The use of a selective, nontoxic dual-acting peptide for breast cancer patients with brain metastasis.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of commonly targeted receptors. Unspecific chemotherapy is currently the main therapeutic option, with poor results. Another major challenge is the frequent appearance of brain metastasis (BM) associated with a significant decrease in patient overall survival. The treatment of BM is even more challenging due to the presence of the blood-brain barrier (BBB). Here, we present a dual-acting peptide (PepH3-vCPP2319) designed to tackle TNBC/BM, in which a TNBC-specific anticancer peptide (ACP) motif (vCPP2319) is joined to a BBB peptide shuttle (BBBpS) motif (PepH3). PepH3-vCPP2319 demonstrated selectivity and efficiency in eliminating TNBC both in monolayers (IC50≈5.0 µM) and in spheroids (IC50≈25.0 µM), with no stringent toxicity toward noncancerous cell lines and red blood cells (RBCs). PepH3-vCPP2319 was also able to cross the BBB in vitro and penetrate the brain in vivo, and was stable in serum with a half-life above 120 min. Tumor cell-peptide interaction is fast, with quick peptide internalization via clathrin-mediated endocytosis without membrane disruption. Upon internalization, the peptide is detected in the nucleus and the cytoplasm, indicating a multi-targeted mechanism of action that ultimately induces irreversible cell damage and apoptosis. In conclusion, we have designed a dual-acting peptide capable of brain penetration and TNBC cell elimination, thus expanding the drug arsenal to fight this BC subtype and its BM.

Dual FGFR-targeting and pH-activatable ruthenium-peptide conjugates for targeted therapy of breast cancer.

Dysregulation of Fibroblast Growth Factor Receptors (FGFRs) signaling has been associated with breast cancer, yet employing FGFR-targeted delivery systems to improve the efficacy of cytotoxic agents is still sparsely exploited. Herein, we report four new bi-functional ruthenium-peptide conjugates (RuPCs) with FGFR-targeting and pH-dependent releasing abilities, envisioning the selective delivery of cytotoxic Ru complexes to FGFR(+)-breast cancer cells, and controlled activation at the acidic tumoral microenvironment. The antiproliferative potential of the RuPCs and free Ru complexes was evaluated in four breast cancer cell lines with different FGFR expression levels (SKBR-3, MDA-MB-134-VI, MCF-7, and MDA-MB-231) and in human dermal fibroblasts (HDF), at pH 6.8 and pH 7.4 aimed at mimicking the tumor microenvironment and normal tissues/bloodstream pHs, respectively. The RuPCs showed higher cytotoxicity in cells with higher level of FGFR expression at acidic pH. Additionally, RuPCs showed up to 6-fold higher activity in the FGFR(+) breast cancer lines compared to the normal cell line. The release profile of Ru complexes from RuPCs corroborates the antiproliferative effects observed. Remarkably, the cytotoxicity and releasing ability of RuPCs were shown to be strongly dependent on the conjugation of the peptide position in the Ru complex. Complementary molecular dynamic simulations and computational calculations were performed to help interpret these findings at the molecular level. In summary, we identified a lead bi-functional RuPC that holds strong potential as a FGFR-targeted chemotherapeutic agent.

Lung abscess in a non-compliant patient with Crohn's disease.

A 66-year-old man was admitted to the emergency department due to malaise, fatigue and anorexia for the last 2 weeks. He presented no fever, no respiratory or gastrointestinal symptoms. The patient had been previously diagnosed with Crohn's Disease (CD) (A2L1L4B1 of Montreal Classification) 10 years before, when he presented complaints of watery diarrhea and unexplained weight loss. Despite refusing to start treatment, in the last staging exams performed 5 years before the admission (colonoscopy and magnetic resonance imaging) the patient was in deep remission. Nevertheless, he frequently missed his medical appointments and his disease had not been monitored since then. He denied previous use of corticosteroids, past abdominal surgery or previous CD related hospital admissions. He also denied smoking habits or chronic lung disease.

Organ damage is a major determinant of work productivity impairment in Behçet's Syndrome: a post-hoc analysis of the BODI validation study.

