Update on the transdifferentiation of pancreatic cells into functional beta cells for treating diabetes.

The increasing global prevalence and associated comorbidities need innovative approaches for type 2 diabetes mellitus (T2DM) prevention and treatment. Genetics contributes significantly to T2DM susceptibility, and genetic counseling is significant in detecting and informing people about the diabetic risk. T2DM is also intricately linked to overnutrition and obesity, and nutritional advising is beneficial to mitigate diabetic evolution. However, manipulating pancreatic cell plasticity and transdifferentiation could help beta cell regeneration and glucose homeostasis, effectively contributing to the antidiabetic fight. Targeted modulation of transcription factors is highlighted for their roles in various aspects of pancreatic cell differentiation and function, inducing non-beta cells' conversion into functional beta cells (responsive to glucose). In addition, pharmacological interventions targeting specific receptors and pathways might facilitate cell transdifferentiation aiming to maintain or increase beta cell mass and function. However, the mechanisms underlying cellular reprogramming are not yet well understood. The present review highlights the primary transcriptional factors in the endocrine pancreas, focusing on transdifferentiation as a primary mechanism. Therefore, islet cell reprogramming, converting one cell type to another and transforming non-beta cells into insulin-producing cells, depends, among others, on transcription factors. It is a promising fact that new transcription factors are discovered every day, and their actions on pancreatic islet cells are revealed. Exploring these pathways associated with pancreatic development and islet endocrine cell differentiation could unravel the molecular intricacies underlying transdifferentiation processes, exploring novel therapeutic strategies to treat diabetes. The medical use of this biotechnology is expected to be achievable within a short time.

Nematicidal Activity of Phytochemicals against the Root-Lesion Nematode Pratylenchus penetrans.

Plant-parasitic nematodes (PPNs) are highly damaging pests responsible for heavy losses in worldwide productivity in a significant number of important plant crops. Common pest management strategies rely on the use of synthetic chemical nematicides, which have led to serious concerns regarding their impacts on human health and the environment. Plant natural products, or phytochemicals, can provide a good source of agents for sustainable control of PPNs, due to their intrinsic characteristics such as higher biodegradability, generally low toxicity for mammals, and lower bioaccumulation in the environment. In this work, the nematicidal activity of 39 phytochemicals was determined against the root-lesion nematode (RLN) Pratylenchus penetrans using standard direct and indirect contact methodologies. Overall, the RLN was tolerant to the tested phytochemicals at the highest concentration, 2 mg/mL, seldom reaching full mortality. However, high activities were obtained for benzaldehyde, carvacrol, 3-octanol, and thymol, in comparison to other phytochemicals or the synthetic nematicide oxamyl. These phytochemicals were seen to damage nematode internal tissues but not its cuticle shape. Also, the environmental and (eco)toxicological parameters reported for these compounds suggest lower toxicity and higher safety of use than oxamyl. These compounds appear to be good candidates for the development of biopesticides for a more sustainable pest management strategy.

Stroke rehabilitation pathways during the first year: A cost-effectiveness analysis from a cohort of 460 individuals.

BACKGROUND: Stroke burden challenges global health, and social and economic policies. Although stroke recovery encompasses a wide range of care, including in-hospital, outpatient, and community-based rehabilitation, there are no published cost-effectiveness studies of integrated post-stroke pathways. OBJECTIVE: To determine the most cost-effective rehabilitation pathway during the first 12 months after a first-ever stroke. METHODS: A cohort of people in the acute phase of a first stroke was followed after hospital discharge; 51 % women, mean (SD) age 74.4 (12.9) years, mean National Institute of Health Stroke Scale score 11.7 (8.5) points, and mode modified Rankin Scale score 3 points. We developed a decision tree model of 9 sequences of rehabilitation care organised in 3 stages (3, 6 and 12 months) through a combination of public, semi-public and private entities, considering both the individual and healthcare service perspectives. Health outcomes were expressed as quality-adjusted life years (QALY) over a 1-year time horizon. Costs included healthcare, social care, and productivity losses. Sensitivity analyses were conducted on model input values. RESULTS: From the individual perspective, pathway 3 (Short-term Inpatient Unit ¼ Community Clinic) was the most cost-effective, followed by pathway 1 (Rehabilitation Centre ¼ Community Clinic). From the healthcare service perspective, pathway 3 was the most cost-effective followed by pathway 7 (Outpatient Hospital ¼ Private Clinic). All other pathways were considered strongly dominated and excluded from the analysis. The total 1-year mean cost ranged between €12104 and €23024 from the individual's perspective and between €10992 and €31319 from the healthcare service perspective. CONCLUSION: Assuming a willingness-to-pay threshold of one times the national gross domestic product (€20633/QALY), pathway 3 (Short-term Inpatient Unit ¼ Community Clinic) was the most cost-effective strategy from both the individual and healthcare service perspectives. Rehabilitation pathway data contribute to the development of a future integrated care system adapted to different stroke profiles.

