Longitudinal deep sequencing informs vector selection and future deployment strategies for transmissible vaccines.

Vaccination is a powerful tool in combating infectious diseases of humans and companion animals. In most wildlife, including reservoirs of emerging human diseases, achieving sufficient vaccine coverage to mitigate disease burdens remains logistically unattainable. Virally vectored "transmissible" vaccines that deliberately spread among hosts are a potentially transformative, but still theoretical, solution to the challenge of immunising inaccessible wildlife. Progress towards real-world application is frustrated by the absence of frameworks to guide vector selection and vaccine deployment prior to major in vitro and in vivo investments in vaccine engineering and testing. Here, we performed deep sequencing on field-collected samples of Desmodus rotundus betaherpesvirus (DrBHV), a candidate vector for a transmissible vaccine targeting vampire bat-transmitted rabies. We discovered 11 strains of DrBHV that varied in prevalence and geographic distribution across Peru. The phylogeographic structure of DrBHV strains was predictable from both host genetics and landscape topology, informing long-term DrBHV-vectored vaccine deployment strategies and identifying geographic areas for field trials where vaccine spread would be naturally contained. Multistrain infections were observed in 79% of infected bats. Resampling of marked individuals over 4 years showed within-host persistence kinetics characteristic of latency and reactivation, properties that might boost individual immunity and lead to sporadic vaccine transmission over the lifetime of the host. Further, strain acquisitions by already infected individuals implied that preexisting immunity and strain competition are unlikely to inhibit vaccine spread. Our results support the development of a transmissible vaccine targeting a major source of human and animal rabies in Latin America and show how genomics can enlighten vector selection and deployment strategies for transmissible vaccines.

Diversification of mammalian deltaviruses by host shifting.

Hepatitis delta virus (HDV) is an unusual RNA agent that replicates using host machinery but exploits hepatitis B virus (HBV) to mobilize its spread within and between hosts. In doing so, HDV enhances the virulence of HBV. How this seemingly improbable hyperparasitic lifestyle emerged is unknown, but it underpins the likelihood that HDV and related deltaviruses may alter other host-virus interactions. Here, we show that deltaviruses diversify by transmitting between mammalian species. Among 96,695 RNA sequence datasets, deltaviruses infected bats, rodents, and an artiodactyl from the Americas but were absent from geographically overrepresented Old World representatives of each mammalian order, suggesting a relatively recent diversification within the Americas. Consistent with diversification by host shifting, both bat and rodent-infecting deltaviruses were paraphyletic, and coevolutionary modeling rejected cospeciation with mammalian hosts. In addition, a 2-y field study showed common vampire bats in Peru were infected by two divergent deltaviruses, indicating multiple introductions to a single host species. One vampire bat-associated deltavirus was detected in the saliva of up to 35% of individuals, formed phylogeographically compartmentalized clades, and infected a sympatric bat, illustrating horizontal transmission within and between species on ecological timescales. Consistent absence of HBV-like viruses in two deltavirus-infected bat species indicated acquisitions of novel viral associations during the divergence of bat and human-infecting deltaviruses. Our analyses support an American zoonotic origin of HDV and reveal prospects for future cross-species emergence of deltaviruses. Given their peculiar life history, deltavirus host shifts will have different constraints and disease outcomes compared to ordinary animal pathogens.

Incorporating environmental heterogeneity and observation effort to predict host distribution and viral spillover from a bat reservoir.

Predicting the spatial occurrence of wildlife is a major challenge for ecology and management. In Latin America, limited knowledge of the number and locations of vampire bat roosts precludes informed allocation of measures intended to prevent rabies spillover to humans and livestock. We inferred the spatial distribution of vampire bat roosts while accounting for observation effort and environmental effects by fitting a log Gaussian Cox process model to the locations of 563 roosts in three regions of Peru. Our model explained 45% of the variance in the observed roost distribution and identified environmental drivers of roost establishment. When correcting for uneven observation effort, our model estimated a total of 2340 roosts, indicating that undetected roosts (76%) exceed known roosts (24%) by threefold. Predicted hotspots of undetected roosts in rabies-free areas revealed high-risk areas for future viral incursions. Using the predicted roost distribution to inform a spatial model of rabies spillover to livestock identified areas with disproportionate underreporting and indicated a higher rabies burden than previously recognized. We provide a transferrable approach to infer the distribution of a mostly unobserved bat reservoir that can inform strategies to prevent the re-emergence of an important zoonosis.

