Many clinical interventions are trialled to manage medical complications following Traumatic Brain Injury (TBI). However, published evidence for the effects of those clinical interventions is limited. This article is an overview of common complications and their management from published systematic reviews in TBI.st January 2021. Methodological quality and evidence were critically appraised using the Grading of Recommendations, Assessment, Development and Evaluations and Revised-Assessment of Multiple Systematic review tools. Overall, only six systematic reviews complied with search criteria, these evaluated fatigue, spasticity and post traumatic seizures . No systematic reviews for other common TBI-related complications met criteria for this review. The included reviews varied from ‘moderate to high’ in methodological quality. The findings suggest beneficial treatment effect of anti-epileptic drugs (phenytoin/levetiracetam) compared with placebo in reducing early seizure incidence, but no significant benefit of phenytoin over levetiracetam, valproate, or neuroprotective agent for early or late posttraumatic seizures. There was ‘limited’ evidence for spasticity-related interventions, and ‘insufficient’ evidence of cardiorespiratory training on fatigue levels.A health science electronic database search for published systematic reviews for management of common complications in TBI was conducted in the last decade till 31Despite the high prevalence and associated functional impact of TBI-related complications, there is limited evidence to guide treating clinicians for management of common TBI complications. More robust studies are needed to build evidence in this population. Traumatic Brain Injury (TBI) is a global health problem and leading cause of death and disability worldwide. It is defined as “an alteration in brain function, or other evidence of brain pathology, caused by an external force” and may include a change in the mental status, loss of consciousness, focal neurological deficit, or loss of memory for the event . Based oAdvances in medical and intensive management have reduced mortality rates for people with severe TBI, but the burden of care remains substantive. TBI can result in multiple complications, the sequelae of which can vary in their nature and severity. These issues can have a significant impact on the daily function with disabilities  and participation . Motor, cognitive, behavioural and personality deficits, which may occur following TBI, can be disabling. Some potential common complications, especially after moderate-severe TBI include posttraumatic seizures (PTS) and epilepsy, hydrocephalus, paroxysmal sympathetic hyperactivity, spasticity, agitation, neuroendocrine dysfunction, heterotrophic ossification, venous thromboembolism, sleep disturbances and cranial nerve dysfunction , 7–10. TAutonomic dysfunction is well documented in TBI survivors, with a reported incidence of 8 to 32% . StudiesTBI complications are complex and multi-faceted, and often require a comprehensive approach using pharmacological and/or non-pharmacological interventions. Rehabilitation following TBI is best managed by a specialised interdisciplinary approach, with goals of minimising complications and optimising function using adaptive environmental modifications. To date, many clinical trials evaluating TBI complications have been conducted and numerous systematic reviews have been published compiling the evidence from these primary studies for the management of TBI complications. However, they differ in their scope, quality and methodology. An overview of published systematic reviews is thus required to qualitatively appraise the methodology and to systematically evaluate evidence for the management of potential medical complications following TBI. Therefore, this article provides an evidence-based overview of the management of common TBI-related medical complications from published systematic reviews of clinical trials. It is envisaged that the findings will provide an evidence-based snapshot to guide treating clinicians and also for future research by highlighting existing gaps in evidence.The review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)  and CochTwo reviewers  screened and shortlisted all abstracts and titles of review identified by the search strategy based on the search criteria. All studies identified through the search process were exported to an EndNote X9  database for the removal of duplicates. The authors then evaluated each study independently, and the full text of all potential articles was assessed to determine eligibility based on the inclusion/exclusion criteria. Any disagreement regarding the eligibility criteria was discussed with a third reviewer (FK) and resolved by a final group consensus. Standard proforma was used for data extraction from all reviews, which included publication and search date, objectives, characteristics of included studies and study subjects, interventions, findings/patient outcomes in the review, and limitations.Two authors  independently assessed the methodological quality of each review, using the Revised-Assessment of Multiple Systematic reviews (R-AMSTAR) appraisal tool  S4 Appe. Any disThe R-AMSTAR consists of 11 questions for methodological quality assessment of systematic reviews , 21. It The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system  on a fouThe initial search identified a total of 207 published systematic reviews  evaluating the management of potential common medical complications following TBI. Of these, 34 met the abstract inclusion criteria and were selected for closer scrutiny. One review was identified from the manual search of the bibliography of relevant articles. Overall, six reviews evaluating fatigue, spasticity and post traumatic seizures were included, . Of these, three reviews were published in the Cochrane Library database and three in other academic journals. Despite the high clinical relevance and common occurrence of other TBI- related complications, no systematic reviews addressing them were identified or met standard selection criteria of this review. A PRISMA flowchart of the study selection process is provided in A priori protocol publication criteria were met for reviews, except for two [The summary results of the R-AMSTAR quality assessment are provided in  for two , 29. All for two  had at l for two –26 proviThe evidence for all relevant outcomes with the GRADE rating is summarised in One systematic review   evaluateSynnot et al.   investigPharmacological treatments. Pharmacological interventions evaluated within the review included intrathecal baclofen [baclofen  and botubaclofen , 35. Onlbaclofen , compareTwo studies compared the effect of BoNT-A versus placebo (with or without casting) for upper and lower limb spasticity for TBI survivors in either an acute or sub-acute setting , 35. TheNon-pharmacological treatments. Non-pharmacological interventions evaluated within the review included: casting, physiotherapy [otherapy , splintiotherapy , electriotherapy . One RCTotherapy  evaluateVerplancke et al.  in anothAnother RCT (n = 25 participants)  evaluateOne systematic review  , 39 compAnother meta-analysis   assessedBakr et al. in another systematic review   evaluateIn summary, three systematic reviews –29 evaluThis review systematically summarizes the up-to-date evidence from published systematic reviews to provide an overview of the interventions currently used for the management of common medical complications following mild to severe TBI. An overview of systematic reviews is an emerging method of appraising and synthesising evidence from published systematic reviews on similar or related topics. It can be a useful tool to summarise up-to-date information on treatment effects of the same or similar interventions in a much broader concept to guide and support decision-making by clinicians, policymakers and clinical guideline developers. Overall, only six systematic reviews met the inclusion criteria and were included in this review. These evaluated three common complications: posttraumatic seizures, fatigue and spasticity. The findings from this review indicate that despite a wide range of treatment modalities for the management of these three complications, the evidence to support them is low or insufficient. Further, this review identified paucity of data from published systematic reviews addressing management of other common complications related to TBI, due to the limited number of methodologically robust studies.The key findings of this review, based on GRADE approach suggest:Moderate quality evidence for the effectiveness of phenytoin with another AED  in reducing early or late seizures [seizures Low-quality evidence for AEDs  in reducing the risk of early seizures compared with placebo or standard care [ard care .Low-quality evidence for the efficacy of levetiracetam or phenytoin in the incidence of early seizure prophylaxis [phylaxis , 29Low-quality evidence for neuroprotective agent (magnesium sulfate) compared with placebo in seizure prophylaxis following moderate-severe brain injury [n injury Low-quality evidence for safety or effectiveness of phenytoin compared with another AED  in reducing early or late seizures [seizures Very low-quality evidence for AEDs  in reducing the risk of late seizures compared with placebo or standard care [ard care Very low-quality evidence for either phenytoin or levetiracetam for late seizure incidence risk, length of hospital stays or for levetiracetam on the long-term neurological outcomes (GOS-E scores) at six months following severe TBI [vere TBI Antiepileptic drugs (AEDs) are recommended for the treatment of early and late posttraumatic seizures. Historically, phenytoin has been the drug of choice for PTS prophylaxis following various brain injuries, including TBI. Although the efficacy of phenytoin has been widely accepted, its side effects remain a significant problem, especially longer-term use . Hence, Based on the current evaluation, AEDs are effective in early seizure prophylaxis and do not appear to alter the natural history of the late seizures or PTE. A recent meta-analysis by Wat et al.  highlighVery low-quality evidence for the beneficial effect of cardiorespiratory exercise program on fatigue compared to usual care, non-exercise intervention or no intervention [rvention Posttraumatic fatigue, similar to sleep disorders, is a well-described complication following TBI. It can be primary  or secondary, and can exacerbate other co-morbidities. It usually occurs in conjunction with sleep disturbances causing cognitive, emotional and physical impairments. However, there are limited systematic reviews evaluating fatigue in the TBI population. Despite numerous narrative reviews –52 proviVery low-quality evidence for the effectiveness of pharmacological  and non-pharmacological interventions , often used in combination for the management of upper and lower limb spasticity [asticity Spasticity is a prevalent physical complication of TBI. This review found only one systematic review  that evaSystemic complications following TBI can affect a multitude of systems including cardiovascular, respiratory, immunological, haematological and neuroendocrine systems. They can occur in the acute setting and continue through to rehabilitation and longer-term. Although these complications are commonly encountered and managed in routine clinical practice, this review found scarcity of data from published systematic reviews. Over the last decade, sleep-wake disturbances/deficits after TBI have been widely studied –58. A meThere are several limitations with regard to the methodology and completeness of this review. The search was limited to the last decade only as most of the relevant qualitative studies were in the last ten years and any search beyond this is unlikely to add any clinically relevant information to guide evidence-based practice. Despite using the multi-pronged search approach to identify relevant studies, we identified only published systematic reviews from the academic databases and no reviews were found in the grey literature search. Publication bias cannot be ruled out as we were unable to include unpublished studies and most of the included systematic reviews were not up to date, and may have missed many recent studies. Therefore, the findings of this review should be interpreted with caution. The included reviews assessed a small number of primary studies evaluating specific TBI-related outcomes, which may have an impact on the formulation of the level or quality of evidence to make any definitive conclusions about the interventions. The settings and measurement tools used in various reviews were different even for the same evaluated intervention, which precluded pooling of data. Further, the evaluation of original data from the primary studies within the included reviews was beyond the scope of this review as the primary objective was to analyse the findings from the included reviews themselves. Systematic reviews addressing other common TBI-related complications  did not met the selection criteria of this review, and hence were excluded. A reference bias may have been introduced by scrutinising only the reference lists within the relevant articles. Although GRADE and R-AMSTAR tools are validated and widely used, they have certain limitations. It was beyond the scope of this review to evaluate the evidence on the safety of some of the included interventions. This review did not evaluate specific cognitive and behaviour therapies in TBI as this topic has already been extensively published –69 and wTBI is a complex injury with complications causing significant societal and financial burden to patients (and families), and health system at large. These TBI-related complications require comprehensive management using pharmacological and/or non-pharmacological approaches, including rehabilitation, and longer-term supportive care. Despite high prevalence of various complications in TBI population, evidence for many is lacking. The most common complications evaluated were posttraumatic seizures, fatigue and spasticity. Unfortunately, management of many of the other common TBI complications were not included given paucity of systematic reviews in this population. Larger robust trials are needed to build evidence for the effectiveness of various TBI-related complications to guide clinical practice.S1 Appendix(DOC)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(DOCX)Click here for additional data file.S4 Appendix(DOCX)Click here for additional data file.S5 Appendix(DOCX)Click here for additional data file.S6 Appendix(DOCX)Click here for additional data file.