OBJECTIVES: To evaluate the prevalence, magnitude, and potential determinants of work productivity impairment in patients with Behçet's Syndrome (BS), focusing on the role of irreversible organ damage. METHODS: A post-hoc analysis of the BS overall damage index (BODI) prospective validation study was performed. Demographics and clinical features were recorded in all patients. The Work Productivity and Activity Impairment: General Health (WPAI: GH) questionnaire was administered to assess the work limitation and the BODI to measure organ damage. The independent effect of BS features on WPAI: GH outcomes was evaluated by regression analysis. RESULTS: Out of 148 patients, 34.5% were unemployed, with age (OR 1.035) and BODI score (OR 1.313 for 1-unit increase) as the only factors significantly (p< 0.05) associated with the unemployment state. An overall work impairment was reported in about 64.2% of the employed patients. Indeed, 22.7% reported missing work h due to their health (absenteeism), with a mean time loss of 34.4%; whereas 60.2% declared a reduced performance at work because of their health (presenteeism), with a mean productivity impairment of 45.4%. Ocular damage was associated with absenteeism (ß 0.225); female sex (ß 0.260), physician global assessment of disease activity (ß 0.502) and an increased BODI score (ß 0.166 for 1-point increase) with presenteeism; fibromyalgia (ß 0.246), physician global assessment (ß 0.469), and musculoskeletal damage (ß 0.325) with overall work impairment. CONCLUSIONS: Disease activity and organ damage accrual remarkably affect work productivity in BS patients. Achieving remission and preventing damage accrual are crucial and complementary objectives.

Exploiting click-chemistry: backbone post-functionalisation of homoleptic gold(I) 1,2,3-triazole-5-ylidene complexes.

The synthesis of a homoleptic azide-functionalised Au(I) bis-1,2,3-triazole-5-ylidene complex is reported, starting from a backbone-modified 1,2,3-triazolium salt ligand precursor. The incorporated azide handle allows for a straightforward modification of the complex according to click-chemistry protocols without impacting the steric shielding around the metal center, demonstrating the superiority of the presented triazole ligand framework over imidazole based systems. Employing the SPAAC and the CuAAC reactions, post-modification of the complex is facilitated with two model substrates, while retaining very high antiproliferative activity (nanomolar range IC50 values) in A2780 and MCF-7 human cancer cells.

Concordance of Dye-Spraying Chromoendoscopy and Virtual Chromoendoscopy for Colonic Dysplasia Detection in Longstanding Inflammatory Bowel Disease.

BACKGROUND/AIMS: In the past, dye-spraying chromoendoscopy was the technique of choice for colonic surveillance in patients with long-standing extensive inflammatory bowel disease. Recent evidence suggests that virtual chromoendoscopy is an equally acceptable technique. MATERIALS AND METHODS: Eleven gastroenterologists were given a survey with 20 pairs of pictures from inflammatory bowel disease surveillance colonoscopies (10 with nondysplastic lesions, 5 with dysplastic lesions, and 5 with no lesions). Each pair contained the same image captured during colonoscopy using indigo carmine and narrow-band imaging. For each picture, the gastroenterologist assessed the presence/absence of lesion and, when a lesion was identified, assessed the presence/absence of dysplasia and delineated its margins. To compare lesion and dysplasia detection between techniques, sensitivity, specificity, and interobserver agreement were calculated. The chi-square test was used to assess the accuracy of margins delineation. RESULTS: When assessing lesion and dysplasia detection, similar sensitivity and specificity values were obtained for both techniques. Interobserver agreement analysis revealed that dye-spraying chromoendoscopy and virtual chromoendoscopy had a moderate agreement in lesion detection but, for dysplasia detection, dye-spraying chromoendoscopy had a slight agreement [K = 0.11 (0.03-0.18), P < .01] and virtual chromoendoscopy a fair agreement [K = 0.30 (0.22-0.37), P < .01]. Margin delineation was similar between techniques. CONCLUSION: Sensitivity and specificity for lesion and dysplasia detection, as well as the accuracy of margins delineation, were similar between dye-spraying chromoendoscopy and virtual chromoendoscopy. Interobserver agreement for dysplasia detection was suboptimal in both techniques; however, it was superior when using virtual chromoendoscopy. These findings suggest that virtual chromoendoscopy constitutes a valid alternative for dysplasia screening in inflammatory bowel disease.

