CO and CO2 adsorption mechanism in Fe(pz)[Pt(CN)4] probed by neutron scattering and density-functional theory calculations.

We study the binding mechanism of CO and CO2 in the porous spin-crossover compound Fe(pz)[Pt(CN)4] by combining neutron diffraction (ND), inelastic neutron scattering (INS) and density-functional theory (DFT) calculations. Two adsorption sites are identified, above the open-metal site and between the pyrazine rings. For CO adsorption, the guest molecules are parallel to the neighboring gas molecules and perpendicular to the pyrazine planes. For CO2, the molecules adsorbed on-top of the open-metal site are perpendicular to the pyrazine rings and those between the pyrazines are almost parallel to them. These configurations are consistent with the INS data, which are in good agreement with the computed generalized phonon density of states. The most relevant signatures of the binding occur in the spectral region around 100 cm-1 and 400 cm-1. The first peak blue-shifts for both CO and CO2 adsorption, while the second red-shifts for CO and remains nearly unchanged for CO2. These spectral changes depend both from steric effects and the nature of the interaction. The interpretation of the INS data as supported by the computed binding energy and the molecular orbital analysis are consistent with a physisorption mechanism for both gases. This work shows the strength of the combination of neutron techniques and DFT calculations to characterize in detail the gas adsorption mechanism in this type of materials.

BRAF/MEK Dual Inhibitors Therapy in Progressive and Anaplastic Pleomorphic Xanthoastrocytoma: Case Series and Literature Review.

Recurrent and anaplastic pleomorphic xanthoastrocytoma (r&aPXA) is a rare primary brain tumor that is challenging to treat. Two-thirds of PXA tumors harbor a BRAF gene mutation. BRAF inhibitors have been shown to improve tumor control. However, resistance to BRAF inhibition develops in most cases. Concurrent therapy with MEK inhibitors may improve tumor control and patient survival. In this study, we identified 5 patients diagnosed with BRAF-mutated PXA who received BRAF and MEK inhibitors over a 10-year interval at our institution. Patient records were evaluated, including treatments, adverse effects (AEs), outcomes, pathology, next-generation sequencing, and MRI. The median age was 22 years (range, 14-66 years), 60% male, and 60% anaplastic PXA. Median overall survival was 72 months (range, 19-112 months); 1 patient died of tumor-related hemorrhage while off therapy, and the other 4 experienced long-term disease control (21, 72, 98, and 112 months, respectively). Dual BRAF/MEK inhibitors were well tolerated, with only grade 1-2 AEs, including rash, neutropenia, fatigue, abdominal discomfort, and diarrhea. No grade 3-5 AEs were detected. A literature review was also performed of patients diagnosed with BRAF-mutated PXA and treated with BRAF and/or MEK inhibitors through August 2021, with a total of 32 cases identified. The median age was 29 years (range, 8-57 years) and the median PFS and OS were 8.5 months (range, 2-35 months) and 35 months (range, 10-80 months), respectively. The most common AEs were grade 1-2 fatigue and skin rash. Results of this case series and literature review indicate that dual-drug therapy with BRAF and MEK inhibitors for r&aPXA with BRAF V600E mutation may delay tumor progression without unexpected AEs.

Impacts of genotypic variants on survival following reoperation for recurrent glioblastoma.