Culiseta melanura, the primary vector for EEEV, which showed a strong correlation with woody wetland, precipitation seasonality and average temperature of driest quarter. Our analyses showed that majority of the studied mosquito species’ abundance and distribution are insignificantly better predicted by the biotic correlations than by environmental variables. Additionally, these mosquito vector species may be habitat generalists, as indicated by the unconditional correlation matrices between species pairs, which could have confounded our analysis, but also indicated that the approach could be operationalized to leverage species co-occurrences as indicators of vector abundances in unsampled areas, or under scenarios where environmental variables are not informative.Mosquito vectors of eastern equine encephalitis virus (EEEV) and West Nile virus (WNV) in the USA reside within broad multi-species assemblages that vary in spatial and temporal composition, relative abundances and vector competence. These variations impact the risk of pathogen transmission and the operational management of these species by local public health vector control districts. However, most models of mosquito vector dynamics focus on single species and do not account for co-occurrence probabilities between mosquito species pairs across environmental gradients. In this investigation, we use for the first time conditional Markov Random Fields (CRF) to evaluate spatial co-occurrence patterns between host-seeking mosquito vectors of EEEV and WNV around sampling sites in Manatee County, Florida. Specifically, we aimed to: (i) quantify correlations between mosquito vector species and other mosquito species; (ii) quantify correlations between mosquito vectors and landscape and climate variables; and (iii) investigate whether the strength of correlations between species pairs are conditional on landscape or climate variables. We hypothesized that either mosquito species pairs co-occur in patterns driven by the landscape and/or climate variables, or these vector species pairs are unconditionally dependent on each other regardless of the environmental variables. Our results indicated that landscape and bioclimatic covariates did not substantially improve the overall model performance and that the log abundances of the majority of WNV and EEEV vector species were positively dependent on other vector and non-vector mosquito species, unconditionally. Only five individual mosquito vectors were weakly dependent on environmental variables with one exception, The online version contains supplementary material available at 10.1186/s13071-022-05530-1. Mosquito vector-borne pathogens such as eastern equine encephalitis virus (EEEV) and West Nile virus (WNV) are maintained and proliferate in the natural environment via a complex set of requirements and interactions with their hosts, underlying environmental variables and interactions with other organisms . Both ofWhile range-wide distributions of single species are now routinely estimated using ecological niche models , 18, theA key challenge in predicting local-scale species distributions and community composition is accounting for covariance between species and the environment. Generalized additive models (GAMS) have been used to explore relationships between abundances of potential competitors in mosquito assemblages and a vegetation gradient , while oIn this study, we leverage the capability of longitudinal collection data for mosquito communities, with the main emphasis on vectors of EEEV and WNV from Manatee County, Florida over the 2020 sampling season (May–December) to: (i) quantify correlations between host-seeking mosquito vector species of WNV and EEEV and other mosquito species, vectors and non-vectors; (ii) quantify correlations between host-seeking mosquito vectors and landscape and climate variables within their flying ranges; and (iii) investigate whether the strength of correlations between species pairs are conditional on landscape or climate variables using CRF analyses.We hypothesized that species composition and abundances of WNV- and EEEV-competent mosquito species are most likely determined by co-occurrences between species pairs in specific landscape and/or climate features; that is, landscape features generally important for modifying species co-occurrence. Alternately, it may be that most vector mosquitoes are habitat generalists and generally co-occur regardless of landscape. The end goal of using this approach is to better understand the joint effects of landscape and other mosquito species drivers on mosquito diversity/density and provide data-driven information for more comprehensive management and control strategies.https://vectorbase.org; 2021). The MCMCD 2020 data resulted from collections using US Centers for Disease Control and Prevention (CDC) CO2-baited light traps set at 56 locations at weekly intervals from approximately May to December , Florida, were acquired from the VectorBase Bioinformatics Resource for Invertebrate Vectors of Human Pathogens repository  Conterminous United States Land Cover Projections 1992–2100 were extracted for 2020  and servhttps://prism.oregonstate.edu/. To reduce the number of variables in our model, five bioclimatic variables were selected for analyses: Bio2 , Bio5 (the maximum temperature of the warmest month), Bio9 (mean temperature of the driest quarter), Bio15  and Bio17 (precipitation of the driest quarter), based on mosquito biology and ecological data reported in previous studies [Bioclimatic variables within buffer sets surrounding each trap site from 2020 daily ‘Parameter-elevation Regressions on Independent Slopes Model’ (PRISM) Climate Group data  were ext studies , 21, 53.Coquillettidia perturbans and Mansonia dyarii indicated by the generated regression correlation matrices package in R  to quants Tables , 3.To prepare data for analysis, we rounded the mean mosquito per trap night value within our ‘site-by-species’ matrix to an integer value to serve as nodes (mosquito species) and added additional columns with percentage landscape and average bioclimatic variables to serve as the conditional variables in the model. To calculate CRF using abundance data, the ‘MRFcov’ package log-transforms species counts before performing pairwise linear regressions across all combinations of species and environmental variables, using an optimized regularization multiplier for variable selection and to reduce overfitting; predicted and observed values for all species combinations are then used in model evaluation . GeograpManatee County, Florida, is located on the western coast of the Florida Peninsula on the Gulf of Mexico Fig. . Along tCulex was the dominant genus found across these sites; however, approximately 14% of sites were dominated by Aedes mosquitoes  and with covariates (CRF) measured within 5-km and 10-km buffer distances indicated that the inclusion of landscape and bioclimatic variables did not substantially improve the overall model performance when evaluated by deviance (DV) or mean squared error (MSE) values Fig.  and withModel regression correlation matrices included key coefficient tables that summarized the relative importance of correlations between log abundances of species pairs or between the log abundance of an individual vector species and environmental variables , or conditional correlations between species pairs where the strength of the correlation changes in specific land cover classes or climate conditions measured within 5-km and 10 km-buffer distances , average temperature of driest quarter  and woody wetland (relative importance = 0.226), and not with other mosquito species , Aedes infirmatus and Aedes fulvus pallens , and Aedes taeniorhynchus and Aedes atlanticus , indicating low log abundances of the former species of each pair at collection sites were associated with high abundances of the respective latter species  geographic overlapping, due to small study area, in the flight ranges between the studied mosquito species, and/or (ii) that some of these vectors are typically broad-habitat generalists, which can present challenges when investigating occurrence patterns using environmental variables alone. For example, the strong co-occurrence between patterns , 64.Cs. melanura, the primary enzootic vector of EEEV, was strongly correlated with landscape and bioclimatic variables, but not with other mosquito species. Compared to the more generalist vectors in our study area, Cs. melanura is a known specialist species with a strong preference for hardwood swamps as breeding habitats [Ae. taeniorhynchus, was most abundant in areas with low mean diurnal temperature ranges, which almost certainly reflects its coastal affinities [Our modeling approach does clearly delineate some broad-scale habitat specialists. For example, habitats , and ourhabitats –68. Anotfinities –71, wherCq. perturbans, demonstrated such conditional correlations. The shifts in the strength of mean coefficient values between Cq. perturbans and Ma. dyarii was affected by cropland habitats. The positive correlation between Cq. perturbans and Ma. dyari in croplands specifically, including wooded areas, reflects the importance of these habitats in predicting the level and strength of correlations between the two species compared to their unconditional correlations with each other in other habitats [Culex. nigripalpus (a competent WNV vector) at the expense of Ae. taeniorhynchus (a less competent WNV vector).Variation in the strength and direction of dependence between pairs of vector species across different environmental variables was of particular interest in terms of the goal of providing more comprehensive information about habitats in which multiple vector species may occur. Only one vector species, habitats –75. ThisWe observed insignificant differences between model performance with and without environmental variables for co-occurrences between species pairs. We also observed only slight variation in model results when comparing effects of environmental variables measured within 5-km buffer distances and within 10-km buffer distances, as indicated by the relative importance values. However, increasing our buffer radius from 5 to 10 km resulted in a slight increase in the number of vector species demonstrating correlations with another mosquito species only, and not with environmental variables, from 32 to 34 pairs. Increased buffer extents capture greater mosquito communities and potential variability in climate and landscape conditions, which may be only marginally variable across smaller geographic areas such as Manatee County. Considerations of scale in the use of such approaches are particularly important to consider, especially given our discussion above regarding complexities with interpreting co-occurrence (or co-abundance) in relation to (here unmeasured) microhabitat drivers.Although the collected mosquito vector diversity in the current study was robust, additional longitudinal data of mosquito collections, which could include other sampling techniques such as ovitraps, are needed to capture intra- and inter-annual population fluctuations between species pairs and to investigate additional environmental covariates at different resolutions across space and time. Moreover, the