People first: a participatory community approach on patient-reported outcomes in tuberculosis.

Patient-reported outcomes (PROs) play a crucial role in understanding the impact of tuberculosis (TB) on both individuals and communities. Despite advances in TB treatment, conventional outcome definitions often overlook essential components of people with TB's experiences, leading to disparities in treatment understanding. The incorporation of PROs in TB scientific research can help bridge the gap between the health system and people's needs and expectations. PROs can offer valuable insights into non-observable constructs like health literacy, self-efficacy and overall wellbeing, contributing to the comprehensive assessment of diagnosis, treatment and research end-points. Participatory community approaches, such as Community-Based Participatory, emphasise the engagement and involvement of relevant stakeholders in designing interventions tailored to their needs. Key stakeholders, including healthcare professionals, researchers, clinical trial investigators, public health officials, and community health workers, TB survivors and people with TB, can play a vital role in promoting patient-centred care and engaging directly with the TB-affected community. An increased and cross-collaborative effort for the inclusion of PROs in TB research can entail their potential role in developing effective treatment regimens and promoting adherence, while maximising community engagement and improving outcomes for those affected by TB.

Bariatric Surgery Induces Alterations in the Immune Profile of Peripheral Blood T Cells.

Low-grade inflammation is closely linked to obesity and obesity-related comorbidities; therefore, immune cells have become an important topic in obesity research. Here, we performed a deep phenotypic characterization of circulating T cells in people with obesity, using flow cytometry. Forty-one individuals with obesity (OB) and clinical criteria for bariatric surgery were enrolled in this study. We identified and quantified 44 different circulating T cell subsets and assessed their activation status and the expression of immune-checkpoint molecules, immediately before (T1) and 7-18 months after (T2) the bariatric surgery. Twelve age- and sex-matched healthy individuals (nOB) were also recruited. The OB participants showed higher leukocyte counts and a higher percentage of neutrophils. The percentage of circulating Th1 cells were negatively correlated to HbA1c and insulin levels. OB Th1 cells displayed a higher activation status and lower PD-1 expression. The percentage of Th17 and Th1/17 cells were increased in OB, whereas the CD4+ Tregs' percentage was decreased. Interestingly, a higher proportion of OB CD4+ Tregs were polarized toward Th1- and Th1/17-like cells and expressed higher levels of CCR5. Bariatric surgery induced the recovery of CD4+ Treg cell levels and the expansion and activation of Tfh and B cells. Our results show alterations in the distribution and phenotype of circulating T cells from OB people, including activation markers and immune-checkpoint proteins, demonstrating that different metabolic profiles are associated to distinct immune profiles, and both are modulated by bariatric surgery.

CD8+ Treg cells play a role in the obesity-associated insulin resistance.

