Therapeutic Importance of Exercise in Neuroplasticity in Adults with Neurological Pathology: Systematic Review.

Neuroplasticity is an essential mechanism by which the nervous system shapes and adapts according to functional requirements. Evidence suggests that physical exercise induces a cascade of cellular processes that favours brain plasticity. The Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin closely linked to neuroplasticity that can be increased due to exercise. To verify the effects of therapeutic exercise on neuroplasticity and/or peripheral BDNF levels in neurological conditions in adults, such as stroke, Parkinson's and Alzheimer's diseases and mild cognitive impairment and address its clinical relevance in the treatment of neurological dysfunctions. A systematic review was carried using PUBMED, Web of Science and Scopus databases. Inclusion criteria were: randomized controlled trials or pilot studies; humans with age > 18 yrs with neurological condition; English language; score ≥ 6 in PEDro Scale (moderate to high quality). Reviews, meta-analyses and other articles that did not meet the criteria were excluded. The PRISMA methodology was applied for studies' selection. A total of 9 studies were selected for a systematic and comprehensive analysis. According to these studies, moderate to high intensity aerobic exercise (AE), increases the level of peripheral BDNF and positively influences functional gains in neurological conditions. Larger outcomes are observed in protocols with minimum session duration of 30 minutes, frequency of 3 times/week and intervention duration of 4 weeks. Current evidence shows that moderate to high intensity AE induces neuroplasticity in neurological patients, thus being a fundamental therapeutic strategy to include in interventions aiming to repair/delay neurological dysfunctions.

Preimplantation genetic testing: A narrative review.

Preimplantation genetic testing (PGT) is a diagnostic procedure that has become a powerful complement to assisted reproduction techniques. PGT has numerous indications, and there is a wide range of techniques that can be used, each with advantages and limitations that should be considered before choosing the more adequate one. In this article, it is reviewed the indications for PGT, biopsy and diagnostic technologies, along with their evolution, while also broaching new emerging methods.

Traumatic abdominal wall hernia in childhood: a bicycle handlebar injury.

A female patient in her middle childhood presented to the paediatric emergency room (ER) after a bicycle accident with an abdominal impact on the bicycle handlebar. On physical examination, a painful ecchymosis on the upper left quadrant was the only abnormal finding. Abdominal ultrasound showed no intra-abdominal lesions, and the patient was discharged home after 24 hours under monitoring. Nine days after the accident, she returned to the ER due to the emergence of an abdominal mass around the area of impact. Abdominal examination detected a tender non-fluctuating mass on the epigastric and left hypochondrium, and abdominal ultrasound revealed a muscle and aponeurosis disruption of the rectus muscle, with fat herniation and cytosteatonecrosis. A conservative approach was chosen, with ambulatory follow-up. One month after the accident, the patient was asymptomatic, no abdominal mass was palpable, and an abdominal CT showed a reduction of the muscle disruption and hernial content.

Using AI-Based Technologies to Help Nurses Detect Behavioral Disorders: Narrative Literature Review.

BACKGROUND: The behavioral and psychological symptoms of dementia (BPSD) are common among people with dementia and have multiple negative consequences. Artificial intelligence-based technologies (AITs) have the potential to help nurses in the early prodromal detection of BPSD. Despite significant recent interest in the topic and the increasing number of available appropriate devices, little information is available on using AITs to help nurses striving to detect BPSD early. OBJECTIVE: The aim of this study is to identify the number and characteristics of existing publications on introducing AITs to support nursing interventions to detect and manage BPSD early. METHODS: A literature review of publications in the PubMed database referring to AITs and dementia was conducted in September 2023. A detailed analysis sought to identify the characteristics of these publications. The results were reported using a narrative approach. RESULTS: A total of 25 publications from 14 countries were identified, with most describing prospective observational studies. We identified three categories of publications on using AITs and they are (1) predicting behaviors and the stages and progression of dementia, (2) screening and assessing clinical symptoms, and (3) managing dementia and BPSD. Most of the publications referred to managing dementia and BPSD. CONCLUSIONS: Despite growing interest, most AITs currently in use are designed to support psychosocial approaches to treating and caring for existing clinical signs of BPSD. AITs thus remain undertested and underused for the early and real-time detection of BPSD. They could, nevertheless, provide nurses with accurate, reliable systems for assessing, monitoring, planning, and supporting safe therapeutic interventions.

Unplanned transfer to acute care during inpatient geriatric rehabilitation: incidence, risk factors, and associated short-term outcomes.