Effective submucosal tunneling endoscopic resection (STER) of a giant esophageal leiomyoma.

We report the successful removal of a giant esophageal leiomyoma using submucosal tunneling endoscopic resection in a 37-year-old woman with significant dysphagia.

Panobinostat-loaded folate targeted liposomes as a promising drug delivery system for treatment of canine B-cell lymphoma.

Introduction: Cancer is a major public health problem with over 19 million cases reported in 2020. Similarly to humans, dogs are also largely affected by cancer, with non-Hodgkin's lymphoma (NHL) among the most common cancers in both species. Comparative medicine has the potential to accelerate the development of new therapeutic options in oncology by leveraging commonalities between diseases affecting both humans and animals. Within this context, in the present study, we investigated the potential of panobinostat (Pan)-loaded folate-targeted PEGylated liposomes (FA-PEG-Pan-Lip) for the treatment of canine B-cell lymphoma, while contributing to new perspectives in comparative oncology. Methods and results: Two formulations were developed, namely: PEG-Pan-Lip and FA-PEG-Pan-Lip. Firstly, folate receptor expression in the CLBL-1 canine B-cell lymphoma cell line was assessed. After confirming receptor expression, both Pan-loaded formulations (PEG-Pan-Lip, FA-PEG-Pan-Lip) demonstrated dose-dependent inhibitory effects on CLBL-1 cell proliferation. The FA-PEG-Pan-Lip formulation (IC50 = 10.9 ± 0.03 nM) showed higher cytotoxicity than the non-targeted PEG-Pan-Lip formulation (IC50 = 12.9 ± 0.03 nM) and the free panobinostat (Pan) compound (IC50 = 18.32±0.03 nM). Moreover, mechanistically, both Pan-containing formulations induced acetylation of H3 histone and apoptosis. Flow cytometry and immunofluorescence analysis of intracellular uptake of rhodamine-labeled liposome formulations in CLBL-1 cells confirmed cellular internalization of PEG-Lip and FA-PEG-Lip formulations and higher uptake profile for the latter. Biodistribution studies of both radiolabeled formulations in CD1 and SCID mice revealed a rapid clearance from the major organs and a 1.6-fold enhancement of tumor uptake at 24 h for 111In-FA-PEG-Pan-Lip (2.2 ± 0.1 %ID/g of tumor) compared to 111In-PEG-Pan-Lip formulation (1.2±0.2 %ID/g of tumor). Discussion: In summary, our results provide new data validating Pan-loaded folate liposomes as a promising targeted drug delivery system for the treatment of canine B-cell lymphoma and open innovative perspectives for comparative oncology.

Pseudomonas aeruginosa increases the susceptibility of Candida albicans to amphotericin B in dual-species biofilms.

BACKGROUND: Biofilms are the leading cause of nosocomial infections and are hard to eradicate due to their inherent antimicrobial resistance. Candida albicans is the leading cause of nosocomial fungal infections and is frequently co-isolated with the bacterium Pseudomonas aeruginosa from biofilms in the cystic fibrosis lung and severe burn wounds. The presence of C. albicans in multispecies biofilms is associated with enhanced antibacterial resistance, which is largely mediated through fungal extracellular carbohydrates sequestering the antibiotics. However, significantly less is known regarding the impact of polymicrobial biofilms on antifungal resistance. RESULTS: Here we show that, in dual-species biofilms, P. aeruginosa enhances the susceptibility of C. albicans to amphotericin B, an effect that was biofilm specific. Transcriptional analysis combined with gene ontology enrichment analysis identified several C. albicans processes associated with oxidative stress to be differentially regulated in dual-species biofilms, suggesting that P. aeruginosa exerts oxidative stress on C. albicans, likely through the secretion of phenazines. However, the mitochondrial superoxide dismutase SOD2 was significantly down-regulated in the presence of P. aeruginosa. Monospecies biofilms of the sod2Δ mutant were more susceptible to amphotericin B, and the susceptibility of these biofilms was further enhanced by exogenous phenazines. CONCLUSIONS: We propose that in dual-species biofilms, P. aeruginosa simultaneously induces mitochondrial oxidative stress, while down-regulating key detoxification enzymes, which prevents C. albicans mounting an appropriate oxidative stress response to amphotericin B, leading to fungal cell death. This work highlights the importance of understanding the impact of polymicrobial interactions on antimicrobial susceptibility.

