Longitudinal neurocognitive trajectories and risk factors in the first three months following pediatric concussion.

OBJECTIVE: To identify differential trajectories of neurocognitive outcomes following pediatric concussion and investigate predictors associated with patterns of recovery up to 3 months. METHODS: 74 participants aged 8-17 years completed attention/working memory, processing speed, and executive function measures at 2 weeks, 1 month, and 3 months post-injury. We used principal component analysis to generate a composite of information processing. Group-based trajectory modeling identified latent trajectories. Multinominal logistic regression was used to examine associations between risk factors and trajectory groups. RESULTS: We identified three trajectories of neurocognitive outcomes. The medium (54.6%) and high improving groups (35.8%) showed ongoing increase in information processing, while the low persistent group showed limited change 3 months post-injury. This group recorded below average scores on Digit Span Forward and Backward at 3 months. History of pre-injury headache was significantly associated with the persistent low scoring group, relative to the medium improving (p = 0.03) but not the high improving group (p = 0.09). CONCLUSIONS: This study indicates variability in neurocognitive outcomes according to three differential trajectories, with groups partially distinguished by preexisting child factors (history of frequent headaches). Modelling that accounts for heterogeneity in individual outcomes is essential to identify clinically meaningful indices that are indicative of children requiring intervention.

First case of adult onset neuronal intranuclear inclusion disease with both typical radiological signs and NOTCH2NLC repeat expansions in a Caucasian individual.

BACKGROUND AND PURPOSE: Adult onset neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder with a heterogeneous clinical presentation that can mimic stroke and various forms of dementia. To date, it has been described almost exclusively in Asian individuals. METHODS: This case presentation includes magnetic resonance imaging (MRI) of the neurocranium, histology by skin biopsy, and long-read genome sequencing. RESULTS: A 75-year-old Caucasian female presented with paroxysmal encephalopathy twice within a 14-month period. Brain MRI revealed high-intensity signals at the cerebral corticomedullary junction (diffusion-weighted imaging) and the paravermal area (fluid-attenuated inversion recovery), a typical distribution observed in adult onset NIID. The diagnosis was corroborated by skin biopsy, which demonstrated eosinophilic intranuclear inclusion bodies, and confirmed by long-read genome sequencing, showing an expansion of the GGC repeat in exon 1 of NOTCH2NLC. CONCLUSIONS: Our case proves adult onset NOTCH2NLC-GGC-positive NIID with typical findings on MRI and histology in a Caucasian patient and underscores the need to consider this diagnosis in non-Asian individuals.

Immunogenicity, Effectiveness, and Safety of Inactivated Virus (CoronaVac) Vaccine in a Two-Dose Primary Protocol and BNT162b2 Heterologous Booster in Brazil (Immunita-001): A One Year Period Follow Up Phase 4 Study.

Background: Effective and safe vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are critical to controlling the COVID-19 pandemic and will remain the most important tool in limiting the spread of the virus long after the pandemic is over. Methods: We bring pioneering contributions on the maintenance of the immune response over a year on a real-life basis study in 1,587 individuals (18-90 yrs, median 39 yrs; 1,208 female/379 male) who underwent vaccination with two doses of CoronaVac and BNT162b2 booster after 6-months of primary protocol. Findings: Elevated levels of anti-spike IgG antibodies were detected after CoronaVac vaccination, which significantly decreased after 80 days and remained stable until the introduction of the booster dose. Heterologous booster restored antibody titers up to-1·7-fold, changing overall seropositivity to 96%. Titers of neutralising antibodies to the Omicron variant were lower in all timepoints than those against Delta variant. Individuals presenting neutralising antibodies against Omicron also presented the highest titers against Delta and anti-Spike IgG. Cellular immune response measurement pointed out a mixed immune profile with a robust release of chemokines, cytokines, and growth factors on the first month after CoronaVac vaccination followed by a gradual reduction over time and no increase after the booster dose. A stronger interaction between those mediators was noted over time. Prior exposure to the virus leaded to a more robust cellular immune response and a rise in antibody levels 60 days post CoronaVac than in individuals with no previous COVID-19. Both vaccines were safe and well tolerated among individuals. Interpretation: Our data approach the effectiveness of CoronaVac association with BNT162b2 from the clinical and biological perspectives, aspects that have important implications for informing decisions about vaccine boosters. Funding: Fiocruz, Brazil.

