Single-centre case series report of regional anaesthesia for pain management in vaso-occlusive crisis.

Sickle cell disease is characterised by episodes of vaso-occlusive crisis, a painful complication. Regional anaesthesia has shown promising results in reducing opioid consumption and pain scores. Patients with vaso-occlusive crises who underwent regional anaesthesia in the paediatric intensive care unit were studied. Data regarding pain location, regional analgesia technique, the local anaesthetic used and dose, daily opioid consumption, daily pain scores, use of adjuvants and complications were recorded. The primary outcome was to evaluate the effect of regional anaesthesia on opioid consumption. In this study, we describe 10 cases, referring to six paediatric patients with the vaso-occlusive crisis who underwent regional anaesthesia for severe pain and were unresponsive to increasing doses of opioids. Six cases received epidural analgesia, three continuous peripheral nerve blocks and one received both techniques. Opioid consumption was reduced (58%), and pain scores decreased (72%), both statistically significant reductions.

Persistence of symptoms and lung function in mild cases of COVID-19 six months after infection: a cross-sectional study.

OBJECTIVES: To describe persistent symptoms and lung function in mild cases of COVID-19 six months after infection. METHODS: Data collection was performed through a semi-structured questionnaire containing information on the participants' demographic and anthropometric data, the disease in the acute phase, and persistent symptoms six months after COVID-19 using spirometry and manovacuometry. RESULTS: A total of 136 participants were evaluated, of whom 64% were male, with a mean age of 38.17 ± 14.08 years and a body mass index (BMI) of 29.71 ± 17.48 kg/m2. The main persistent symptoms reported were dyspnea on exertion (39.7%), memory loss (38.2%), and anxiety (48.5%). Considering lung function, the participants reached 88.87 ± 17.20% of the predicted forced vital capacity (FVC), 86.03 ± 22.01% of the forced expiratory volume in one second (FEV1), and 62.71 ± 25.04% of peak expiratory flow (PEF). Upon manovacuometry, 97.41 ± 34.67% of the predicted inspiratory force (Pimax) and 66.86 ± 22.97% of the predicted expiratory force (Pemax) were observed. CONCLUSIONS: Six months after COVID-19 infection, a reduction in PEF and MEP was observed. Among the most commonly reported persistent symptoms were fatigue, tiredness with the slightest exertion, anxiety and depression, memory loss, and deficits in concentration.

Neuro-immune interactions in health and disease: Insights from FENS-Hertie 2022 Winter School.

In a great partnership, the Federation of European Neuroscience Societies (FENS) and the Hertie Foundation organized the FENS-Hertie 2022 Winter School on 'Neuro-immune interactions in health and disease'. The school selected 27 PhD students and 13 postdoctoral fellows from 20 countries and involved 14 faculty members experts in the field. The Winter School focused on a rising field of research, the interactions between the nervous and both innate and adaptive immune systems under pathological and physiological conditions. A fine-tuned neuro-immune crosstalk is fundamental for healthy development, while disrupted neuro-immune communication might play a role in neurodegeneration, neuroinflammation and aging. However, much is yet to be understood about the underlying mechanisms of these neuro-immune interactions in the healthy brain and under pathological scenarios. In addition to new findings in this emerging field, novel methodologies and animal models were presented to foment research on neuro-immunology. The FENS-Hertie 2022 Winter School provided an insightful knowledge exchange between students and faculty focusing on the latest discoveries in the biology of neuro-immune interactions while fostering great academic and professional opportunities for early-career neuroscientists from around the world.

Design and Evaluation of PROTACs Targeting Acyl Protein Thioesterase 1.

PROTAC linker design remains mostly an empirical task. We employed the PRosettaC computational software in the design of sulfonyl-fluoride-based PROTACs targeting acyl protein thioesterase 1 (APT1). The software efficiently generated ternary complex models from empirically-designed PROTACs and suggested alkyl linkers to be the preferred type of linker to target APT1. Western blotting analysis revealed efficient degradation of APT1 and activity-based protein profiling showed remarkable selectivity of an alkyl linker-based PROTAC amongst serine hydrolases. Collectively, our data suggests that combining PRosettaC and chemoproteomics can effectively assist in triaging PROTACs for synthesis and providing early data on their potency and selectivity.

