermatology and Venereology (EADV) and the European Organization of Research and Treatment of Cancer (EORTC), was formed to update recommendations on cSCC, based on current literature and expert consensus. Part 1 of the guidelines addresses the updates on classification, epidemiology, diagnosis, risk stratification, staging and prevention in immunocompetent as well as immunosuppressed patients.

Risk Factors for Fibrous Ingrowth in Eyes Requiring Primary Keratoplasty.

PURPOSE: The aim of this study was to define risks for corneal transplantation associated with fibrous ingrowth among first-time transplant recipients. METHODS: We performed a retrospective case-control study of patients with a histopathologic diagnosis of fibrous ingrowth between 2002 and 2019. Patients with fibrous ingrowth from a first corneal specimen were included. Those with incomplete records were excluded. A 1:2 case-control ratio was used. Controls were matched using surgical indication, surgery year, transplantation method, sex, and age. RESULTS: Seventy-eight eyes (76 patients) were included and matched with 160 control eyes. The incidence of fibrous ingrowth found on a first corneal transplant was 0.6% per year. The most common keratoplasty indications were pseudophakic corneal edema (n = 25, 32%) and aphakic corneal edema (n = 15, 19%). Cases were more likely to have a history of ocular trauma (odds ratio [OR], 2.94; 95% CI, 1.30-6.30; P = 0.007), uveitis (OR, 2.73; 95% CI, 1.12-6.63; P = 0.022), retinal detachment or previous retinal surgery (OR, 2.40; 95% CI, 1.34-4.30; P = 0.003), glaucoma tube-shunt surgery (OR, 2.70; 95% CI, 1.29-5.65; P = 0.007), aphakia (OR, 3.02; 95% CI, 1.61-5.67; P = 0.0004), or iris derangement (OR, 10.52; 95% CI, 5.45-20.30; P <0.0001). A multivariate logistic regression model using iris derangement, history of ocular trauma, history of uveitis, and history of cataract surgery demonstrated 81% sensitivity and 66% specificity in predicting presence of fibrous ingrowth. CONCLUSIONS: A history of ocular trauma, uveitis, retinal detachment or previous retinal surgery, glaucoma tube-shunt surgery, aphakia, and iris derangement are risks for detecting fibrous ingrowth among first-time keratoplasty recipients. Patients with these conditions should be monitored closely for corneal decompensation.

Neuromuscular end-point predictive capability of published rocuronium pharmacokinetic/pharmacodynamic models: An observational trial.

BACKGROUND: Objective neuromuscular monitoring remains the single most reliable method to ensure optimal perioperative neuromuscular management. Nevertheless, the prediction of clinical neuromuscular endpoints by means of Pharmacokinetic (PK) and Pharmacodynamic (PD) modelling has the potential to complement monitoring and improve perioperative neuromuscular management.s STUDY OBJECTIVE: The present study aims to assess the performance of published Rocuronium PK/PD models in predicting intraoperative Train-of-four (TOF) ratios when benchmarked against electromyographic TOF measurements. DESIGN: Observational trial. SETTING: Tertiary Belgian hospital, from August 2020 up to September 2021. PATIENTS AND INTERVENTIONS: Seventy-four patients undergoing general anaesthesia for elective surgery requiring the administration of rocuronium and subject to continuous EMG neuromuscular monitoring were included. PK/PD-simulated TOF ratios were plotted and synchronised with their measured electromyographic counterparts and their differences analysed by means of Predictive Error derivatives (Varvel criteria). MAIN RESULTS: Published rocuronium PK/PD models overestimated clinically registered TOF ratios. The models of Wierda, Szenohradszky, Cooper, Alvarez-Gomez and McCoy showed significant predictive consistency between themselves, displaying Median Absolute Performance Errors between 38% and 41%, and intra-individual differences (Wobble) between 14 and 15%. The Kleijn model outperformed the former with a lower Median Absolute Performance Error (16%, 95%CI [0.01; 57]) and Wobble (11%, 95%CI [0.01; 34]). All models displayed considerably wide 95% confidence intervals for all performance metrics, suggesting a significantly variable performance. CONCLUSIONS: Simulated TOF ratios based on published PK/PD models do not accurately predict real intraoperative TOF ratio dynamics. TRIAL REGISTRATION: NCT04518761 (clinicaltrials.gov), registered on 19 August 2020.