Long COVID-19 syndrome: a 14-months longitudinal study during the two first epidemic peaks in Southeast Brazil.

BACKGROUND: A growing number of long COVID cases after infection have been reported. By definition, long COVID is the condition whereby affected individuals do not recover for several weeks or months following the onset of symptoms suggestive of COVID-19, the profile and timeline of which remains uncertain. METHODS: In this work, in-home, outpatient and hospitalized COVID-19 positive patients were monitored for up to 14 mo to establish the prevalence of long COVID symptoms and their correlation with age, pre-existing comorbidities and course of acute infection. The longitudinal study included 646 positive patients who were monitored once a month. RESULTS: From the whole population, 50.2% presented with long COVID syndrome. Twenty-three different symptoms were reported. Most frequent were fatigue (35.6%), persistent cough (34.0%), dyspnea (26.5%), loss of smell/taste (20.1%) and frequent headaches (17.3%). Mental disorders (20.7%), change in blood pressure (7.4%) and thrombosis (6.2%) were also reported. Most patients presented with 2-3 symptoms at the same time. Long COVID started after mild, moderate and severe infection in 60, 13 and 27% of cases, respectively, and it was not restricted to specific age groups. CONCLUSIONS: Older patients tended to have more severe symptoms, leading to a longer post-COVID-19 period. The presence of seven comorbidities was correlated with the severity of infection, and severity itself was the main factor that determined the duration of symptoms in long COVID cases.

Booster dose of BNT162b2 in a CoronaVac primary vaccination protocol improves neutralization of SARS-CoV-2 Omicron variant

The emergence of the new SARS-CoV-2 Omicron variant, which is known to accumulate a huge number of mutations when compared to other variants, brought to light the concern about vaccine escape, especially from the neutralization by antibodies induced by vaccination. In this scenario, we evaluated the impact on antibody neutralization induction, against Omicron variant, by a booster dose of BNT162b2 mRNA vaccine after the CoronaVac primary vaccination scheme. The percentage of seroconverted individuals 30 and 60 days after CoronaVac scheme was 17% and 10%, respectively. After booster dose administration, the seroconvertion rate increased to 76.6%. The neutralization mean titer against Omicron in the CoronaVac protocol decreased over time, but after the booster dose, the mean titer increased 43.1 times, indicating a positive impact of this vaccine combination in the serological immune response.

MRI-Derived Radiomics Features of Hepatic Fat Predict Metabolic States in Individuals without Cardiovascular Disease.

RATIONALE AND OBJECTIVES: To investigate radiomics features of hepatic fat as potential biomarkers of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) in individuals without overt cardiovascular disease, and benchmarking against hepatic proton density fat fraction (PDFF) and the body mass index (BMI). MATERIALS AND METHODS: This study collected liver radiomics features of 310 individuals that were part of a case-controlled imaging substudy embedded in a prospective cohort. Individuals had known T2DM (n = 39; 12.6 %) and MetS (n = 107; 34.5 %) status, and were divided into stratified training (n = 232; 75 %) and validation (n = 78; 25 %) sets. Six hundred eighty-four MRI radiomics features were extracted for each liver volume of interest (VOI) on T1-weighted dual-echo Dixon relative fat water content (rfwc) maps. Test-retest and inter-rater variance was simulated by additionally extracting radiomics features using noise augmented rfwc maps and deformed volume of interests. One hundred and seventy-one features with test-retest reliability (ICC(1,1)) and inter-rater agreement (ICC(3,k)) of ≥0.85 on the training set were considered stable. To construct predictive random forest (RF) models, stable features were filtered using univariate RF analysis followed by sequential forward aggregation. The predictive performance was evaluated on the independent validation set with area under the curve of the receiver operating characteristic (AUROC) and balanced accuracy (AccuracyB). RESULTS: On the validation set, the radiomics RF models predicted T2DM with AUROC of 0.835 and AccuracyB of 0.822 and MetS with AUROC of 0.838 and AccuracyB of 0.787, outperforming the RF models trained on the benchmark parameters PDFF and BMI. CONCLUSION: Hepatic radiomics features may serve as potential imaging biomarkers for T2DM and MetS.

