Fetal gene therapy.

Fetal gene therapy was first proposed toward the end of the 1990s when the field of gene therapy was, to quote the Gartner hype cycle, at its "peak of inflated expectations." Gene therapy was still an immature field but over the ensuing decade, it matured and is now a clinical and market reality. The trajectory of treatment for several genetic diseases is toward earlier intervention. The ability, capacity, and the will to diagnose genetic disease early-in utero-improves day by day. A confluence of clinical trials now signposts a trajectory toward fetal gene therapy. In this review, we recount the history of fetal gene therapy in the context of the broader field, discuss advances in fetal surgery and diagnosis, and explore the full ambit of preclinical gene therapy for inherited metabolic disease.

Detection of Viable Streptococcus equi equi Using Propidium Monoazide Polymerase Chain Reaction.

There is debate around the clinical significance of Streptococcus equi subsp. equi detection in low numbers using quantitative real-time PCR (qPCR). Propidium monoazide (PMA) qPCR has been used to differentiate DNA from viable and nonviable bacterial cells. The aim of this study was to evaluate the ability of PMA eqbE SEQ2190 triplex qPCR to differentiate DNA from viable and nonviable S. equi in positive and suspect positive clinical specimens. Fifty-seven stored (frozen and refrigerated) positive (36) or suspect positive (21) clinical specimens (determined via SeeI qPCR as the gold standard) were tested using eqbE SEQ2190 triplex qPCR with (+) and without (-) PMA pretreatment. Cycle thresholds were higher when using PMA indicating a mixture of heat killed and viable cells. Number of S. equi positive specimens were as follows: 6/57 eqbE + PMA, 13/57 eqbE -PMA (Chi- squared 3.1, p = .079); 10/57 SEQ2190 +PMA, 53/57 SEQ2190 -PMA (Chi- squared 65.6, p < .0001). The mean cycle thresholds were as follows: 23.88 eqbE -PMA, 29.89 eqbE + PMA (p = .04); 24.9 SEQ2190 -PMA, 31.9 SEQ2190 +PMA (p < .0001). PMA qPCR can be used to determine S. equi viability, but testing should be performed on fresh specimens.

Transfer of naturally acquired specific passive immunity against Anaplasma phagocytophilum in foals in Southeastern Pennsylvania and Northern Maryland.

BACKGROUND: Equine granulocytic anaplasmosis (EGA) is a common disease in adult horses, but clinical disease in foals is rarely reported. The relationship between equine maternal and neonatal antibodies to Anaplasma phagocytophilum is unclear. HYPOTHESIS/OBJECTIVES: That mares in an endemic region would be seropositive for A. phagocytophilum and that mare and foal serum IgG concentrations for A. phagocytophilum would correlate. Additionally, we hypothesized that foal IgG concentrations for A. phagocytophilum acquired by passive immunity would decline by 6 months of age. ANIMALS: Twenty-two healthy mare-foal pairs. METHODS: This prospective observational study investigated serum IgG concentrations specific for A. phagocytophilum in mares and foals using an immunofluorescent antibody test (IFA). The association between foal titer (as a binary variable) and age in months was assessed using a mixed-effects logistic regression. RESULTS: A positive correlation between newborn foal antibody titers and mare titers was identified at both the pre-foaling (τa = 0.38, τb = 0.50, P = .009) and foaling timepoints (τa = 0.36, τb = 0.47, P = .01). In A. phagocytophilum seropositive neonates, it was unlikely that a positive titer would be detected by 3 months of age (OR = 0.002, P = .02, 95% CI: 0.00001-0.38). Three out of 20 foals seroconverted between 3 and 6 months of age. CONCLUSIONS AND CLINICAL IMPORTANCE: Transfer of specific passive immunity to A. phagocytophilum occurred in 80% of foals born to seropositive mares and declined by 3 months of age. A. phagocytophilum infection should be considered in foals displaying clinical signs consistent with EGA.

Development of a novel real-time PCR multiplex assay for detection of Streptococcus equi subspecies equi and Streptococcus equi subspecies zooepidemicus.

