Nanotechnology-driven therapies for neurodegenerative diseases: a comprehensive review.

Neurological diseases, characterized by neuroinflammation and neurodegeneration, impose a significant global burden, contributing to substantial morbidity, disability and mortality. A common feature of these disorders, including stroke, traumatic brain injury and Alzheimer's disease, is the impairment of the blood-brain barrier (BBB), a critical structure for maintaining brain homeostasis. The compromised BBB in neurodegenerative conditions poses a significant challenge for effective treatment, as it allows harmful substances to accumulate in the brain. Nanomedicine offers a promising approach to overcoming this barrier, with nanoparticles (NPs) engineered to deliver therapeutic agents directly to affected brain regions. This review explores the classification and design of NPs, divided into organic and inorganic categories and further categorized based on their chemical and physical properties. These characteristics influence the ability of NPs to carry and release therapeutic agents, target specific tissues and ensure appropriate clearance from the body. The review emphasizes the potential of NPs to enhance the diagnosis and treatment of neurodegenerative diseases through targeted delivery, improved drug bioavailability and real-time therapeutic efficacy monitoring. By addressing the challenges of the compromised BBB and targeting inflammatory biomarkers, NPs represent a cutting-edge strategy in managing neurological disorders, promising better patient outcomes.

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Probiotic therapy modulates the brain-gut-liver microbiota axis in a mouse model of traumatic brain injury.

The interplay between gut microbiota and host health is crucial for maintaining the overall health of the body and brain, and it is even more crucial how changes in the bacterial profile can influence the aftermath of traumatic brain injury (TBI). We studied the effects of probiotic treatment after TBI to identify potential changes in hepatic lipid species relevant to brain function. Bioinformatic analysis of the gut microbiota indicated a significant increase in the Firmicutes/Bacteroidetes ratio in the probiotic-treated TBI group compared to sham and untreated TBI groups. Although strong correlations between gut bacteria and hepatic lipids were found in sham mice, TBI disrupted these links, and probiotic treatment did not fully restore them. Probiotic treatment influenced systemic glucose metabolism, suggesting altered metabolic regulation. Behavioral tests confirmed memory improvement in probiotic-treated TBI mice. While TBI reduced hippocampal mRNA expression of CaMKII and CREB, probiotics reversed these effects yet did not alter BDNF mRNA levels. Elevated pro-inflammatory markers TNF-α and IL1-ß in TBI mice were not significantly affected by probiotic treatment, pointing to different mechanisms underlying the probiotic benefits. In summary, our study suggests that TBI induces dysbiosis, alters hepatic lipid profiles, and preemptive administration of Lactobacillus helveticus and Bifidobacterium longum probiotics can counter neuroplasticity deficits and memory impairment. Altogether, these findings highlight the potential of probiotics for attenuating TBI's detrimental cognitive and metabolic effects through gut microbiome modulation and hepatic lipidomic alteration, laying the groundwork for probiotics as a potential TBI therapy.

Sex-dependent improvement in traumatic brain injury outcomes after liposomal delivery of dexamethasone in mice.

Traumatic brain injury (TBI) can have long-lasting physical, emotional, and cognitive consequences due to the neurodegeneration caused by its robust inflammatory response. Despite advances in rehabilitation care, effective neuroprotective treatments for TBI patients are lacking. Furthermore, current drug delivery methods for TBI treatment are inefficient in targeting inflamed brain areas. To address this issue, we have developed a liposomal nanocarrier (Lipo) encapsulating dexamethasone (Dex), an agonist for the glucocorticoid receptor utilized to alleviate inflammation and swelling in various conditions. In vitro studies show that Lipo-Dex were well tolerated in human and murine neural cells. Lipo-Dex showed significant suppression of inflammatory cytokines, IL-6 and TNF-α, release after induction of neural inflammation with lipopolysaccharide. Further, the Lipo-Dex were administered to young adult male and female C57BL/6 mice immediately after controlled cortical impact injury (a TBI model). Our findings demonstrate that Lipo-Dex can selectively target the injured brain, thereby reducing lesion volume, cell death, astrogliosis, the release of pro-inflammatory cytokines, and microglial activation compared to Lipo-treated mice in a sex-dependent manner, showing a major impact only in male mice. This highlights the importance of considering sex as a crucial variable in developing and evaluating new nano-therapies for brain injury. These results suggest that Lipo-Dex administration may effectively treat acute TBI.