conditional correlations between host-seeking disease-vector species and other species not involved in the transmission of pathogens in specific habitats and climate conditions need further investigation to identify variation in both intra- and inter-seasonal correlations using a robust data collection across time and space. Additionally, because our study focused on host-seeking female mosquitoes, further investigation into the contribution of mosquito flight distances and their contributions to observed patterns is warranted. The purpose of this study was not to dissect the underlying processes and mechanisms that determine community abundances across our study area; however, our results highlight points of interest for continued investigation in the context of understanding underlying transmission risk. Specifically, continued investigation into the contributions of competition/exclusion in mature and immature habitats and the role of such biotic interactions in the distribution of vector mosquitoes will be critical.Culiseta melanura, the primary vector for EEEV, showed a strong conditional correlation with woody wetland, precipitation seasonality and average temperature of driest quarter, but not any other species. Some of the studied mosquito vector species are habitat generalists, indicated by a low number of conditional correlations with environmental variables but which also indicated that the approach could be operationalized to leverage species co-occurrences as indicators of vector abundances in unsampled areas, or under scenarios where environmental variables are not informative. Also, considerations of geographic scale in the use of CRF approach are particularly important to be addressed in future studies to explain the complexities of co-occurrence (or co-abundance) in relation to microhabitat drivers.The landscape and bioclimatic covariates did not substantially improve the overall model performance, and the majority of WNV and EEEV vector species were positively correlated with other vector and non-vector mosquito species. This may reflect: (i) the small geographic size of the study area with less environmental heterogeneity and that distances between habitats are within the foraging range of most of mosquito species; (ii) that mosquito abundance and distribution in our study sites are predicted by the biotic factors (here unmeasured) in the water habitats, such as abundance of other mosquito species, and not climate; and/or (iii) that the mosquito community in Manatee County is habitat generalist, according to literature from similar studies. Only one exception, Additional file 1: Data file S1.  Data and r code developed for the analysis (https://github.com/slmmhm/MRFcov-Manatee-county.git). Figure S1. Box plots of MRF analyses with covariates (left) and without covariates (right) show MSE and deviance within 10 km.Additional file 2: Table S1. Key coefficient values derived from 500 bootstrap replicates for models run with environmental covariates measured within a 5-km distance from trap locations. SpName is the mosquito species response variable, Variable is the explanatory variable and rows with two variables separated by an "_" indicate conditional dependence. Rel_importance represents the relative importance of the Variable on the log abundance of the SpName count out of all combinations of variables for the individual SpName. Lower is the lower 10% confidence level, Mean_coef is the mean coefficient value and Upper is the upper 90% confidence value. Rows with NA values indicate that the log abundances SpName did not demonstrate dependence on another variable  included in the data set.Additional file 3: Table S2. Key coefficient values derived from 500 bootstrap replicates for models run with environmental covariates measured within a 10-km distance from trap locations. SpName is the mosquito species response variable, Variable is the explanatory variable and rows with two variables separated by an "_" indicate conditional dependence. Rel_importance represents the relative importance of the Variable on the log abundance of the SpName count out of all combinations of variables for the individual SpName. Lower is the lower 10% confidence level, Mean_coef is the mean coefficient value and Upper is the upper 90% confidence value. Rows with NA values indicate that the log abundances SpName did not demonstrate dependence on another variable  included in the data set.


Parenchymal lung disease is the fourth leading cause of death in the United States; among the top causes, it continues on the rise. Telomeres and telomerase have historically been linked to cellular processes related to aging and cancer, but surprisingly, in the recent decade genetic discoveries have linked the most apparent manifestations of telomere and telomerase dysfunction in humans to the etiology of lung disease: both idiopathic pulmonary fibrosis (IPF) and emphysema. The short telomere defect is pervasive in a subset of IPF patients, and human IPF is the phenotype most intimately tied to germline defects in telomere maintenance. One-third of families with pulmonary fibrosis carry germline mutations in telomerase or other telomere maintenance genes, and one-half of patients with apparently sporadic IPF have short telomere length. Beyond explaining genetic susceptibility, short telomere length uncovers clinically relevant syndromic extrapulmonary disease, including a T-cell immunodeficiency and a propensity to myeloid malignancies. Recognition of this subset of patients who share a unifying molecular defect has provided a precision medicine paradigm wherein the telomere-mediated lung disease diagnosis provides more prognostic value than histopathology or multidisciplinary evaluation. Here, we critically evaluate this progress, emphasizing how the genetic findings put forth a new pathogenesis paradigm of age-related lung disease that links telomere abnormalities to alveolar stem senescence, remodeling, and defective gas exchange. CLINICAL HIGHLIGHTSTelomerase mutations are the most common cause of autosomal dominant pulmonary fibrosis, explaining the genetic basis in up to one-third of familial cases.Identifying affected patients with genetic evaluation and telomere length testing has important implications, may be prognostic, and is predictive of certain extrapulmonary comorbidities including a risk of infections, intolerance to immunosuppression, and a propensity to liver disease among other conditions.Short telomere reserves limit alveolar epithelial regenerative potential and with aging lower the threshold to additive acquired damage mediating lung remodeling that may appear as fibrosis and in some cases, especially in females, emphysema.Tetrahymena thermophila, a pond protozoan chosen for study for its thousands of chromosomes  repeats at chromosome ends; they are bound by specialized proteins. Their length is heritable. With each cell replication somatic cell telomeres shorten, and critically short telomere length, at certain thresholds, signals a p53-dependent DNA damage response that triggers apoptosis in high-turnover tissues  mutations and a history of lung adenocarcinoma being associated with surfactant protein A1 and A2 (SFTPA1 and SFTPA2) mutations.Germline mutations in telomerase and other telomere maintenance genes predispose to IPF by mediating short telomere length genetically at birth. Collectively, mutations are deleterious because they compromise telomerase abundance or function . Most murichment . Among arichment –33 , and RTEL1, the regulator of telomere elongation helicase 1; importantly, rare mutations in all three of these genes also cause autosomal dominant forms of IPF  has allowed for measuring the average telomere length in leukocyte subsets with standardization and high reproducibility. This has been integrated in guideline testing for patients with bone marrow failure because of susceptibility to cytotoxic therapies in patients with short telomere length . The abiIn our discussion of the flowFISH method as a gold standard for clinical use, we take this opportunity to make comparisons with other techniques commonly used in epidemiological studies. The first method developed historically used restriction fragment analysis (Southern blotting) derived from total leukocyte DNA; however, this requires specialized equipment and large DNA input and does not distinguish leukocyte lineage-specific changes . QuantitTERT explain the inheritance of 15% of familial IPF and are its most common cause   . TERT muunctions . Rarely,unctions . The exqunctions . Among pRT or TR , 29. Thuof cases , 66, 67.TERT and other telomere maintenance genes, short telomere length is the primary mediator of disease onset and severity  and NAF1, both of which are required for TR’s stability, biogenesis, and nucleolar localization  that have regenerative potential , 96, affOne hurdle to establishing a faithful animal model of telomere-mediated lung disease is that these pathologies evolve over many decades and are age dependent . AttemptThe earliest insights into the biology of telomere-mediated lung disease came from studies of late-generation telomerase-knockout mice that were bred to acquire short telomeres in late generation. Although they develop disease in high-turnover tissues faithfully, these animals do not develop de novo lung disease , 106. ThClinically relevant insights in studies of mice with short telomeres emerged from studies uncovering their sensitivity to chronic cigarette smoke exposure. When these mice were exposed to cigarette smoke for 6 mo, even though there was no de novo defect, the animals showed a susceptibility to emphysema  FIGURE . The acqBecause conditional models where short telomeres can be directed to a specific cellular compartment are not feasible given the long telomere length of laboratory mice, models that induce telomere dysfunction by telomere uncapping have also been generated. In these experiments, mice were engineered to acquire adult-onset telomere dysfunction by conditional deletion of telomere binding proteins such as TRF2. This lesion is nonphysiological and is not acquired with aging, but it serves as a surrogate for studying the consequences of DNA damage restricted to AEC2s . When thHow does telomere-mediated senescence mediate lung remodeling? The answers are not entirely understood, but there is evidence that the transcriptional and proteomic profile of short telomere AEC2s is altered. Changes include an upregulated DNA damage response as well as upregulation and secretion of proinflammatory cytokines and growth factors that represent a telomere-mediated senescence-associated secretory phenotype (SASP) in this setting , 109. AlTERT promoter gain-of-function mutations); however, even when nearly all cells acquire this advantageous mutation, there are no obvious telomere length or blood count improvements detected after a decade  Grants R01 HL-135062 and work in the Armanios laboratory by NIH R01 CA-225027 and R01 HL-119476; an award from the S&R Kuno Foundation; and a gift in the name of Mrs. P. Godrej.No conflicts of interest, financial or otherwise, are declared by the authors.J.K.A. and M.A. prepared figures, drafted manuscript, edited and revised manuscript, and approved final version of manuscript.