Strangles is a contagious bacterial disease of horses caused by Streptococcus equi subspecies equi (SEE) that occurs globally. Rapid and accurate identification of infected horses is essential for controlling strangles. Because of limitations of existing PCR assays for SEE, we sought to identify novel primers and probes that enable simultaneous detection and differentiation of infection with SEE and S. equi subsp. zooepidemicus (SEZ). Comparative genomics of U.S. strains of SEE and SEZ (n = 50 each) identified SE00768 from SEE and comB from SEZ as target genes. Primers and probes for real-time PCR (rtPCR) were designed for these genes and then aligned in silico with the genomes of strains of SEE (n = 725) and SEZ (n = 343). Additionally, the sensitivity and specificity relative to microbiologic culture were compared between 85 samples submitted to an accredited veterinary medical diagnostic laboratory. The respective primer and probe sets aligned with 99.7 % (723/725) isolates of SEE and 97.1 % (333/343) of SEZ. Of 85 diagnostic samples, 20 of 21 (95.2 %) SEE and 22 of 23 SEZ (95.6 %) culture-positive samples were positive by rtPCR for SEE and SEZ, respectively. Both SEE (n = 2) and SEZ (n = 3) were identified by rtPCR among 32 culture-negative samples. Results were rtPCR-positive for both SEE and SEZ in 21 of 44 (47.7 %) samples that were culture-positive for SEE or SEZ. The primers and probe sets reported here reliably detect SEE and SEZ from Europe and the U.S., and permit detection of concurrent infection with both subspecies.

Factors Influencing Equine Affiliate Opinion on Reporting of Equine Strangles in the United States.

Although equine strangles is reportable in all states, synchronous reporting of this disease does not occur across the country. States have variable regulations on reporting (actionable, notifiable, and monitored) and no mandatory comprehensive databases exist for tracking prevalence. In this study, which is a companion to our recent publication on veterinarians' opinions on this topic, we solicited equine affiliates' (including horse owners, horse business owners/trainers, breeders, and barn managers) opinions on reporting of strangles and factors influencing their opinion. A total of 518 equine affiliates/stakeholders living within the United States. A structured survey was administered online. Eighty-one participants (17.8%) believed that strangles should continue to be nationally monitored and that individual states should have jurisdiction over laboratory confirmed positive cases; 124 (27.2%) believed strangles should become nationally monitored with mandatory notification of positive cases to a central forum; 77 participants (16.9%) thought strangles should become notifiable nationally; and 157 (34.4%) thought strangles should become notifiable and actionable. Participants who ranked strangles as "important" or "very important" compared to other infectious disease were more likely to want increased reporting (OR = 3.62, P = .054), and participants who were more familiar with the disease were more likely to rank it as important: for every 1-point increase in correct total score on the 5-question basic knowledge exam included, there was a 49% increase in odds of ranking strangles as important or very important (P = .003). Equine stakeholders who perceived their horses to be at medium or high risk of acquiring the disease were 2.76 times more likely to rank strangles as important or very important (P = .014). Of the sampled equine stakeholder community, the majority of respondents (78.5%) favored increased reporting. Information obtained in this study regarding current views of those involved in the equine industry on strangles reporting could inform future policy regarding the disease.

Streptococcus equi Subspecies equi.

Strangles, caused by the bacteria Streptococcus equi subsp equi, is a highly contagious disease of equids classically characterized by a high fever and enlarged lymph nodes of the head. Diagnostic sampling depends on the stage of the disease. The goal of treating strangles is to control transmission and to eliminate infection while providing future host immunity. Daily temperature checking and isolation of febrile horses is the key to controlling outbreaks. Eradication of this disease will not be possible until S equi carriers are eliminated from the equine population.

Interventions for Infection and Inflammation-Induced Preterm Birth: a Preclinical Systematic Review.

Spontaneous preterm births (< 37 weeks gestation) are frequently associated with infection. Current treatment options are limited but new therapeutic interventions are being developed in animal models. In this PROSPERO-registered preclinical systematic review, we aimed to summarise promising interventions for infection/inflammation-induced preterm birth. Following PRISMA guidance, we searched PubMed, EMBASE, and Web of Science using the themes: "animal models", "preterm birth", "inflammation", and "therapeutics". We included original quantitative, peer-reviewed, and controlled studies applying prenatal interventions to prevent infection/inflammation-induced preterm birth in animal models. We employed two risk of bias tools. Of 4020 identified studies, 23 studies (24 interventions) met our inclusion criteria. All studies used mouse models. Preterm birth was most commonly induced by lipopolysaccharide (18 studies) or Escherichia coli (4 studies). Models varied according to infectious agent serotype, dose, and route of delivery. Gestational length was significantly prolonged in 20/24 interventions (83%) and markers of maternal inflammation were reduced in 20/23 interventions (87%). Interventions targeting interleukin-1, interleukin-6, and toll-like receptors show particular therapeutic potential. However, due to the heterogeneity of the methodology of the included studies, meta-analysis was impossible. All studies were assigned an unclear risk of bias using the SYRCLE risk of bias tool. Interventions targeting inflammation demonstrate therapeutic potential for the prevention of preterm birth. However, better standardisation of preterm birth models, including the dose, serotype, timing of administration and pathogenicity of infectious agent, and outcome reporting is urgently required to improve the reproducibility of preclinical studies, allow meaningful comparison of intervention efficacy, and aid clinical translation.