BACKGROUND: Information is scarce on unplanned transfers from geriatric rehabilitation back to acute care despite their potential impact on patients' functional recovery. This study aimed 1) to determine the incidence rate and causes of unplanned transfers; 2) to compare the characteristics and outcomes of patients with and without unplanned transfer. METHODS: Consecutive stays (n = 2375) in a tertiary geriatric rehabilitation unit were included. Unplanned transfers to acute care and their causes were analyzed from discharge summaries. Data on patients' socio-demographics, health, functional, and mental status; length of stay; discharge destination; and death, were extracted from the hospital database. Bi- and multi-variable analyses investigated the association between patients' characteristics and unplanned transfers. RESULTS: One in six (16.7%) rehabilitation stays was interrupted by a transfer, most often secondary to infections (19.3%), cardiac (16.8%), abdominal (12.7%), trauma (12.2%), and neurological problems (9.4%). Older patients (AdjORage≥85: 0.70; 95%CI: 0. 53-0.94, P = .016), and those admitted for gait disorders (AdjOR: 0.73; 95%CI: 0.53-0.99, P = .046) had lower odds of transfer to acute care. In contrast, men (AdjOR: 1.71; 95%CI: 1.29-2.26, P < .001), patients with more severe disease (AdjORCIRS: 1.05; 95%CI: 1.02-1.07, P < .001), functional impairment before (AdjOR: 1.69; 95%CI: 1.05-2.70, P = .029) and at rehabilitation admission (AdjOR: 2.07; 95%CI: 1.56- 2.76, P < .001) had higher odds of transfer. Transferred patients were significantly more likely to die than those without transfer (AdjOR 13.78; 95%CI: 6.46-29.42, P < .001) during their stay, but those surviving had similar functional performance and rate of home discharge at the end of the stay. CONCLUSION: A significant minority of patients experienced an unplanned transfer that potentially interfered with their rehabilitation and was associated with poorer outcomes. Men, patients with more severe disease and functional impairment appear at increased risk. Further studies should investigate whether interventions targeting these patients may prevent unplanned transfers and modify associated adverse outcomes.

Direct coupled electrical stimulation towards improved osteogenic differentiation of human mesenchymal stem/stromal cells: a comparative study of different protocols.

Electrical stimulation (ES) has been described as a promising tool for bone tissue engineering, being known to promote vital cellular processes such as cell proliferation, migration, and differentiation. Despite the high variability of applied protocol parameters, direct coupled electric fields have been successfully applied to promote osteogenic and osteoinductive processes in vitro and in vivo. Our work aims to study the viability, proliferation, and osteogenic differentiation of human bone marrow-derived mesenchymal stem/stromal cells when subjected to five different ES protocols. The protocols were specifically selected to understand the biological effects of different parts of the generated waveform for typical direct-coupled stimuli. In vitro culture studies evidenced variations in cell responses with different electric field magnitudes (numerically predicted) and exposure protocols, mainly regarding tissue mineralization (calcium contents) and osteogenic marker gene expression while maintaining high cell viability and regular morphology. Overall, our results highlight the importance of numerical guided experiments to optimize ES parameters towards improved in vitro osteogenesis protocols.

How does the electric field induced by tDCS influence motor-related connectivity? Model-guided perspectives.

Over the last decade, transcranial direct current stimulation (tDCS) has been applied not only to modulate local cortical activation, but also to address communication between functionally-related brain areas. Stimulation protocols based on simple two-electrode placements are being replaced by multi-electrode montages to target intra- and inter-hemispheric neural networks using multichannel/high definition paradigms.Objective. This study aims to investigate the characteristics of electric field (EF) patterns originated by tDCS experiments addressing changes in functional brain connectivity.Methods. A previous selection of tDCS experimental studies aiming to modulate motor-related connectivity in health and disease was conducted. Simulations of the EF induced in the cortex were then performed for each protocol selected. The EF magnitude and orientation are determined and analysed in motor-related cortical regions for five different head models to account for inter-subject variability. Functional connectivity outcomes obtained are qualitatively analysed at the light of the simulated EF and protocol characteristics, such as electrode position, number and stimulation dosing.Main findings. The EF magnitude and orientation predicted by computational models can be related with the ability of tDCS to modulate brain functional connectivity. Regional differences in EF distributions across subjects can inform electrode placements more susceptible to inter-subject variability in terms of brain connectivity-related outcomes.Significance. Neuronal facilitation/inhibition induced by tDCS fields may indirectly influence intra and inter-hemispheric connectivity by modulating neural components of motor-related networks. Optimization of tDCS using computational models is essential for adequate dosing delivery in specific networks related to clinically relevant connectivity outcomes.

