Mechanically Induced Highly Efficient Hydrogen Evolution from Water over Piezoelectric SnSe nanosheets.

Piezoelectric nanomaterials open new avenues in driving green catalysis processes (e.g., H2 evolution from water) through harvesting mechanical energy, but their catalytic efficiency is still limited. The predicted enormous piezoelectricity for 2D SnSe, together with its high charge mobility and excellent flexibility, renders it an ideal candidate for stimulating piezocatalysis redox reactions. In this work, few-layer piezoelectric SnSe nanosheets (NSs) are utilized for mechanically induced H2 evolution from water. The finite elemental method simulation demonstrates an unprecedent maximal piezoelectric potential of 44.1 V for a single SnSe NS under a pressure of 100 MPa. A record-breaking piezocurrent density of 0.3 mA cm-2 is obtained for SnSe NSs-based electrode under ultrasonic excitation (100 W, 45 kHz), which is about three orders of magnitude greater than that of reported piezocatalysts. Moreover, an exceptional H2 production rate of 948.4 µmol g-1 h-1 is achieved over the SnSe NSs without any cocatalyst, far exceeding most of the reported piezocatalysts and competitive with the current photocatalysis technology. The findings not only enrich the potential piezocatalysis materials, but also provide useful guidance toward high-efficiency mechanically driven chemical reactions such as H2 evolution from water.

Selective Electrochemical Bleaching of the Outer Leaflet of Fluorescently Labeled Giant Liposomes.

Electrochemistry and confocal fluorescence microscopy were successfully combined to selectively bleach and monitor the fluorescence of NBD (7-nitrobenz-2-oxa-1,3-diazole)-labeled phospholipids of giant liposomes. Three types of giant unilamellar vesicles have been investigated, the fluorescent phospholipids being localized either mainly on their outer-, inner-, or both inner/outer leaflets. We established that only the fluorescent lipids incorporated in the outer leaflet of the vesicles underwent electrochemical bleaching upon reduction. The relative fluorescence intensity decay was quantified all along the electrochemical extinction through an original fluorescence loss in electrobleaching (FLIE) assay. As expected, the reorganization of the fluorescent phospholipids followed diffusion-driven dynamics. This was also evidenced by comparison with fluorescence loss in photobleaching (FLIP) and the corresponding numerical model. The value of the lateral diffusion coefficient of phospholipids was found to be similar to that obtained by other methods reported in the literature. This versatile and selective bleaching procedure appears reliable to explore important biological and pharmacological issues.

Successful treatment of multidrug-resistant Pseudomonas aeruginosa breakthrough bacteremia with ceftolozane/tazobactam.

INTRODUCTION: Ceftolozane/tazobactam is a novel antibiotic approved for the treatment of complicated intra-abdominal and complicated urinary tract infections. CASE DESCRIPTION: We describe the use of off-label ceftolozane/tazobactam in the management of a multidrug-resistant Pseudomonas aeruginosa bacteremia that was already being treated with colistin and amikacin, the only active antibiotics according to the antibiogram.

In vitro and in vivo efficacy of SYL040012, a novel siRNA compound for treatment of glaucoma.

Glaucoma is a progressive ocular syndrome characterized by degeneration of the optic nerve and irreversible visual field loss. Elevated intraocular pressure (IOP) is the main risk factor for glaucoma. Increased IOP is the result of an imbalance between synthesis and outflow of aqueous humor (AH). Blocking ß2 adrenergic receptor (ADRB2) has shown to reduce IOP by decreasing production of AH at the ciliary body (CB). SYL040012 is a siRNA designed to specifically silence ADRB2 currently under development for glaucoma treatment. Here, we show that SYL040012 specifically reduces ADRB2 expression in cell cultures and eye tissues. The compound enters the eye shortly after administration in eye drops and is rapidly distributed among structures of the anterior segment of the eye. In addition, SYL040012 is actively taken up by cells of the CB but not by cells of systemic organs such as the lungs, where inhibition of ADRB2 could cause undesirable side effects. Moreover, SYL040012 reduces IOP in normotensive and hypertensive animal models and the effect appears to be long lasting and extremely well tolerated both locally and systemically.