Persistence of symptoms and lung function in mild cases of COVID-19 six months after infection: a cross-sectional study / Persistência de sintomas e função pulmonar em casos leves de COVID-19 seis meses após a infecção: um estudo transversal

ABSTRACT Objectives: To describe persistent symptoms and lung function in mild cases of COVID-19 six months after infection. Methods: Data collection was performed through a semi-structured questionnaire containing information on the participants' demographic and anthropometric data, the disease in the acute phase, and persistent symptoms six months after COVID-19 using spirometry and manovacuometry. Results: A total of 136 participants were evaluated, of whom 64% were male, with a mean age of 38.17 ± 14.08 years and a body mass index (BMI) of 29.71 ± 17.48 kg/m2. The main persistent symptoms reported were dyspnea on exertion (39.7%), memory loss (38.2%), and anxiety (48.5%). Considering lung function, the participants reached 88.87 ± 17.20% of the predicted forced vital capacity (FVC), 86.03 ± 22.01% of the forced expiratory volume in one second (FEV1), and 62.71 ± 25.04% of peak expiratory flow (PEF). Upon manovacuometry, 97.41 ± 34.67% of the predicted inspiratory force (Pimax) and 66.86 ± 22.97% of the predicted expiratory force (Pemax) were observed. Conclusions: Six months after COVID-19 infection, a reduction in PEF and MEP was observed. Among the most commonly reported persistent symptoms were fatigue, tiredness with the slightest exertion, anxiety and depression, memory loss, and deficits in concentration.

RESUMO Objetivos: Descrever os sintomas persistentes e a função pulmonar em casos leves de COVID-19 seis meses após a infecção. Métodos: A coleta de dados foi realizada por meio de um questionário semiestruturado contendo informações sobre dados demográficos e antropométricos dos participantes, a doença na fase aguda e os sintomas persistentes seis meses após a COVID-19, utilizando espirometria e manovacuometria. Resultados: Um total de 136 participantes foram avaliados, dos quais 64% eram do sexo masculino, com uma idade média de 38,17 ± 14,08 anos e índice de massa corporal (IMC) de 29,71 ± 17,48 kg/m2. Os principais sintomas persistentes relatados foram dispneia ao esforço (39,7%), perda de memória (38,2%) e ansiedade (48,5%). Considerando a função pulmonar, os participantes atingiram 88,87 ± 17,20% da capacidade vital forçada (CVF) prevista, 86,03 ± 22,01% do volume expiratório forçado no primeiro segundo (VEF1) e 62,71 ± 25,04% do pico de fluxo expiratório (PFE). Na manovacuometria, observou-se 97,41 ± 34,67% da força inspiratória prevista (Pimáx) e 66,86 ± 22,97% da força expiratória prevista (Pemáx). Conclusões: Seis meses após a infecção por COVID-19, observou-se uma redução no PFE e na PEM. Dentre os sintomas persistentes mais comumente relatados estavam fadiga, cansaço com o mínimo esforço, ansiedade e depressão, perda de memória e déficits de concentração.

Repeated mild traumatic brain injury causes sex-specific increases in cell proliferation and inflammation in juvenile rats.

Childhood represents a period of significant growth and maturation for the brain, and is also associated with a heightened risk for mild traumatic brain injuries (mTBI). There is also concern that repeated-mTBI (r-mTBI) may have a long-term impact on developmental trajectories. Using an awake closed head injury (ACHI) model, that uses rapid head acceleration to induce a mTBI, we investigated the acute effects of repeated-mTBI (r-mTBI) on neurological function and cellular proliferation in juvenile male and female Long-Evans rats. We found that r-mTBI did not lead to cumulative neurological deficits with the model. R-mTBI animals exhibited an increase in BrdU + (bromodeoxyuridine positive) cells in the dentate gyrus (DG), and that this increase was more robust in male animals. This increase was not sustained, and cell proliferation returning to normal by PID3. A greater increase in BrdU + cells was observed in the dorsal DG in both male and female r-mTBI animals at PID1. Using Ki-67 expression as an endogenous marker of cellular proliferation, a robust proliferative response following r-mTBI was observed in male animals at PID1 that persisted until PID3, and was not constrained to the DG alone. Triple labeling experiments (Iba1+, GFAP+, Brdu+) revealed that a high proportion of these proliferating cells were microglia/macrophages, indicating there was a heightened inflammatory response. Overall, these findings suggest that rapid head acceleration with the ACHI model produces an mTBI, but that the acute neurological deficits do not increase in severity with repeated administration. R-mTBI transiently increases cellular proliferation in the hippocampus, particularly in male animals, and the pattern of cell proliferation suggests that this represents a neuroinflammatory response that is focused around the mid-brain rather than peripheral cortical regions. These results add to growing literature indicating sex differences in proliferative and inflammatory responses between females and males. Targeting proliferation as a therapeutic avenue may help reduce the short term impact of r-mTBI, but there may be sex-specific considerations.