Antibiotic treatment induces microbiome dysbiosis and reduction of neuroinflammation following traumatic brain injury in mice.

Background: The gut microbiome is linked to brain pathology in cases of traumatic brain injury (TBI), yet the specific bacteria that are implicated are not well characterized. To address this gap, in this study, we induced traumatic brain injury (TBI) in male C57BL/6J mice using the controlled cortical impact (CCI) injury model. After 35 days, we administered a broad-spectrum antibiotics (ABX) cocktail (ampicillin, gentamicin, metronidazole, vancomycin) through oral gavage for 2 days to diminish existing microbiota. Subsequently, we inflicted a second TBI on the mice and analyzed the neuropathological outcomes five days later. Results: Longitudinal analysis of the microbiome showed significant shifts in the diversity and abundance of bacterial genera during both acute and chronic inflammation. These changes were particularly dramatic following treatment with ABX and after the second TBI. ABX treatment did not affect the production of short-chain fatty acids (SCFA) but did alter intestinal morphology, characterized by reduced villus width and a lower count of goblet cells, suggesting potential negative impacts on intestinal integrity. Nevertheless, diminishing the intestinal microbiome reduced cortical damage, apoptotic cell density, and microglial/macrophage activation in the cortical and thalamic regions of the brain. Conclusions: Our findings suggest that eliminating colonized gut bacteria via broad-spectrum ABX reduces neuroinflammation and enhances neurological outcomes in TBI despite implications to gut health.

Probiotic treatment causes sex-specific neuroprotection after traumatic brain injury in mice.

Background: Recent studies have shed light on the potential role of gut dysbiosis in shaping traumatic brain injury (TBI) outcomes. Changes in the levels and types of Lactobacillus bacteria present might impact the immune system disturbances, neuroinflammatory responses, anxiety and depressive-like behaviors, and compromised neuroprotection mechanisms triggered by TBI. Objective: This study aimed to investigate the effects of a daily pan-probiotic (PP) mixture in drinking water containing strains of Lactobacillus plantarum, L. reuteri, L. helveticus, L. fermentum, L. rhamnosus, L. gasseri, and L. casei, administered for either two or seven weeks before inducing TBI on both male and female mice. Methods: Mice were subjected to controlled cortical impact (CCI) injury. Short-chain fatty acids (SCFAs) analysis was performed for metabolite measurements. The taxonomic profiles of murine fecal samples were evaluated using 16S rRNA V1-V3 sequencing analysis. Histological analyses were used to assess neuroinflammation and gut changes post-TBI, while behavioral tests were conducted to evaluate sensorimotor and cognitive functions. Results: Our findings suggest that PP administration modulates the diversity and composition of the microbiome and increases the levels of SCFAs in a sex-dependent manner. We also observed a reduction of lesion volume, cell death, and microglial and macrophage activation after PP treatment following TBI in male mice. Furthermore, PP-treated mice show motor function improvements and decreases in anxiety and depressive-like behaviors. Conclusion: Our findings suggest that PP administration can mitigate neuroinflammation and ameliorate motor and anxiety and depressive-like behavior deficits following TBI. These results underscore the potential of probiotic interventions as a viable therapeutic strategy to address TBI-induced impairments, emphasizing the need for gender-specific treatment approaches.

Microbial Community Profiling Protocol with Full-length 16S rRNA Sequences and Emu.