European consensus-based interdisciplinary guideline for diagnosis and treatment of basal cell carcinoma-update 2023.

Basal cell carcinoma (BCC) is the most common malignant tumour in white populations. Multidisciplinary experts from European Association of Dermato-Oncology (EADO), European Dermatology Forum, European Society for Radiotherapy and Oncology (ESTRO), Union Européenne des Médecins Spécialistes, and the European Academy of Dermatology and Venereology developed updated recommendations on diagnosis and treatment of BCC. BCCs were categorised into 'easy-to-treat' (common) and 'difficult-to-treat' according to the new EADO clinical classification. Diagnosis is based on clinico-dermatoscopic features, although histopathological confirmation is mandatory in equivocal lesions. The first-line treatment of BCC is complete surgery. Micrographically controlled surgery shall be offered in high-risk and recurrent BCC, and BCC located on critical anatomical sites. Topical therapies and destructive approaches can be considered in patients with low-risk superficial BCC. Photodynamic therapy is an effective treatment for superficial and low-risk nodular BCCs. Management of 'difficult-to-treat' BCCs should be discussed by a multidisciplinary tumour board. Hedgehog inhibitors (HHIs), vismodegib or sonidegib, should be offered to patients with locally advanced and metastatic BCC. Immunotherapy with anti-PD1 antibodies (cemiplimab) is a second-line treatment in patients with a progression of disease, contraindication, or intolerance to HHI therapy. Radiotherapy represents a valid alternative in patients who are not candidates for or decline surgery, especially elderly patients. Electrochemotherapy may be offered when surgery or radiotherapy is contraindicated. In Gorlin patients, regular skin examinations are required to diagnose and treat BCCs at an early stage. Long-term follow-up is recommended in patients with high-risk BCC, multiple BCCs, and Gorlin syndrome.

Long-term strategies for management of advanced basal cell carcinoma with hedgehog inhibitors.

Basal cell carcinoma (BCC), the most common type of skin cancer, is characterized by aberrant activation of the hedgehog molecular pathway. Systemic therapy is indicated when local approaches, such as surgery and radiation, are inappropriate. In this article, a group of clinical experts recommends the long-term management strategy for advanced BCC patients treated with systemic therapy. The hedgehog inhibitors sonidegib and vismodegib are first-line treatments for advanced BCC with a long-lasting response, but long-term treatment with hedgehog inhibitors is often challenged by tolerability issues. However, several strategies for adverse effect management are available, such as dose interruptions, on-label alternate-day dosing and supportive medications. In conclusion, although BCC shows a high tumor mutational burden that favors a response to immunotherapy, experts recommend keeping patients on hedgehog inhibitors limiting immunotherapy to those who developed resistance during hedgehog inhibitor therapy or in case of persisting toxicity despite long-term management of adverse events.

Treatment of Refractory Ischemic Priapism: A Case Report and Literature Review.

Recurrent priapism is a rare and poorly known entity. It is defined by recurrent episodes of painful erections that last less than four hours. The etiology is similar to that of ischemic priapism. Episodes lasting more than four hours require immediate intervention to prevent penile fibrosis and subsequent erectile dysfunction. A 42-year-old male with no significant chronic-degenerative history was referred to our medical center from his second-level medical unit after a 56-hour history of ischemic priapism with the persistence of tumescence despite medical and surgical treatment. Upon interrogation, the patient reported stuttering (recurrent) episodes of painful erections lasting approximately three to four hours, not associated with sexual activity or arousal, in the past two years, with spontaneous resolution. He denied the use of psychotropics or drugs for erectile dysfunction. As a palliative measure, a left saphenous-cavernous (Grayhack) bypass was performed, with a 90% decrease in tumescence and total resolution of pain during the first 12 hours. There is little information and treatment recommendations for patients with recurrent priapism, and even less for patients who are refractory to conventional medical and surgical treatment. Recurrent or stuttering priapism is a condition with a low incidence and a pathophysiology compatible with low-flow priapism. It is difficult to treat and has a poor prognosis in terms of erectile function. Likewise, it is mostly associated with the use of psychotropic drugs such as cocaine and marijuana, medications for erectile dysfunction such as phosphodiesterase inhibitors, prostaglandin E1 analogues, and hematological malignancies such as sickle cell anemia and multiple myeloma. The aim of this article is to share our experience with a patient refractory to multiple medical and surgical treatments.