Novel approaches to motoneuron disease/ALS treatment using non-invasive brain and spinal stimulation: IFCN handbook chapter.

Non-invasive brain stimulation techniques have been exploited in motor neuron disease (MND) with multifold objectives: to support the diagnosis, to get insights in the pathophysiology of these disorders and, more recently, to slow down disease progression. In this review, we consider how neuromodulation can now be employed to treat MND, with specific attention to amyotrophic lateral sclerosis (ALS), the most common form with upper motoneuron (UMN) involvement, taking into account electrophysiological abnormalities revealed by human and animal studies that can be targeted by neuromodulation techniques. This review article encompasses repetitive transcranial magnetic stimulation methods (including low-frequency, high-frequency, and pattern stimulation paradigms), transcranial direct current stimulation as well as experimental findings with the newer approach of trans-spinal direct current stimulation. We also survey and discuss the trials that have been performed, and future perspectives.

Is There a Role for Risk-Reducing Bilateral Breast Surgery in BRCA1/2 Ovarian Cancer Survivors? An Observational Study.

BACKGROUND: Risk-reducing surgeries are an option for cancer risk management in BRCA1/2 individuals. However, while adnexectomy is commonly recommended in breast cancer (BC) survivors, risk-reducing bilateral breast surgery (RRBBS) is controversial in ovarian cancer (OC) survivors due to relapse rates and mortality. METHODS: We conducted a retrospective analysis of BRCA1/2-OC survivors, with OC as first cancer diagnosis. RESULTS: Median age at OC diagnosis for the 69 BRCA1/2-OC survivors was 54 years. Median overall survival was 8 years, being significantly higher for BRCA2 patients than for BRCA1 patients (p = 0.011). Nine patients (13.2%) developed BC at a median age of 61 years. The mean overall BC-free survival was 15.5 years (median not reached). Eight patients (11.8%) underwent bilateral mastectomy (5 simultaneous with BC treatment; 3 RRBBS) at a median age of 56.5 years. The median time from OC to bilateral mastectomy/RRBBS was 5.5 years. CONCLUSIONS: This study adds evidence regarding a lower BC risk after BRCA1/2-OC and higher survival for BRCA2-OC patients. A comprehensive analysis of the competing risks of OC mortality and recurrence against the risk of BC should be individually addressed. Surgical BC risk management may be considered for longer BRCA1/2-OC disease-free survivors. Ultimately, these decisions should always be tailored to patients' characteristics and preferences.

Extending AAV Packaging Cargo through Dual Co-Transduction: Efficient Protein Trans-Splicing at Low Vector Doses.

Adeno-associated viral (AAV) vectors represent one of the leading platforms for gene delivery. Nevertheless, their small packaging capacity restricts their use for diseases requiring large-gene delivery. To overcome this, dual-AAV vector systems that rely on protein trans-splicing were developed, with the split-intein Npu DnaE among the most-used. However, the reconstitution efficiency of Npu DnaE is still insufficient, requiring higher vector doses. In this work, two split-inteins, Cfa and Gp41-1, with reportedly superior trans-splicing were evaluated in comparison with Npu DnaE by transient transfections and dual-AAV in vitro co-transductions. Both Cfa and Gp41-1 split-inteins enabled reconstitution rates that were over two-fold higher than Npu DnaE and 100% of protein reconstitution. The impact of different vector preparation qualities in split-intein performances was also evaluated in co-transduction assays. Higher-quality preparations increased split-inteins' performances by three-fold when compared to low-quality preparations (60-75% vs. 20-30% full particles, respectively). Low-quality vector preparations were observed to limit split-gene reconstitutions by inhibiting co-transduction. We show that combining superior split-inteins with higher-quality vector preparations allowed vector doses to be decreased while maintaining high trans-splicing rates. These results show the potential of more-efficient protein-trans-splicing strategies in dual-AAV vector co-transduction, allowing the extension of its use to the delivery of larger therapeutic genes.

Mammalian Stable Cell Platforms for Recombinant Adeno-associated Virus (rAAV) Production: Development Strategies and their Impact on Viral Productivity.