SumStatsRehab: an efficient algorithm for GWAS summary statistics assessment and restoration.

BACKGROUND: Generating polygenic risk scores for diseases and complex traits requires high quality GWAS summary statistic files. Often, these files can be difficult to acquire either as a result of unshared or incomplete data. To date, bioinformatics tools which focus on restoring missing columns containing identification and association data are limited, which has the potential to increase the number of usable GWAS summary statistics files. RESULTS: SumStatsRehab was able to restore rsID, effect/other alleles, chromosome, base pair position, effect allele frequencies, beta, standard error, and p-values to a better extent than any other currently available tool, with minimal loss. CONCLUSIONS: SumStatsRehab offers a unique tool utilizing both functional programming and pipeline-like architecture, allowing users to generate accurate data restorations for incomplete summary statistics files. This in turn, increases the number of usable GWAS summary statistics files, which may be invaluable for less researched health traits.

Ecological determinants of rabies virus dynamics in vampire bats and spillover to livestock.

The pathogen transmission dynamics in bat reservoirs underpin efforts to reduce risks to human health and enhance bat conservation, but are notoriously challenging to resolve. For vampire bat rabies, the geographical scale of enzootic cycles, whether environmental factors modulate baseline risk, and how within-host processes affect population-level dynamics remain unresolved. We studied patterns of rabies exposure using an 11-year, spatially replicated sero-survey of 3709 Peruvian vampire bats and co-occurring outbreaks in livestock. Seroprevalence was correlated among nearby sites but fluctuated asynchronously at larger distances. A generalized additive mixed model confirmed spatially compartmentalized transmission cycles, but no effects of bat demography or environmental context on seroprevalence. Among 427 recaptured bats, we observed long-term survival following rabies exposure and antibody waning, supporting hypotheses that immunological mechanisms influence viral maintenance. Finally, seroprevalence in bats was only weakly correlated with outbreaks in livestock, reinforcing the challenge of spillover prediction even with extensive data. Together our results suggest that rabies maintenance requires transmission among multiple, nearby bat colonies which may be facilitated by waning of protective immunity. However, the likelihood of incursions and dynamics of transmission within bat colonies appear largely independent of bat ecology. The implications of these results for spillover anticipation and controlling transmission at the source are discussed.

Demographic and environmental drivers of metagenomic viral diversity in vampire bats.

Viruses infect all forms of life and play critical roles as agents of disease, drivers of biochemical cycles and sources of genetic diversity for their hosts. Our understanding of viral diversity derives primarily from comparisons among host species, precluding insight into how intraspecific variation in host ecology affects viral communities or how predictable viral communities are across populations. Here we test spatial, demographic and environmental hypotheses explaining viral richness and community composition across populations of common vampire bats, which occur in diverse habitats of North, Central and South America. We demonstrate marked variation in viral communities that was not consistently predicted by a null model of declining community similarity with increasing spatial or genetic distances separating populations. We also find no evidence that larger bat colonies host greater viral diversity. Instead, viral diversity follows an elevational gradient, is enriched by juvenile-biased age structure, and declines with local anthropogenic food resources as measured by livestock density. Our results establish the value of linking the modern influx of metagenomic sequence data with comparative ecology, reveal that snapshot views of viral diversity are unlikely to be representative at the species level, and affirm existing ecological theories that link host ecology not only to single pathogen dynamics but also to viral communities.

Host-pathogen evolutionary signatures reveal dynamics and future invasions of vampire bat rabies.