Obesity-related chronic low-grade inflammation may trigger insulin resistance and type 2 diabetes (T2D) development. Cells with regulatory phenotype have been shown to be reduced during obesity, especially CD4+ Treg cells. However, little is known about the CD8+ Treg cells. Therefore, we aim to characterize the CD8+ Treg cells in human peripheral blood and adipose tissue, specifically, to address the effect of obesity and insulin resistance in this regulatory immune cell population. A group of 42 participants with obesity (OB group) were recruited. Fourteen of them were evaluated pre- and post-bariatric surgery. A group of age- and sex-matched healthy volunteers (n = 12) was also recruited (nOB group). CD8+ Treg cell quantification and phenotype were evaluated by flow cytometry, in peripheral blood (PB), subcutaneous (SAT), and visceral adipose tissues (VAT). The OB group displayed a higher percentage of CD8+ Treg cells in PB, compared to the nOB. In addition, they were preferentially polarized into Tc1- and Tc1/17-like CD8+ Treg cells, compared to nOB. Moreover, SAT displayed the highest content of CD8+ Tregs infiltrated, compared to PB or VAT, while CD8+ Tregs infiltrating VAT displayed a higher percentage of cells with Tc1-like phenotype. Participants with pre-diabetes displayed a reduced percentage of TIM-3+CD8+ Tregs in circulation, and PD-1+CD8+ Tregs infiltrated in the VAT. An increase in the percentage of circulating Tc1-like CD8+ Treg cells expressing PD-1 was observed post-surgery. In conclusion, obesity induces significant alterations in CD8+ Treg cells, affecting their percentage and phenotype, as well as the expression of important immune regulatory molecules.

Probable 4-Repeat Tauopathy Criteria Predict Brain Amyloid Negativity, Distinct Clinical Features, and FDG-PET/MRI Neurodegeneneration Patterns in Corticobasal Syndrome.

BACKGROUND: Corticobasal syndrome (CBS) is associated with diverse underlying pathologies, including the four-repeat (4R)-tauopathies. The Movement Disorders Society (MDS) criteria for progressive supranuclear palsy (PSP) proposed the novel category "probable 4R-tauopathy" to address the phenotypic overlap between PSP and corticobasal degeneration (CBD). OBJECTIVES: To investigate the clinical ability of the MDS-PSP criteria for probable 4R-tauopathy in predicting a negative amyloid-PET in CBS. Additionally, this study aims to explore CBS patients classified as 4R-tauopathy concerning their clinical features and neuroimaging degeneration patterns. METHODS: Thirty-two patients with probable CBS were prospectively evaluated and split into those who fulfilled or did not fulfill the 4R-tauopathy criteria (CBS-4RT+ vs. CBS-4RT-). All patients underwent positron emission tomographies (PET) with [18 F]fluorodeoxyglucose and [11 C]Pittsburgh Compound-B (PIB) on a hybrid PET-MRI scanner to perform multimodal quantitative comparisons with a control group. RESULTS: Eleven patients were clinically classified as CBS-4RT+, and only one had a positive PIB-PET. The CBS-4RT+ classification had 92% specificity, 52% sensitivity, and 69% accuracy in predicting a negative PIB-PET. The CBS-4RT+ group presented with dysarthria and perseveration more often than the CBS-4RT- group. Moreover, the CBS-4RT+ group showed a prominent frontal hypometabolism extending to the supplementary motor area and striatum, and brain atrophy at the anterior cingulate and bilateral striata. CONCLUSIONS: The 4R-tauopathy criteria were highly specific in predicting a negative amyloid-PET in CBS. Patients classified as 4R-tauopathy presented distinct clinical aspects, as well as brain metabolism and atrophy patterns previously associated with tauopathies.

Neurological gait assessment.

Gait disorders are a common feature of neurological disease. The gait examination is an essential part of the neurological clinical assessment, providing valuable clues to a myriad of causes. Understanding how to examine gait is not only essential for neurological diagnosis but also for treatment and prognosis. Here, we review aspects of the clinical history and examination of neurological gait to help guide gait disorder assessment. We focus particularly on how to differentiate between common gait abnormalities and highlight the characteristic features of the more prevalent neurological gait patterns such as ataxia, waddling, steppage, spastic gait, Parkinson's disease and functional gait disorders. We also offer diagnostic clues for some unusual gait presentations, such as dystonic, stiff-person and choreiform gait, along with red flags that help differentiate atypical parkinsonism from Parkinson's disease.

Antifungal potential of the new copper(II)-theophylline/1,10-phenanthroline complex against drug-resistant Candida species.