16S rRNA targeted amplicon sequencing is an established standard for elucidating microbial community composition. While high-throughput short-read sequencing can elicit only a portion of the 16S rRNA gene due to their limited read length, third generation sequencing can read the 16S rRNA gene in its entirety and thus provide more precise taxonomic classification. Here, we present a protocol for generating full-length 16S rRNA sequences with Oxford Nanopore Technologies (ONT) and a microbial community profile with Emu. We select Emu for analyzing ONT sequences as it leverages information from the entire community to overcome errors due to incomplete reference databases and hardware limitations to ultimately obtain species-level resolution. This pipeline provides a low-cost solution for characterizing microbiome composition by exploiting real-time, long-read ONT sequencing and tailored software for accurate characterization of microbial communities. © 2024 Wiley Periodicals LLC. Basic Protocol: Microbial community profiling with Emu Support Protocol 1: Full-length 16S rRNA microbial sequences with Oxford Nanopore Technologies sequencing platform Support Protocol 2: Building a custom reference database for Emu.

iDISCO Tissue Clearing Whole-Brain and Light Sheet Microscopy for High-Throughput Imaging in a Mouse Model of Traumatic Brain Injury.

Immunolabeling-enabled imaging of solvent-cleared organs (iDISCO) (Renier N, Wu Z, Simon DJ, Yang J, Ariel P, Tessier-Lavigne M, Cell 159:896-910, 2014) aims to match the refractive index (RI) of tissue to the surrounding medium, thereby facilitating three-dimensional (3D) imaging and quantification of cellular points and tissue structures. Once cleared, transparent tissue samples allow for rapid imaging with no mechanical sectioning. This imaging technology enables us to visualize brain tissue in situ and quantify the morphology and extent of glial cell branches or neuronal processes extending from the epicenter of a traumatic brain injury (TBI). In this way, we can more accurately assess and quantify the damaging consequences of TBI not only in the impact region but also in the extended pericontusional regions.

The Renin Angiotensin System as a Therapeutic Target in Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major public health problem, with limited pharmacological options available beyond symptomatic relief. The renin angiotensin system (RAS) is primarily known as a systemic endocrine regulatory system, with major roles controlling blood pressure and fluid homeostasis. Drugs that target the RAS are used to treat hypertension, heart failure and kidney disorders. They have now been used chronically by millions of people and have a favorable safety profile. In addition to the systemic RAS, it is now appreciated that many different organ systems, including the brain, have their own local RAS. The major ligand of the classic RAS, Angiotensin II (Ang II) acts predominantly through the Ang II Type 1 receptor (AT1R), leading to vasoconstriction, inflammation, and heightened oxidative stress. These processes can exacerbate brain injuries. Ang II receptor blockers (ARBs) are AT1R antagonists. They have been shown in several preclinical studies to enhance recovery from TBI in rodents through improvements in molecular, cellular and behavioral correlates of injury. ARBs are now under consideration for clinical trials in TBI. Several different RAS peptides that signal through receptors distinct from the AT1R, are also potential therapeutic targets for TBI. The counter regulatory RAS pathway has actions that oppose those stimulated by AT1R signaling. This alternative pathway has many beneficial effects on cells in the central nervous system, bringing about vasodilation, and having anti-inflammatory and anti-oxidative stress actions. Stimulation of this pathway also has potential therapeutic value for the treatment of TBI. This comprehensive review will provide an overview of the various components of the RAS, with a focus on their direct relevance to TBI pathology. It will explore different therapeutic agents that modulate this system and assess their potential efficacy in treating TBI patients.

Sex-dependent improvement in traumatic brain injury outcomes after liposomal delivery of dexamethasone in mice.

Traumatic Brain Injury (TBI) can have long-lasting physical, emotional, and cognitive consequences due to the neurodegeneration caused by its robust inflammatory response. Despite advances in rehabilitation care, effective neuroprotective treatments for TBI patients are lacking. Furthermore, current drug delivery methods for TBI treatment are inefficient in targeting inflamed brain areas. To address this issue, we have developed a liposomal nanocarrier (Lipo) encapsulating dexamethasone (Dex), an agonist for the glucocorticoid receptor utilized to alleviate inflammation and swelling in various conditions. In vitro studies show that Lipo-Dex were well tolerated in human and murine neural cells. Lipo-Dex showed significant suppression of inflammatory cytokines, IL-6 and TNF-α, release after induction of neural inflammation with lipopolysaccharide. Further, the Lipo-Dex were administered to young adult male and female C57BL/6 mice immediately after a controlled cortical impact injury. Our findings demonstrate that Lipo-Dex can selectively target the injured brain, thereby reducing lesion volume, cell death, astrogliosis, the release of proinflammatory cytokines, and microglial activation compared to Lipo-treated mice in a sex-dependent manner, showing a major impact only in male mice. This highlights the importance of considering sex as a crucial variable in developing and evaluating new nano-therapies for brain injury. These results suggest that Lipo-Dex administration may effectively treat acute TBI.