Organ function relies on microvascular networks to maintain homeostatic equilibrium, which varies widely in different organs and during different physiological challenges. The endothelium role in this critical process can only be evaluated in physiologically relevant contexts. Comparing the responses to oxygen flux in primary murine microvascular EC (MVEC) obtained from brain and lung tissue reveals that supra-physiological oxygen tensions can compromise MVEC viability. Brain MVEC lose mitochondrial activity and undergo significant alterations in electron transport chain (ETC) composition when cultured under standard, non-physiological atmospheric oxygen levels. While glycolytic capacity of both lung and brain MVEC are unchanged by environmental oxygen, the ability to trigger a metabolic shift when oxygen levels drop is greatly compromised following exposure to hyperoxia. This is particularly striking in MVEC from the brain. This work demonstrates that the unique metabolism and function of organ-specific MVEC (1) can be reprogrammed by external oxygen, (2) that this reprogramming can compromise MVEC survival and, importantly, (3) that ex vivo modelling of endothelial function is significantly affected by culture conditions. It further demonstrates that physiological, metabolic and functional studies performed in non-physiological environments do not represent cell function in situ, and this has serious implications in the interpretation of cell-based pre-clinical models. When stretched too far or for too long beyond the normal physiological range, these cellular responses can exacerbate pathologies, typically involving vascular dysfunction  and andlMVEC2 oscillations  used to treat refractory diabetic lower extremity wounds or radiation injuries result in an increase in Odard air ,29; in rdard air . Visibledard air , but eard air [2 . Even thd air [2 . With thd air [2 ,95,96, wd air [2 ,93,97, ad air [2 ,99.MVEC are highly responsive cells, with morphological and functional aspects that uniquely match the tissues they reside in; oxygen-sensing by these cells differs in sensitivity, timing and amplitude in different organs. While glycolytic capacity is essentially constant across organ sites, mitochondrial function is dependent on the tissue of origin.Understanding the unique nature and response of tissue-specific microvasculature will allow the identification of particular organ vulnerabilities to oxygen oscillations resulting from physiological, pathological or therapeutic settings. Most molecular studies are performed in cells maintained in atmospheric oxygen, which this study unambiguously demonstrates is hyperoxic, which in turn affects baseline cell metabolism and subsequent cell behaviour.Our data show that adaptation to hypoxia is compromised when cells are exposed to supra-physiological levels of oxygen: while glycolytic capacity is not affected, mitochondrial damage impacts the cell’s ability to perceive hypoxia in a timely fashion. In brain MVEC, this results in the loss of viability.It further highlights the detrimental effects of hyperoxia, which are far less considered, albeit demonstrably no less harmful, underscoring the importance of research into organ-specific MVEC reprogramming by environmental challenges and the downstream effects in disease, treatment and long-term recovery.The unique metabolism and function of organ-specific MVEC is shown to be reprogrammed by external oxygen. These findings establish the inadequacy of molecular and physiological studies performed at atmospheric oxygen tensions, while raising the need for refinement and functional outputs to confirm and measure the benefits of oxygen therapy.


Survivors of traumatic brain injury (TBI) have an unpredictable clinical course. This unpredictability makes clinical resource allocation for clinicians and anticipatory guidance for patients difficult. Historically, experienced clinicians and traditional statistical models have insufficiently considered all available clinical information to predict functional outcomes for a TBI patient. Here, we harness artificial intelligence and apply machine learning and statistical models to predict the Functional Independence Measure (FIM) scores after rehabilitation for traumatic brain injury (TBI) patients. Tree-based algorithmic analysis of 629 TBI patients admitted to a large acute rehabilitation facility showed statistically significant improvement in motor and cognitive FIM scores at discharge. Traumatic brain injury (TBI) is a leading cause of death and disability in America . TBI repEach patient and their specific brain injury are uniquely multifaceted, posing challenges in predicting the long-term outcomes of any single treatment. Countless permutations of anatomic and physiologic mechanisms of traumatic brain injury account for the heterogeneity in clinical phenotype. These mechanisms can vary from direct blunt contact to penetrating brain injury. Widely accepted clinical outcome measures such as the Glasgow Outcome Score , Disability Rating Scale (DRS), and the Coma Recovery Scale (CRS) standardize communication by calculating patient clinical data and documenting progress but fail to provide the prognostic granularity sought after by patients and their families –8. CliniPrediction algorithms developed by leading statisticians have transformed modern-day medical research using machine learning. These sophisticated algorithms “learn” from large patient datasets to predict outcomes and guide decision-making . MachineIn this study, we collaborated with data scientists and expert statisticians to apply advanced machine learning and statistical modeling to predict functional independence measure (FIM) scores in a large cohort of traumatic brain injury patients completing a comprehensive rehabilitation program –26. We eRetrospective analysis of a prospectively collected data set of all traumatic brain injury patients admitted to a single acute rehabilitation facility  between 2010 and 2015 identified 629 patients. Pediatric, pregnant, and deceased patients were excluded from the study. Target inclusion criteria included adult patients with traumatic brain injury requiring inpatient rehabilitation after hospital discharge. Documented functional independence measure (FIM) scores were obtained at the time of admission and upon discharge. The Institutional Review Board (IRB) at the University of California, Los Angeles (UCLA) has exempted our study from its formal review, given the study's retrospective nature, under IRB #15-001380.The Functional Independence Measure (FIM) is a widely accepted, 18-item motor and cognitive function score that originated from the American Academy of Physical Medicine and Rehabilitation and the American Congress of Rehabilitation Medicine , 28. TheWe first examined the efficacy of rehabilitation by testing whether the FIM scores at discharge improved compared to the FIM scores at admission. Specifically, we conducted paired t-tests for each of the 18 items. Then, we adjusted for multiple testing using the Bonferroni procedure. We applied established statistical and novel machine learning algorithms to predict patients' FIM scores at the end of rehabilitation. Our responses of interest are patients' FIM scores at discharge, each of which is an ordinal variable that takes integer values from 1 to 7. An ordinal variable differs from either a categorical variable because of its ordering  and differs from a continuous variable because of its discrete nature . Although both the statistics and the machine learning communities have developed various prediction methods, most of them are tailored to continuous or categorical responses. Ordinal regression is a statistical method designed to handle ordinal responses by considering their ordering and discreteness. Tree-based machine learning algorithms designed to predict continuous responses are capable of handling ordinal responses if we round the predicted value to the nearest integer .Input features included 40 predictors including demographic information, diagnostic characteristics, comorbidities, FIM scores at admission, length of stay, etc. as seen in By using the above features as predictors and each FIM item at discharge as the response, we applied the following eight algorithms to our prediction analyses: statistical methods, including parallel or semi-parallel ordinal regression with lasso, ridge, or elastic net penalty and machine learning methods including tree-based algorithms such as XGBoost and random forests –34. FiguWe evaluated the prediction accuracy of statistical and machine learning methods using five-fold cross-validation. Hyperparameters were tuned again by five-fold cross-validation using only the training set. The algorithms were subsequently trained with optimized hyperparameters on the full training set and evaluated on the test set. We evaluated predictive accuracy by computing the L1 loss, defined as the absolute difference between the true outcome and the predicted outcome averaged over patients. For benchmarking, we used the FIM scores at admission as the predicted value at discharge, which we referred to as the baseline approach. We implemented ordinal regression in R using R package ordinalNet (version 2.9), random forests using R package randomForest (version 4.6-14), and XGBoost using R package xgboost –35.  is critical, carrying far-reaching implications for their families, health systems, and society. Yet, expert opinion and traditional statistical analyses have been unable to reliably incorporate the numerous clinical data points to accurately forecast a patient's outcome, reintegration into society, and ultimately, the precise financial resources required. Because the Functional Independence Measure (FIM) has emerged as an externally validated, comprehensive clinical score of a patient's level of disability, we focus on these points as surrogate markers of functional improvement , 36–39. Tree-based decision algorithms such as random forest and XGBoost demonstrated the highest degree of error for bowel/bladder control and stairs categories. Deterministic algorithms are notoriously sensitive to statistical noise and reflect the inherent variability within the data, such as during collection, entry, and interpretation. For example, at separate timepoints, FIM scores are determined by direct observation by one or multiple members of a multidisciplinary team of physicians, nurses, and physical/occupational therapists. Since FIM scores are designed to describe the burden of care required, a single FIM score of 7 for independent bladder control, for instance, may describe a patient who either voids normally, self-catheterizes, or is completely dependent on dialysis. Furthermore, grading may be nuanced and subject to the amount of time “reasonably expected” to complete any given task.Semi-parallel ordinal regression algorithms showed lower accuracy than the other algorithms, most notably in eating, bladder control, and stairs. Because of their increased model flexibility compared to parallel ordinal regression, semi-parallel regression models severely overfit the data. This may be explained by the subjectivity of FIM scoring, resulting in unfavorable prediction accuracy.High-quality statistical modeling and applications of machine learning to the traumatic brain injury population after hospital discharge are sparse and concentrate mostly on predicting in-hospital mortality. Satyadev et al. similarly recognized the insufficiency of traditional prognostic calculators and ultimately selected a random forest model to predict hospital discharge disposition after traumatic brain injury . Tu et aOur study is limited by our moderate sample size of 629 patients and reflects patients at a single inpatient rehabilitation center in southern California. Specifically, it is not completely generalizable to all TBI patients and captures only the subset who have the resources to enter and stay in a rehabilitation facility. Selection to enter inpatient rehabilitation is based on a number of factors, namely a patient's severity of injury, insurance status, and level of family support.Our study's greatest limitation likely lies within the gradient of the clinical pathology itself. The unique combination of patient factors, mechanism of injury, and resulting clinical phenotype can only be approximated by advanced statistics, but never completely defined. With further refinement of the models and the data, it is plausible that machine learning algorithms could be used in practice.Future study could expand to multiple centers, capturing a diversity of patients and allowing for focused investigation on different categories of traumatic brain injury. Additional patient demographics, such as ethnicity, education level, and socioeconomic status could be collected to reflect social determinats of functional outcome. Furthermore, data quality may be improved by consistent, standardized formal training of FIM score evaluators. Although machine learning prediction algorithms are positioned to surpass expert interpretation and traditional statistical analysis, the models remain vulnerable to the inherent variability, quality, and bias based on the training data.Machine learning statistical models and artificial intelligence may accurately provide valuable, granular clinical predictions of neurologic outcomes for TBI patients receiving rehabilitation services. Our study is the first to apply machine learning statistical algorithms to this population, TBI patients receiving acute rehabilitation. We found that acute rehabilitation services significantly improve FIM scores for TBI patients and ultimately, their clinical recovery and reintegration into society.