Candida spp. are the commonest fungal pathogens worldwide. Antifungal resistance is a problem that has prompted the discovery of novel anti-Candida drugs. Herein, 25 compounds, some of them containing copper(II), cobalt(II) and manganese(II) ions, were initially evaluated for inhibiting the growth of reference strains of Candida albicans and Candida tropicalis. Eight (32%) of the compounds inhibited the proliferation of these yeasts, displaying minimum inhibitory concentrations (MICs) ranging from 31.25 to 250 µg/mL and minimum fungicidal concentration (MFCs) from 62.5 to 250 µg/mL. Drug-likeness/pharmacokinetic calculated by SwissADME indicated that the 8 selected compounds were suitable for use as topical drugs. The complex CTP, Cu(theo)2phen(H2O).5H2O (theo = theophylline; phen = 1,10-phenanthroline), was chosen for further testing against 10 medically relevant Candida species that were resistant to fluconazole/amphotericin B. CTP demonstrated a broad spectrum of action, inhibiting the growth of all 20 clinical fungal isolates, with MICs from 7.81 to 62.5 µg/mL and MFCs from 15.62 to 62.5 µg/mL. Conversely, CTP did not cause lysis in erythrocytes. The toxicity of CTP was evaluated in vivo using Galleria mellonella and Tenebrio molitor. CTP had no or low levels of toxicity at doses ranging from 31.25 to 250 µg/mL for 5 days. After 24 h of treatment, G. mellonella larvae exhibited high survival rates even when exposed to high doses of CTP (600 µg/mL), with the 50% cytotoxic concentration calculated as 776.2 µg/mL, generating selectivity indexes varying from 12.4 to 99.4 depending on each Candida species. These findings suggest that CTP could serve as a potential drug to treat infections caused by Candida species resistant to clinically available antifungals.

Cotadutide improves brown adipose tissue thermogenesis in obese mice.

We studied the effect of cotadutide, a dual agonist glucagon-like peptide 1 (GLP1)/Glucagon, on interscapular brown adipose tissue (iBAT) remodeling and thermogenesis of obese mice. Twelve-week-old male C57BL/6 mice were fed a control diet (C group, n = 20) or a high-fat diet (HF group, n = 20) for ten weeks. Then, animals were redivided, adding cotadutide treatment: C, CC, HF, and HFC for four additional weeks. The multilocular brown adipocyte structure showed fat conversion (whitening), hypertrophy, and structural disarray in the HF group, which was reverted in cotadutide-treated animals. Cotadutide enhances the body temperature, thermogenesis, and sympathetic innervation (peroxisome proliferator-activated receptor-α, ß3 adrenergic receptor, interleukin 6, and uncoupled protein 1), reduces pro-inflammatory markers (disintegrin and metallopeptidase domain, morphogenetic protein 8a, and neuregulin 4), and improves angiogenesis (vascular endothelial growth factor A, and perlecan). In addition, cotadutide enhances lipolysis (perilipin and cell death-inducing DNA fragmentation factor α), mitochondrial biogenesis (nuclear respiratory factor 1, transcription factor A mitochondrial, mitochondrial dynamin-like GTPase, and peroxisome proliferator-activated receptor gamma coactivator 1α), and mitochondrial fusion/fission (dynamin-related protein 1, mitochondrial fission protein 1, and parkin RBR E3 ubiquitin protein ligase). Cotadutide reduces endoplasmic reticulum stress (activating transcription factor 4, C/EBP homologous protein, and growth arrest and DNA-damage inducible), and extracellular matrix markers (lysyl oxidase, collagen type I α1, collagen type VI α3, matrix metallopeptidases 2 and 9, and hyaluronan synthases 1 and 2). In conclusion, the experimental evidence is compelling in demonstrating cotadutide's thermogenic effect on obese mice's iBAT, contributing to unraveling its action mechanisms and the possible translational benefits.

Building bridges: multidisciplinary teams in tuberculosis prevention and care.

People with or affected by tuberculosis (TB) experience complex social and cultural constraints that may affect treatment outcomes by impeding access to proper care or by hindering treatment adherence. Low levels of health literacy which leads to inadequate disease information; stigma, discrimination and other forms of prejudice that may result in marginalisation and ostracisation; and socioeconomic vulnerabilities that hamper one's capacity to access essential goods or increase the risk of exposure to the disease are some of the barriers highlighted. These complex hurdles are also disproportionately felt by people with or affected by TB due to gender-related inequalities that need to be properly addressed. Additionally, TB prevention and care should encompass interventions aimed at improving and promoting mental health, given that mental unhealth may further thwart treatment adherence and success. A multifaceted and multidisciplinary approach to TB is required to answer these complex barriers.