INTRODUCTION: Recurrent glioblastoma (rGBM) prognosis is dismal. In the absence of effective adjuvant treatments for rGBM, re-resections remain prominent in our arsenal. This study evaluates the impact of reoperation on post-progression survival (PPS) considering rGBM genetic makeup. METHODS: To assess the genetic heterogeneity and treatment-related changes (TRC) roles in re-operated or medically managed rGBMs, we compiled demographic, clinical, histopathological, and next-generation genetic sequencing (NGS) characteristics of these tumors from 01/2005 to 10/2019. Survival data and reoperation were analyzed using conventional and random survival forest analysis (RSF). RESULTS: Patients harboring CDKN2A/B loss (p = 0.017) and KDR mutations (p = 0.031) had notably shorter survival. Reoperation or bevacizumab were associated with longer PPS (11.2 vs. 7.4-months, p = 0.006; 13.1 vs 6.2, p < 0.001). Reoperated patients were younger, had better performance status and greater initial resection. In 136/273 (49%) rGBMs undergoing re-operation, CDKN2A/B loss (p = 0.03) and KDR mutations (p = 0.02) were associated with shorter survival. In IDH-WT rGBMs with NGS data (n = 166), reoperation resulted in 7.0-month longer survival (p = 0.004) than those managed medically. This reoperation benefit was independently identified by RSF analysis. Stratification analysis revealed that EGFR-mutant, CDKN2A/B-mutant, NF1-WT, and TP53-WT rGBM IDH-WT subgroups benefit most from reoperation (p = 0.03). Lastly, whether or not TRC was prominent at re-operation does not have any significant impact on PPS (10.5 vs. 11.5-months, p = 0.77). CONCLUSIONS: Maximal safe re-resection significantly lengthens PPS regardless of genetic makeup, but reoperations are especially beneficial for IDH-WT rGBMs with EGFR and CDKN2A/B mutations with TP53-WT, and NF1-WT. Histopathology at recurrence may be an imperfect gauge of disease severity at progression and the imaging progression may be more reflective of the prognosis.

Clinical ApoA-IV amyloid is associated with fibrillogenic signal sequence.

Apolipoprotein A-IV amyloidosis is an uncommon form of the disease normally resulting in renal and cardiac dysfunction. ApoA-IV amyloidosis was identified in 16 patients attending the National Amyloidosis Centre and in eight clinical samples received for histology review. Unexpectedly, proteomics identified the presence of ApoA-IV signal sequence residues (p.18-43 to p.20-43) in 16/24 trypsin-digested amyloid deposits but in only 1/266 non-ApoA-IV amyloid samples examined. These additional signal residues were also detected in the cardiac sample from the Swedish patient in which ApoA-IV amyloid was first described, and in plasma from a single cardiac ApoA-IV amyloidosis patient. The most common signal-containing peptide observed in ApoA-IV amyloid, p.20-43, and to a far lesser extent the N-terminal peptide, p.21-43, were fibrillogenic in vitro at physiological pH, generating Congo red-positive fibrils. The addition of a single signal-derived alanine residue to the N-terminus has resulted in markedly increased fibrillogenesis. If this effect translates to the mature circulating protein in vivo, then the presence of signal may result in preferential deposition as amyloid, perhaps acting as seed for the main circulating native form of the protein; it may also influence other ApoA-IV-associated pathologies. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Flipped Learning 4.0. An extended flipped classroom model with Education 4.0 and organisational learning processes.

This article integrates two visions on the creation of knowledge by students: an academic vision where the person who creates knowledge uses high-level cognitive abilities and, therefore, acquires deeper learning, and an organisational learning vision, where the creation of knowledge adds value to the organisation and the individuals who work in this matter. It starts from a validated flipped classroom model and then adds procedures and cycles of knowledge that make it an active methodology, in such a way that it simultaneously supports organisational learning, using cooperative competencies characteristic of Education 4.0. This proposed hybrid model has been applied online during confinement due to the COVID-19 pandemic and, subsequently, in dual mode (students partly in person and the rest online at the same time) and face-to-face mode. The evidence of this research shows that the creation of knowledge by the students, cooperatively and with an organisational learning perspective, has repercussions for improvements in their academic performance by producing deeper learning. In addition, the development of cooperative skills is observed to create and manage a large amount of helpful knowledge for them and other students in their learning process.

Genomic alterations predictive of response to radiosurgery in recurrent IDH-WT glioblastoma.