R451C, Shank3 KO, 15q dup), phenotype-first (BTBR) and environmental , valproate) mouse models of autism. Overall, we report changes in fecal microbial communities relevant to ASD based on both clinical and preclinical studies. Here, we identify an overlapping cluster of genera that are modified in both fecal samples from individuals with ASD and mouse models of autism. Specifically, we describe an increased abundance of Bilophila, Clostridium, Dorea and Lactobacillus and a decrease in Blautia genera in both humans and rodents relevant to this disorder. Studies in both humans and mice highlighted multidirectional changes in abundance (i.e. in some cases increased abundance whereas other reports showed decreases) for several genera including Akkermansia, Bacteroides, Bifidobacterium, Parabacteroides and Prevotella, suggesting that these genera may be susceptible to modification in autism. Identification of these microbial profiles may assist in characterising underlying biological mechanisms involving host-microbe interactions and provide future therapeutic targets for improving gut health in autism.Many individuals diagnosed with autism spectrum disorder (ASD) experience gastrointestinal (GI) dysfunction and show microbial dysbiosis. Variation in gut microbial populations is associated with increased risk for GI symptoms such as chronic constipation and diarrhoea, which decrease quality of life. Several preclinical models of autism also demonstrate microbial dysbiosis. Given that much pre-clinical research is conducted in mouse models, it is important to understand the similarities and differences between the gut microbiome in humans and these models in the context of autism. We conducted a systematic review of the literature using PubMed, ProQuest and Scopus databases to compare microbiome profiles of patients with autism and transgenic (NL3 Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition diagnosed based on stereotyped or repetitive patterns of behavior, impaired communication interactions as well as language delay . SeveralGI dysfunction experienced by individuals with ASD is likely driven by disruption of the microbiota-gut brain axis. This crucial interplay between the gut microbiome, the nervous system and the immune system maintains homeostatic microbial levels and maintains health. Changes in each of these domains are well established in both clinical and preclinical studies of autism , MargoliDespite evidence for dysbiosis in both clinical and mouse model studies further characterisation of microbiome profiles across both clinical and animal model datasets is needed to pinpoint how microbial changes impact gut physiology in people with ASD. Identifying overlapping patterns of microbial variation in clinical populations and mouse models of autism will provide the basis for modulating the microbiome to improve gut health in individuals with ASD. Therefore, the characterization of gut microbial dysbiosis in people with ASD may provide insights into the underlying mechanisms of GI dysfunction symptoms in autism.The gut microbiome is influenced by multiple interlinked factors including genetics, the environment  and/or immune status. The microbiome interacts directly with both the immune and nervous system to modulate not only gut function but also influence mood and behaviour . ChildreGenetic changes are prominent in ASD with more than 1000 single nucleotide (point) mutations associated with this disorder . As yet,In addition to genetic influences, environmental factors can modify microbial profiles and could contribute to the etiology of complex disorders. Several medications, including the anti-epileptic drug, valproate, modify gut microbial function including fatty acid production . It has Gut microbial changes and the development of ASD-relevant behaviors have been assessed in multiple preclinical models to assist in unravelling the impacts of autism-associated gene mutations on gut microbiota . To undeR451C, SHANK3 KO and 15q dup mice express autism-associated gene mutations/duplications and show autism-relevant behaviors such as repetitive grooming and reduced interest in novel mice  guidelines were applied for the included studies .The criteria set for this systematic review included inclusion/exclusion criteria and study eligibility. The inclusion criteria were as follows: primary studies focused only on data relating to changes in the GI microbiome sampled from people with autism and from mouse models of autism. There were no limitations regarding age groups, gender/sex, time frame or location. Exclusion criteria applied included: discarding any study focused on species other than human or mice, studies that did not assess microbial diversity (such as studies focused on specific microbes), studies that did not use molecular methods for microbial analysis, or that included subjects receiving specific treatments or factors which influence the GI microbial community. Furthermore, studies that did not provide relevant results but instead focused on the GI microbiome products such as chemical metabolites or toxins, studies that were not primary articles such as reviews, case reports or meta-analysis studies were omitted.The PubMed, ProQuest, and Scopus electronic database searches identified 1457 articles  based on screening the titles and abstracts for the search terms used Figure 1A data extraction form was designed for the eligible studies based on the selection criteria applied [61]. The information extracted for analysis included: the first author’s name, year of publication, species (human or mice), sample size, gender for human and sex for mice, background strain (mice only), type of mutation or environmental agent (mice only), type of specimen collected for analysis, diagnostic methods used for microbial diversity, the unit used to describe microbial community results, microbial taxonomic rank .Thirteen clinical studies met the selection criteria and were assessed in the current study. Most cases reported were male children, where the percentage of males exceeded 80% of the total cases in each study. DNA extraction from faecal specimens and next generation sequencing 16S rRNA gene sequencing were the main methods used for all studies. Since bacteria within gut microbial populations are grouped/classified taxonomically into species, genera, families, orders and classes as well as phyla, analytical methods of interest for this review appropriately classified gut bacterial groupings. Specifically, all studies included in the current review classified microbial taxa and diversity using operational taxonomic unit (OTU) calling using 97% similarity thresholds.Gut microbial differences occurring in individuals with ASD were compared Table 3.Veillonellaceae, Pseudomonadaceae, Enterobacteriaceae, Bacteroidaceae, Ruminucoccaceae, Lachnospiraceae, Prevotellaceae in individuals with ASD  or rod shaped .When considering morphology Figure 2R451C (Nlgn3tm1Sud/J), SHANK3 KO and 15q dup mice, and BTBR (BTBR T tf/J). Three of the included studies were conducted on models expressing ASD-associated genetic mutations  (Nine studies investigating the microbiome in mouse models of ASD met the selection criteria for this study. The mouse models studied in these publications were: NL3up mice) , in addiup mice)  as well up mice) , maternaup mice) , or tranup mice) .Lachnospiraceae is more abundant in NL3R451C mice, ii) a decrease in S24–7 family Enterobacteriacea and Lachnospiraceae in BTBR mice and iii) the Bifidobacteriaceae and Eggerthellaceae families are predominant in Shank3 KO mice compared to controls.Gut microbial differences in mouse models of ASD were compared Table 4.Lachnospiraceae, Prevotellaceae and Porphyromonadaceae at the family level in MIA offspring mice .At the genus level, a range of bacteria including out mice . Similarecreased . In conte strain . One repwith ASD . IncidenDetailed comparisons made at multiple classification levels between ASD clinical samples and autism mouse models revealed subtle changes in the composition of the faecal microbiome. Firmicutes and Bacteroidetes remained the predominant phyla in both control and autism-relevant groups in both human and mouse studies. Differences in the Firmicutes : Bacteroidetes ratio were observed in 6 clinical studies  and in fPeptostreptococcaceae, Lachnospiraceae, Prevotellaceae showed altered abundance in both patient and mouse models .Gut microbial differences occurring in both ASD patients and mouse models of ASD were identified Figure 2e models . At the e models . Also ate models . In cont studies . InteresBacteroides, Akkermansia, Bifidobacterium, Bilophila, Blautia, Clostridium and Dorea, Parabacteroides, Prevotella and Lactobacillus are seen in both children with ASD and mouse models (highlighted in mauve). The direction of change in abundance levels in each of these clinical samples/models are specified in Changes in specific components of gut microbiota profiles are observed in samples from children with ASD and across multiple mouse models of autism. Changes in the abundance of We conducted a systematic review of microbial diversity in ASD patients and in mouse models of ASD. Twenty-two studies were included  which further validate mouse models with respect to observations from clinical cohorts.Clostridium, Blautia, Dialister, Escherichia-Shigella, Prevotella and Streptococcus. Others, such as microbes belonging to the Akkermansia genus of mucin-degrading bacterium, were increased in prevalence in ASD individuals, and are known to affect the structure of the gastrointestinal tract through metabolic activities and correlate with changes in gut permeability  in the gut  that focused on the phylum and genera level, we identified changes in the predominance of Firmicutes and Bacteroidetes, as well as altered abundance of Proteobacteria, Actinobacteria and Verrucomicrobia in stool samples of ASD patients. As per our findings, these authors also showed an increase in bundance . AdditioClostridium in several clinical studies. In individuals with autism, an increased abundance of Clostridium, a gram-positive anaerobic bacterium, is associated with increased GI inflammation in the colon  and hydrolytic enzymes  of the probiotic the host . Similarsyndrome .via gut-brain axis dysfunction.Overall, analyses of stool samples from participants diagnosed with ASD revealed an imbalance of gut microbial communities including bacteria previously reported to alter gut function. Although precise biological mechanisms are unknown, microbial alterations may contribute to GI symptoms and behavioral changes in ASD Bifidobacterium and Blautia abundance has been shown to reduce bile-metabolism due to impaired tryptophan metabolism in the gut . Nevertheless, we observed subtle differences in predominant bacterial phyla in each of the ASD mice models, which likely reflects differences in genetic mutations and environmental factors. In a study by Lim and colleagues, mice exposed to polyinosinic: polycytidylic acid (poly I:C) or valproic acid (VPA) showed a subtle increase in the abundance of Firmicutes and a decrease in abundance of Bacteroidetes . In cont the gut . This ob the gut . In the  the gut . CollectClostridium) and a decreased abundance of probiotic microbes  such as Bifidobacterium and Blautia was observed.In the majority of ASD mouse models assessed, an increased abundance of potentially pathogenic microbes  and a National Health and Medical Research Council Ideas grant to EH-Y and AF (APP2003848).