Multicenter Retrospective Andalusian Study of the Use of Sonidegib for the Treatment of Local Advanced Basal Cell Carcinoma in Real Clinical Practice.

INTRODUCTION: Locally advanced basal cell carcinoma (LA-BCC) is defined as that BCC in which there is radiological confirmation of invasion of certain neighboring structures in depth and also, usually, a BCC that is of a sufficient size and invasion (although there is no radiological demonstration of deep invasion) in which surgery and radiotherapy are not adequate, are insufficient or are contraindicated to achieve the cure of the tumor, either due to characteristics of the tumor itself or of the patient. Sonidegib is indicated for the treatment of adult patients with locally advanced basal cell carcinoma that is not amenable to curative surgery or radiotherapy. MATERIAL AND METHODS: This is a retrospective, multicenter and descriptive study in nine centers in Andalusia, Spain. Patients treated with sonidegib for >3 months for locally advanced BCC were included from 1 January 2021 to 1 January 2023. Epidemiological, efficacy and safety data were collected. RESULTS: In the present study, a total of 38 patients were included, with a median age of 76.23 years (range 40-101). Prior treatment was surgery (31.57%; n = 25), radiotherapy (15.78%; n = 6), vismodegib (31.57%; n = 12). Eleven patients had not received prior treatment. LA-BCC were located in the cephalic pole, face or scalp. There was a total response in 9/38 patients (23.7%), partial response in 25/38 patients (65.8%) and no response in 4 patients (10.52%). In 6/34 patients, the dose was reduced to 200 mg every other day until it was discontinued due to adverse effects. The main adverse effects reported were dysgeusia (n = 8), asthenia (n = 8), = 6), muscle spasms (n = 6), alopecia (n = 4) and gastrointestinal intolerance (n = 4). DISCUSSION: Sonidegib is the second iHh authorized for the treatment of adult patients with locally advanced BCC who are not amenable to curative surgery or radiotherapy, based on the results of the phase II clinical trial, BOLT. Sonidegib shows good effectiveness and an acceptable safety profile in routine clinical practice in the sample presented.

Effectiveness and adherence to closed face shields in the prevention of COVID-19 transmission: a non-inferiority randomized controlled trial in a middle-income setting (COVPROSHIELD).

BACKGROUND: The use of respiratory devices can mitigate the spread of diseases such as COVID-19 in community settings. We aimed to determine the effectiveness of closed face shields with surgical face masks to prevent SARS-CoV-2 transmission in working adults during the COVID-19 pandemic in Bogotá, Colombia. METHODS: An open-label non-inferiority randomized controlled trial that randomly assigned participants to one of two groups: the intervention group was instructed to wear closed face shields with surgical face masks, and the active control group was instructed to wear only surgical face masks. The primary outcome was a positive reverse transcription polymerase chain reaction test, IgG/IgM antibody test for SARS-CoV-2 detection, or both during and at the end of the follow-up period of 21 days. The non-inferiority limit was established at - 5%. RESULTS: A total of 316 participants were randomized, 160 participants were assigned to the intervention group and 156 to the active control group. In total, 141 (88.1%) participants in the intervention group and 142 (91.0%) in the active control group completed the follow-up. PRIMARY OUTCOME: a positive SARS-CoV-2 test result was identified in one (0.71%) participant in the intervention group and three (2.1%) in the active control group. In the intention-to-treat analysis, the absolute risk difference was - 1.40% (95% CI [- 4.14%, 1.33%]), and in the per-protocol analysis, the risk difference was - 1.40% (95% CI [- 4.20, 1.40]), indicating non-inferiority of the closed face shield plus face mask (did not cross the non-inferiority limit). CONCLUSIONS: The use of closed face shields and surgical face masks was non-inferior to the surgical face mask alone in the prevention of SARS-CoV-2 infection in highly exposed groups. Settings with highly active viral transmission and conditions such as poor ventilation, crowding, and high mobility due to occupation may benefit from the combined use of masks and closed face shields to mitigate SARS-CoV-2 transmission. TRIAL REGISTRATION: ClinicalTrials.gov NCT04647305 . Registered on November 30, 2020.

Exposure to a media intervention helps promote support for peace in Colombia.