Herpetic Esophagitis: A Cause of Dysphagia in a Malnourished Patient.

Herpetic esophagitis (HE) is an esophageal infection caused by herpes simplex virus (HSV). Although less common, it can occasionally affect immunocompetent hosts. It can manifest as odynophagia and/or dysphagia and should lead to an investigation by upper digestive endoscopy with a biopsy. The authors report a case of a 65-year-old man with a past medical history relevant for schizophrenia, oligophrenia, and malnutrition, and no other history or evidence of immunosuppression, who presented with severe dysphagia over weeks and recent episodes of food aspiration with consequent pneumonia. An upper gastrointestinal endoscopy was performed, revealing severe stenosis at the level of the gastroesophageal junction with scar tissue, not transposable with the endoscope. The biopsy led to the diagnosis of hepatic esophagitis. Despite the immunocompetent status (excepting only the risk factor malnutrition) and treatment with acyclovir, with initial clinical improvement, the patient died a few weeks after diagnosis after multiple respiratory complications such as nosocomial infection. This case highlights that herpetic esophagitis is sometimes observed in immunocompetent hosts. HE has a self-limited course, with severe complications more frequent in immunosuppressed patients. However, it is also important to suspect this condition in immunocompetent patients and look for risk factors, given the potential morbidity this disease entails. In this group of patients, the presence of predisposing factors and associated comorbidities, such as malnutrition, alcohol consumption, or use of corticosteroids, have been associated with the development of viral esophagitis (including HE). HE remains a clinical challenge, especially in patients with risk factors for immunosuppression, such as malnutrition, as in the reported case.

Malignant Peritoneal Mesothelioma: A Case Report.

Malignant peritoneal mesothelioma (MPM) is a rare tumor of the serous membranes of the peritoneum and has been linked to exposure to asbestos and other risk factors. The clinical manifestations are vague, with a wide clinical spectrum, predominantly related to the abdominal involvement of the disease. Localized mesothelioma is an uncommon manifestation of the disease. Common symptoms include abdominal pain or abdominal distention, nausea, anorexia, and weight loss. Rarely, patients present with paraneoplastic syndrome. Due to the nonspecific symptoms, many patients already have advanced disease at the time of diagnosis. The authors report a case of a 75-year-old female patient who presented with symptoms of asthenia, anorexia, progressive paleness, and weight loss lasting five months. She reports later new-onset symptoms of diffuse abdominal pain and diarrhea associated with nausea. Laboratory tests showed anemia, mild leukocytosis, thrombocytosis, elevated C-reactive protein (CRP), and elevated liver enzymes. An abdominal and pelvic computed tomography (CT) scan revealed marked tissue thickening of an irregular and striated configuration of the leaflets and peritoneal reflections in an omental cake pattern, and a chest CT scan showed multiple bilateral pulmonary nodules, suggesting diffuse malignant disease. A CT-guided biopsy of a peritoneal implant was performed, establishing the diagnosis of malignant peritoneal mesothelioma. Due to rapid clinical deterioration, the patient did not receive any systemic treatment, surgery, or radiotherapy and was transitioned to comfort care. As in the presented case, most cases of MPM have diffuse peritoneal involvement at the time of diagnosis, although extra-abdominal involvement is very rare. This disease presentation is associated with high morbidity and mortality compared to cases of localized disease. There is no specific imaging diagnostic modality or valuable tumor markers for MPM. Although a CT scan remains important in the diagnostic approach, the changes found are not specific. Radiographically, MPM may present as mesenteric or parietal peritoneal nodules, visceral peritoneal thickening, ascites, or omental masses. Although these features may raise suspicion of MPM, a biopsy is necessary to confirm the diagnosis. Therefore, due to the rarity of this disease and its nonspecific signs or symptoms, MPM is difficult to diagnose, and the prognosis remains poor.