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cisgender women in Kenya are at elevated risk of HIV acquisition during pregnancy and post partum. Acute HIV infection during pregnancy and breastfeeding accounts for approximately one-third of all vertical HIV transmissions. The World Health Organization recommends offering oral tenofovir-based pre-exposure prophylaxis (PrEP) to pregnant and postpartum women who are HIV negative but at substantial and ongoing risk for HIV acquisition. PrEP delivery for pregnant and postpartum women is expanding within routine maternal child health clinics in Kenya. However, approximately half of pregnant women discontinue PrEP within 30 days of initiation. Therefore, it is crucial to develop PrEP adherence strategies that enhance support for adherence when peripartum events and health issues pose challenges to sustaining PrEP adherence.We are conducting a randomized controlled trial to determine the effect of a bidirectional communication platform named Mobile Solutions for Women’s and Children’s Health (mWACh), which utilizes two-way SMS text messaging between patients and remote nurses to support PrEP adherence and address maternal health concerns in real time during the peripartum period.The mWACh-PrEP study is a randomized trial designed to support PrEP adherence during the peripartum period by comparing mWACh-PrEP to the standard of care  among women who are HIV negative and initiating PrEP. Purposive sampling was used to select 5 facilities offering PrEP in antenatal clinics in Kisumu and Siaya Counties, and block randomization will be used to divide participants into groups. Participants in the intervention arm will receive a customized messaging curriculum via SMS text messages targeted toward their particular perinatal stage. The primary outcome, PrEP adherence at 6 months post partum, will be evaluated using a log-binomial regression model, adjusting for imbalanced baseline characteristics. Based on a previous study of directly observed dosing conditions, we will use a hair tenofovir concentration cutoff of 0.038 ng/mg (corresponding to 7 doses/week) as the primary adherence outcome measured at 6 months post partum (binary outcome). Qualitative interviews and cost-effective analyses will be conducted to understand the feasibility, acceptability, and economic impact of the intervention.Enrollment began in March 2022 and is projected to continue until July 2023, with follow-up through March 2024. The study results are expected to be reported in 2025.This trial will provide insights into using mobile health to enhance PrEP adherence among pregnant and postpartum mothers. Additionally, the findings will have implications for the use of mobile health technology to improve adherence to other daily medications during the peripartum period.ClinicalTrials.gov NCT04472884; https://clinicaltrials.gov/ct2/show/NCT04472884DERR1-10.2196/41170 Young cisgender women in East and Southern Africa have a high incidence of HIV, which persists during pregnancy and the postpartum period, with evidence of an over 2-fold increased acquisition risk during these periods ,2. HIV iPrEP provision to pregnant and breastfeeding women may prevent primary maternal HIV infections and help eliminate vertical HIV transmission globally. Kenya is a world leader in PrEP implementation for pregnant and postpartum women within maternal and child health (MCH) settings ,8. In a Mobile health  technologies for public health have enormous potential to support HIV prevention and adherence among at-risk populations -22, inclOur team developed a bidirectional communication platform, Mobile Solutions for Women’s and Children’s Health (mWACh), utilizing two-way SMS text messaging between patients and remote nurses to support ART adherence and MCH among peripartum women . The mWAIt is essential to develop PrEP adherence strategies for pregnant women that address PrEP side effects that may overlap with pregnancy symptoms and enhance support for adherence when peripartum life events and health issues pose challenges to sustained PrEP adherence. Therefore, we are conducting a randomized controlled trial (RCT) to determine the effect of mWACh-PrEP on PrEP adherence during pregnancy and the postpartum period.The mWACh-PrEP trial (NCT04472884) aims to improve PrEP adherence among peripartum women using an IMB-informed approach. Our overall goal is to determine the effect of the mWACh-PrEP tool on PrEP adherence during pregnancy and the postpartum period among women at high risk for HIV acquisition who initiate PrEP within ANC and to estimate the cost-effectiveness for potential scale-up. We hypothesize that the mWACh-PrEP tool will improve PrEP adherence among women at risk for HIV, be acceptable to patients and providers, and be cost effective. We are conducting a nonblinded individual-level RCT comparing 2 arms of PrEP adherence to determine the effect of the mWACh-PrEP tool on PrEP adherence among pregnant women at risk for HIV acquisition initiating PrEP within ANC clinics.The study is being conducted in 5 public health facilities offering routine MCH services within Kisumu and Siaya Counties in Kenya. The facilities were selected based on high HIV prevalence areas, existing infrastructure, established rapport, and discussions with the Kenyan Ministry of Health and the local government of Kisumu County.Participating facilities are enrolling 600 pregnant women who are HIV negative (300 in each arm), between 24 and 32 weeks of gestational age , and receiving ANC at MCH clinics. Gestational age is ascertained using the last menstrual period and fundal height measurement, which is part of the routine care for women in this region. Eligibility criteria include HIV and tuberculosis negative, HIV acquisition risk score ≥6 (translating to HIV incidence 7.3 per 100 person-years) , initiatTwo PrEP adherence models are compared: standard of care (SOC) comprising in-clinic adherence counseling only versus SOC plus the mWACh-PrEP tool. All women receive routine MCH care and PrEP services that include health education, clinical assessments, safety monitoring, screening for sexually transmitted infections (STIs), and treatment per national guidelines (including expedited partner treatment for those with STI diagnoses), HIV risk reduction counseling, assessment of psychosocial barriers, and standard in-clinic adherence counseling per national guidelines. Participants randomized to SOC receive in-clinic counseling on PrEP. Participants randomized to the intervention arm are registered in the mWACh-PrEP system, a bidirectional SMS text message communication platform that sends PrEP-tailored, theory-based, preprogrammed texts on PrEP adherence weekly during pregnancy and the postpartum period, in addition to receiving SOC services .Block randomization using a 1:1 allocation in random-sized blocks stratified by recruitment site is being used to ensure a balanced allocation of each arm within sites. Before randomization, study nurses ensure all routine PrEP initiation services and study enrollment procedures are complete. Treatment allocation (mWACh-PrEP or SOC) for each consented participant is done by the study nurses within the individual’s health facility using Research Electronic Data Capture . The randomization code is stored in an electronic format, and once assigned, it is unblinded. The randomization key for the database is restricted to the data manager and statistician.Pregnant women initiating PrEP as part of routine care are approached by the study staff while waiting for ANC and invited to participate in the study. Participants undergo screening, and all eligible participants who express interest undergo an informed consent process at the ANC clinic before the initiation of study procedures. Information on facility volume, clients approached, clients screened, and participants enrolled are reported daily by the study staff. Reasons for nonparticipation are captured from those who decline.At enrollment, electronic questionnaires are administered to capture demographic, pregnancy, and medical history; mental health status; HIV results; risk perception; risk assessment; partner characteristics; PrEP attitudes; expected maternity care; health literacy; and COVID-19 experiences. Socioeconomic status is measured using the validated standard Demographic and Health Survey (DHS) Wealth Index . Health Per national guidelines, all women initiated on PrEP in both arms receive in-clinic counseling on the benefits of sustained PrEP adherence at enrollment and subsequent refill clinic visits, HIV risk reduction, and assessment of psychosocial barriers.. Participants have the option to respond to automated messages or extemporaneously contact the study nurses at any time. Study nurses encourage participants to respond with concerns and questions , and day of the week and time for SMS text message delivery. Once registered, the participants receive weekly automated “push” messages on the day/time of their choice from enrollment until they are 6 months post partum. All automated “push” messages include the participant’s nickname, clinic, and nurse name; an educational message or actionable advice targeting PrEP adherence and continuation and/or MCH topics; and a question related to the content. Through multiple messaging tracks, participants receive messages targeted to their perinatal status as well as supportive messages if they decide to discontinue or restart PrEP. SMS text message topics include adherence encouragement (IMB domain: motivation), PrEP efficacy and safety (IMB domain: information), self-efficacy for prevention of HIV, support for potential PrEP side effects, behavioral skills , anduestions . Particiuestions .Study participants are followed up until 9 months post partum to ascertain sustained PrEP adherence at 3 months after cessation of SMS text messages. All study visits for both arms will be aligned with Kenyan national guidelines for standard ANC and infant immunization visit schedules: monthly visits during pregnancy until delivery and then after delivery at 6 weeks, 14 weeks, 6 months, and 9 months post partum. At each visit, nurses administer questionnaires to assess sexual behavior; infant outcomes; IPV; symptoms of depression; and PrEP attitudes, use, and adherence. PrEP use disclosure is assessed at each follow-up visit by asking participants whether they have disclosed to anyone that they use PrEP and, if so, to whom they disclosed this  and birth length are abstracted from the MCH medical record or interview.Additional data on infant growth, birth weight, estimated gestation at birth, diagnosed preterm birth, and serial growth are abstracted from medical records. Additionally, A combination of red blood