Phase I clinical trial of SYL040012, a small interfering RNA targeting ß-adrenergic receptor 2, for lowering intraocular pressure.

The objective of this study was to evaluate ocular tolerance, safety, and effect on intraocular pressure (IOP) of a topically administered small interfering RNA; SYL040012, on healthy volunteers. The study was an open-label, controlled, single-center study comprised of two intervals that enrolled 30 healthy subjects having IOP below 21 mmHg. SYL040012 was administered to one eye as a single dose to six subjects during interval 1. During interval 2 two different doses of SYL040012 were administered to one eye on a daily basis to two separate groups of 12 subjects each, over a period of 7 days. The contralateral eye was evaluated but not administered and served as control for the tolerance study. SYL040012 was well tolerated locally. No local or systemic adverse events related to the product developed in response to any of the doses studied. SYL040012 was not detected in plasma at any time point. Administration of SYL040012 over a period of 7 days reduced IOP values in 15 out of 24 healthy subjects regardless of the dose used. IOP decrease was statistically significant in response to one of the doses tested and responsiveness to SYL040012 seemed to be greater in individuals with higher baseline IOP.

Silencing human genetic diseases with oligonucleotide-based therapies.

RNA interference is an endogenous mechanism present in most eukaryotic cells that enables degradation of specific mRNAs. Pharmacological exploitation of this mechanism for therapeutic purposes attracted a whole amount of attention in its initial years, but was later hampered due to difficulties in delivery of the pharmacological agents to the appropriate organ or tissue. Advances in recent years have to a certain level started to address this specific issue. Genetic diseases are caused by aberrations in gene sequences or structure; these particular abnormalities are in theory easily addressable by RNAi therapeutics. Sequencing of the human genome has largely contributed to the identification of alterations responsible for genetic conditions, thus facilitating the design of compounds that can address these diseases. This review addresses the currently on-going programs with the aim of developing RNAi and other antisense compounds for the treatment of genetic conditions and the pros and cons that these products may encounter along the way. The authors have focused on those programs that have reached clinical trials or are very close to do so.

Impact of probe sonication and sulfuric acid pretreatment on graphene exfoliation in water.

Graphene is a 2D material with promising commercial applications due to its physicochemical properties. Producing high-quality graphene economically and at large scales is currently of great interest and demand. Here, the potential of producing high-quality graphene at a large scale via water-phase exfoliation methods is investigated. By altering exfoliation parameters, the production yield of graphene and flake size are evaluated. Pretreatment of the precursor graphite powder using acidic solutions of H2SO4 at different concentrations is found to increase further the yield and structural quality of the exfoliated graphene flakes. These findings are confirmed through various spectroscopy and surface characterization techniques. Controlling flake size, thickness, and yield are demonstrated via optimization of the sonication process, centrifuge time, and H2SO4 pretreatment.

Safety of COVID-19 vaccination in patients with previous cerebral venous sinus thrombosis.

INTRODUCTION: Cerebral venous sinus thrombosis (CVST) after coronavirus (COVID-19) vaccination has been reported. There are no data about thrombosis risk in prior CVST patients. The objective of the study was to describe short-term serious adverse events to COVID-19 vaccines in patients with history of CVST. MATERIAL AND METHODS: We present an observational prospective study of patients with known CVST who received COVID-19 vaccination. Serious event rates within 30 days after second dose vaccination (except one dose for Janssen) were evaluated, including recurrences, hospital admission and death. RESULTS: The 62 vaccinated patients received: BNT162b2 (Pfizer-BioNTech) in 43 patients (69.4%), mRNA-1273 (Moderna) in 7 patients (11.3%), AZD1222 (ChAdOx1) in 7 patients (11.3%) and Ad26.COV2.S (Janssen) in 5 patients (8.1%). There were no thrombotic recurrences within 30 days of vaccination (95% confidence interval, 0.0-5.8). There was one death (1.6%), not attributable to the vaccine. CONCLUSIONS: COVID-19 vaccines are safe for previous CVST patients.

Latent Microsporidia Infection Prevalence as a Risk Factor in Colon Cancer Patients.