Whereas politicians broker peace deals, it falls to the public to embrace peace and help sustain it. The legacy of conflicts can make it difficult for people to support reconciling and reintegrating with former enemies. Here we create a five-minute media intervention from interviews we conducted with Colombian Revolutionary Armed Forces (FARC) ex-combatants in a Colombian demobilization camp and non-FARC Colombians in neighbouring communities. We show that exposure to the media intervention humanizes FARC ex-combatants and increases support for peace and reintegration. These effects persisted at least three months post-exposure, were replicated in an independent sample of non-FARC Colombians and affected both attitudes (for example, support for reintegration policies) and behaviour (for example, donations to organizations supporting ex-combatants). As predicted, the intervention's effects were mediated by changing conflict-associated cognitions-reducing the belief that ex-combatants are unwilling and unable to change-beyond affective pathways (for example, increased empathy or reduced prejudice).

Surgery for Cutaneous Squamous Cell Carcinoma and its Limits in Advanced Disease.

Surgery remains the first-line therapeutic option for most patients with cutaneous squamous cell carcinoma (cSCC). However, in the current therapeutic landscape, surgery must attempt to the complete tumor resection (R0 resection) with the lowest risk of surgical complications. This double aim is usually accomplished through standard excision with clinical margins in patients with low-risk tumors or by some of the micrographically controlled surgery procedures for patients with tumors at high-risk of local recurrence and metastasis. Surgery is also a first-line treatment for nodal metastases of cSCC as well as an option to consider in patients who develop recurrences while receiving immunotherapy, or as a palliation procedure in patients with advanced tumors. Neoadjuvant immunotherapy, that is the use of a medical treatment before surgery, is under investigation in patients with cSCC. The decision-making process and guidelines recommendations regarding cSCC surgery are reviewed in this manuscript.

In science we (should) trust: Expectations and compliance across nine countries during the COVID-19 pandemic.

The magnitude and nature of the COVID-19 pandemic prevents public health policies from relying on coercive enforcement. Practicing social distancing, wearing masks and staying at home becomes voluntary and conditional on the behavior of others. We present the results of a large-scale survey experiment in nine countries with representative samples of the population. We find that both empirical expectations (what others do) and normative expectations (what others approve of) play a significant role in compliance, beyond the effect of any other individual or group characteristic. In our vignette experiment, respondents evaluate the likelihood of compliance with social distancing and staying at home of someone similar to them in a hypothetical scenario. When empirical and normative expectations of individuals are high, respondents' evaluation of the vignette's character's compliance likelihood goes up by 55% (relative to the low expectations condition). Similar results are obtained when looking at self-reported compliance among those with high expectations. Our results are moderated by individuals' trust in government and trust in science. Holding expectations high, the effect of trusting science is substantial and significant in our vignette experiment (22% increase in compliance likelihood), and even larger in self-reported compliance (76% and 127% increase before and after the lockdown). By contrast, trusting the government only generates modest effects. At the aggregate level, the country-level trust in science, and not in government, becomes a strong predictor of compliance.

Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer's Disease Brains.

Alzheimer's disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid ß-peptide (Aß) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aß vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aß deposits on the NVU and the blood-brain barrier (BBB) are unknown. In this study, we analyze different Aß species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immunofluorescence assays were performed against different species of Aß and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aß species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aß in AD.

Role of the NO-cGMP-K+ channels pathway in the peripheral antinociception induced by α-bisabolol.

The aim of this study was to examine if the peripheral antinociception of α-bisabolol involves the participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by K+ channel opening in the formalin test. Wistar rats were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous injection into the dorsal surface of the paw of vehicles or increasing doses of α-bisabolol (100-300 µg/paw). To determine whether the peripheral antinociception induced by α-bisabolol was mediated by either the opioid receptors or the NO-cGMP-K+ channels pathway, the effect of pretreatment (10 min before formalin injection) with the appropriate vehicles, naloxone, naltrexone, NG-nitro-l-arginine methyl ester (L-NAME), 1H-[1,2,4]-oxadiazolo[4,2-a]quinoxalin-1-one (ODQ), glibenclamide, glipizide, apamin, charybdotoxin, tetraethylammonium, or 4-aminopyridine on the antinociceptive effects induced by local peripheral α-bisabolol (300 µg/paw) were assessed. α-Bisabolol produced antinociception during both phases of the formalin test. α-Bisabolol antinociception was blocked by L-NAME, ODQ, and all the K+ channels blockers. The peripheral antinociceptive effect produced by α-bisabolol was not blocked by the opioid receptor inhibitors. α-Bisabolol was able to active the NO-cGMP-K+ channels pathway to produce its antinoceptive effect. The participation of opioid receptors in the peripheral local antinociception induced by α-bisabolol is excluded.