Anticipating how epidemics will spread across landscapes requires understanding host dispersal events that are notoriously difficult to measure. Here, we contrast host and virus genetic signatures to resolve the spatiotemporal dynamics underlying geographic expansions of vampire bat rabies virus (VBRV) in Peru. Phylogenetic analysis revealed recent viral spread between populations that, according to extreme geographic structure in maternally inherited host mitochondrial DNA, appeared completely isolated. In contrast, greater population connectivity in biparentally inherited nuclear microsatellites explained the historical limits of invasions, suggesting that dispersing male bats spread VBRV between genetically isolated female populations. Host nuclear DNA further indicated unanticipated gene flow through the Andes mountains connecting the VBRV-free Pacific coast to the VBRV-endemic Amazon rainforest. By combining Bayesian phylogeography with landscape resistance models, we projected invasion routes through northern Peru that were validated by real-time livestock rabies mortality data. The first outbreaks of VBRV on the Pacific coast of South America could occur by June 2020, which would have serious implications for agriculture, wildlife conservation, and human health. Our results show that combining host and pathogen genetic data can identify sex biases in pathogen spatial spread, which may be a widespread but underappreciated phenomenon, and demonstrate that genetic forecasting can aid preparedness for impending viral invasions.

Arabidopsis COGWHEEL1 links light perception and gibberellins with seed tolerance to deterioration.

Light is a major regulator of plant growth and development by antagonizing gibberellins (GA), and we provide evidence for a role of light perception and GA in seed coat formation and seed tolerance to deterioration. We have identified two activation-tagging mutants of Arabidopsis thaliana, cog1-2D and cdf4-1D, with improved seed tolerance to deterioration linked to increased expression of COG1/DOF1.5 and CDF4/DOF2.3, respectively. These encode two homologous DOF transcription factors, with COG1 most highly expressed in seeds. Improved tolerance to seed deterioration was reproduced in transgenic plants overexpressing these genes, and loss of function from RNA interference resulted in opposite phenotypes. Overexpressions of COG1 and CDF4 have been described to attenuate various light responses mediated by phytochromes. Accordingly, we found that phyA and phyB mutants exhibit increased seed tolerance to deterioration. The phenotype of tolerance to deterioration conferred by gain of function of COG1 and by loss of function of phytochromes is of maternal origin, is also observed under natural aging conditions and correlates with a seed coat with increased suberin and reduced permeability. In developing siliques of the cog1-2D mutant the expression of the GA biosynthetic gene GA3OX3 and levels of GA1 are higher than in the wild type. These results explain the antagonism between phytochromes and COG1 in terms of the inhibition and the activation, respectively, of GA action.

Adolescent idiopathic scoliosis: is there a relationship between Risser staging and the proximal humerus ossification system?

PURPOSE: To evaluate whether there is a mismatch between Risser staging and the proximal humerus ossification system (PHOS); and to analyze the correlation in the skeletal maturity stages between the two humeral epiphyses. METHODS: Data from patients aged 10 to 18 years with adolescent idiopathic scoliosis (AIS) seen between 2018 to 2021 were analyzed. In an anteroposterior (AP) spine radiograph the ossification process was evaluated using the Risser classification method and bilateral PHOS (if both humeral epiphyses were visualized). A mismatch between methods was defined as a Risser 0-1 (relatively skeletally immature) with a PHOS 4-5 (skeletally mature), or a Risser 2-5 (relatively skeletally mature) with a PHOS 1-3 (skeletally immature). The McNemar test was used to calculate the significance of the mismatch. RESULTS: A mismatch between Risser and PHOS stages was observed in 28.5% of 105 patients, which was statistically significant (p < 0.001). Of the 49 patients with a Risser 0-1, 55.1% (n = 27) had a PHOS 4-5. None of the patients with a Risser 2-5 had a PHOS 1-3. In the 47 patients in whom both humeri were visualized, the absolute correlation between the left and right PHOS values was 95.7%. CONCLUSION: Of AIS patients who are relatively skeletally immature according to Risser staging, more than half may be skeletally mature when measured with PHOS. In patients with a Risser 0-1, it is recommended to measure skeletal maturity in an AP spine radiograph using the PHOS method, which may more accurately guide treatment decision-making, without the need to visualize both humeral epiphyses in this radiographic projection. LEVEL OF EVIDENCE: IV.

Evaluation of outpatient halo-gravity traction in patients with severe scoliosis: development of a monitoring device.