INTRODUCTION: Despite aggressive treatment, glioblastoma invariably recurs. The optimal treatment for recurrent glioblastoma (rGBM) is not well defined. Stereotactic radiosurgery (SRS) for rGBM has demonstrated favorable outcomes for selected patients; however, its efficacy in molecular GBM subtypes is unknown. We sought to identify genetic alterations that predict response/outcomes from SRS in rGBM-IDH-wild-type (IDH-WT). METHODS: rGBM-IDH-WT patients undergoing SRS at first recurrence and tested by next-generation sequencing (NGS) were reviewed (2009-2018). Demographic, clinical, and molecular characteristics were evaluated. NGS interrogating 205-genes was performed. Primary outcome was survival from GK-SRS assessed by Kaplan-Meier method and multivariable Cox proportional-hazards. RESULTS: Sixty-three lesions (43-patients) were treated at 1st recurrence. Median age was 61-years. All patients were treated with resection and chemoradiotherapy. Median time from diagnosis to 1st recurrence was 8.7-months. Median cumulative volume was 2.895 cm3 and SRS median marginal dose was 18 Gy (median isodose-54%). Bevacizumab was administered in 81.4% patients. PFS from SRS was 12.9-months. Survival from SRS was 18.2-months. PTEN-mutant patients had a longer PFS (p = 0.049) and survival from SRS (p = 0.013) in multivariable analysis. Although no statistically significant PTEN-mutants patients had higher frequency of radiation necrosis (21.4% vs. 3.4%) and lower in-field recurrence (28.6% vs. 37.9%) compared to PTEN-WT patients. CONCLUSIONS: SRS is a safe and effective treatment option for selected rGBM-IDH-WT patients following first recurrence. rGBM-IDH-WT harboring PTEN-mutation have improved survival with salvage SRS compared to PTEN-WT patients. PTEN may be used as a molecular biomarker to identify a subset of rGBM patients who may benefit the most from SRS.

Diagnostic amyloid proteomics: experience of the UK National Amyloidosis Centre.

Systemic amyloidosis is a serious disease which is caused when normal circulating proteins misfold and aggregate extracellularly as insoluble fibrillary deposits throughout the body. This commonly results in cardiac, renal and neurological damage. The tissue target, progression and outcome of the disease depends on the type of protein forming the fibril deposit, and its correct identification is central to determining therapy. Proteomics is now used routinely in our centre to type amyloid; over the past 7 years we have examined over 2000 clinical samples. Proteomics results are linked directly to our patient database using a simple algorithm to automatically highlight the most likely amyloidogenic protein. Whilst the approach has proved very successful, we have encountered a number of challenges, including poor sample recovery, limited enzymatic digestion, the presence of multiple amyloidogenic proteins and the identification of pathogenic variants. Our proteomics procedures and approaches to resolving difficult issues are outlined.

A novel simple, fast, and safe approach for effective superior vena cava isolation using the third-generation cryoballoon.

BACKGROUND: Superior vena cava (SVC) isolation with radiofrequency energy remains a challenge due to potential side effects, especially phrenic nerve (PN) or sinus node injury. The purpose of this study was to evaluate the feasibility of a novel SVC isolation technique using the third-generation cryoballoon (CB3). METHODS: Patients undergoing atrial fibrillation (AF) ablation were prospectively included. The procedure was performed with the CB3, beginning with the pulmonary veins and ending with SVC isolation. During applications in the SVC, continuous PN capture and sinus rate were monitored. Once reached SVC isolation during the application, 60 s more was applied, with no bonus application. If after 90 s the SVC was not isolated, application was stopped. A maximum number of four applications were permitted. RESULTS: Thirty patients (62 ± 9 years; 74% male, 78% paroxysmal AF) were included. No SVC activity was observed in two patients. Success rate for SVC isolation was 89%. Mean number of applications per patient was 2.3 ± 1. Mean time to SVC isolation was 37 ± 20  s. Mean duration of application was 92 ± 15 s. Mean total time of procedure for SVC isolation was 218 ± 43 s. We recorded only two complications: one transient PN palsy and one short and transient sinus arrest. After a mean follow-up of 5 ± 2 months, 89% are free from arrhythmia recurrence. CONCLUSIONS: We present a promising simple SVC-isolation technique using CB3, featuring a high success rate and very low incidence of complications.

Manifest preexcitation with a prolonged PR interval: What is the mechanism?