A multinational Delphi consensus to end the COVID-19 public health threat.

Despite notable scientific and medical advances, broader political, socioeconomic and behavioural factors continue to undercut the response to the COVID-19 pandemic1,2. Here we convened, as part of this Delphi study, a diverse, multidisciplinary panel of 386 academic, health, non-governmental organization, government and other experts in COVID-19 response from 112 countries and territories to recommend specific actions to end this persistent global threat to public health. The panel developed a set of 41 consensus statements and 57 recommendations to governments, health systems, industry and other key stakeholders across six domains: communication; health systems; vaccination; prevention; treatment and care; and inequities. In the wake of nearly three years of fragmented global and national responses, it is instructive to note that three of the highest-ranked recommendations call for the adoption of whole-of-society and whole-of-government approaches1, while maintaining proven prevention measures using a vaccines-plus approach2 that employs a range of public health and financial support measures to complement vaccination. Other recommendations with at least 99% combined agreement advise governments and other stakeholders to improve communication, rebuild public trust and engage communities3 in the management of pandemic responses. The findings of the study, which have been further endorsed by 184 organizations globally, include points of unanimous agreement, as well as six recommendations with >5% disagreement, that provide health and social policy actions to address inadequacies in the pandemic response and help to bring this public health threat to an end.

Long-COVID in children and adolescents: a systematic review and meta-analyses.

The objective of this systematic review and meta-analyses is to estimate the prevalence of long-COVID in children and adolescents and to present the full spectrum of symptoms present after acute COVID-19. We have used PubMed and Embase to identify observational studies published before February 10th, 2022 that included a minimum of 30 patients with ages ranging from 0 to 18 years that met the National Institute for Healthcare Excellence (NICE) definition of long-COVID, which consists of both ongoing (4 to 12 weeks) and post-COVID-19 (≥ 12 weeks) symptoms. Random-effects meta-analyses were performed using the MetaXL software to estimate the pooled prevalence with a 95% confidence interval (CI). Heterogeneity was assessed using I2 statistics. The Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) reporting guideline was followed (registration PROSPERO CRD42021275408). The literature search yielded 8373 publications, of which 21 studies met the inclusion criteria, and a total of 80,071 children and adolescents were included. The prevalence of long-COVID was 25.24%, and the most prevalent clinical manifestations were mood symptoms (16.50%), fatigue (9.66%), and sleep disorders (8.42%). Children infected by SARS-CoV-2 had a higher risk of persistent dyspnea, anosmia/ageusia, and/or fever compared to controls. Limitations of the studies analyzed include lack of standardized definitions, recall, selection, misclassification, nonresponse and/or loss of follow-up, and a high level of heterogeneity.

Emu: species-level microbial community profiling of full-length 16S rRNA Oxford Nanopore sequencing data.

16S ribosomal RNA-based analysis is the established standard for elucidating the composition of microbial communities. While short-read 16S rRNA analyses are largely confined to genus-level resolution at best, given that only a portion of the gene is sequenced, full-length 16S rRNA gene amplicon sequences have the potential to provide species-level accuracy. However, existing taxonomic identification algorithms are not optimized for the increased read length and error rate often observed in long-read data. Here we present Emu, an approach that uses an expectation-maximization algorithm to generate taxonomic abundance profiles from full-length 16S rRNA reads. Results produced from simulated datasets and mock communities show that Emu is capable of accurate microbial community profiling while obtaining fewer false positives and false negatives than alternative methods. Additionally, we illustrate a real-world application of Emu by comparing clinical sample composition estimates generated by an established whole-genome shotgun sequencing workflow with those returned by full-length 16S rRNA gene sequences processed with Emu.