Network pharmacology and topological analysis on tibolone metabolites and their molecular mechanisms in traumatic brain injury.

Traumatic brain injury (TBI) is a pathology of great social impact, affecting millions of people worldwide. Despite the scientific advances to improve the management of TBI in recent years, we still do not have a specific treatment that controls the inflammatory process after mechanical trauma. The discovery and implementation of new treatments is a long and expensive process, making the repurpose of approved drugs for other pathologies a clinical interest. Tibolone is a drug in use for the treatment of symptoms associated with menopause and has been shown to have a broad spectrum of actions by regulating estrogen, androgen and progesterone receptors, whose activation exerts potent anti-inflammatory and antioxidant effects. In the present study, we aimed to investigate the therapeutic potential of the tibolone metabolites 3α-Hydroxytibolone, 3ß-Hydroxytibolone, and Δ4-Tibolone as a possible therapy in TBI using network pharmacology and network topology analysis. Our results demonstrate that the estrogenic component mediated by the α and ß metabolites can regulate synaptic transmission and cell metabolism, while the Δ metabolite may be involved in modulating the post-TBI inflammatory process. We identified several molecular targets, including KDR, ESR2, AR, NR3C1, PPARD, and PPARA, which are known to play critical roles in the pathogenesis of TBI. Tibolone metabolites were predicted to regulate the expression of key genes involved in oxidative stress, inflammation, and apoptosis. Overall, the repurposing of tibolone as a neuroprotective treatment for TBI holds promise for future clinical trials. However, further studies are needed to confirm its efficacy and safety in TBI patients.

European e-Delphi process to define expert consensus on electrochemotherapy treatment indications, procedural aspects, and quality indicators in melanoma.

BACKGROUND: Skin metastases are an important co-morbidity in melanoma. Despite broad adoption, electrochemotherapy implementation is hindered by a lack of treatment indications, uncertainty regarding procedural aspects, and the absence of quality indicators. An expert consensus may harmonize the approach among centres and facilitate comparison with other therapies. METHODS: An interdisciplinary panel was recruited for a three-round e-Delphi survey. A literature-based 113-item questionnaire was proposed to 160 professionals from 53 European centres. Participants rated each item for relevance and degree of agreement on a five-point Likert scale, and received anonymous controlled feedback to allow revision. The items that reached concordant agreement in two successive iterations were included in the final consensus list. In the third round, quality indicator benchmarks were defined using a real-time Delphi method. RESULTS: The initial working group included 122 respondents, of whom 100 (82 per cent) completed the first round, thus qualifying for inclusion in the expert panel (49 surgeons, 29 dermatologists, 15 medical oncologists, three radiotherapists, two nurse specialists, two clinician scientists). The completion rate was 97 per cent (97 of 100) and 93 per cent (90 of 97) in the second and third rounds respectively. The final consensus list included 54 statements with benchmarks (treatment indications, (37); procedural aspects, (1); quality indicators, (16)). CONCLUSION: An expert panel achieved consensus on the use of electrochemotherapy in melanoma, with a core set of statements providing general direction to electrochemotherapy users to refine indications, align clinical practices, and promote quality assurance programmes and local audits. The residual controversial topics set future research priorities to improve patient care.