INTRODUCTION: Patients with severe spinal deformities represent a major clinical and surgical challenge. Halo-gravity traction (HGT) is a traditional method to correct the deformity prior to surgery. Typically, children undergoing HGT remain in the hospital until surgery. Therefore, it has been suggested to treat these children at lower level healthcare centers or even at home. The aim of this study was to develop a tool to assess patient adherence to HGT together with a program to analyze traction results. MATERIALS AND METHODS: An original recording system was designed with an Arduino Nano®. The data extracted from the memory card were compiled into a text file and then analyzed with the MatLab R2018a MathWorks®. RESULTS: Five patients receiving HGT for severe scoliosis were asked to use the device both in the wheelchair and in bed to evaluate its usefulness. CONCLUSIONS: A device was developed to monitor the use of HGT at home. The device provides information on the time of HGT use and the traction weight placed throughout the day, as well as on the correct functioning of the system in bed and in the wheelchair.

Hemivertebra Resection in Small Children. A Literature Review.

STUDY DESIGN: Systematic review. OBJECTIVE: To evaluate the lowest possible age to resect an HV in very young patients with a congenital deformity. METHODS: We sought to retrieve all studies reporting age at HV excision in patients with congenital scoliosis. Studies written in English were included. No publication date restrictions were imposed. A search of the PubMed and LiLacs databases was conducted. Additionally, a hand search was performed to supplement the database search. RESULTS: We found 140 articles. Twenty two studies were included into the final assessment. There was considerable heterogeneity in the included studies, both regarding age and the surgical techniques used. There was also a broad spectrum of recommendations regarding suggested age for treatment. The youngest patient undergoing resection and fusion was 3 months of life at the time of surgery. CONCLUSION: How young a patient could and should be submitted to HV resection surgery is still a matter of debate in the literature. Prophylactic surgery might be a proper treatment for young children with congenital scoliosis before malformation becomes a deformity, adding no additional neurological, vascular, or anesthesia-related complications. The defect can be treated early while the deformity is treated late.

Early onset scoliosis: modern treatment and results.

BACKGROUND: Early onset scoliosis (EOS) is a potentially fatal, challenging group of diseases the management of which has markedly changed in the last decade. The purpose of this review is to provide the reader with a brief description of each of these new therapeutic modalities, their indications for use, and early clinical results. METHODS: A systematic review of peer-reviewed publications and abstracts related to the treatment of EOS in the last decade was carried out and synthesized into a review of modern treatment methods. RESULTS: Recent advances in techniques and understanding of preserving the thoracic space have improved the morbidity and mortality of children with progressive EOS. Derotational casting may be used in younger patients with curves between 25 and 60 degrees. The vertical expandable prosthetic titanium rib is best suited for patients with thoracic insufficiency syndrome. Single or dual growing rods may be used alone or in combination with vertical expandable prosthetic titanium rib to treat patients with progressive EOS who are not candidates for casting. Shilla technique is an alternative to growing rods that avoids the morbidity of repeated lengthenings but is not as well proven as the techniques described above. Other methods such as automatic growing rods and growth modulation techniques are still investigational, and their role needs to be defined after further study. CONCLUSIONS: Recent advances have improved the treatment of children with EOS. Treatment continues to be challenging with complication rates higher than treatment of idiopathic scoliosis. LEVEL OF EVIDENCE: Level V.

Neuromuscular lordoscoliosis: an unusual response to post-operative halo-gravity traction.

PURPOSE: To report the results of prolonged post-operative halo-gravity traction in a patient in whom the surgery had to be interrupted unexpectedly and for whom subsequently specific clinical circumstances contraindicated completion of the surgical procedure. METHODS: The patient was a 15-year-old male with severe cervico-dorsolumbar lordoscoliosis who was being studied for associated diffuse axonal injury. He performed halo-gravity traction for 12 weeks. Subsequent surgical management consisted of occipito-lumbar posterior instrumented fusion. During the surgical approach, electrocardiographic changes with hemodynamic decompensation were detected that did not improve with anesthetic reanimation. The intervention was stopped, the surgical wound was closed, and the patient was transferred to the intensive care unit (ICU). It was decided that a revision surgery with the aim to continue with the previous strategy would imply a high risk of perioperative morbidity and mortality. RESULTS: Orthopedic management was decided upon consisting of continued halo-gravity traction with wheelchair modification at home, which was extended to a period of 12 months because of the good results obtained in terms of cervicothoracic realignment. Two years after halo-gravity discontinuation, clinical and radiographic occipito-cervical alignment was good and the patient conserved certain occipito-cervical range of motion and had the capacity of maintaining a horizontal gaze. CONCLUSION: We considered the outcome extraordinary and relevant in this complex and unusual patient. A longer follow-up will provide more data regarding the final outcome of this treatment.