Fecal Microbiota Transplantation Derived from Alzheimer's Disease Mice Worsens Brain Trauma Outcomes in Wild-Type Controls.

Traumatic brain injury (TBI) causes neuroinflammation and neurodegeneration, both of which increase the risk and accelerate the progression of Alzheimer's disease (AD). The gut microbiome is an essential modulator of the immune system, impacting the brain. AD has been related with reduced diversity and alterations in the community composition of the gut microbiota. This study aimed to determine whether the gut microbiota from AD mice exacerbates neurological deficits after TBI in control mice. We prepared fecal microbiota transplants from 18 to 24 month old 3×Tg-AD (FMT-AD) and from healthy control (FMT-young) mice. FMTs were administered orally to young control C57BL/6 (wild-type, WT) mice after they underwent controlled cortical impact (CCI) injury, as a model of TBI. Then, we characterized the microbiota composition of the fecal samples by full-length 16S rRNA gene sequencing analysis. We collected the blood, brain, and gut tissues for protein and immunohistochemical analysis. Our results showed that FMT-AD administration stimulates a higher relative abundance of the genus Muribaculum and a decrease in Lactobacillus johnsonii compared to FMT-young in WT mice. Furthermore, WT mice exhibited larger lesion, increased activated microglia/macrophages, and reduced motor recovery after FMT-AD compared to FMT-young one day after TBI. In summary, we observed gut microbiota from AD mice to have a detrimental effect and aggravate the neuroinflammatory response and neurological outcomes after TBI in young WT mice.

Alterations to the gut microbiome after sport-related concussion in a collegiate football players cohort: A pilot study.

Concussions, both single and repetitive, cause brain and body alterations in athletes during contact sports. The role of the brain-gut connection and changes in the microbiota have not been well established after sports-related concussions or repetitive subconcussive impacts. We recruited 33 Division I Collegiate football players and collected blood, stool, and saliva samples at three time points throughout the athletic season: mid-season, following the last competitive game (post-season), and after a resting period in the off-season. Additional samples were collected from four athletes that suffered from a concussion. 16S rRNA sequencing of the gut microbiome revealed a decrease in abundance for two bacterial species, Eubacterium rectale, and Anaerostipes hadrus, after a diagnosed concussion. No significant differences were found regarding the salivary microbiome. Serum biomarker analysis shows an increase in GFAP blood levels in athletes during the competitive season. Additionally, S100ß and SAA blood levels were positively correlated with the abundance of Eubacterium rectale species among the group of athletes that did not suffer a diagnosed concussion during the sports season. These findings provide initial evidence that detecting changes in the gut microbiome may help to improve concussion diagnosis following head injury.

A contemporary review of therapeutic and regenerative management of intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) remains a common and debilitating form of stroke. This neurological emergency must be diagnosed and treated rapidly yet effectively. In this article, we review the medical, surgical, repair, and regenerative treatment options for managing ICH. Topics of focus include the management of blood pressure, intracranial pressure, coagulopathy, and intraventricular hemorrhage, as well as the role of surgery, regeneration, rehabilitation, and secondary prevention. Results of various phase II and III trials are incorporated. In summary, ICH patients should undergo rapid evaluation with neuroimaging, and early interventions should include systolic blood pressure control in the range of 140 mmHg, correction of coagulopathy if indicated, and assessment for surgical intervention. ICH patients should be managed in dedicated neurosurgical intensive care or stroke units where continuous monitoring of neurological status and evaluation for neurological deterioration is rapidly possible. Extravasation of hematoma may be helpful in patients with intraventricular extension of ICH. The goal of care is to reduce mortality and enable multimodal rehabilitative therapy.

More than 50 long-term effects of COVID-19: a systematic review and meta-analysis.