Electrochemotherapy is an effective locoregional therapy for skin metastases from melanoma, a problem faced by almost half of patients with metastatic disease. The lack of comparative studies and the heterogeneity of its clinical application among centres make it challenging to support consistent, evidence-based recommendations. To address this unmet need, a three-round online survey was conducted to establish a consensus on treatment indications, standard operating procedures, and quality indicators. In the survey, a panel of 100 European melanoma experts agreed on 56 statements that can be used to improve patient selection, homogenize treatment application, and monitor outcomes.

Experiencia del tratamiento de la hernia incisional en un hospital de tercer nivel en Colombia / Experience of the treatment of incisional hernia in a third level hospital in Colombia

Introducción. El manejo de las hernias se ha instaurado como un problema quirúrgico común, estimándose su aumento en los próximos años. El objetivo del presente trabajo fue describir el curso clínico, los aspectos del tratamiento quirúrgico y factores asociados a la presencia de complicaciones en pacientes intervenidos por hernia incisional. Métodos. Estudio descriptivo en el que se analizaron las características de una cohorte de pacientes llevados a corrección quirúrgica de hernia incisional en el Hospital Universitario Hernando Moncaleano Perdomo, un centro de alta complejidad en Neiva, Colombia, entre 2012 y 2019. Los datos fueron recolectados en programa Microsoft Excel® y analizados en SPSSTM, versión 21. Resultados. Se realizaron 133 correcciones de hernias incisionales, 69,9 % en mujeres y la mayoría ubicadas en la línea media (84,2 %). La edad media de los pacientes al momento de la intervención fue de 52 años ±14,6. Las comorbilidades más frecuentes fueron obesidad, hipertensión y diabetes. La causa más frecuente de la hernia fue traumática (61,7 %). La frecuencia de complicaciones fue superior al 50 %, en su mayoría menores; se encontró asociación con obesidad para la presencia de seroma. La mortalidad fue del 2,3 %. Conclusión.La hernia incisional es un problema de salud pública. Consideramos que la obesidad y el uso de malla pueden ser factores de riesgo asociados con la presentación de complicaciones postoperatorias, así como el aumento de los gastos relacionados con días de hospitalización

Introduction. Hernias management has become a common surgical problem, with an estimated increase in the coming years. The objective of this study was to describe the clinical course, aspects of surgical treatment and factors associated with the presence of complications in patients operated on for incisional hernia. Methods. Descriptive study, in which the characteristics of a cohort of patients taken to surgical correction of incisional hernia at the Hospital Universitario Hernando Moncaleano Perdomo, a high complexity medical center located in Neiva, Colombia, between 2012 and 2019 were analyzed, whose data were collected in Microsoft Excel® software and analyzed in SPSSTM, version 21. Results. One-hundred-thirty-three incisional hernia corrections were performed. The mean age at the intervention was 52 years ±14.6. The most frequent comorbidities were weight disorders, hypertension and diabetes. Only one laparoscopy was performed, the first etiology of the hernia was traumatic (61.7%) and midline (84.2%). The frequency of complications was greater than 50%, mostly minors. An association with obesity was found for the presence of seroma. Mortality was 2.3%. Conclusion. Incisional hernia is a public health problem. We consider that obesity and the use of mesh are a risk factor associated with the presentation of postoperative complications as well as the increase in costs related to days of hospitalization

A phase II study of neoadjuvant atezolizumab and nab-paclitaxel in patients with anthracycline-resistant early-stage triple-negative breast cancer.