Microsporidia are opportunistic intracellular parasites, generating serious pathology in individuals with a compromised immune system. Infection by microsporidia inhibits p53 and Caspase 3, proteins involved in apoptosis and the cell cycle, which are vital in the malignant process of epithelial cells. The presence of microsporidia in the intestinal tissues of 87 colon cancer (CC) patients and 25 healthy controls was analyzed by real-time PCR and an immunofluorescence antibody test. Anti-Encephalitozoon antibodies were analyzed in serum samples by ELISA (enzyme linked immunosorbent assay). In 36 (41.3%) CC cases, microsporidia infections were identified in their tissues vs. no cases among control subjects (p < 0.0001). An increase in IgG and IgE anti-Encephalitozoon antibodies was found in patients with CC, which would demonstrate continuous and previous contact with the parasite. The high prevalence of microsporidia in tissues and the seroprevalence in patients with CC suggest a relationship between microsporidia and the etiopathogenesis of CC.

The Impact of Frailty Screening on Radiation Treatment Modification.

BACKGROUND: Care overburden makes it difficult to perform comprehensive geriatric assessments (CGAs) in oncology settings. We analyzed if screening tools modified radiotherapy in oncogeriatric patients. METHODS: Patients ≥ 65 years, irradiated between December 2020 and March 2021 at the Hospital Provincial de Castellón, completed the frailty G8 and estimated survival Charlson questionnaires. The cohort was stratified between G8 score ≤ 14 (fragile) or >14 (robust); the cutoff point for the Charlson index was established at five. RESULTS: Of 161 patients; 69.4% were male, the median age was 75 years (range 65-91), and the prevailing performance status (PS) was 0-1 (83.1%). Overall, 28.7% of the cohort were frail based on G8 scores, while the estimated survival at 10 years was 2.25% based on the Charlson test. The treatment administered changed up to 21% after frailty analysis. The therapies prescribed were 5.8 times more likely to be modified in frail patients based on the G8 test. In addition, patients ≥ 85 years (p = 0.01), a PS ≥ 2 (p = 0.008), and limited mobility (p = 0.024) were also associated with a potential change. CONCLUSIONS: CGAs remain the optimal assessment tool in oncogeriatry. However, we found that the G8 fragility screening test, which is easier to integrate into patient consultations, is a reliable and efficient aid to rapid decision making.

Play Behavior in Two Captive Bottlenose Dolphin Calves (Tursiops Truncatus): Ethogram, Ontogeny, and Individual Differences.

This research focused on different aspects of play behavior including ethogram, ontogeny, and individual differences, in one male and one female captive bottlenose dolphin calves (Tursiops truncatus) from November 2003 to June 2004. We presented the first peer-reviewed description of a play ethogram in bottlenose dolphin calves whose behaviors were grouped into three hierarchical levels: two categories: solitary and social play; four subcategories: locomotor, object, bubble play, and in the presence of humans, and 35 entries. It was conducted in two phases: the descriptive phase - from 3 to 5 months old - with 29 entries and the quantitative phase - from 6 to 10 months old -with six entries. All social and solitary locomotor behaviors appeared when animals were 3 months old meanwhile more complex behaviors concerning playing with objects, bubbles, and in the presence of humans were observed for 6 months old. There were no statistically significant intra-individual and inter-individual differences in the play behavioral diversity, in the time invested in play and in the Shannon's evenness index. However, we observed statistically significant inter-individual but not intra-individual differences for the Shannon's diversity index.

siRNA Therapeutics in Ocular Diseases.

The field of RNAi therapeutics has quickly adapted to the treatment of ocular diseases. Although the eye provides a unique system for the delivery of siRNAs, its complex structure and composition fostered the development of novel strategies for efficient gene silencing in the target compartment. Moreover, anterior and posterior segments differ in their multiple drug barriers and clearance mechanisms. This chapter summarizes the recent achievements in terms of routes of administration, chemical modifications, and delivery systems for siRNAs that specifically apply to eye disorders. Methods employed for siRNA detection/quantitation in ocular tissues are also described, together with safety concerns that need to be addressed to fulfill regulatory requirements of new drug approval. Even though RNAi therapies for ocular diseases have not yet translated into patient care, we document herein the rising number of candidate drugs currently under preclinical or clinical development.