Merging the Isonitrile-Tetrazine (4+1) Cycloaddition and the Ugi Four-Component Reaction into a Single Multicomponent Process.

Multicomponent reactions are of utmost importance at generating a unique, wide, and complex chemical space. Herein we describe a novel multicomponent approach based on the combination of the isonitrile-tetrazine (4+1) cycloaddition and the Ugi four-component reaction to generate pyrazole amide derivatives. The scope of the reaction as well as mechanistic insights governing the 4H-pyrazol-4-imine tautomerization are provided. This multicomponent process provides access to a new chemical space of pyrazole amide derivatives and offers a tool for peptide modification and stapling.

Customizing 3D Structures of Vertically Aligned Carbon Nanotubes to Direct Neural Stem Cell Differentiation.

Neural tissue-related illnesses have a high incidence and prevalence in society. Despite intensive research efforts to enhance the regeneration of neural cells into functional tissue, effective treatments are still unavailable. Here, a novel therapeutic approach based on vertically aligned carbon nanotube forests (VA-CNT forests) and periodic VA-CNT micropillars produced by thermal chemical vapor deposition is explored. In addition, honeycomb-like and flower-like morphologies are created. Initial viability testing reveals that NE-4C neural stem cells seeded on all morphologies survive and proliferate. In addition, free-standing VA-CNT forests and capillary-driven VA-CNT forests are created, with the latter demonstrating enhanced capacity to stimulate neuritogenesis and network formation under minimal differentiation medium conditions. This is attributed to the interaction between surface roughness and 3D-like morphology that mimics the native extracellular matrix, thus enhancing cellular attachment and communication. These findings provide a new avenue for the construction of electroresponsive scaffolds based on CNTs for neural tissue engineering.

Unlocking the Potential of Bio-Based Nitrogen-Rich Furanic Platforms as Biomass Synthons.

The demand for new biomass-derived fine and commodity chemicals propels the discovery of new methodologies and synthons. Whereas furfural and 5-hydroxymethylfurfural are cornerstones of sustainable chemistry, 3-acetamido-5-acetyl furan (3A5AF), an N-rich furan obtained from chitin biomass, remains unexplored, due to the poor reactivity of the acetyl group relative to previous furanic aldehydes. Here we developed a reactive 3-acetamido-5-furfuryl aldehyde (3A5F) and demonstrated the utility of this synthon as a source of bio-derived nitrogen-rich heteroaromatics, carbocycles, and as a bioconjugation reagent.

Lane-Hamilton Syndrome in an Adult With Down Syndrome: A Case Report.

The Lane-Hamilton syndrome (LHS) is an extremely rare association between celiac disease (CD) and idiopathic pulmonary hemosiderosis (IPH), with only a few cases reported in the literature. The authors report a case of a 32-year-old man with Down syndrome who presented to the emergency department with a history of hemoptysis and chronic diarrhea. The complementary investigation revealed iron deficiency anemia and features suggestive of diffuse alveolar hemorrhage on computed tomography (CT) scan of the chest. After excluding all competing diagnosis, the IPH diagnosis was made. The biopsy of the small intestine confirmed CD and the diagnosis of LHS was established. A gluten-free diet and steroids were given to the patient with a very good clinical response. Since there is an established association between IPH and CD, if the diagnosis of IPH is made, it's recommended to screen for CD even in patients without gastrointestinal symptoms.

Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype.