The Therapeutic Use of Impella Device in Cardiogenic Shock: A Systematic Review.

Impella (Abiomed, Danvers, MA) devices nowadays have been linked to cardiogenic shock (CS) due to the importance of their use as therapeutic instruments. This study aims to review pathophysiologic mechanisms of cardiogenic shock and the implementation of Impella to overcome this condition. To investigate several different types of studies and analyze the use of Impella device in cardiogenic shock and the outcomes of heart malfunctioning and determine its positive and negative impacts as a therapeutic tool in cardiac ischemia and use as a resource in critical patients, we conducted a systematic review through different databases (PubMed, ScienceDirect, and Google Scholar) following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist and used the Medical Subjects Heading (MeSH) search strategy to obtain significant articles. We found 883 papers in total, and after removing duplicates, applying inclusion/exclusion criteria, and finding the most significant information, we ended up with 30 articles that were reviewed containing information about the impact of Impella device in cardiogenic shock in different locations. The study strongly concludes that Impella device in the setting of cardiogenic shock has more advantages than disadvantages in terms of outcomes and complications as a non-pharmacologic tool. Improvements in left ventricular ejection fraction and signs and symptoms of cardiogenic shock criteria were determinants. Nevertheless, complications during the implementation and use of the device were established; in this manner, the evaluation and treatment of each patient separately are imperative. Consequently, more studies on this relevant topic are needed.

Role of Fecal Microbiota Transplantation in Reducing Clostridioides difficile Infection-Associated Morbidity and Mortality: A Systematic Review.

Clostridioides difficile (C. difficile) is a gram-positive, anaerobic, spore-forming bacterium that produces toxins A and B, disrupting the intestinal brush border and resulting in severe diarrhea. The most common causes of infection include prolonged antibiotic use, proton pump inhibitors (PPIs), and long-term hospitalization resulting in complications such as pseudomembranous colitis and toxic megacolon. This systematic review aims to consider fecal microbiota transplantation (FMT) as an early treatment modality in C. difficile infection to prevent complications and reduce related morbidity and mortality. We systematically screened three databases using regular keywords such as "fecal microbiota transplantation," "C. difficile," "pseudomembranous colitis," and "toxic megacolon" and Medical Subject Headings (MeSH) terms. We applied the inclusion and exclusion criteria and performed a thorough quality appraisal using standardized checklists. We were finally left with 10 articles, including seven case reports, one case series, and two observational studies. Questions remain as to the route of administration of FMT, timing, safety, availability, and the number of sittings required. More randomized controlled trials are needed to address all these questions and to assess the safety of FMT. We believe the role of FMT is very important as it can prevent C. difficile related complications and would be an ideal treatment option in a population group that is often unfit for surgical management.

Multimodal Treatment and Diagnostic Modalities in the Setting of Heyde's Syndrome: A Systematic Review.

Heyde's syndrome encompasses the triad of aortic stenosis (AS), angiodysplasia, and acquired Von Willebrand's disease (aVWD). The disease itself is a rare association that affects a small subset of patients who suffer from aortic stenosis. Nonetheless, it represents a vital area of clinical interest and is woefully underreported in the literature. Patients with Heyde's syndrome develop gastrointestinal bleeding (GI) as a result of angiodysplasia and due to lack of adequate hemostasis, they tend to be positively predisposed toward developing gastrointestinal hemorrhage. Due to the glaring lack of comprehensive literature on Heyde's syndrome, this systematic review aims to bridge the gap by elucidating the various diagnostic and treatment options available to clinicians for Heyde's syndrome patients as well as to give a detailed account of the pathophysiology of the disease. This systematic review was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Google Scholar, Gulf Medical University (GMU) e-library, and PubMed were thoroughly searched for studies done in the last 10 years, which corresponds with our outlined inclusion and exclusion criteria. Relevant studies were then selected on the basis of their abstracts and titles. These studies then underwent a comprehensive quality assessment in which any papers which did not meet this study's eligibility criteria were omitted. Overall, 18 studies fulfilled the criteria of this systematic review.