Adeno-associated viruses (AAV) are widely used as a recombinant vectors in gene therapy. AAVs are non-pathogenic. They present reduced cytotoxicity and can transduce both dividing and non-dividing cells. The existence of different serotypes provides flexibility for targeting different tissues and organs. Its therapeutic success was already shown by the approval of three products by the European and American regulatory agencies. To satisfy the high dosage, safety, and reproducibility required in each clinical trial, production platforms based on stable mammalian cell lines have been proposed as the best strategy. However, the methodologies employed must be adapted to each cell line, which often results in distinct productivities. In this article, we review the published and commercially available mammalian stable cell lines, discussing the key factors that impact viral production yields, such as integration sites and copy numbers.

ANKRD11 pathogenic variants and 16q24.3 microdeletions share an altered DNA methylation signature in patients with KBG syndrome.

Pathogenic variants in ANKRD11 or microdeletions at 16q24.3 are the cause of KBG syndrome (KBGS), a neurodevelopmental syndrome characterized by intellectual disability, dental and skeletal anomalies, and characteristic facies. The ANKRD11 gene encodes the ankyrin repeat-containing protein 11A transcriptional regulator, which is expressed in the brain and implicated in neural development. Syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show unique patterns of DNA methylation (DNAm) in peripheral blood, termed DNAm signatures. Given ANKRD11's role in chromatin modification, we tested whether pathogenic ANKRD11 variants underlying KBGS are associated with a DNAm signature. We profiled whole-blood DNAm in 21 individuals with ANKRD11 variants, 2 individuals with microdeletions at 16q24.3 and 28 typically developing individuals, using Illumina's Infinium EPIC array. We identified 95 differentially methylated CpG sites that distinguished individuals with KBGS and pathogenic variants in ANKRD11 (n = 14) from typically developing controls (n = 28). This DNAm signature was then validated in an independent cohort of seven individuals with KBGS and pathogenic ANKRD11 variants. We generated a machine learning model from the KBGS DNAm signature and classified the DNAm profiles of four individuals with variants of uncertain significance (VUS) in ANKRD11. We identified an intermediate classification score for an inherited missense variant transmitted from a clinically unaffected mother to her affected child. In conclusion, we show that the DNAm profiles of two individuals with 16q24.3 microdeletions were indistinguishable from the DNAm profiles of individuals with pathogenic variants in ANKRD11, and we demonstrate the diagnostic utility of the new KBGS signature by classifying the DNAm profiles of individuals with VUS in ANKRD11.

Transcriptome analysis of Sf9 insect cells during production of recombinant Adeno-associated virus.

The insect cell-baculovirus expression vector system (IC-BEVS) has emerged as an alternative time- and cost-efficient production platform for recombinant Adeno-associated virus (AAV) for gene therapy. However, a better understanding of the underlying biological mechanisms of IC-BEVS is fundamental to further optimize this expression system toward increased product titer and quality. Here, gene expression of Sf9 insect cells producing recombinant AAV through a dual baculovirus expression system, with low multiplicity of infection (MOI), was profiled by RNA-seq. An 8-fold increase in reads mapping to either baculovirus or AAV transgene sequences was observed between 24 and 48 h post-infection (hpi), confirming a take-over of the host cell transcriptome by the baculovirus. A total of 336 and 4784 genes were identified as differentially expressed at 24 hpi (vs non-infected cells) and at 48 hpi (vs. infected cells at 24 hpi), respectively, including dronc, birc5/iap5, and prp1. Functional annotation found biological processes such as cell cycle, cell growth, protein folding, and cellular amino acid metabolic processes enriched along infection. This work uncovers transcriptional changes in Sf9 in response to baculovirus infection, which provide new insights into cell and/or metabolic engineering targets that can be leveraged for rational bioprocess engineering of IC-BEVS for AAV production.

Awake airway endoscopy in mucopolysaccharidosis: a case report.

Mucopolysaccharidosis (MPS) are a group of rare genetic inherited diseases with a progressive course due to the accumulation of glycosaminoglycans resulting in anatomic abnormalities and organ dysfunction, including the respiratory, cardiovascular, skeletal, and neurological systems that can increase the risk of anesthesia complications. Clinical manifestations are variable, multisystemic, and include severe morphological changes. The anesthetic management of these patients is complex, particularly airway management, which can be planned to include a fiberoptic airway investigation prior to surgery. We present two cases of patients with MPS type VI and VII who underwent fiberoptic airway mapping under conscious sedation, with no complications. Since MPS is a rare but challenging disease concerning the airway management, we propose a safe and effective anesthetic technique that could be used for fiberoptic bronchoscopy and allow fiberoptic-assisted tracheal intubation at the time of surgery.