Polo-like kinase 4 (Plk4), the major regulator of centriole biogenesis, has emerged as a putative therapeutic target in cancer due to its abnormal expression in human carcinomas, leading to centrosome number deregulation, mitotic defects and chromosomal instability. Moreover, Plk4 deregulation promotes tumor growth and metastasis in mouse models and is significantly associated with poor patient prognosis. Here, we further investigate the role of Plk4 in carcinogenesis and show that its overexpression significantly potentiates resistance to cell death by anoikis of nontumorigenic p53 knock-out (p53KO) mammary epithelial cells. Importantly, this effect is independent of Plk4's role in centrosome biogenesis, suggesting that this kinase has additional cellular functions. Interestingly, the Plk4-induced anoikis resistance is associated with the induction of a stable hybrid epithelial-mesenchymal phenotype and is partially dependent on P-cadherin upregulation. Furthermore, we found that the conditioned media of Plk4-induced p53KO mammary epithelial cells also induces anoikis resistance of breast cancer cells in a paracrine way, being also partially dependent on soluble P-cadherin secretion. Our work shows, for the first time, that high expression levels of Plk4 induce anoikis resistance of both mammary epithelial cells with p53KO background, as well as of breast cancer cells exposed to their secretome, which is partially mediated through P-cadherin upregulation. These results reinforce the idea that Plk4, independently of its role in centrosome biogenesis, functions as an oncogene, by impacting the tumor microenvironment to promote malignancy.

Curcumin-based molecular probes for fluorescence imaging of fungi.

Fluorescence imaging is a powerful and widely used method to visualize and study living organisms. However, fungi are notoriously difficult to visualize using fluorescence microscopy, given that their cell wall represents a diffusion barrier, and the synthetic organic dyes available are very limited when compared to molecular probes available for other organisms. Moreover, these dyes are usually available in only one colour, preventing co-staining experiments. To fill this gap, curcumin-based molecular probes were designed based on the rationale that curcumin is fluorescent and has moderate toxicity toward fungi, implying its ability to cross the cell wall to reach targets in the intracellular compartments. A family of boron diketonate complexes was synthesized, based on a curcumin backbone, tuning their emission color from blue to red. These probes did not present noticeable toxicity to filamentous fungus and, when applied to their visualization, readily entered the cells and precisely localized in sub-cellular organelles, enabling their visualization.

Upper Extremity Deep Vein Thrombosis as the Tip of the Iceberg: Case Report and Review of Literature.

Unprovoked venous thromboembolism (VTE) may be the earliest manifestation of cancer. According to recent studies, approximately 5% of patients with unprovoked VTE will be diagnosed with cancer within the first year of follow-up. Although screening extensively at the time of VTE diagnosis is attractive for clinicians, current clinical guidance documents suggest only a limited cancer screening strategy. The authors describe a rare case of Krukenberg tumor of the ovary arising from a primary gastric adenocarcinoma whose first sign was an unprovoked venous thrombosis of the upper extremity.

Cell therapies for spinal cord injury: a review of the clinical trials and cell-type therapeutic potential.

Spinal cord injury (SCI) is an as yet untreatable neuropathology that causes severe dysfunction and disability. Cell-based therapies hold neuroregenerative and neuroprotective potential, but, although being studied in SCI patients for more than two decades, long-term efficacy and safety remain unproven, and which cell types result in higher neurological and functional recovery remains under debate. In a comprehensive scoping review of 142 reports and registries of SCI cell-based clinical trials, we addressed the current therapeutical trends and critically analysed the strengths and limitations of the studies. Schwann cells, olfactory ensheathing cells (OECs), macrophages and various types of stem cells have been tested, as well as combinations of these and other cells. A comparative analysis between the reported outcomes of each cell type was performed, according to gold-standard efficacy outcome measures like the ASIA impairment scale, motor and sensory scores. Most of the trials were in the early phases of clinical development (phase I/II), involved patients with complete chronic injuries of traumatic aetiology and did not display a randomized comparative control arm. Bone marrow stem cells and OECs were the most commonly tested cells, while open surgery and injection were the main methods of delivering cells into the spinal cord or submeningeal spaces. Transplantation of support cells, such as OECs and Schwann cells, resulted in the highest ASIA Impairment Scale (AIS) grade conversion rates (improvements in ∼40% of transplanted patients), which surpassed the spontaneous improvement rate expected for complete chronic SCI patients within 1 year post-injury (5-20%). Some stem cells, such as peripheral blood-isolated and neural stem cells, offer potential for improving patient recovery. Complementary treatments, particularly post-transplantation rehabilitation regimes, may contribute highly to neurological and functional recovery. However, unbiased comparisons between the tested therapies are difficult to draw, given the great heterogeneity of the design and outcome measures used in the SCI cell-based clinical trials and how these are reported. It is therefore crucial to standardize these trials when aiming for higher value clinical evidence-based conclusions.