First Report on the Synergistic Interaction between Essential Oils against the Pinewood Nematode Bursaphelenchus xylophilus.

Control of the pinewood nematode (PWN), the causal agent of pine wilt disease, can be achieved through the trunk injection of nematicides; however, many pesticides have been linked to environmental and human health concerns. Essential oils (EOs) are suitable alternatives due to their biodegradability and low toxicity to mammals. These complex mixtures of plant volatiles often display multiple biological activities and synergistic interactions between their compounds. The present work profiled the toxicity of eight EOs against the PWN in comparison to their 1:1 mixtures, to screen for successful synergistic interactions. Additionally, the main compounds of the most synergistic mixtures were characterized for their predicted environmental fate and toxicity to mammals in comparison to emamectin benzoate, a commercial nematicide used against PWN. The mixtures of Cymbopogon citratus with Mentha piperita and of Foeniculum vulgare with Satureja montana EOs showed the highest activities, with half-maximal effective concentrations (EC50) of 0.09 and 0.05 µL/mL, respectively. For these, complete PWN mortality was reached after only ca. 15 min or 2 h of direct contact, respectively. Their major compounds had a higher predicted affinity to air and water environmental compartments and are reported to have very low toxicity to mammals, with low acute oral and dermal toxicities. In comparison, emamectin benzoate showed lower nematicidal activity, a higher affinity to the soil and sediments environmental compartments and higher reported oral and dermal toxicity to mammals. Overall, uncovering synergistic activities in combinations of EOs from plants of different families may prove to be a source of biopesticides with optimized toxicity against PWNs.

AMPK/mTOR pathway significance in healthy liver and non-alcoholic fatty liver disease and its progression.

Obesity is related to several organs, but the liver is particularly affected. Adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy sensor and regulator of liver lipid dysfunction and glucose metabolism. The mechanistic target of rapamycin (mTOR) is a protein kinase regulating cell growth, survival, metabolism, and immunity. Together, these pathways are involved in obesity, insulin resistance, non-alcoholic fatty liver disease (NAFLD) and its progression, and autophagy. During energy demand, liver kinase B (LKB) phosphorylation helps activate the AMPK/mTOR pathways. Likewise, the protein forkhead box O family (FOXO) negatively regulates adipogenesis by binding to the promoter sites of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha, initiating adipogenesis. In addition, acetyl-CoA carboxylase, which regulates de novo lipogenesis, is linked to LKB and FOXO in developing NAFLD. The kinase complex, consisting of Unc-51-like autophagy-activating kinase 1 or 2 (ULK1, ULK2) by stimulating autophagy, and eliminating fat droplets in NAFLD, is regulated by mTORC1 and negatively regulated by AMPK that suppresses liver lipogenesis and increases fatty acid oxidation. Also, ULK1 is essential for initiating phagophore formation, establishing macrophagy, and generating autophagosomes. The selective breakdown of lipid droplets through macroautophagy, or macrolipophagy, occurs on a cellular energy level using free fatty acids. In addition, mTORC1 promotes lipogenesis by activating sterol regulatory element-binding protein. Finding new components and novel regulatory modes in signaling is significant for a better understanding of the AMPK/mTOR pathways, potentially facilitating the development of future diagnostic and therapeutic strategies for NAFLD and its progression to non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma.

A Multicentre Study of the Clinical and Epidemiological Profile of Inflammatory Bowel Disease in Northeast Brazil.