Tocolytic effect of the monoterpenic phenol isomer, carvacrol, on the pregnant rat uterus.

Despite the wide application of carvacrol (CAR) in different biological and medical areas, there is still insufficient electrophysiological data on the mechanisms of action of CAR, particularly in the pregnant uterine function. The aim of this study was to evaluate the in vitro tocolytic effect of CAR on the contractility of isolated pregnant rat uterus in the presence of a calcium channel antagonist (nifedipine) and a cyclooxygenase inhibitor (indomethacin). The uteri were isolated from pregnant Wistar rats at 16-18 days of pregnancy and suspended in an isolated organ bath chamber containing a Ringer's physiological solution and aerated with 95% O2and 5% CO2. Samples were used in functional tests to evaluate the inhibitory effect of CAR at increasing concentrations on the rhythmic spontaneous, oxytocin-induced phasic, K+-induced tonic, and Ca2+-induced contractions. The differences in inhibitory concentration-50 and Emaxamong the compounds were determined using the one-way ANOVA followed by a post hoc Student-Newman-Keuls or Bonferroni test, in all casesP < 0.05 was considered statistically significant. Nifedipine was used as positive controls where required. CAR caused a significant concentration-dependent inhibition of the uterine contractions induced by the pharmaco- and electro-mechanic stimuli. We showed that the inhibitory effects of CAR depends on the type of muscle contraction stimuli, and that it acts stronger in spontaneous rhythmic activity and in contractions of isolated rat uterus induced by Ca2+. Nifedipine was more potent than CAR and indomethacin on the uterine contractility (P < 0.05), but none of them was more effective than nifedipine. Therefore, the tocolytic effect induced by CAR was associated with the blockade of the calcium channels in the pregnant rat uterus. This property placed CAR as a potentially safe and effective adjuvant agent in cases of preterm labor, an area of pharmacological treatment that requires urgent improvement.

Analysis of the Relationship Between Metalloprotease-9 and Tau Protein in Alzheimer's Disease.

BACKGROUND: Neurofibrillary tangles (NFTs) and amyloid plaques are the neuropathological hallmarks in brains with Alzheimer's disease (AD). Post-translational modifications of tau, such as phosphorylation and truncation, have been proposed as initiators in the assembly of the abnormal paired helical filaments that constitute the NFTs. Neurons and NFTs are sites of matrix metalloproteinases (MMPs). OBJECTIVE: The aim of this study was to analyze the relationship of MMP-9 and tau protein in brain samples with AD. METHODS: This study was performed on brain tissue samples from patients with early, moderate, and late AD. MMPs and tau levels were analyzed by western blot and gelatin-substrate zymography. Immunofluorescence techniques and confocal microscopy were used to analyze the presence of both proteins in NFTs. Further, molecular dynamics simulations (MDS) and protein-protein docking were conducted to predict interaction between MMP-9 and tau protein. RESULTS: MMP-9 expression was greatest in moderate and late AD, whereas MMP-2 expression was only increased in late-stage AD. Interestingly, confocal microscopy revealed NFTs in which there was co-localization of MMP-9 and tau protein. MDS and protein-protein docking predictions indicate that a high-affinity complex can be formed between MMP-9 and full-length tau protein. CONCLUSION: These observations provide preliminary evidence of an interaction between these two proteins. Post-translational modifications of tau protein, such as C-terminal truncation or phosphorylation of amino acid residues in the MMP-9 recognition site and conformational changes in the protein, such as folding of the N-terminal sequence over the three-repeat domain, could preclude the interaction between MMP-9 and tau protein during stages of NFT development.

Intrachiasmatic craniopharyngioma: Assessment of visual outcome with optical coherence tomography after complete surgical removal.