A 44-year-old woman with a past history of surgical ablation of an accessory pathway presented to our facility with episodes of palpitations and dizziness. An ECG showed sinus rhythm with a prolonged PR interval and a preexcited QRS complex. An EP study revealed AV conduction through a postero-septal accessory pathway and a prolonged PR interval due to severe intra-atrial conduction delay.

Thinking Outside the "Blue Box": Induced Fit within a Unique Self-Assembled Polycationic Cyclophane.

We present herein the development of a new polycationic molecular receptor, inspired by the ubiquitous cyclobis(paraquat- p-phenylene)cyclophane ("blue box"). Our analogue, the "white box", has been easily self-assembled on a preparative scale in water, using a template-assisted process by acyl hydrazone bonding of complementary bis(pyridinium)xylylene tweezers, followed by kinetic trapping of the empty receptor. The obtained macrocycle was found to display a marked pH responsiveness in water, because of an abnormal acidity of the amide protons within its structure. Consequently, and because of the concurrence of rotational isomerism under acidic conditions (fixed at higher pH values), the compound was found to display a dual behavior as a conformationally locked/flexible molecular host, being able to recognize appropriate aromatic substrates, in a lock and key or induced fit fashion, by a conjunction of π-π, C-H···π, and, crucially, the hydrophobic effect.

Cerebral Radiation Necrosis: Incidence, Pathogenesis, Diagnostic Challenges, and Future Opportunities.

PURPOSE OF REVIEW: Cerebral radiation necrosis (CRN) is a major dose-limiting adverse event of radiotherapy. The incidence rate of RN varies with the radiotherapy modality, total dose, dose fractionation, and the nature of the lesion being targeted. In addition to these known and controllable features, there is a stochastic component to the occurrence of CRN-the genetic profile of the host or the lesion and their role in the development of CRN. RECENT FINDINGS: Recent studies provide some insight into the genetic mechanisms underlying radiation-induced brain injury. In addition to these incompletely understood host factors, the diagnostic criteria for CRN using structural and functional imaging are also not clear, though multiple structural and functional imaging modalities exist, a combination of which may prove to be the ideal diagnostic imaging approach. As the utilization of novel molecular therapies and immunotherapy increases, the incidence of CNR is expected to increase and its diagnosis will become more challenging. Tissue biopsies can be insensitive and suffer from sampling biases and procedural risks. Liquid biopsies represent a promising, accurate, and non-invasive diagnostic strategy, though this modality is currently in its infancy. A better understanding of the pathogenesis of CRN will expand and optimize the diagnosis and management of CRN by better utilizing existing treatment options including bevacizumab, pentoxifylline, hyperbaric oxygen therapy, and laser interstitial thermal therapy.

P-wave and interatrial block: New predictor for atrial high rate episodes in patients with cardiac implantable electronic devices.

BACKGROUND: The presence of interatrial block (IAB) is associated with the development of atrial fibrillation (AF). The aim of this study was to determine whether P-wave duration and presence of IAB before the implantation of a cardiac implantable electronic device (CIED) are associated with the presence of atrial high rate episodes (AHRE), during long-term follow-up. METHODS: 380 patients (57% men; 75 ± 10 years) were included. IAB was defined according to the International Consensus Criteria. AHRE was defined as an episode of atrial rate ≥225 beats/min with a minimum duration of 5 minutes. RESULTS: Documented paroxysmal AF before the implantation was present in 24% of the patients; 80% had hypertension and 32% structural heart disease. Mean P-wave duration was 123 ± 23 ms, and 39% of the patients had IAB (32% partial, 7% advanced). After a mean follow-up of 18 ± 12 months, 33% of the patients presented AHRE. Patients with AHRE had a P-wave duration significantly longer (130 ± 24 ms vs 119 ± 21 ms; P < 0.001) and a greater prevalence of IAB (53% vs 32%; P < 0.001). In a multivariate analysis, predictors of AHRE were: IAB (odds ratio [OR] 2.1; 95% confidence interval [CI] [1.3-3.4], P < 0.001) and previous paroxysmal AF (OR 2.6; 95% CI [1.5-4.3], P < 0.001). In patients without previous AF, the presence of IAB was also a significant predictor of AHRE (OR 3.1; 95% CI [1.8-5.5], P < 0.001). CONCLUSIONS: IAB is a strong predictor of AHRE in patients with CIED. This finding is independent of the presence of prior paroxysmal AF.