Bulletproof Temporal Bone: A Case of Self-Inflicted Ballistic Injury.

Temporal bone injuries due to gunshot wounds are uncommon but devastating, with a high risk of damage to critical neurovascular structures. The high resistance of the temporal bone, the densest bone in the human body, can sometimes avoid a fatal outcome. However, the complications are in many cases devastating and include hearing loss, facial paralysis, cerebrospinal fluid leakage, intracranial damage, and vascular injuries. Our goal was to report a case of ballistic injury to the temporal bone and describe the surgical approach taken for treatment. A 74-year-old man was transferred to the emergency room of our tertiary hospital, intubated and sedated, after an attempted suicide with a firearm. The CT scan showed the metal projectile lodged within the temporal bone on the right side, with the destruction of the ossicular chain and bony labyrinth. After stabilization, sedation was reversed, and the otolaryngology team was called. On examination, the entry wound was located in the cavum concha, with no active bleeding but presenting active otorrhea of cerebrospinal fluid. The patient had complete peripheral facial paralysis on the right side and spontaneous horizontal nystagmus toward the left side. Empirical antibiotic therapy was initiated. A subtotal petrosectomy was performed, with the removal of the foreign body, repair of the cerebrospinal fluid fistula, obliteration of the cavity with abdominal fat, and closure of the external auditory canal. He was discharged on the 11th-day post-surgery, maintaining complete facial paralysis and right-side anacusis, but was able to walk with assistance. In conclusion, penetrating trauma of the temporal bone is a potentially life-threatening situation, and patients that survive have a guarded prognosis, as it often leads to permanent sequelae even when managed promptly.

[Diagnosis and Treatment of Neuro-Behçet: A Clinical Update]. / Diagnóstico e Tratamento do Neuro-Behçet: Uma Actualização Clínica.

Behçet's disease is a relapsing multisystemic inflammatory syndrome characterized by recurrent oral and/or genital ulcers, uveitis, arthritis, skin lesions, and gastrointestinal and neurological involvement. Neuro-Behçet corresponds to nervous system involvement and is one of the most severe complications of Behçet disease. It occurs in 3% to 30% of cases and is categorized into parenchymal (most common) or non-parenchymal disease. The most common manifestation of parenchymal neuro-Behçet is meningoencephalitis with involvement of the brainstem, where patients present with cranial neuropathies, encephalopathy, sensory-motor syndromes, epilepsy, or myelitis. The main non-parenchymal manifestation is cerebral venous thrombosis. Neuro-Behçet has a predominantly subacute course, with remission within weeks, or clinical progression in one third of the cases. The diagnosis is essentially clinical and diagnostic tests help to corroborate the suspicion, distinguish from differential diagnoses, and exclude complications. Brain magnetic resonance imaging allows the identification of acute lesions (hypointense or isointense on T2-weighted and hypointense on T1-weighted sequences) contrast-enhanced, and chronic lesions characterized by non-contrast enhanced small lesions and brainstem atrophy. If non-parenchymal involvement is suspected, cerebral veno-magnetic resonance imaging /computed tomography should be performed. Cerebrospinal fluid shows elevated proteinorachia and pleocytosis in parenchymal and no changes in non-parenchymal neuro-Behçet (except increased opening pressure). Outbursts of parenchymal disease should be treated with high dose intravenous corticosteroid therapy, with subsequent switch to oral corticoids, followed by biologic therapy, usually an anti-TNF. The treatment of cerebral venous thrombosis is controversial and may consist of a combination of corticosteroids and anticoagulation.