Removal of Extended-Spectrum Beta-Lactamase-Producing Escherichia coli, ST98, in Water for Human Consumption by Black Ceramic Water Filters in Low-Income Ecuadorian Highlands.

Fecal contamination in natural water sources is a common problem in low-income countries. Several health risks are associated with unprotected water sources, such as gastrointestinal infections caused by parasites, viruses, and bacteria. Moreover, antibiotic-resistant bacteria in water sources have become an increasing problem worldwide. This study aimed to evaluate the bacterial pathogens present in water within a rural context in Ecuador, along with the efficiency of black ceramic water filters (BCWFs) as a sustainable household water treatment. We monitored five natural water sources that were used for human consumption in the highlands of Ecuador and analyzed the total coliforms and E. coli before and after BCWF installation. The results indicated a variable bacterial contamination (29-300 colony-forming units/100mL) in all unfiltered samples, and they were considered as high risk for human consumption, but after filtration, no bacteria were present. Moreover, extended-spectrum beta-lactamase-producing E. coli with blaTEM, blaCTX-M9, and blaCTX-M1 genes, and two E. coli classified in the clonal complex ST10 (ST98) were detected in two of the locations sampled; these strains can severely impact public health. The clonal complex ST10, found in the E. coli isolates, possesses the potential to spread bacteria-resistant genes to humans and animals. The results of the use of BCWFs, however, argue for the filters' potential impact within those contexts, as the BCWFs completely removed even antibiotic-resistant contaminants from the water.

Sotos syndrome and scoliosis surgical treatment: a 10-year follow-up.

Sotos syndrome is caused by a gene deletion with an autosomal dominant pattern of inheritance. Cerebral gigantism, hypotonia and joint hyperextensibility are characteristic features of this syndrome. A percentage of these patients develop progressive scoliosis early in life. In the literature, few studies on the evolution of scoliosis in Sotos syndrome have been published. We retrospectively evaluated eight patients diagnosed with Sotos syndrome and scoliosis treated at the Garrahan Children Hospital between 1988 and March 2009. Clinical charts and imaging studies were assessed. Eight patients (19%) presented with scoliosis and seven of them (87.5%) required surgical treatment. The mean follow-up was 9.5 years (range 3-18). Mean age at first consultation was 5.2 years (range 1.1-11.2). Mean Cobb angle for scoliosis at first consultation was 34.3° (range 20°-42°) and the mean Cobb angle for kyphosis was 45.6° (range 30°-90°). Mean age at surgery was 11.2 years (range 3.7-18.10). The surgical procedures performed were instrumented posterior arthrodesis, alone or combined with anterior arthrodesis, instrumented anterior arthrodesis, while one patient is currently in treatment with growing rods. Preoperative mean Cobb angle for scoliosis was 72.3° (range 54°-130°) and for kyphosis was 59.8° (range 30°-108°); postoperative mean Cobb angle for scoliosis was 45.5° (range 6°-90°) and for kyphosis was 40.2° (range 30°-80°). There were three early complications (pleural effusion in two cases and death due to sepsis in one) and two late complications (kyphosis above the instrumentation area and dislodgement of the proximal hooks). Incidence of scoliosis in Sotos syndrome is high and thus close monitoring of patients with Sotos syndrome during growth is important for early detection of this entity. Joint hyperextensibility and hypotonia that are characteristic of the syndrome should be considered at the moment of surgery to avoid short fusions.

Detection of Trypanosoma cruzi in the saliva of diverse neotropical bats.

Trypanosoma cruzi is widely reported in bats, yet transmission routes remain unclear. We present evidence from metagenomic sequence data that T. cruzi occurs in the saliva of diverse Neotropical bats. Phylogenetic analyses demonstrated that the bat-associated T. cruzi sequences described here formed part of a bat-specific clade, suggesting an independent transmission cycle. Our results highlight the value in repurposing metagenomic data generated for viral discovery to reveal insights into the biology of other parasites. Evaluating whether the presence of T. cruzi in the saliva of two hematophagous bat species represents an ecological route for zoonotic transmission of Chagas disease is an interesting avenue for future research.