PURPOSE: Neoadjuvant anti-PD-(L)1 therapy improves the pathological complete response (pCR) rate in unselected triple-negative breast cancer (TNBC). Given the potential for long-term morbidity from immune-related adverse events (irAEs), optimizing the risk-benefit ratio for these agents in the curative neoadjuvant setting is important. Suboptimal clinical response to initial neoadjuvant therapy (NAT) is associated with low rates of pCR (2-5%) and may define a patient selection strategy for neoadjuvant immune checkpoint blockade. We conducted a single-arm phase II study of atezolizumab and nab-paclitaxel as the second phase of NAT in patients with doxorubicin and cyclophosphamide (AC)-resistant TNBC (NCT02530489). METHODS: Patients with stage I-III, AC-resistant TNBC, defined as disease progression or a < 80% reduction in tumor volume after 4 cycles of AC, were eligible. Patients received atezolizumab (1200 mg IV, Q3weeks × 4) and nab-paclitaxel (100 mg/m2 IV,Q1 week × 12) as the second phase of NAT before undergoing surgery followed by adjuvant atezolizumab (1200 mg IV, Q3 weeks, × 4). A two-stage Gehan-type design was employed to detect an improvement in pCR/residual cancer burden class I (RCB-I) rate from 5 to 20%. RESULTS: From 2/15/2016 through 1/29/2021, 37 patients with AC-resistant TNBC were enrolled. The pCR/RCB-I rate was 46%. No new safety signals were observed. Seven patients (19%) discontinued atezolizumab due to irAEs. CONCLUSION: This study met its primary endpoint, demonstrating a promising signal of activity in this high-risk population (pCR/RCB-I = 46% vs 5% in historical controls), suggesting that a response-adapted approach to the utilization of neoadjuvant immunotherapy should be considered for further evaluation in a randomized clinical trial.

Creatividad, identidad y subjetividad de personas con enfermedades crónicas: Estado del arte / Creativity, Identity, and Subjectivity of People with Chronic Diseases: State of the Art

Resumen Este artículo es parte de una investigación que pretende identificar el impacto que tienen las enfermedades crónicas en el desarrollo de la creatividad, la identidad y la subjetividad de los sujetos que las padecen. El documento presenta la revisión de 50 artículos con resultados de estudios que, en la última década, investigaron sobre la creatividad en relación con la identidad y la subjetividad de niños, niñas, adolescentes y jóvenes que viven con enfermedades crónicas. Desde lo metodológico, se trata de un estudio no probabilístico de tipo intencional, en el cual se abordaron datos bibliométricos construidos a partir de bases de datos especializadas y, posteriormente, se efectuó un análisis interpretativo crítico de estas investigaciones desde una perspectiva cualitativa, para el que se recurrió a la categorización de la información. Los resultados evidencian que el uso del arte como estrategia terapéutica facilita el afrontamiento de la enfermedad; sin embargo, también se evidencian afectaciones relevantes en el sistema familiar y relacional de quienes viven con estas enfermedades. Se concluye que la investigación en este campo se ha dado principalmente desde la medicina y la psicología, pero dejó un campo abierto que puede ser explorado por la investigación social.

Abstract This article presents a state of the art that integrates the review of fifty articles of the results of studies that, in the last decade, investigated creativity in relation to the identity and subjectivity of children, adolescents and young people living with chronic diseases .The document is part of a doctoral research that aims to identify the transformations that creativity undergoes in relation to the development of identity and subjectivity of children living with chronic diseases, such as HIV/AIDS, cancer and diabetes, given that these are the diseases that Sontag (2008) relates as the diseases that cause the greatest social and economic impacts and that modify the life project of people in the long term. From the methodological point of view, bibliometric data constructed from specialized databases such as PubMed, APA, Science Direct, Proquest, Redalyc, Scielo and Scopus were approached; subsequently a critical interpretive analysis of these investigations was carried out from a qualitative perspective. The results show that the use of art as a therapeutic strategy facilitates coping with the disease; however, relevant effects are also evident in the family and relational system of those who live with these diseases. It is also found that a large part of the research, as suggested by Sontag (2008), assumes diseases as an enemy, making use of the language of war, in addition to locating whoever experiences the disease as a battle hero or as a survivor when it is possible to go through the disease in a satisfactory way, however, it is also evident that this position implies a struggle of the subject with himself. Also, some of the authors state that the disease facilitates the recognition of abilities, tastes and skills of which one was not aware before experiencing it. Through these investigations, the understanding of the importance of relationships with peers as a key aspect for the development of self-regulation is broadened, which facilitates self-care practices far from victimization and family overprotection. Creativity has been understood mainly from artistic exercises, art-therapy and the use of some resources such as painting, drawing, music and dance for the approach to the subject who lives with chronic diseases, from the research exercises themselves, but also from an attempt to allow the subject to establish diverse communications with his context and to establish communication bridges with himself and with his new life circumstances. However, this perspective leaves aside the proposal of Lavie, Narayan and Rosaldo (1993), who argue that creativity is the human capacity to respond to daily circumstances in different ways, which allows expanding the field of action of what creative, facilitating that it is linked to the daily lives of the subjects and other ways of displaying creativity are explored, from relationships, from the practices of self-recognition and self-care regarding the same disease.It is also found that chronic diseases are related to metaphors that force the subject who experiences them to assume the role of warrior, war hero or war victim; these postures assume burdens for the subject and, although in some cases they help to assume the disease with a spirit of improvement, they also increase responsibility, guilt and difficulties in cases in which the disease is not overcome.