Health management of malnourished elderly in primary health care: a scoping review.

OBJECTIVES: The aim of this study, as the first review directed at Primary Health Care, is to identify the screening practices and health outcomes related to the care provided by Family Health Teams to the malnourished elderly people/population. METHODS: Following PRISMA and PICO strategies, searches were conducted in four electronic databases (PubMed, Web of Science, Scopus & EMBASE) on observational, qualitative, quantitative, or mixed studies, written in Portuguese, Spanish and English language, with participants of 65 years old or older at a community setting. The literature selected for this study ranges from the period 2011 to 2021; additional articles were included through reference lists. RESULTS: From the 483 studies identified, 16 were considered eligible to use in this work. The Mini Nutritional Assessment (MNA) score appears as the main criteria of choice, however, a standardized practice in the health systems regarding the use of screening methods has not been demonstrated. Studies are more oriented towards the analysis of the relationship of mortality/morbidity and malnutrition than towards the relationship of the cost and quality of life and malnutrition of the elderly. DISCUSSION: Malnutrition is one of the modifiable risk factors which contributes to the vulnerable condition of the elderly, with serious effects, especially when related to other comorbidities. Yet, several authors argue that the Primary Health Care intervention can minimize the negative impacts and improve the health outcomes.

Selective Inhibition of Bruton's Tyrosine Kinase by a Designed Covalent Ligand Leads to Potent Therapeutic Efficacy in Blood Cancers Relative to Clinically Used Inhibitors.

Bruton's tyrosine kinase (BTK) is a member of the TEC-family kinases and crucial for the proliferation and differentiation of B-cells. We evaluated the therapeutic potential of a covalent inhibitor (JS25) with nanomolar potency against BTK and with a more desirable selectivity and inhibitory profile compared to the FDA-approved BTK inhibitors ibrutinib and acalabrutinib. Structural prediction of the BTK/JS25 complex revealed sequestration of Tyr551 that leads to BTK's inactivation. JS25 also inhibited the proliferation of myeloid and lymphoid B-cell cancer cell lines. Its therapeutic potential was further tested against ibrutinib in preclinical models of B-cell cancers. JS25 treatment induced a more pronounced cell death in a murine xenograft model of Burkitt's lymphoma, causing a 30-40% reduction of the subcutaneous tumor and an overall reduction in the percentage of metastasis and secondary tumor formation. In a patient model of diffuse large B-cell lymphoma, the drug response of JS25 was higher than that of ibrutinib, leading to a 64% "on-target" efficacy. Finally, in zebrafish patient-derived xenografts of chronic lymphocytic leukemia, JS25 was faster and more effective in decreasing tumor burden, producing superior therapeutic effects compared to ibrutinib. We expect JS25 to become therapeutically relevant as a BTK inhibitor and to find applications in the treatment of hematological cancers and other pathologies with unmet clinical treatment.

The impact of modes of administration on self-reports of offending: evidence from a methodological experiment with university students.

Objectives: Current knowledge about the causes of offending behavior is heavily reliant on self-reports of offending (SRO). However, methodological research on the impact of modes of administration on SRO is very scarce. Further, the existing evidence conflicts with the general knowledge about responding to sensitive questions. In this study, we aimed to test whether SRO are affected by modes of administration. Methods: We carried out a methodological experiment, with a 2 (interviewer-administered vs. self-administered surveys) × 2 (paper-and-pencil vs. computer- assisted surveys) factorial design. A total of 181 undergraduate students were randomly assigned to one of these conditions and completed the International Self-Report Delinquency 3 (ISRD3) questionnaire. Results: Findings showed an increased odds of reporting offending behavior in self-administered surveys, compared to face-to-face interviews. Paper-and-pencil and computer-assisted modes resulted in comparable estimates of offending. Conclusions: This experiment provides evidence that SRO provide more accurate estimates of offending behavior using self-administered surveys.