BACKGROUND: Optic chiasm invasion by a craniopharyngioma (CP) is exceptional. Surgical treatment of intrachiasmatic CPs associates a high risk of chiasm injury, which should be properly addressed before surgery. CASE DESCRIPTION: We present a 46-year-old woman admitted to the hospital with low visual acuity (0.1 in the right eye and 0.5 in the left) and a severe defect in her visual fields, in addition to headaches, diabetes insipidus, and a long-term depressive disorder. Her visual deficit progressed from a right homonymous temporal inferior quadrantanopia to an almost complete loss of vision in both eyes that only spared the upper nasal quadrants. Brain MRI showed a rounded third ventricle tumor with a potbelly expansion of the optic chiasm, suggesting chiasm invasion by the tumor. Optical coherence tomography (OCT) showed the thinning of the retinal nerve fiber layer (RNFL) in the superior and temporal wedges of the right eye and in the temporal wedge of the left one. The tumor was completely removed by employing a frontotemporal craniotomy and a translamina terminalis approach. Histological analysis showed a squamous-papillary CP. Postoperatively, a significant worsening of the visual defect was evidenced on the perimetry, which was related to a marked RNFL atrophy measured with OCT, as compared to the preoperative study. The poor long-term visual outcome in this patient correlated well with the results of postoperative OCT. CONCLUSIONS: Preoperative analysis of retinal atrophy with optic coherence tomography allows a reliable assessment of the patient's visual outcome in CPs involving the optic chiasm.

A Calcium/Cation Exchanger Participates in the Programmed Cell Death and in vitro Virulence of Entamoeba histolytica.

Entamoeba histolytica is the etiologic agent of human amoebiasis, disease that causes 40,000 to 100,000 deaths annually worldwide. The cytopathic activity as well as the growth and differentiation of this microorganism is dependent on both, extracellular and free cytoplasmic calcium. However, few is known about the proteins that regulate the calcium flux in this parasite. In many cells, the calcium extrusion from the cytosol is performed by plasma membrane Ca2+-ATPases and calcium/cation exchangers. The aim of this work was to identify a calcium/cation exchanger of E. histolytica and to analyze its possible role in some cellular processes triggered by calcium flux, such as the programmed cell death and in vitro virulence. By searching putative calcium/cation exchangers in the genome database of E. histolyica we identified a protein belonging to the CCX family (EhCCX). We generated a specific antibody against EhCCX, which showed that this protein was expressed in higher levels in E. histolytica than its orthologous in the non-pathogenic amoeba E. dispar. In addition, the expression of EhCCX was increased in trophozoites incubated with hydrogen peroxide. This E. histolytica exchanger was localized in the plasma membrane and in the membrane of some cytoplasmic vesicles. However, after 10 min of erythrophagocytosis, EhCCX was found predominantly in the plasma membrane of the trophozoites. On the other hand, the parasites that overexpress this exchanger contained higher cytosolic calcium levels than control, but the extrusion of calcium after the addition of hydrogen peroxide was more efficient in EhCCX-overexpressing trophozoites; consequently, the programmed cell death was retarded in these parasites. Interestingly, the overexpression of EhCCX increased the in vitro virulence of trophozoites. These results suggest that EhCCX plays important roles in the programmed cell death and in the in vitro virulence of E. histolytica.

A putative calcium-ATPase of the secretory pathway family may regulate calcium/manganese levels in the Golgi apparatus of Entamoeba histolytica.

Calcium regulates many cellular processes in protozoa, including growth, differentiation, programmed cell death, exocytosis, endocytosis, phagocytosis, fusion of the endosomes of distinct stages with phagosomes, fusion of phagosomes with lysosomes, and recycling the membrane. In Entamoeba histolytica, the protozoa responsible for human amoebiasis, calcium ions are essential for signaling pathways that lead to growth and development. In addition, calcium is crucial in the modulation of gene expression in this microorganism. However, there is scant information about the proteins responsible for regulating calcium levels in this parasite. In this work, we characterized a protein of E. histolytica that shows a close phylogenetic relationship with Ca2+ pumps that belong to the family of secretory pathway calcium ATPases (SPCA), which for several organisms are located in the Golgi apparatus. The amoeba protein analyzed herein has several amino acid residues that are characteristic of SPCA members. By an immunofluorescent technique using specific antibodies and immunoelectron microscopy, the protein was detected on the membrane of some cytoplasmic vacuoles. Moreover, this putative calcium-ATPase was located in vacuoles stained with NBD C6-ceramide, a Golgi marker. Overall, the current findings support the hypothesis that the presently analyzed protein corresponds to the SPCA of E. histolytica.

A Novel Actinic Keratosis Field Assessment Scale for Grading Actinic Keratosis Disease Severity.