The presence of microvascular complications is associated with a poor evolution of metabolic control in patients with type 1 diabetes mellitus.

OBJECTIVE: To report the evolution of metabolic control and to assess the clinical and metabolic factors associated with the presence of microvascular complications in patients with type 1 diabetes mellitus (T1DM). MATERIAL AND METHODS: This was a retrospective, observational study analysing clinical, laboratory, and therapeutic data from a registry of patients with T1DM created in 2010. RESULTS: Data recorded from 586 patients (males: 50.2%; mean age: 36.1±13.5 years; T1DM duration: 18.0±12.1 years) followed for a mean of 6.0±3.1 years were assessed, and 8133 HbA1c levels (13.2±7.6 measurements/patient) were analysed, with a mean evolutionary HbA1c of 7.9%±1.2%. The mean annual HbA1c level gradually improved from 8.6%±1.6% in 2010 to 7.5%±1.4% in 2019, with 34.3% and 69.0% of patients having HbA1c levels ≤7% and ≤8% respectively. Patients with T1DM duration of <10 years and ≥20 years, non-smokers, CSII users, and those using the insulin/carbohydrate ratio had better current and evolutionary HbA1c levels. The presence of microvascular complications was independently associated with T1DM lasting ≥20 years, the presence of HBP, and evolutionary HbA1c≥7.0%. CONCLUSION: A progressive but still inadequate improvement in metabolic control over 10 years was seen in patients with T1DM. Poor metabolic control (mean HbA1c over 10 years ≥7%) was independently associated with the presence of microvascular complications.

Safety and diagnostic performance of parathyroid hormone assay in fine-needle aspirate in suspicious parathyroid adenomas.

OBJECTIVE: To evaluate the safety and diagnostic performance of parathyroid hormone assay in fine-needle aspirate (PTH-FNA) in patients with primary hyperparathyroidism and suspicious parathyroid adenomas. METHODOLOGY: A retrospective observational study was performed in 47 patients (57.7 ±â€¯11.2 years of average age, 74% women) attending an endocrinology clinic for primary hyperparathyroidism (average calcemia: 11.6 ±â€¯1.6 mg/dl and PTH: 276 ±â€¯477 pg/mL) in which PTH-FNA was made. Sensibility, specificity, positive predictive value and negative predictive value were calculated in all surgical patients. RESULTS: Forty-seven lesions were punctured (mean adenoma maximum diameter: 1.8 ±â€¯2.6 cm): negative image in the sestamibi scan (26 patients); the discordance between ultrasonography and the sestamibi scan (6 patients); possible intrathyroidal adenomas (4 patients); a positive sestamibi scan in 2 or more localizations (4 patients); ectopic adenoma (3 patients); persistent primary hyperparathyroidism (2 patients) and atypical adenomas (2 patients). Mean PTH-FNA was 2853 ±â€¯3957 pg/mL and 68% were considered positive (PTH-FNA ≥ 100 pg/mL). No complications were detected during or after the puncture. Thirty-seven patients were operated on, 95% were cured and no parathyromatosis cases were detected. PTH-FNA ≥ 100 pg/mL as a diagnostic test had a sensitivity of 93.7%, a specificity of 100%, a positive predictive value of 100% and an negative predictive value of 71.4%. CONCLUSION: PTH-FNA is an easy and safe diagnostic test and has a high sensitivity and specificity for differentiating between parathyroid adenomas and other cervical masses in patients with primary hyperparathyroidism.

High capacity of ultrasound for locating parathyroid adenomas in endocrinology (the ETIEN 4 study). / Elevada capacidad de localización ecográfica de adenomas paratiroideos en endocrinología (estudio ETIEN 4).