Pericytes Act as Key Players in Spinal Cord Injury.

Spinal cord injury results in locomotor impairment attributable to the formation of an inhibitory fibrous scar, which prevents axonal regeneration after trauma. The scarcity of knowledge about the molecular and cellular mechanisms involved in scar formation after spinal cord lesion impede the design of effective therapies. Recent studies, by using state-of-the-art technologies, including genetic tracking and blockage of pericytes in combination with optogenetics, reveal that pericyte blockage facilitates axonal regeneration and neuronal integration into the local neural circuitry. Strikingly, a pericyte subset is essential during scarring after spinal cord injury, and its arrest results in motor performance improvement. The arising knowledge from current research will contribute to novel approaches to develop therapies for spinal cord injury. We review novel advances in our understanding of pericyte biology in the spinal cord.

Reconstituted Discoidal High-Density Lipoproteins: Bioinspired Nanodiscs with Many Unexpected Applications.

PURPOSE OF REVIEW: Summarize the initial discovery of discoidal high-density lipoprotein (HDL) in human plasma and review more recent innovations that span the use of reconstituted nanodisc HDL for membrane protein characterization to its use as a drug carrier and a novel therapeutic agent for cardiovascular disease. RECENT FINDINGS: Using a wide variety of biophysical techniques, the structure and composition of endogenous discoidal HDL have now largely been solved. This has led to the development of new methods for the in vitro reconstitution of nanodisc HDL, which have proven to have a wide variety of biomedical applications. Nanodisc HDL has been used as a platform for mimicking the plasma membrane for the reconstitution and investigation of the structures of several plasma membrane proteins, such as cytochrome P450s and ABC transporters. Nanodisc HDL has also been designed as drug carriers to transport amphipathic, as well as hydrophobic small molecules, and has potential therapeutic applications for several diseases. Finally, nanodisc HDL itself like native discoidal HDL can mediate cholesterol efflux from cells and are currently being tested in late-stage clinical trials for cardiovascular disease. The discovery of the characterization of native discoidal HDL has inspired a new field of synthetic nanodisc HDL, which has offered a growing number of unanticipated biomedical applications.

Role of Schwann cells in cutaneous wound healing.

Dermal wound healing is the process of repairing and remodeling skin following injury. Delayed or aberrant cutaneous healing poses a challenge for the health care system. The lack of detailed understanding of cellular and molecular mechanisms involved in this process hampers the development of effective targeted treatments. In a recent study, Parfejevs et al.-using state-of-the-art technologies, including in vivo sophisticated Cre/loxP techniques in combination with a mouse model of excisional cutaneous wounding-reveal that Schwann cells induce adult dermal wound healing. Strikingly, genetic ablation of Schwann cells delays wound contraction and closure, decreases myofibroblast formation, and impairs skin re-epithelization after injury. From a drug development perspective, Schwann cells are a new cellular candidate to be activated to accelerate skin healing. Here, we summarize and evaluate recent advances in the understanding of Schwann cells roles in the skin microenvironment.

Targeting glioblastoma-derived pericytes improves chemotherapeutic outcome.

Glioblastoma is the most common malignant brain cancer in adults, with poor prognosis. The blood-brain barrier limits the arrival of several promising anti-glioblastoma drugs, and restricts the design of efficient therapies. Recently, by using state-of-the-art technologies, including thymidine kinase targeting system in combination with glioblastoma xenograft mouse models, it was revealed that targeting glioblastoma-derived pericytes improves chemotherapy efficiency. Strikingly, ibrutinib treatment enhances chemotherapeutic effectiveness, by targeting pericytes, improving blood-brain barrier permeability, and prolonging survival. This study identifies glioblastoma-derived pericyte as a novel target in the brain tumor microenvironment during carcinogenesis. Here, we summarize and evaluate recent advances in the understanding of pericyte's role in the glioblastoma microenvironment.

Pericytes in the Premetastatic Niche.

The premetastatic niche formed by primary tumor-derived molecules contributes to fixation of cancer metastasis. The design of efficient therapies is limited by the current lack of knowledge about the details of cellular and molecular mechanisms involved in the premetastatic niche formation. Recently, the role of pericytes in the premetastatic niche formation and lung metastatic tropism was explored by using state-of-the-art techniques, including in vivo lineage-tracing and mice with pericyte-specific KLF4 deletion. Strikingly, genetic inactivation of KLF4 in pericytes inhibits pulmonary pericyte expansion and decreases metastasis in the lung. Here, we summarize and evaluate recent advances in the understanding of pericyte contribution to premetastatic niche formation. Cancer Res; 78(11); 2779-86. ©2018 AACR.