Purpose: Ulcerative colitis (UC) and Crohn's disease (CD) are inflammatory bowel diseases (IBDs) with multifactorial causes. They are becoming more prevalent in developing countries such as Brazil; however, relevant studies in poorer regions of the country are limited. Here, we report the clinical-epidemiological profile of patients with IBD treated at reference centers in three states of Northeast Brazil. Patients and Methods: This was a prospective cohort study involving patients at referral outpatient clinics for IBD from January 2020 through December 2021. Results: Of 571 patients with IBD, 355 (62%) had UC, and 216 (38%) had CD. The patients were predominantly women (355, 62%) for both UC and CD. Extensive colitis was the pattern present in 39% of the UC cases. For CD, ileocolonic disease was the predominant manifestation (38%), with 67% of cases showing penetrating and/or stenosing behavior. The majority of patients were diagnosed between the ages of 17 and 40, corresponding to 60.2% in CD and 52.7% in UC. The median time between symptom onset and diagnosis was 12 months for CD and 8 months for UC (p=0.042). Joint involvement was the most frequent extraintestinal manifestation, with arthralgia and arthritis present in 41.9% and 18.6% of the patients, respectively. Biological therapy was prescribed to 73% of CD patients and 26% of UC patients. A progressive increase in new cases was observed in every 5-year interval over the last five decades, with 58.6% being diagnosed in the last 10 years. Conclusion: More extensive disease behavior patterns predominated in UC, while forms associated with complications were prevalent in CD. A prolonged time to diagnosis may have contributed to these findings. A progressive increase in IBD incidence was observed and may be related to greater urbanization and better access to specialized outpatient clinics, resulting in improvements in diagnosis.

HPV virus and biomarkers of resistance to chemoradiation in circulating tumor cells from patients with squamous cell carcinoma of the anus.

Localized anal cancer is mostly represented by squamous cell carcinoma of the anus (SCCA) and is cured in ≥80 % of cases by chemoradiation (CRT). Development of techniques for detection/evaluating circulating tumor cells (CTCs) for diagnosis/ prognosis/response to therapy can change the manner we treat/follow SCCA patients. OBJECTIVE: to detect CTCs from patients with SCCA and evaluate the presence of HPV virus, p16 expression and markers related to resistance to CRT (RAD23B/ ERCC1/ TYMS) in CTCs at baseline and after CRT. METHODS: CTCs were isolated/quantified by ISET®, protein expressions were analyzed by immunocytochemistry and HPV DNA was detected by chromogenic in situ hybridization. RESULTS: We enrolled 15 patients: median age was 61 (43-73) years, the majority was women (10/15). CTCs were detected in all patients at baseline (median= 0.4 (0.4-3.33) CTCs/mL) and in 8/9 patients, after CRT (median= 2.33 (0-7.0) CTCs/mL). DNA from HPV was found in CTCs in 14/15 patients (93.33 %) at baseline and in 7/9 (77.7 %) after treatment. At a median follow-up of 22.20 (1.45-38.55) months, three patients expressed ERCC1 in CTCs after treatment, with one of them having disease recurrence. CONCLUSION: We showed that detection of HPV in CTCs from patients with non-metastatic SCCA is feasible and appears to be a sensitive diagnostic method. These results may be clinically useful for better monitoring these patients. However, future larger cohorts may demonstrate whether there is any correlation between the presence of HPV and the expression of screening markers for CRT in SCCA.

Using passive Wi-Fi for community crowd sensing during the COVID-19 pandemic.

Sensing passersby and detecting crowded locations is a growing area of research and development in the last decades. The COVID-19 pandemic compelled authorities and public and private institutions to monitor access and occupancy of crowded spaces. This work addresses the detection of crowds in points of interest (POI) by using a territory grid analysis categorizing POIs by the services available in each location and comparing data gathered from a community passive Wi-Fi infrastructure against mobile cellular tower association data from telecom companies. In Madeira islands (Portugal), we used data from the telecom provider NOS for the timespan of 4 months as ground truth and found a strong correlation with sparse passive Wi-Fi. An official regional mobile application shows the occupancy data to end-users based on the territory categorization and the passive Wi-Fi infrastructure in POIs. Occupancy data shows historical hourly trends of each location, and the real-time occupation, helping visitors and locals plan their commutes better to avoid crowded spaces.

From healthcare system to individuals through stroke rehabilitation pathways.Outcomes, information, and satisfaction along 12 months prospective cohort in Portugal.