An "inappropriately appropriate" shock in a subcutaneous implantable cardioverter-defibrillator: The importance of the SMART pass algorithm.

We report on a case of a 78-years-old patient with a subcutaneous implantable cardioverter defibrillator (S-ICD) and an episode of a sustained ventricular tachycardia (VT) at a rate slower than the programmed shock zone. Because of T-wave oversensing the device interpreted it as fast VT that triggered the delivery of an "inappropriately appropriate shock" that terminated it. The patient had again more VT episodes but after programming the SMART pass algorithm (previously programmed "OFF") the device showed no longer frequent T-wave oversensing and no additional inappropriate shocks occurred.

Diversity and Pathogenicity of Rhizoctonia Species from the Brazilian Cerrado.

Eighty-one Rhizoctonia-like isolates were identified based on morphology and nuclei-staining methods from natural and agricultural soils of the Cerrado (Brazilian savanna). The nucleotide similarity analysis of ITS1-5.8S-ITS2 regions identified 14 different taxa, with 39.5% of isolates assigned to Waitea circinata (zeae, oryzae, and circinata varieties), while 37.0% belonged to Thanatephorus cucumeris anastomosis groups (AGs) AG1-IB, AG1-ID, AG1-IE, AG4-HGI, and AG4-HGIII. Ceratobasidium spp. AG-A, AG-F, AG-Fa, AG-P, and AG-R comprised 23.5%. Rhizoctonia zeae (19.8%), R. solani AG1-IE (18.6%), and binucleate Rhizoctonia AG-A (8.6%) were the most frequent anamorphic states found. Root rot severity caused by the different taxa varied from low to high on common beans, and tended to be low to average in maize. Twenty-two isolates were pathogenic to both hosts, suggesting difficulties in managing Rhizoctonia root rots with crop rotation. These results suggest that cropping history affects the geographical arrangement of AGs, with a prevalence of AG1 in the tropical zone from central to north Brazil while the AG4 group was most prevalent from central to subtropical south. W. circinata var. zeae was predominant in soils under maize production. To our knowledge, this is the first report on the occurrence of W. circinata var. circinata in Brazil.

Using game authoring platforms to develop screen-based simulated functional assessments in persons with executive dysfunction following traumatic brain injury.

The assessment of functional status is a critical component of clinical neuropsychological evaluations used for both diagnostic and therapeutic purposes in patients with cognitive brain disorders. There are, however, no widely adopted neuropsychological tests that are both ecologically valid and easily administered in daily clinical practice. This discrepancy is a roadblock to the widespread adoption of functional assessments. In this paper, we propose a novel approach using a serious game authoring platform (eAdventure) for creating screen-based simulated functional assessments. We created a naturalistic functional task that consisted of preparing a cup of tea (SBS-COT) and applied the assessment in a convenience sample of eight dyads of therapists/patients with mild executive dysfunction after traumatic brain injury. We had three main aims. First, we performed a comprehensive review of executive function assessment in activities of daily living. Second, we were interested in measuring the feasibility of this technology with respect to staffing, economic and technical requirements. Third, a serious game was administered to patients to study the feasibility of this technology in the clinical context (pre-screening test). In addition, quantitative (Technology Acceptance Model (TAM) questionnaires) and qualitative (semistructured interviews) evaluations were applied to obtain user input. Our results suggest that the staffing, economic and technical requirements of the SBS-COT are feasible. The outcomes of the pre-screening test provide evidence that this technology is useful in the functional assessment of patients with executive dysfunction. In relation to subjective data, the TAM questionnaire showed good user acceptability from a professional perspective. Interview analyses with professionals and patients showed positive experiences related to the use of the SBS-COT. Our work indicates that the use of these types of authoring platforms could have positive long-term implications for neuropsychological research, opening the door to more reproducible, cooperative and efficient research by allowing the facilitated production, reuse and sharing of neuropsychological assessment tools.