Adipocytes role in the bone marrow niche.

Adipocyte infiltration in the bone marrow follows chemotherapy or irradiation. Previous studies indicate that bone marrow fat cells inhibit hematopoietic stem cell function. Recently, Zhou et al. (2017) using state-of-the-art techniques, including sophisticated Cre/loxP technologies, confocal microscopy, in vivo lineage-tracing, flow cytometry, and bone marrow transplantation, reveal that adipocytes promote hematopoietic recovery after irradiation. This study challenges the current view of adipocytes as negative regulators of the hematopoietic stem cells niche, and reopens the discussion about adipocytes' roles in the bone marrow. Strikingly, genetic deletion of stem cell factor specifically from adipocytes leads to deficiency in hematopoietic stem cells, and reduces animal survival after myeloablation, The emerging knowledge from this research will be important for the treatment of multiple hematologic disorders. © 2017 International Society for Advancement of Cytometry.

LepR+ cells dispute hegemony with Gli1+ cells in bone marrow fibrosis.

Bone marrow fibrosis is a reactive process, and a central pathological feature of primary myelofibrosis. Revealing the origin of fibroblastic cells in the bone marrow is crucial, as these cells are considered an ideal, and essential target for anti-fibrotic therapy. In 2 recent studies, Decker et al. (2017) and Schneider et al. (2017), by using state-of-the-art techniques including in vivo lineage-tracing, provide evidence that leptin receptor (LepR)-expressing and Gli1-expressing cells are responsible for fibrotic tissue deposition in the bone marrow. However, what is the relationship between these 2 bone marrow cell populations, and what are their relative contributions to bone marrow fibrosis remain unclear. From a drug development perspective, these works bring new cellular targets for bone marrow fibrosis.

Identity of Gli1+ cells in the bone marrow.

Bone marrow fibrosis is a critical component of primary myelofibrosis in which normal bone marrow tissue and blood-forming cells are gradually replaced with scar tissue. The specific cellular and molecular mechanisms that cause bone marrow fibrosis are not understood. A recent study using state-of-the-art techniques, including in vivo lineage tracing, provides evidence that Gli1+ cells are the cells responsible for fibrotic disease in the bone marrow. Strikingly, genetic depletion of Gli1+ cells rescues bone marrow failure and abolishes myelofibrosis. This work introduces a new central cellular target for bone marrow fibrosis. The knowledge that emerges from this research will be important for the treatment of several malignant and nonmalignant disorders.

Retrospective review of oral and maxillofacial pathology in a Brazilian paediatric population.

AIM: To describe the relative frequencies of oral biopsies among a sample of children aged 0-16 years and compare the results with an adult population as well as with previous studies. METHODS: Information about age, gender, anatomic site, and histopathological diagnosis was retrieved from the files of the Oral Pathology Laboratory of the University of Fortaleza (Brazil). Diagnosis data of 1240 biopsies were classified into eight groups. RESULTS: Relative frequencies of biopsies increased with age. The 16 most frequent lesions accounted for 70% of all biopsies. The most frequent diagnostic group was salivary gland pathology (30.4%). Mucocele was the most common lesion (27.1%), followed by dental follicle (5.6%) and fibroma (4.4%). These results were statistically different from those of the comparable adult population (p < 0.05). CONCLUSIONS: The most frequent lesion was mucocele, and this result is in agreement with the literature. There was a significant difference between the study paediatric and adult populations. The variations in distribution of lesions observed between the several studies were probably due to cultural differences between geographic areas but also to differing elements of the study design.

Fluid dynamics of moving fish in a two-dimensional multiparticle collision dynamics model.