A doença de Behçet é uma síndrome inflamatória multissistémica recidivante, caraterizada por úlceras orais e/ou genitais recorrentes, uveítes, artrite, lesões cutâneas e envolvimento gastrointestinal e neurológico. O neuro-Behçet corresponde ao envolvimento do sistema nervoso e é uma das complicações mais graves da doença de Behçet. Ocorre em 3% a 30% dos casos e categoriza-se em doença parenquimatosa (mais frequente) ou não-parenquimatosa. A manifestação mais comum do neuro-Behçet parenquimatoso é a meningoencefalite com acometimento do tronco cerebral, sendo que os doentes se apresentam com neuropatias cranianas, encefalopatia, síndromes sensitivo-motoras, epilepsia ou mielite. A principal manifestação não-parenquimatosa é a trombose venosa cerebral. O neuro-Behçet apresenta uma evolução maioritariamente subaguda, com remissão em semanas, ou com progressão clínica, em um terço dos casos. O diagnóstico é essencialmente clínico e os exames complementares auxiliam a corroborar a suspeita, a diferenciar de diagnósticos diferenciais e a excluir complicações. A ressonância magnética cerebral permite observar lesões agudas (hipo ou isointensas em T2 e hipointensas em T1) que captam contraste, e lesões crónicas caraterizadas por pequenas lesões que não captam contraste e atrofia do tronco cerebral. Na suspeita de envolvimento não-parenquimatoso deve ser realizada venoressonância magnética/tomografia computorizada cerebral. O líquido cefalorraquidiano apresenta elevação da proteinorraquia e da pleocitose no neuro-Behçet parenquimatoso e não tem alterações no não-parenquimatoso (exceto aumento da pressão de abertura). Os surtos de doença parenquimatosa devem ser tratados com corticoterapia endovenosa em alta dose, com posterior desmame para corticoterapia oral, seguida de terapêutica biológica, habitualmente anti-TNF. O tratamento da trombose venosa cerebral é controverso, podendo consistir na associação de corticoterapia e anticoagulação.

Hybrid Argon Plasma Coagulation for Barrett's Esophagus and for Colonic Mucosal Resection-A Systematic Review and Meta-Analysis.

Hybrid argon plasma coagulation (hAPC) is a novel technique that combines conventional argon plasma coagulation and waterjet submucosal expansion. The aims of this metanalysis were to evaluate the efficacy and safety of hAPC in the setting of Barret's esophagus (BE) ablation and as an adjunct to colonic endoscopic mucosal resection (EMR). Four electronic databases were searched, and the results were analyzed by two independent authors. Random-effects meta-analyses of the proportions of endoscopic and histologic remission (for BE), recurrence, and post-procedure adverse events were performed using R. Studies' reporting quality was also assessed. From the 979 identified records, 13 studies were included (10 regarding BE and three colonic EMR). The pooled percentages of endoscopic and histologic remission after hAPC for BE were 95% (95% confidence interval [CI] 91-99, I2 = 34) and 90% (95%CI 84-95, I2 = 46), respectively, while major adverse events and recurrence were registered in 2% (95%CI 0-5, I2 = 41) and 11% (95%CI 2-27, I2 = 11), respectively. Concerning hAPC-assisted EMR, the pooled percentages of major adverse events and recurrence were 5% (95%CI 2-10, I2 = 0) and 1% (95%CI 0-3, I2 = 40). Evidence suggests that the main advantages of hAPC are the increase in safety in the setting of BE ablation and the reduction of local recurrence after colonic EMR. Trials comparing hAPC with standard strategies are required to support its use for these indications.

Validation and Application of Predictive Models for Inadequate Bowel Preparation in Colonoscopies in a Tertiary Hospital Population.

Background: Bowel preparation is a major quality criterion for colonoscopies. Models developed to identify patients with inadequate preparation have not been validated in external cohorts. We aim to validate these models and determine their applicability. Methods: Colonoscopies between April and November 2019 were retrospectively included. Boston Bowel Preparation Scale ≥2 per segment was considered adequate. Insufficient data, incomplete colonoscopies, and total colectomies were excluded. Two models were tested: model 1 (tricyclic antidepressants, opioids, diabetes, constipation, abdominal surgery, previous inadequate preparation, inpatient status, and American Society of Anesthesiology [ASA] score ≥3); model 2 (co-morbidities, tricyclic antidepressants, constipation, and abdominal surgery). Results: We included 514 patients (63% males; age 61.7 ± 15.6 years), 441 with adequate preparation. The main indications were inflammatory bowel disease (26.1%) and endoscopic treatment (24.9%). Previous surgery (36.2%) and ASA score ≥3 (23.7%) were the most common comorbidities. An ASA score ≥3 was the only identified predictor for inadequate preparation in this study (p < 0.001, OR 3.28). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of model 1 were 60.3, 64.2, 21.8, and 90.7%, respectively. Model 2 had a sensitivity, specificity, PPV, and NPV of 57.5, 67.4, 22.6, and 90.5%, respectively. The AUC for the ROC curves was 0.62 for model 1, 0.62 for model 2, and 0.65 for the ASA score. Conclusions: Although both models accurately predict adequate bowel preparation, they are still unreliable in predicting inadequate preparation and, as such, new models, or further optimization of current ones, are needed. Utilizing the ASA score might be an appropriate approximation of the risk for inadequate bowel preparation in tertiary hospital populations.