Effect of the I/E ratio on CO2 removal during high-frequency oscillatory ventilation with volume guarantee in a neonatal animal model of RDS.

UNLABELLED: The objective of this study was to analyze the effect of I/E ratio on carbon dioxide (CO2) elimination during high-frequency oscillatory ventilation (HFOV) combined with volume guarantee (VG). Five 2-day-old piglets were studied before and after a bronchoalveolar lavage (BAL). The effect of an I/E ratio of 1:1 and 1:2 with (VG-ON) and without VG (VG-OFF) on PaCO2, as well as delta and mean airway pressures at the airway opening (∆Phf-ao, mPaw-ao) and at the tracheal level (∆Phf-t, mPaw-t) were evaluated at frequencies of 5, 8, 11, and 14 Hz. With the VG-ON, PaCO2 was significant lower with the I/E ratio of 1:2 at 5 Hz compared with the 1:1. mPaw-t was higher than mPaw-ao, with 1:1 I/E ratio, and on VG-ON, this difference was statistically significant. CONCLUSION: "In this animal study and with this ventilator, the I/E ratio of 1:1 compared to 1:2 in HFOV and VG-ON did not produce a higher CO2 lavage as when HFOV was used without the VG modality. Even more, a lower PaCO2 was found when using the lower frequency and 1:2 ratio compared to 1:1. So in contrast to non-VG HFOV mode, using a fixed tidal volume, no significant changes on CO2 elimination are observed during HFOV when the I/E ratios of 1:1 and 1:2 are compared at different frequencies." WHAT IS KNOWN: •The tidal volume on HFOV is determinant in CO 2 removal, and this is generated by delta pressure and the length of the inspiratory time. What is New: •HFOV combined with VG, an I/E ratio of 1:2 is more effective to remove CO 2 , and this is not related to the tidal volume.

Chronological and environmental context of the first hominin dispersal into Western Europe: The case of Barranco León (Guadix-Baza Basin, SE Spain).

The early Pleistocene site of Barranco León (Guadix-Baza Basin, SE Spain), dated to 1.4 Ma (millions of years ago), records the oldest hominin occurrence in Western Europe, as evidenced by the discovery of one tooth and thousands of Mode 1 stone tools. In this paper a detailed analysis of the microvertebrate content of the D1 and D2 units from this site is presented. The early Pleistocene in the Guadix-Baza Basin is characterized by a sharp climatic deterioration, which possibly impeded the settlement of this region by the early hominin population from the southern Caucasus. Shortly afterwards, when the climatic conditions were again favorable, a hominin presence is suddenly evidenced at the units D1 and D2 of Barranco León. According to the microvertebrate analysis of these units, the mean annual temperature at the time of deposition was significantly higher than 13 °C, with prevalent humid conditions. However, although most of the species were inhabitants of water edges, an open landscape was present in the vicinity of the lake. The data reported here clearly support the idea that the early hominin occupation of Europe was strongly constrained by climatic and environmental conditions, rather than by physiography or cultural factors.

Acro-Ischemia Associated With SARS-CoV-2: A Case Report.

COVID-19 is known to cause various cutaneous lesions, including acro-ischemic lesions (AIL), which are associated with poor prognosis. Anticoagulant therapy has shown positive responses in AIL patients. However, in this case study, we present a fatal AIL case despite anticoagulant therapy. We propose different treatment approaches based on the limited current data on acro-ischemia pathogenesis related to SARS-CoV-2. The clinical case involved a 59-year-old male with severe COVID-19 symptoms, including acrocyanosis and right hemiparesis. Despite receiving anticoagulant therapy, the patient's condition worsened, leading to necrosis in the left foot. The discussion focuses on the high-risk nature of AIL, the potential link between angiotensin-converting enzyme 2 (ACE2) receptors and vasculitis or thromboembolic manifestations, and the role of immune clots in AIL pathogenesis. Behçet syndrome is referenced as a model of inflammation-induced thrombosis, guiding the suggestion for immunosuppressant-based treatment in addition to anticoagulants. Additionally, three substances, N-acetyl cysteine, sulodexide, and hydroxychloroquine, are proposed.