BACKGROUND: The nature and quality of stroke survivor rehabilitation varies throughout Europe, including in Portugal, having not been widely monitored or benchmarked. OBJECTIVES: This study analyses the stroke care pathway from three perspectives: healthcare system, process, and patient. METHODS: The study uses data from a one-year single-center prospective cohort of first stroke patients, assessed at baseline, 3, 6, and 12 months. Care pathways and settings were described in terms of organizational model, funding, patient involvement, frequency and intensity and multidisciplinary team. Patient-level information and satisfaction were evaluated using a 10-point numeric rating scale. Kruskal - Wallis and post-hoc tests were used to compare EQ-5D-3 L, National Institute of Health Stroke Scale (NIHSS), Modified Rankin Scale (mRS), Barthel Index, Mini-Mental State Examination scores between pathways and settings. RESULTS: A total of 391 acute stroke patients, with a mean disability of 3.7 (mRS) and severity of 11.7 (NIHSS) participated. Six pathways and eight settings were described. A lack of compliance between guidelines and care was identified. There were significant differences in the four outcomes between the six pathways (p-values 0.007 to 0.020) suggesting inefficiency and inequalities, with an inadequate level of information and patient satisfaction. After post-hoc analysis, pathways 1 and 2 showed highest outcomes (p-values 0.001 to 0.002). Within settings, short-term units showed high scores, followed by rehabilitation center, outpatient hospital, and community clinic (p-values 0.001 to 0.040). CONCLUSION: A multilevel characterization of the post-stroke rehabilitation pathway showed a more complete perspective on stroke management which may contribute to future rehabilitation and stroke policies.

A single dose of COVID-19 vaccine induces a strong T cell and B cell response in healthcare professionals recovered from SARS-CoV-2 infection.

A broad understanding on how SARS-CoV-2 infection and vaccination mobilize the immune system is necessary to find the best predictors of long-term protection and identify individuals that would benefit from additional vaccine doses. This study aims to understand the effect of a single dose of Pfizer-BioNTech BNT162b2 COVID-19 vaccine, in individuals recovered from SARS-CoV-2 infection, on circulating CD4+ T follicular helper (Tfh)-cells, Spike-specific T-cells and IgG/IgA antibodies. For that, peripheral blood samples from 50 healthcare professionals, recovered from SARS-CoV-2 infection, collected immediately before (T1) and 15 days after (T2) vaccine administration, were used to analyze the frequency and numbers of Tfh-cells and their subsets, serum titers of SARS-CoV-2-specific antibodies, and SARS-CoV-2-specific T-cells. Six months after infection (T1), 96% of recovered participants presented either IgG or T-cells specific for Spike, however, Spike-specific T-cells were missing in 16% of them. These individuals presented lower levels of Spike-specific IgG (T1 and T2), IgA (T1), and Spike-specific T-cells (T2). Vaccination increased the percentage of participants reactive for Spike-specific T-cells (from 64 to 98%), IgG (from 90 to 100%) and IgA (from 48 to 98%). It also mobilized circulating Tfh-cells, increasing their frequency and activation, and promoting Tfh17 polarization, restoring the decreased numbers of Tfh-cells (especially Tfh17) observed in recovered participants. Interestingly, Tfh percentage correlated with Spike-specific IgG levels. Our data showed that a single dose of vaccine efficiently restored Spike-specific T-cells, and IgG and IgA antibodies. Mobilization of Tfh-cells, and their correlation with IgG levels, suggest that vaccination induced a functional Tfh cell response.

Expression of O-glycosylated oncofetal fibronectin in alternatively activated human macrophages.

Macrophage (Mϕ) polarization is an essential phenomenon for the maintenance of homeostasis and tissue repair, and represents the event by which Mϕ reach divergent functional phenotypes as a result to specific stimuli and/or microenvironmental signals. Mϕ can be polarized into two main phenotypes, M1 or classically activated and M2 or alternatively activated. These two categories diverge in many aspects, such as secreted cytokines, markers of cell surface, and biological functions. Over the last 10 years, many potential markers have been proposed for both M1 and M2 human Mϕ. However, there is scarce information regarding the glycophenotype adopted by these cells. Here, we show that M2- but not M1-polarized Mϕ expresses high levels of an unusual glycoform of fibronectin (FN), named O-glycosylated oncofetal FN (onf-FN), found in fetal/cancer cells, but not in healthy tissues. The onf-FN expression was confirmed in vitro by Western blot and real-time RT-qPCR in primary and cell line monocyte-derived Mϕ. onf-FN was induced by IL-4 and IL-13, but not by pro-inflammatory stimuli (LPS and INF-γ). RNA and protein analysis clearly demonstrated that it is specifically associated with the M2 polarization. In conclusion, we show by the first time that O-glycosylated onf-FN is expressed by M2-polarized Mϕ.