Introdução: A preparação intestinal é um dos principais critérios de qualidade na colonoscopia. Modelos desenvolvidos para identificar doentes com preparação inadequada nunca foram validados em coortes externas. Pretendemos validar esses modelos e determinar sua aplicabilidade clínica. Métodos: Colonoscopias entre abril-novembro/2019 foram incluídas retrospectivamente. A Escala de Preparação Intestinal de Boston ≥2 por segmento foi considerada adequada. Dados insuficientes, colonoscopias incompletas e colectomias totais foram excluídos. Dois modelos foram testados: modelo 1 (antidepressivos tricíclicos, opióides, diabetes, obstipação, cirurgia abdominal, preparação prévia inadequada, internamento e American Society of Anesthesiology [ASA] ≥3); modelo 2 (comorbilidades, antidepressivos tricíclicos, obstipação e cirurgia abdominal). Resultados: Foram incluídos 514 doentes (63% homens; idade 61.7 ± 15.6), 441 com preparação adequada. As principais indicações foram doença inflamatória intestinal (26.1%) e tratamento endoscópico (24.9%). Cirurgias anteriores (36.2%) e ASA ≥3 (23.7%) foram as comorbilidades mais comuns. Um score ASA ≥3 foi o único fator de risco identificado para preparação inadequada (p < 0.001, OR 3.28). A sensibilidade, especificidade, valor preditivo positivo (VPP) e valor preditivo negativo (VPN) do modelo 1 foi de 60.3, 64.2, 21.8 e 90.7%. O modelo 2 apresentou sensibilidade, especificidade, VPP e VPN de 57.5, 67.4, 22.6 e 90.55%. A AUC para a curva ROC foi de 0.62 para o modelo 1, 0.62 para o modelo 2 e 0.65 para o score ASA. Conclusões: Embora ambos os modelos sejam eficazes a prever preparação intestinal adequada, não se verifica o mesmo para a preparação inadequada e como tal, novos modelos ou otimização dos atuais são ainda necessários. Utilizar o score ASA pode ser uma aproximação adequada do risco de preparação intestinal inadequada em populações de hospitais terciários.

Rabbit derived VL single-domains as promising scaffolds to generate antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are among the fastest-growing classes of therapeutics in oncology. Although ADCs are in the spotlight, they still present significant engineering challenges. Therefore, there is an urgent need to develop more stable and effective ADCs. Most rabbit light chains have an extra disulfide bridge, that links the variable and constant domains, between Cys80 and Cys171, which is not found in the human or mouse. Thus, to develop a new generation of ADCs, we explored the potential of rabbit-derived VL-single-domain antibody scaffolds (sdAbs) to selectively conjugate a payload to Cys80. Hence, a rabbit sdAb library directed towards canine non-Hodgkin lymphoma (cNHL) was subjected to in vitro and in vivo phage display. This allowed the identification of several highly specific VL-sdAbs, including C5, which specifically target cNHL cells in vitro and present promising in vivo tumor uptake. C5 was selected for SN-38 site-selective payload conjugation through its exposed free Cys80 to generate a stable and homogenous C5-DAB-SN-38. C5-DAB-SN-38 exhibited potent cytotoxicity activity against cNHL cells while inhibiting DNA-TopoI activity. Overall, our strategy validates a platform to develop a novel class of ADCs that combines the benefits of rabbit VL-sdAb scaffolds and the canine lymphoma model as a powerful framework for clinically translation of novel therapeutics for cancer.