A randomised trial of anti-GM-CSF otilimab in severe COVID-19 pneumonia (OSCAR).

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19. METHODS: In this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18-79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti-GM-CSF monoclonal antibody) plus standard care (NCT04376684). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28. RESULTS: In Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28 versus 67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI -0.8-11.4%, p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2-33.1%, p=0.009) was observed in the predefined 70-79 years subgroup, but this was not confirmed in Part 2 (n=350 randomised) where the model-adjusted difference was 0.9% (95% CI -9.3-11.2%, p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CC chemokine ligand 17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19. CONCLUSIONS: There was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile.

The Prevalence of Potentially Inappropriate Prescribing in Two Family Health Units in Portugal.

OBJECTIVE: Polypharmacy and potentially inappropriate prescribing (PIP) are growing concerns in the ageing population. They carry the risk of increasing adverse effects, medical interactions, and difficulties managing the medication. Few studies in Portugal evaluate the prevalence of polypharmacy and PIP in primary care. No previous studies in the primary care setting in Portugal have been conducted using the European Union (EU)(7)-PIM (potentially inappropriate medication) list tool. In this study, we aimed to estimate the prevalence of polypharmacy and PIP in two family health units in Portugal.  Methods: To answer this question, we enrolled a sample of 361 elderly patients from two family health units in a descriptive observational transversal study. We randomly selected patients, consulted their prescription records in the previous 12 months, and applied the EU(7)-PIM list tool, validated for the Portuguese population. The data was then analyzed using descriptive and inferential statistics and the Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, IBM Corp., Version 24.0, Armonk, NY). RESULTS: Our results showed a prevalence of 79.8% of polypharmacy in the elderly population and 73.4% of PIP. These values are higher than predicted in the literature, but different screening tools have been used among papers. The mean number of prescribed drugs per patient was nine in one unit and seven in the other, and the mode was eleven per patient. The most identified PIP-associated drugs were proton pump inhibitors in 46.4% of the patients in one unit and 43.7% in the other. We also found a statistically significant higher prevalence of PIP and polypharmacy in females and patients over 75 years. CONCLUSION: From a prevalence perspective, we found higher-than-expected prevalences of PIP and polypharmacy in our population. Contributing factors might be a higher ageing index in the Portuguese population, modern practices using combination therapy, and the use of a screening tool that does not take into account the personal clinical history of patients. Further limitations involve only including patients with follow-up in the units studied. Even so, it suggests both PIP and polypharmacy as concerns to address, and we will strive to educate both health teams on PIP, polypharmacy, and deprescribing. We also emphasize the need to widen the study to other family health units.

JANUS: an open-source 3D printable perfusion bioreactor and numerical model-based design strategy for tissue engineering.

Bioreactors have been employed in tissue engineering to sustain longer and larger cell cultures, managing nutrient transfer and waste removal. Multiple designs have been developed, integrating sensor and stimulation technologies to improve cellular responses, such as proliferation and differentiation. The variability in bioreactor design, stimulation protocols, and cell culture conditions hampered comparison and replicability, possibly hiding biological evidence. This work proposes an open-source 3D printable design for a perfusion bioreactor and a numerical model-driven protocol development strategy for improved cell culture control. This bioreactor can simultaneously deliver capacitive-coupled electric field and fluid-induced shear stress stimulation, both stimulation systems were validated experimentally and in agreement with numerical predictions. A preliminary in vitro validation confirmed the suitability of the developed bioreactor to sustain viable cell cultures. The outputs from this strategy, physical and virtual, are openly available and can be used to improve comparison, replicability, and control in tissue engineering applications.

Posterior Reversible Encephalopathy Syndrome in a Pediatric Intensive Care Unit: A Case Series.

Posterior reversible encephalopathy syndrome (PRES) is a reversible clinical-radiographic abnormality. It is characterized by headache, altered consciousness, seizures, and visual disruption, in addition to characteristic white matter edema lesions in the parieto-occipital areas of the brain. Early detection and treatment are crucial to prevent irreversible damage. This paper presents the cases of three patients with PRES with concurrent diagnoses of glomerulonephritis, Guillain-Barré syndrome, and sickle cell disease. All patients experienced systemic hypertension, seizures, and altered consciousness. All patients were admitted to intensive care for decreased level of awareness or status epilepticus requiring invasive mechanical ventilation. Anticonvulsants and antihypertensive therapy were essential. No chronic complications were recorded.