OBJECTIVE: To assess the diagnostic performance of neck ultrasound examination performed by endocrinologists to locate parathyroid adenomas in patients with primary hyperparathyroidism (PHPT). METHODOLOGY: A retrospective observational study in 135 patients (mean age, 60.0±12.3 years; 74.8% females) seen at endocrinology for PHPT (mean calcium level, 11.3±1.2mg/dL mean PTH level, 240.4±346.8pg/mL) who underwent neck ultrasound examinations at the endocrinology department. 99mTc-MIBI parathyroid scintigraphy was performed before surgery in all patients. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated in surgical patients. RESULTS: Ninety-eight patients underwent surgery for PHPT and 97.8% were cured at 6 months. Parathyroid ultrasound had a sensitivity of 85% (95% CI: 75.7%-91.2%) and a positive predictive value (PPV) of 95.2% (95% CI: 87.5%-98.4%) to locate parathyroid adenomas 1.7±0.9cm in maximum diameter (69.4% in smaller glands), showing a high correlation (r=0.661 and r=0.716) with maximum diameter and volume of the excised adenoma. Sixty percent of patients had nodular thyroid disease (64.2% bilateral nodules with mean maximum diameter of 1.5±0.9cm), and thyroidectomy was performed in 31.6%. The highest diagnostic performance was seen with a combination of neck ultrasound and 99mTc-MIBI scintigraphy (sensitivity: 96.8% and PPV: 95.8%). CONCLUSION: In our area, parathyroid adenoma localization with ultrasound performed by endocrinologists has a high diagnostic yield and allows for detecting nodular thyroid disease in 60% of patients.

Diagnostic performance of the American Thyroid Association ultrasound risk assessment of thyroid nodules in endocrinology (the ETIEN 3 study). / Rendimiento diagnóstico del sistema de evaluación de riesgo ecográfico del nódulo tiroideo de la American Thyroid Association en endocrinología (estudio ETIEN 3).

INTRODUCTION: No study has been published to date in Spain about the value of the American Thyroid Association (ATA) ultrasound risk assessment of thyroid nodules applied by endocrinologists. OBJECTIVES: To assess the diagnostic performance of ATA thyroid nodule risk classification applied by endocrinologists with respect to histological results. METHODS: A retrospective, observational study of 317 patients (mean age, 51.7±13.7 years; 83.3% women) with thyroid nodules (maximum diameter: 3.2±1.4cm) who underwent US-guided FNA in endocrinology between October 2015 and December 2018, were classified based on the ATA ultrasound risk assessment. Surgery was performed in all of them. Quality criteria of the ultrasound classification were assessed as compared to histological results. RESULTS: Overall, 61.2% of nodules assessed were classified as benign (n=3) and very low (n=60) or low suspicion (n=131), 11.7% as intermediate suspicion (n=37), and 27.1% as high suspicion (n=86). Benign nodular disease was found in 260 patients, and thyroid cancer in 57 patients. There were 14 incidental papillary microcarcinomas. Classification of thyroid nodules as high suspicion showed a high diagnostic performance to identify malignant nodules (87.7% sensitivity, 86.2% specificity, negative predictive value 97.0%), improving sensitivity (93.0%) and reducing specificity (73.1%) when considering high and intermediate suspicion nodules as a risk for thyroid cancer. CONCLUSIONS: Application by endocrinologists of the ATA ultrasound risk assessment of thyroid nodules shows a high diagnostic performance to identify malignant thyroid nodules before surgery.

Surface-enhanced Raman spectroscopy: benefits, trade-offs and future developments.

Surface-enhanced Raman spectroscopy (SERS) is a vibrational spectroscopy technique with sensitivity down to the single molecule level that provides fine molecular fingerprints, allowing for direct identification of target analytes. Extensive theoretical and experimental research, together with continuous development of nanotechnology, has significantly broadened the scope of SERS and made it a hot research field in chemistry, physics, materials, biomedicine, and so on. However, SERS has not been developed into a routine analytical technique, and continuous efforts have been made to address the problems preventing its real-world application. The present minireview focuses on analyzing current and potential strategies to tackle problems and realize the SERS performance necessary for translation to practical applications.

Differences in circulating γδ T cells in patients with primary colon cancer and relation with prognostic factors.