Atrial fibrillation as a new prognosis factor in chronic patients after hospitalization: the CHRONIBERIA index.

A collaborative project in different areas of Spain and Portugal was designed to find out the variables that influence the mortality after discharge and develop a prognostic model adapted to the current healthcare needs of chronic patients in an internal medicine ward. Inclusion criteria were being admitted to an Internal Medicine department and at least one chronic disease. Patients' physical dependence was measured through Barthel index (BI). Pfeiffer test (PT) was used to establish cognitive status. We conducted logistic regression and Cox proportional hazard models to analyze the influence of those variables on one-year mortality. We also developed an external validation once decided the variables included in the index. We enrolled 1406 patients. Mean age was 79.5 (SD = 11.5) and females were 56.5%. After the follow-up period, 514 patients (36.6%) died. Five variables were identified as significantly associated with 1 year mortality: age, being male, lower BI punctuation, neoplasia and atrial fibrillation. A model with such variables was created to estimate one-year mortality risk, leading to the CHRONIBERIA. A ROC curve was made to determine the reliability of this index when applied to the global sample. An AUC of 0.72 (0.7-0.75) was obtained. The external validation of the index was successful and showed an AUC of 0.73 (0.67-0.79). Atrial fibrillation along with an advanced age, being male, low BI score, or an active neoplasia in chronic patients could be critical to identify high risk multiple chronic conditions patients. Together, these variables constitute the new CHRONIBERIA index.

Endoscopic "purse-string" to close a rectal endoscopic submucosal dissection eschar with intentional muscular sectioning.

This case demonstrates the utility of the "purse string" to close large defects and shows that optical diagnosis may have pitfalls in evaluating the invasion of neoplastic lesions, particularly large ones.

Hemostasis of a bleeding inverted colonic diverticulum.

The authors report a case of a 62-year-old male presenting to the emergency department with hematochezia. Urgent colonoscopy revealed numerous diverticula in the sigmoid colon, two of them inverted. Oozing bleeding from a visible vessel was identified on the top of the most distal inverted diverticulum. An over-the-scope clip was released after suction into the transparent cap and successful hemostasis was achieved.

A full hemostatic repertoire in a complex cirrhotic patient.

A 55-year-old woman with cirrhosis was admitted for acute decompensation caused by portal vein thrombosis. Ten days later, the patient presented melena. Esophagogastroscopy revealed two gastric polyps, both with bleeding stigmata. One of the polyps was removed with a diathermic loop, after adrenalin injection, while in the other the "ligate and let go" technique was applied, after biopsy. A "metallic tulip-bundle" technique, combining through the scope and over-the-scope clips, was applied for hemostasis. This case underlines how the combination of various endoscopic techniques may be useful to manage upper gastrointestinal bleeding, especially in patients with important comorbidities.

Septorhinoplasty and the Late Impact on Olfactory Function: A Review and Meta-analysis.

Septorhinoplasty (SRP) is one of the most commonly performed procedures worldwide. There is a recognized debate about the impact of nasal surgery on olfactory function (OF). The study's objective was to assess the effect of SRP on late postoperative OF. A comprehensive review and meta-analysis were employed to assess OF after SRP. All the integrated studies used objective instruments to quantify OF before and after surgery. A literature search was conducted, and the selected works were evaluated, computed, and finally included in a meta-analysis. The risk of bias was assessed using the NIH Guidance for Evaluating the Quality of Before-After (Pre-Post) Studies with No Control Group. Only the latest follow-up OF measurements provided by each research were considered in the analysis. The 95% confidence interval of the effect magnitude for each study was calculated to elucidate effect sizes. Eleven studies were included in the analysis. Five studies reported late OF improvement (45.5%), five reported no alteration in OF (45.5%), and only one study reported OF impairment after SRP (9%). Some works described a transitory decline in OF shortly following surgery, followed by postoperative improvement. A pooled meta-analysis showed that OF was not significantly altered after SRP (p = 0.10) in the late follow-up. SRP surgery seems to constitute a safe procedure concerning OF in the long term. According to research, OF may deteriorate temporarily after surgery with later improvement, sometimes to higher values than baseline. The anticipated evolution of OF after intervention could be discussed during the preoperative consultation for SRP.