The fluid dynamics of animal locomotion, such as that of an undulating fish, are of great interest to both biologists and engineers. However, experimentally studying these fluid dynamics is difficult and time consuming. Model studies can be of great help because of their simpler and more detailed analysis. Their insights may guide empirical work. Particularly the recently introduced multiparticle collision dynamics method may be suitable for the study of moving organisms because it is computationally fast, simple to implement, and has a continuous representation of space. As regards the study of hydrodynamics of moving organisms, the method has only been applied at low Reynolds numbers (below 120) for soft, permeable bodies, and static fishlike shapes. In the present paper we use it to study the hydrodynamics of an undulating fish at Reynolds numbers 1100-1500, after confirming its performance for a moving insect wing at Reynolds number 75. We measure (1) drag, thrust, and lift forces, (2) swimming efficiency and spatial structure of the wake, and (3) distribution of forces along the fish body. We confirm the resemblance between the simulated undulating fish and empirical data. In contrast to theoretical predictions, our model shows that for steadily undulating fish, thrust is produced by the rear 2/3 of the body and that the slip ratio U/V (with U the forward swimming speed and V the rearward speed of the body wave) correlates negatively (instead of positively) with the actual Froude efficiency of swimming. Besides, we show that the common practice of modeling individuals while constraining their sideways acceleration causes them to resemble unconstrained fish with a higher tailbeat frequency.

The choreography of multidrug export.

Multidrug transporters have a crucial role in causing the drug resistance that can arise in infectious micro-organisms and tumours. These integral membrane proteins mediate the export of a broad range of unrelated compounds from cells, including antibiotics and anticancer agents, thus reducing the concentration of these compounds to subtoxic levels in target cells. In spite of intensive research, it is not clear exactly how multidrug transporters work. The present review focuses on recent advancements in the biochemistry and structural biology of bacterial and human multidrug ABC (ATP-binding cassette) transporters. These advancements point to a common mechanism in which polyspecific drug-binding surfaces in the membrane domains are alternately exposed to the inside and outside surface of the membrane in response to the ATP-driven dimerization of nucleotide-binding domains and their dissociation following ATP hydrolysis.

Understanding polyspecificity of multidrug ABC transporters: closing in on the gaps in ABCB1.

Multidrug ABC transporters can transport a wide range of drugs from the cell. Ongoing studies of the prototype mammalian multidrug resistance ATP-binding cassette transporter P-glycoprotein (ABCB1) have revealed many intriguing functional and biochemical features. However, a gap remains in our knowledge regarding the molecular basis of its broad specificity for structurally unrelated ligands. Recently, the first crystal structures of ligand-free and ligand-bound ABCB1 showed ligand binding in a cavity between its two membrane domains, and earlier observations on polyspecificity can now be interpreted in a structural context. Comparison of the new ABCB1 crystal structures with structures of bacterial homologs suggests a critical role for an axial rotation of transmembrane helices for high-affinity binding and low-affinity release of ligands during transmembrane transport.

A multidrug ABC transporter with a taste for salt.

BACKGROUND: LmrA is a multidrug ATP-binding cassette (ABC) transporter from Lactococcus lactis with no known physiological substrate, which can transport a wide range of chemotherapeutic agents and toxins from the cell. The protein can functionally replace the human homologue ABCB1 (also termed multidrug resistance P-glycoprotein MDR1) in lung fibroblast cells. Even though LmrA mediates ATP-dependent transport, it can use the proton-motive force to transport substrates, such as ethidium bromide, across the membrane by a reversible, H(+)-dependent, secondary-active transport reaction. The mechanism and physiological context of this reaction are not known. METHODOLOGY/PRINCIPAL FINDINGS: We examined ion transport by LmrA in electrophysiological experiments and in transport studies using radioactive ions and fluorescent ion-selective probes. Here we show that LmrA itself can transport NaCl by a similar secondary-active mechanism as observed for ethidium bromide, by mediating apparent H(+)-Na(+)-Cl(-) symport. Remarkably, LmrA activity significantly enhances survival of high-salt adapted lactococcal cells during ionic downshift. CONCLUSIONS/SIGNIFICANCE: The observations on H(+)-Na(+)-Cl(-) co-transport substantiate earlier suggestions of H(+)-coupled transport by LmrA, and indicate a novel link between the activity of LmrA and salt stress. Our findings demonstrate the relevance of investigations into the bioenergetics of substrate translocation by ABC transporters for our understanding of fundamental mechanisms in this superfamily. This study represents the first use of electrophysiological techniques to analyze substrate transport by a purified multidrug transporter.