COVID-19 can involve persistence, sequelae, and other medical complications that last weeks to months after initial recovery. This systematic review and meta-analysis aims to identify studies assessing the long-term effects of COVID-19. LitCOVID and Embase were searched to identify articles with original data published before the 1st of January 2021, with a minimum of 100 patients. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. PRISMA guidelines were followed. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included (age 17-87 years). The included studies defined long-COVID as ranging from 14 to 110 days post-viral infection. It was estimated that 80% of the infected patients with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). Multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address long COVID-19 care.

Biomimetic Nanoparticles as a Theranostic Tool for Traumatic Brain Injury.

Traumatic brain injury (TBI) triggers both central and peripheral inflammatory responses. Existing pharmacological drugs are unable to effectively and quickly target the brain inflamed regions, setting up a major roadblock towards effective brain trauma treatments. Nanoparticles (NPs) have been used in multiple diseases as drug delivery tools with remarkable success due to their rapid diffusion and specificity in the target organ. Here, leukocyte-based biomimetic NPs are fabricated as a theranostic tool to directly access inflamed regions in a TBI mouse model. This NP systemic delivery is visualized using advanced in vivo imaging techniques, including intravital microscopy and in vivo imaging system. The results demonstrate selective targeting of NPs to the injured brain and increased NPs accumulation among the peripheral organs 24 h after TBI. Interestingly, increased microglial proliferation, decreased macrophage infiltration, and reduced brain lesion following the NPs treatments compared to sham vehicle-treated mice are also found. In summary, the results suggest that NPs represent a promising future theranostic tool for TBI treatment.

COVID-SCORE Spain: public perceptions of key government COVID-19 control measures.

BACKGROUND: Spain was initially one of the countries most affected by the coronavirus disease 2019 (COVID-19) pandemic. In June 2020, the COVID-SCORE-10 study reported that the Spanish public's perception of their government's response to the pandemic was low. This study examines these perceptions in greater detail. METHODS: We employed an ordered logistic regression analysis using COVID-SCORE-10 data to examine the Spanish public's perception of 10 key aspects of their government's COVID-19 control measures. These included support for daily needs, mental and general health services, communication, information and coordination, which were examined by gender, age, education level, having been affected by COVID-19 and trust in government's success in addressing unexpected health threats. RESULTS: 'Trust in the government' showed the greatest odds of positive perception for the 10 measures studied. Odds of positive perception of communication significantly varied by gender, education level and having been affected by COVID-19, whereas for information and coordination of disease control, odds significantly varied by gender and having been affected by COVID-19. Odds of positive perception for access to mental health services significantly varied by gender and education level. Age was not significant. CONCLUSION: Public perception of the government's pandemic response in Spain varied by socio-demographic and individual variables, particularly by reported trust in the government. Fostering public trust during health threats may improve perception of response efforts. Future efforts should tailor interventions that consider gender, education level and whether people have been affected by COVID-19.