cells from DBS and hair samples is used to assess PrEP adherence. A strong correlation between dosing frequency and TFV levels in hair has been demonstrated , and sigHair samples will be collected from participants at pregnancy follow-up visits and from both the participants and their babies at postpartum follow-up visits. These hair samples will be analyzed for TFV using validated liquid chromatography-tandem mass spectrometry methods at the University of California San Francisco (UCSF) Hair Analytical Lab (HAL). The UCSF HAL found that TFV concentrations in the hair under directly observed dosing conditions are similar by sex, and the same adherence benchmarks can be used for both women and men . AdditioThe study staff is trained on data collection using REDCap and communication with participants in the intervention arm using the two-way mWACh-PrEP platform to send, receive, and respond to SMS text messages. Baseline and follow-up data are collected and stored electronically via REDCap, transported via a secure socket layer, and only accessible by authenticated users. Designated study staff generate weekly reports on study progress, performance indicators, adverse events, and troubleshooting problems. All study laptops used to collect data and study databases are encrypted and password protected. All data collected in this study will be available free of charge after registration to access or download files on a study-related website (URL to be determined) after the completion of primary analyses.The sample size was calculated to detect a difference between trial arms dependent on the frequency of PrEP adherence in the SOC arm of the cohort. Prior data from our PrEP in pregnancy studies indicate that the frequency of detectable PrEP drug levels is approximately 50% among pregnant women who initiate PrEP in MCH clinics within fully programmatic settings . Since tThe primary outcome, PrEP adherence at 6 months post partum, will be assessed in an intention-to-treat analysis comparing randomization arms mWACh-PrEP versus SOC. Enrollment characteristics will be compared between randomization arms to assess the balance between arms and control for any imbalanced factors. Based on a previous study of directly observed dosing conditions, we will use a hair TFV concentration cutoff of 0.038 ng/mg (corresponding to 7 doses/week) as the threshold of detection for the primary adherence outcome measured at 6 months post partum (detectable/nondetectable binary outcome) . ProtectFocus group discussions and semistructured in-depth interviews will be conducted to evaluate potential barriers and facilitators to the acceptability and feasibility of mWACh-PrEP implementation within routine ANC delivery settings . To evalDiscussions will be conducted in English, Kiswahili, or Luo depending on participants' preferences and be guided by prepiloted topic guides with the flexibility to explore additional probes and newly emerging content as necessary. All in-depth interviews and focus group discussions will be audio recorded, transcribed, and translated to English for analysis as necessary. Thematic analysis will be used to identify key elements of the patient/provider experience, including convenience, comfort level, and satisfaction of the mWACh-PrEP model, that influence intervention acceptability, feasibility, and potential scale-up.We will project the cost-effectiveness of implementing mWACh-PrEP intervention within ANC compared to the SOC per averted disability-adjusted life year (DALY) using a payer perspective and collect intervention costs from expense reports, staff, and expert interviews. Costs will be divided into mutually exclusive categories, including personnel, equipment, supplies, buildings and overhead, and start-up. We will convert the local currency, Kenyan shillings, to US dollars. Sensitivity analyses will be conducted to identify influential assumptions.Time and motion observation of intervention activities will be conducted to calculate staff time and resources necessary for the mWACh-PrEP intervention. A research assistant (RA) will collect data on the time and motion of patient/provider interactions to inform costs and productivity assumptions. The RA will also conduct a survey with health care workers to assess daily responsibilities associated with the mWACh-PrEP intervention, including time to send and respond to client SMS text messages and routine service provision. Research time  and other research costs will be separated from programmatic costs.We will parameterize a previously developed mathematical model with cost and outcome data from the mWACh-PrEP trial and project the averted HIV infections, HIV-related deaths, and DALYs associated with scaling up the mWACh-PrEP intervention in Kenya. We will calculate the incremental cost-effectiveness ratio as the difference in costs divided by the difference in effects (DALYs) for the intervention compared to SOC over a 20-year period. Costs and benefits will be discounted annually at 3%.Secondary outcome analyses will include sustained PrEP adherence by determining levels of detectable TFV in the hair at 9 months post partum, adherence cofactors, STI incidence, and prevention-effective adherence . Exploratory analyses will include HIV incidence, perinatal outcomes, and expedited partner treatment outcomes by randomization arms  and the Kenyatta National Hospital Ethics and Research Committee (P319.05/2021). This study was registered at ClinicalTrials.gov. (NCT04472884). Any critical protocol deviations, adverse events, and future modifications will be communicated promptly to these organizations. Additional permissions will be sought from all participating clinical sites.A written informed consent before recruitment is administered to all study participants, with each receiving a copy of the signed form. Additional permission will be obtained for audio recording and note-taking during the qualitative interviews.All participants are informed that their participation is voluntary, and they can stop receiving the SMS text messages at any time by contacting the study staff or texting “STOP,” which will cease communication between the study staff and the participant. All study staff is trained in protecting human participants and the clinical and emotional needs of pregnant and postpartum women on PrEP. The MWACh system is point-to-point encrypted; therefore, only study team members can access it through a password-protected laptop stored in a locked office. All data are deidentified and kept in password-protected databases in a locked study office that is accessible only to study personnel.A CAB has been established in Kisumu County to review the study objectives, methodology, and other study activities. The team comprises local community leaders, women from the community, the Kenyan Ministry of Health, and county health representatives from MCH departments. The CAB is anticipated to meet 2 times per year to review this study’s progress. An external advisory panel (EAP) has been established to oversee the data and safety of study participants by reviewing study aims, statistical analysis plan, and progress. EAP meetings will be routinely convened to review study enrollment, retention, data missingness, and pooled study outcomes. Study results will be disseminated through peer-reviewed journals, technical reports, policy briefings, and oral presentations at relevant local and international conferences. Additionally, we will present results to clinical experts and policy advisors at the local county level, the Kenyan Ministry of Health, and the WHO. Routine hybrid meetings in the form of progress updates with CABs engaged in the study activities, facility staff, and study collaborators will be conducted to share study progress and findings.Study enrollment began in March 2022 and is projected to continue until July 2023, with patient participant follow-up through March 2024. The study results are expected to be reported in 2025.This intervention study aims to determine the effect of the mWACh-PrEP tool on PrEP adherence among pregnant and breastfeeding women at high risk for HIV acquisition who initiate PrEP during ANC. The primary outcome is adherence at 6 months, while the secondary outcomes include sustained adherence at 3 months after cessation of the SMS text messaging intervention and other HIV and MCH indicators. This is the first intervention that aims to enhance PrEP adherence among women in the peripartum period research, and we anticipate that our findings will inform clinical practice for PrEP delivery during the peripartum period by providing effectiveness data on an mHealth PrEP adherence tool tailored for the peripartum period.This is the first intervention study aiming to improve PrEP adherence among peripartum women using an IMB-guided approach tailored to pregnant and postpartum women on PrEP for HIV prevention. The development of adherence strategies for periods during and after pregnancy can have implications for other daily medications taken during pregnancy and the postpartum period when medication side effects overlap with typical symptoms, and life events pose challenges to sustained adherence. Furthermore, collected microcosting data will guide researchers and policy makers on the cost of scale-up and use of mHealth and the IMB-informed approach.Daily oral tenofovir disoproxil fumarate (TDF)/emtricitabine is currently the only medication with a label indication as PrEP in Kenya and the only regimen recommended by the WHO for cisgender women. While several novel PrEP agents are being tested, including long-acting injectable cabotegravir (CAB-LA) , forthcoTo provide insights on the effects of mWACh-PrEP, we will communicate the study protocol, progress report, and results to the scientific community and policy makers. This will guide the clinical management of pregnant women who choose to initiate PrEP, informing future scale-up of the intervention as a population-level program. Dissemination of the results will potentially improve communication between researchers, ethical bodies, and policy makers and strengthen collaborations between participating partners through technical reports and policy briefings. For the scientific community, we will publish our findings in peer-reviewed journals and present them at international scientific conferences. Presentations and progress reports regarding the study will be shared with study participants and presented to the public at the facility level and to the Kenyan Ministry of Health.This study will inform clinical practice and contribute to advancing strategies to enhance PrEP and other daily medication adherence during pregnancy and the postpartum period, which are both critical periods for MCH. If our mWACh approach positively affects MCH outcomes , it could be readily integrated into other mHealth platforms aiming to improve MCH in the future. The study will also contribute to an mHealth adherence tool for pregnant women on PrEP with the goal of enhancing PrEP use and ultimately reducing HIV incidence in this important population that is disproportionately affected by HIV.