The Ocular Trauma Score Underestimates Visual Recovery for the Most Severe Open-Globe Injuries.

PURPOSE: To compare visual outcomes after open-globe injury (OGI) with those predicted by the Ocular Trauma Score (OTS), and to investigate the effect of treatment with pars plana vitrectomy (PPV). DESIGN: Retrospective cohort study. SUBJECTS: Patients presenting with OGI to an academic United States ophthalmology department from 2017 to 2020. METHODS: Best-corrected visual acuity (VA) measurements at the most recent follow-up were compared with final VA predicted by the OTS, based on preoperative injury characteristics. The most recently measured VA of patients treated with PPV during initial OGI repair (primary PPV group) was compared with patients treated with PPV after initial OGI repair (secondary PPV group) and patients never treated with PPV (No PPV group). MAIN OUTCOME MEASURES: Best-corrected VA in the injured eye at last follow-up; secondary outcome measures included the occurrence of vitreous hemorrhage at any time, occurrence of retinal detachment at any time, rates of additional surgery, and rates of enucleation. RESULTS: One-hundred and thirty-three subjects with OGI were identified and analyzed. The overall rate of PPV was 32%. Predictors of worse VA at last follow-up included older age (P = 0.047) and worse presenting VA (P < 0.001). Visual acuity outcomes for eyes in OTS categories 2 to 5 did not significantly differ from OTS predictions. However, eyes in OTS category 1 had a higher likelihood of last follow-up VA of light perception (LP) to hand motion (46% in the study cohort vs. 15% predicted by the OTS, P = 0.004) and a lower likelihood of no LP (33% vs. 74%, P < 0.001). The secondary PPV group had the worst VA at presentation among the 3 groups (P = 0.016), but VA at last follow-up did not significantly differ between the study groups (P = 0.338). CONCLUSIONS: The most severe OGIs (i.e., OTS category 1) had better visual outcomes than predicted by the published OTS expectations, and secondary PPV was associated with significant visual improvement despite poor prognostic predictions. Evaluation by a vitreoretinal surgeon should be considered for all patients with severe OGI, especially those in OTS category 1. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Difficult to Diagnose Cutaneous Melanoma in a Patient with BAP1 Tumor Predisposition Syndrome.

BRCA1-associated protein 1 (BAP1)-inactivated melanomas can occur sporadically or in germline contexts, particularly in recently recognized BAP1-tumor predisposition syndrome. Diagnosis represents a clinical and histopathological challenge, requiring comprehensive analysis of morphology and sometimes molecular analysis in addition to immunohistochemistry. We report a BAP1-inactivated cutaneous melanoma initially diagnosed as an atypical Spitz tumor on the auricle in a patient with BAP1-tumor predisposition syndrome. Immunohistochemistry, fluorescence in situ hybridization, and comparative genomic hybridization allowed diagnosis. Cutaneous BAP1-inactivated melanocytic tumors, previously classified as atypical Spitz Nevi, may have a dermal mitotic activity that can resemble melanoma and on the other hand, atypical Spitz tumors are sometimes difficult to differentiate from BAP1-inactivated melanoma. Specific criteria, requiring molecular diagnosis have been proposed in order to support melanoma diagnosis.