Actinic keratosis (AK) lesions are surrounded by field cancerization (areas of subclinical, non-visible sun damage). Existing AK grading tools rely on AK counts, which are not reproducible. An Actinic Keratosis Field Assessment Scale (AK-FAS) for grading the severity of AK/field was developed. Standardized photographs of patients representing the full range of AK severity were collected. Six investigators independently rated each photograph according to 3 criteria: AK area (total skin area affected by AK lesions), hyperkeratosis and sun damage. Inter-rater reproducibility was good for all 3 criteria. Validation of the AK-FAS showed good reproducibility for AK area and hyperkeratosis, even for dermatologists untrained on use of the scale. In conclusion, the AK-FAS is objective, easy to use and implement, and reproducible. It incorporates assessment of the entire field affected by AK instead of relying on lesion counts. Use of the AK-FAS may standardize AK diagnosis, making it relevant to routine clinical practice.

Increasing Frequency of Seborrheic Keratosis Diagnoses as a Favorable Consequence of Teledermatology-Based Skin Cancer Screening: A Cross-sectional Study of 34,553 Patients.

BACKGROUND: Screening of skin cancer by teledermatology (TD) has improved the early detection of skin cancer by enhancing access to skin cancer clinics. OBJECTIVE: We sought to analyze how TD-based skin cancer screening has changed the frequency of consultations for benign lesions. PATIENTS AND METHODS: A cross-sectional study including teleconsultations received during a 7-year period was conducted to analyze and compare the trendlines of each lesion type over the study period. Trendlines were analyzed using a linear regression model with the R-squared (R 2) test for goodness of fit. RESULTS: A total of 34,553 teleconsultations were included in the study. Seborrheic keratoses, followed by benign melanocytic lesions, were the most frequent lesions diagnosed. The pick-up rate for malignant lesions was 1:8.6 teleconsultations. Seborrheic keratoses and precancerous lesions showed a positive trendline with good fit to the linear model (R 2 = 0.8 and R 2 = 0.8, respectively). Tis-T1 malignant melanoma (in situ melanoma or melanoma with a Breslow thickness <1 mm) showed an increasing trendline with moderate-to-low fit to the model (R 2 = 0.4). CONCLUSIONS: TD-based screening of skin cancer is associated with an increasing rate of consultations involving seborrheic keratoses, which can be considered a consequence of improved access to dermatologists resulting from TD implementation.

Internet-based skin cancer screening using clinical images alone or in conjunction with dermoscopic images: A randomized teledermoscopy trial.

BACKGROUND: Teledermoscopy involves the use of dermoscopic images for remote consultation and decision-making in skin cancer screening. OBJECTIVE: We sought to analyze the potential benefits gained from the addition of dermoscopic images to an internet-based skin cancer screening system. METHODS: A randomized clinical trial assessed the diagnostic performance and cost-effectiveness of clinical teleconsultations (CTC) and clinical with dermoscopic teleconsultations. RESULTS: A total of 454 patients were enrolled in the trial (nCTC = 226, nclinical with dermoscopic teleconsultation = 228). Teledermoscopy improved sensitivity and specificity (92.86% and 96.24%, respectively) compared with CTC (86.57% and 72.33%, respectively). Correct decisions were made in 94.30% of patients through clinical with dermoscopic teleconsultations and in 79.20% in CTC (P < .001). The only variable associated with an increased likelihood of correct diagnosis was management using teledermoscopy (odds ratio 4.04; 95% confidence interval 2.02-8.09; P < .0001). The cost-effectiveness analysis showed teledermoscopy as the dominant strategy, with a lower cost-effectiveness ratio (65.13 vs 80.84). LIMITATIONS: Potentially, a limitation is the establishment of an experienced dermatologist as the gold standard for the in-person evaluation. CONCLUSIONS: The addition of dermoscopic images significantly improves the results of an internet-based skin cancer screening system, compared with screening systems based on clinical images alone.

Identification of calcium-transporting ATPases of Entamoeba histolytica and cellular localization of the putative SERCA.

Calcium has an important role on signaling of different cellular processes in the protozoa parasite Entamoeba histolytica, including development and pathogenesis. However, the systems that control calcium responses in this parasite are incompletely understood. Calcium-ATPases (Ca(2+)-ATPases) are proteins that play an important role in calcium homeostasis by catalyzing the active efflux of this ion from cytoplasm and are essential to the correct functioning of the cell machinery. Here, we reported the identification of five E. histolytica genes encoding putative Ca(2+)-ATPases, three related to PMCA, and two related to organellar ATPases. RT-PCR assays showed that all those genes are expressed in trophozoites and specific antibodies against the SERCA-like member located this protein in a continuous cytoplasmic network, supporting the hypothesis that it corresponds to the Ca(2+)-ATPase responsible to sequester calcium in the endoplasmic reticulum of this parasite.