Downregulation of the T cell system has been proposed as a mechanism to block immunity in colonic cancer (CC). However, little has been studied about circulating αß and γδ T cells and their immunological status in newly diagnosed patients. The aim of this study was to characterize the αß and γδ T cell subsets in peripheral blood of patients with CC matched with healthy volunteers. In this prospective case-control study, blood samples were obtained from 96 patients with newly diagnosed treatment-naïve infiltrating colonic adenocarcinoma and 48 healthy volunteers. Pathological report at surgery was obtained from all CC patients. A significant decrease in CD3+ γδ T cells and CD3+CD8+ γδ T cells (p<0.001) were observed in CC patients. Apoptosis was significantly increased in all conventional and both αß and γδ T cell subsets in patients with CC vs healthy subjects. γδ T cells were decreased in peripheral blood of patients with microscopic infiltration in tissues, history of cancer and synchronous colon cancer (p < 0.05). IFN-γ was significantly reduced in CC patients compared to controls. Cytotoxic effector γδ T cells TEMRA (CD8 and CD56) are the proportionally most abundant T cells in peripheral blood of CC patients. Patients with CC present a deep downregulation in the systemic T-cell immunity. These variations are evident through all tumor stages and suggest that a deficiency in γδ T cell populations could be preventing control of tumor progression. This fact prove the role of immunomodulation on CC carcinogenesis.

Tivanisiran, a novel siRNA for the treatment of dry eye disease.

INTRODUCTION: Dry eye disease (DED) is characterized by an alteration of the tear film with ocular inflammation and neurosensory abnormalities. The main clinical signs of this condition are tear instability and ocular damage. Although DED has gained significant attention in the past few years, limited prescription treatment options are available for patients. Areas covered: The current manuscript summarizes the pre-clinical and clinical development of tivanisiran, a novel small interfering oligonucleotide of RNA (siRNA) used for the treatment of DED. Tivanisiran was designed to silence Transient Receptor Potential Vanilloid 1 (TRPV1); herein the chemistry and mechanism of action of this new compound is also described. Expert opinion: Drugs currently on the market mostly target the inflammatory component of the disease and show only partial efficacy. New compounds addressing other aspects of the disease would provide significant advantages and contribute to a more personalized treatment of the disease. Tivanisiran has been designed to reduce ocular discomfort and pain, and was shown to improve ocular hyperemia and tear quality in human and animal models. Consequently, if the results of the ongoing and future clinical trials meet their study endpoints, tivanisiran could be submitted to obtain approval for the treatment of DED.

Gingivitis descamativa crónica: una manifestación gingival del liquen plano bucal / Chronic desquamative gingivitis: a gingival manifestation of oral lichen planus

RESUMEN El término de gingivitis descamativa ha evolucionado con el decursar de los años. La clasificación de la enfermedad periodontal vigente en Cuba la incluye dentro de los procesos inflamatorios crónicos superficiales. La Academia Americana de Periodontología y la Federación Europea de Periodoncia, han destinado un apartado para esta enfermedad denominado: alteraciones inflamatorias e inmunes. Se presentó una paciente de 27 años de edad, con ardor, sangramiento gingival y molestias al cepillado, la cual acudió a la consulta de Estomatología General Integral. Durante el examen clínico se constató la presencia de zonas eritematosas a nivel de encía marginal e insertada, con exposición del tejido conectivo. Luego de concluida la atención primaria en Periodoncia, la paciente fue remitida a la atención secundaria donde se le diagnosticó un liquen plano bucal con manifestaciones gingivales. Se instauró el tratamiento adecuado hasta la desaparición de las lesiones.

ABSTRACT The term desquamative gingivitis has evolved over the years. The current classification of periodontal disease in Cuba includes it among chronic superficial inflammatory processes. The American Academy of Periodontology and the European Federation of Periodontology have assigned a section for this disease called inflammatory and immune alterations. We present a 27-year-old female patient with burning, gingival bleeding and discomfort when brushing, who came to the General Comprehensive Dentistry consultation. Erythematous areas were observed during clinical examination, at the level of the inserted and marginal gingiva, with exposure of the connective tissue. After the completion of primary periodontal care, the patient was referred to secondary care where she was diagnosed with oral lichen planus with gingival manifestations. Appropriate treatment was instituted until the lesions disappeared.