De novo centriole formation is triggered by the removal of all pre-existing centrioles in the cell in various manners. Moreover, overexpression of polo-like kinase 4 (Plk4), a master regulatory kinase for centriole biogenesis, can induce de novo centriole formation in some cell types. Under these conditions, structurally and functionally normal centrioles can be formed de novo. While de novo centriole formation is normally suppressed in cells with intact centrioles, depletion of certain suppressor proteins leads to the ectopic formation of centriole-related protein aggregates in the cytoplasm. It has been shown that de novo centriole formation also occurs naturally in some species. For instance, during the multiciliogenesis of vertebrate epithelial cells, massive de novo centriole amplification occurs to form numerous motile cilia. In this review, we summarize the previous findings on de novo centriole formation, particularly under experimental conditions, and discuss its regulatory mechanisms.In cycling cells, new centrioles are assembled in the vicinity of pre-existing centrioles. Although this canonical centriole duplication is a tightly regulated process in animal cells, centrioles can also form in the absence of pre-existing centrioles; this process is termed  Centrioles are organelles that organize centrosomes and cilia. They are cylindrical structures with a nine-fold radial symmetry of triplet or doublet microtubules. The centrosome, which consists of the centriole and the pericentriolar material (PCM)—a matrix of proteins surrounding the centriole—acts as a microtubule-organizing center (MTOC) in the cell. In addition, it plays a pivotal role in the formation of the mitotic spindle, subsequent chromosome segregation, and cytokinesis. The centriole also serves as a basal body in the formation of cilia and flagella.In cycling somatic cells, new centrioles (daughter centrioles) are formed at the proximal end of pre-existing centrioles (mother centrioles). This process is referred to as “centriole duplication”, and occurs only once during the cell cycle; only one daughter centriole is formed from its mother centriole. At the end of mitosis, the daughter centrioles are disengaged from the mother centrioles and are converted into functional centrosomes, acquiring the ability to assemble new centrioles in the daughter cells. In this way, the number of centrosomes in a cell is constantly maintained at two  Loncare.Drosophila and ZYG-1 in Caenorhabditis elegans) is a serine/threonine kinase that localizes around the mother centriole and acts as a master regulator of centriole biogenesis (Drosophila and SAS-5 in Caenorhabditis elegans) during the G1/S phase, thereby facilitating the STIL/SAS-6 interaction and the formation of a cartwheel structure (the basis for centriole assembly) , SCL/TAL1 interrupting locus (STIL), and spindle assembly 6 homolog (SAS-6), have been identified as conserved essential factors for daughter centriole assembly  Arquint. Loss ofogenesis . Plk4 dissembly) . SAS-6 issembly) .Caenorhabditis elegans, while asterless  is responsible for the centriolar localization of Plk4/Sak in Drosophila  is responsible for the centriolar localization of ZYG-1 in osophila . In mammosophila . Followiosophila  (Kim et osophila .Drosophila and Caenorhabditis elegans) facilitates the formation of the centriole microtubule wall (Drosophila) seems to connect SAS-6 with CPAP for the stabilization and elongation of the centriole wall (Drosophila)  , also posophila) .de novo pathway). In addition to its occurrence under physiological conditions in various species, de novo centriole formation can be induced artificially under experimental conditions in eukaryotic cells. While centriole duplication via the canonical pathway has been extensively studied in recent years, the mechanisms regulating the de novo pathway remain largely unexplored. In this review, we will summarize the findings of recent studies on de novo centriole formation under experimental conditions and discuss the regulatory mechanisms of the de novo pathway in comparison with the canonical pathway.It has also been established that numerous species utilize an alternative pathway for centriole biogenesis, which is driven without pre-existing centrioles in the cell  initially appeared. This was followed by the appearance of centrioles with a normal ultrastructure within the PCM cloud ] ] . Followiytoplasm   also support de novo centriole formation, at least to some extent, in Drosophila cells. In particular, the contribution of γ-tubulin is relatively significant, as its depletion attenuates de novo centriole assembly in both cultured cells and unfertilized eggs of Drosophila  can induce de novo centriole formation in human cultured cells  has shown that Centrin foci emerge, being scattered throughout the cytoplasm  prevents the ectopic formation of centriole protein condensates. In TRIM37-depleted cells, condensates containing Centrobin and Plk4 are observed in the cytoplasm, acquiring PCM proteins and serving as MTOCs during mitosis . Centrobde novo pathway, as the cytoplasmic aggregates observed in each case do not have the complete centriole ultrastructure. These findings imply that the suppression of de novo centriole formation in somatic cells is achieved through complicated mechanisms mediated by various factors; however, these mechanisms remain unclear. Considering the possibility of unidentified suppressors, future studies are warranted to comprehensively identify the factors that prevent ectopic aggregation of centriole proteins.Different assembly processes appear to underlie the aggregation of centriole-associated proteins upon depletion of each of the above factors. Thus, the mechanisms by which these factors suppress the formation of aggregates are also considered distinct. It is also conceivable that each factor only partially suppresses ectopic centriole formation through the de novo pathway in various manners , and POC1 are required for bicentriole-mediated de novo centriole biogenesis . In MCCs, hundreds of centrioles form, serving as basal bodies to assemble numerous cilia . These cntrioles . Cep152 ntrioles . Plk4 anntrioles , and cenntrioles . Major cntrioles . It has ntrioles . Neverthntrioles , illustrntrioles .Deup1−/− mice, which are unable to form deuterosomes (de novo centriole biogenesis in proliferating cells at a larger scale. Intriguingly, most centriole amplification in MCCs occurs in a PCM cloud containing Pericentrin; this process is also observed in the absence of deuterosomes and/or pre-existing centrioles (de novo centriole formation for multiciliogenesis, independently of either pre-existing centrioles or deuterosomes. This process is reminiscent of the involvement of PCM in de novo centriole formation in proliferating cells (de novo centriole formation in proliferating cells.The number and morphology of basal bodies that appear during multiciliogenesis are not affected in ependymal cells derived from erosomes . Furthererosomes  (Mercey erosomes . In othentrioles ; 2019b. ng cells . Furtherng cells . Throughng cells . A recenng cells . Thus, ide novo pathway has been studied less extensively than the canonical pathway. Further studies on the mechanisms underlying the de novo pathway, in conjunction with the canonical pathway, will lead to a deeper insight into the common and divergent mechanisms involved in centriole assembly. Another critical research question is the mechanism through which centriolar cells suppress the de novo pathway. This can be a medically significant question, since disruption of the suppression mechanisms would potentially result in uncontrolled centriole amplification and subsequent tumorigenesis (de novo centriole formation in various species would be important in the future.Regarding the molecular mechanisms of centriole biogenesis, the igenesis . Therefo


Fusobacterium nucleatum play an important role in the pathogenesis of colorectal cancer. Here, we describe the case of a 47-year-old patient presenting with endophthalmitis and a liver abscess due to Fusobacterium nucleatum that prompted the diagnosis of colorectal cancer as the most likely source of infection. This case highlights that colorectal cancer needs to be considered in patients with systemic infection with Fusobacterium nucleatum and colonoscopy should be performed.Intestinal microbiota such as  Fusobacterium nucleatum including increased proliferation of colorectal cancer cells [The pathogenesis of colorectal cancer is marked by accumulating mutations in pathways of cell cycle, proliferation and cell death leading to uncontrolled tumor growth . Howeverer cells , the proer cells  and resier cells  has beenFusobacterium nucleatum that resulted in the diagnosis of rectal cancer and facilitated successful therapy.Here, we report the unique case of a patient with systemic infection with We describe the case of a 47-year-old male Caucasian patient who presented with progressive loss of vision on the right eye. He also reported abdominal discomfort over the past three weeks as well as fevers and chills during the previous 10 days.Upon admission, the patient had a temperature of 39 °C. Clinical examination revealed a hypopyon of the right eye A. LaboraUpon referral to diagnostic ultrasound, B-mode sonography and contrast-enhanced ultrasound A identifTropheryma whipplei, Staphylococcus aureus, cytomegalovirus, herpes simplex and varicella zoster virus DNA. Serologic results for galactomannan, Candida antigen, beta-D-glucan, Borrelia burgdorferi and Treponema pallidum were negative. However, PCR of the vitreous humor and the liver abscess using pan-bacterial primers were positive and Fusobacterium nucleatum was exclusively detected by sequence analysis (sequencing performed by eurofins) in both materials. Moreover, Fusobacterium nucleatum grew on Schaedler agar with vitamin K and was subsequently detected by mass spectrometry (MALDI-TOF) in cultures of the liver abscess. Since a dental focus had been ruled out a few days prior to hospital admission, these results were overall consistent with systemic Fusobacterium nucleatum infection without an obvious port of entry.No pathogens grew in blood cultures and cultures of the vitreous humor. Real-time PCR of the vitreous humor was negative for Hence, a thoracic/abdominal/pelvic CT scan revealed a tumor in the rectum B in addiFusobacterium nucleatum has previously been demonstrated for both agents [The drainage of the liver abscess was stopped after four days. Antibiotic treatment included four weeks of IV meropenem followed by four weeks of an oral sequential therapy with amoxicillin/clavulanic acid. Activity against h agents . Follow-Fusobacterium nucleatum in this patient. Fusobacterium nucleatum is an oral bacterium rarely found in healthy gut and colorectal cancer is a precondition for its colonization [Fusobacterium nucleatum [Fusobacterium nucleatum in cancer tissue from our patient, we did not find an oral–gingival or other port of entry. Notably, in contrast to vitreous humor and liver abscess material, tissue samples were obtained after several days of antibiotic treatment substantially reducing the probability of successful detection [Taken together, we consider the rectal cancer as the most likely source of invasive infection with nization . Severalnization  and receucleatum ,10,11. Aetection .Fusobacterium nucleatum. It shows that bacteria involved in the pathogenesis of colorectal cancer may not only play a local role, but also become invasive. This highlights the necessity to consider colorectal cancer in the differential diagnosis of systemic infection with Fusobacterium nucleatum and to include endoscopy in the diagnostic work-up, since this might expedite diagnosis and treatment and, thus, improve prognosis.Thus, to our knowledge, we describe the first case of undiagnosed colorectal cancer presenting primarily with systemic infection with