Natural tannin extracts supplementation for COVID-19 patients (TanCOVID): a structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: This research aims to study the efficacy of tannins co-supplementation on disease duration, severity and clinical symptoms, microbiota composition and inflammatory mediators in SARS-CoV2 patients. TRIAL DESIGN: This is a prospective, double-blind, randomized, placebo-controlled, parallel-group trial to evaluate the efficacy of the administration of the dietary supplement ARBOX, a molecular blend of quebracho and chestnut tannins extract and Vit B12, in patients affected by COVID-19. PARTICIPANTS: 18 years of age or older, admitted to Hospital de Clinicas Jose de San Martin, Buenos Aires University (Argentina), meeting the definition of "COVID-19 confirmed case" ( https://www.argentina.gob.ar/salud/coronavirus-COVID-19/definicion-de-caso ). Inclusion Criteria Participants are eligible to be included in the study if the following criteria apply: 1. Any gender 2. ≥18 years old 3. Informed consent for participation in the study 4. Virological diagnosis of SARS-CoV-2 infection (real-time PCR) Exclusion Criteria Participants are excluded from the study if any of the following criteria apply: 1. Pregnant and lactating patients 2. Patients who cannot take oral therapy (with severe cognitive decline, assisted ventilation, or impaired consciousness) 3. Hypersensitivity to polyphenols 4. Patients already in ICU or requiring mechanical ventilation 5. Patients already enrolled in other clinical trials 6. Decline of consent INTERVENTION AND COMPARATOR: Experimental: TREATED ARM Participants will receive a supply of 28 -- 390 mg ARBOX capsules for 14 days. Patients will be supplemented with 2 capsules of ARBOX per day. Placebo Comparator: CONTROL ARM Participants will receive placebo supply for 14 days. The placebo will be administered with the identical dose as described for the test product. All trial participants will receive standard therapy, which includes: Antipyretics or Lopinavir / Ritonavir, Azithromycin and Hydroxychloroquine, as appropriate (treatment currently recommended by the department of Infectious Diseases of the Hospital de Clínicas that could undergo to modifications). In addition, if necessary: supplemental O2, non-invasive ventilation, antibiotic therapy. MAIN OUTCOMES: Primary Outcome Measures: Time to hospital discharge, defined as the time from first dose of ARBOX to hospital discharge [ Time Frame: Throughout the Study (Day 0 to Day 28) ] Secondary Outcome Measures: 28-day all-cause mortality [ Time Frame: Throughout the Study (Day 0 to Day 28) ]-proportion Invasive ventilation on day 28 [ Time Frame: Throughout the Study (Day 0 to Day 28) ]-proportion Level of inflammation parameters and cytokines [ Time Frame: day 1-14 ] -mean difference Difference in fecal intestinal microbiota composition and intestinal permeability [ Time Frame: day 1-14 ] Negativization of COVID-PCR at day 14 [ Time Frame: day 14 ]-proportion RANDOMIZATION: Potential study participants were screened for eligibility 24 hours prior to study randomization. Patients were randomly assigned via computer-generated random numbering (1:1) to receive standard treatment coupled with tannin or standard treatment plus placebo (control group). BLINDING (MASKING): Study personnel and participants are blinded to the treatment allocation, as both ARBOX and placebo were packed in identical containers. Thus, all the used capsules had identical appearance. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Considering an alpha error of 5%, a power of 80% a sample size of 70 patients per branch was estimated. 140 patients in total. TRIAL STATUS: The protocol version is number V2, dated May 23, 2020. The first patient, first visit was on June 12, 2020; the recruitment end date was October 6, 2020. The protocol was not submitted earlier because the enrollment of some patients took place after the closure of the recruitment on the clinicaltrials platform. In fact, due to the epidemiological conditions, due to the decrease of the cases in Argentina during the summer period, the recruitment stopped t before reaching the number of 140 patients (as indicated in the webpage). However, since there was a new increase in cases, the enrolment was resumed in order to reach the number of patients initially planned in the protocol. The final participant was recruited on February 14, 2021. TRIAL REGISTRATION: ClinicalTrials.gov, number: NCT04403646 , registered on May 27th, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

More Than 50 Long-Term Effects of COVID-19: A Systematic Review and Meta-Analysis.

Background. COVID-19, caused by SARS-CoV-2, can involve sequelae and other medical complications that last weeks to months after initial recovery, which has come to be called Long-COVID or COVID long-haulers. This systematic review and meta-analysis aims to identify studies assessing long-term effects of COVID-19 and estimates the prevalence of each symptom, sign, or laboratory parameter of patients at a post-COVID-19 stage. Methods . LitCOVID (PubMed and Medline) and Embase were searched by two independent researchers. All articles with original data for detecting long-term COVID-19 published before 1 st of January 2021 and with a minimum of 100 patients were included. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. Heterogeneity was assessed using I 2 statistics. This systematic review followed Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) guidelines, although the study protocol was not registered. Results. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included. The follow-up time ranged from 14 to 110 days post-viral infection. The age of the study participants ranged between 17 and 87 years. It was estimated that 80% (95% CI 65-92) of the patients that were infected with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). All meta-analyses showed medium (n=2) to high heterogeneity (n=13). Conclusions . In order to have a better understanding, future studies need to stratify by sex, age, previous comorbidities, the severity of COVID-19 (ranging from asymptomatic to severe), and duration of each symptom. From the clinical perspective, multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address long COVID-19 care.