Conservation of vaccine antigen sequences encoded by sequenced strains of Streptococcus equi subsp. equi.

BACKGROUND: Streptococcus equi subspecies equi (S equi) is the cause of Strangles, one of the most prevalent diseases of horses worldwide. Variation within the immunodominant SeM protein has been documented, but a new eight-component fusion protein vaccine, Strangvac, does not contain live S equi or SeM and conservation of the antigens it contains have not been reported. OBJECTIVE: To define the diversity of the eight Strangvac antigens across a diverse S equi population. STUDY DESIGN: Genomic description. METHODS: Antigen sequences from the genomes of 759 S equi isolates from 19 countries, recovered between 1955 and 2018, were analysed. Predicted amino acid sequences in the antigen fragments of SEQ0256(Eq5), SEQ0402(Eq8), SEQ0721(EAG), SEQ0855(SclF), SEQ0935(CNE), SEQ0999(IdeE), SEQ1817(SclI) and SEQ2101(SclC) in Strangvac and SeM were extracted from the 759 assembled genomes and compared. RESULTS: The predicted amino acid sequences of SclC, SclI and IdeE were identical across all 759 genomes. CNE was truncated in the genome of five (0.7%) isolates. SclF was absent from one genome and another encoded a single amino acid substitution. EAG was truncated in two genomes. Eq5 was truncated in four genomes and 123 genomes encoded a single amino acid substitution. Eq8 was truncated in three genomes, one genome encoded four amino acid substitutions and 398 genomes encoded a single amino acid substitution at the final amino acid of the Eq8 antigen fragment. Therefore, at least 1579 (99.9%) of 1580 amino acids in Strangvac were identical in 743 (97.9%) genomes, and all genomes encoded identical amino acid sequences for at least six of the eight Strangvac antigens. MAIN LIMITATIONS: Three hundred and seven (40.4%) isolates in this study were recovered from horses in the UK. CONCLUSIONS: The predicted amino acid sequences of antigens in Strangvac were highly conserved across this collection of S equi.

Factors Influencing Veterinarian Opinion on Reporting of Equine Strangles in the United States.

Although equine strangles is reportable in all states, synchronous reporting of this disease does not occur across the country. States have variable regulations on reporting (actionable, notifiable, and monitored) and no mandatory comprehensive databases exist for tracking prevalence. In this study, we solicited veterinarians' opinions on reporting of strangles and factors influencing their opinion. Two hundred and fifty veterinarians practicing within the United States A structured survey was administered online. A total of 250 veterinarians participated: 84 participants (34%) believed that strangles should continue to be nationally monitored and that individual states should have jurisdiction over laboratory-confirmed positive cases; 58 (23.2%) believed strangles should become nationally monitored with mandatory notification of positive cases to a central forum; 24 participants (9.6%) thought strangles should become notifiable nationally; and 44 (17.6%) thought strangles should become notifiable and actionable. Veterinarians who were currently in the habit of reporting strangles were also more likely to want increased reporting (Or=1.87), though this association was not quite statistically significant  (P = 0.054), as did veterinarians who ranked strangles as "very important" or "important" relative to other infectious disease (OR 3.77, P = .037). Veterinarians practicing in the Southwest (P = .01) and West (P = .04) were significantly less likely than northeast practitioners to rank strangles of higher importance. Opinions on equine strangles and desire for increased reporting were varied in the sampled veterinary community. Information obtained in this study regarding veterinarians' current views on strangles reporting could inform future policy regarding the disease.

Horses vaccinated with live attenuated intranasal strangles vaccine seroconvert to SEQ2190 and SeM.

BACKGROUND: The dual antigen iELISA uses two Streptococcus equi subsp equi surface protein antigens composed of N-terminal portions of SEQ2190 (Antigen A) and SeM (Antigen C). It is currently used to identify animals exposed to S. equi which have developed an immune response to the target antigens. OBJECTIVES: To determine the usefulness of the dual antigen iELISA in a population of horses vaccinated with Pinnacle IN. We hypothesised that horses vaccinated for strangles with a live attenuated, non-encapsulated SeM-2 strain of S. equi, would seroconvert when tested 5 weeks later by the dual antigen iELISA. STUDY DESIGN: Prospective case-control study. METHODS: Three separate serum samples were obtained from 26 client-owned horses vaccinated annually with Pinnacle® IN and 26 university-owned (non-vaccinates): at annual strangles vaccination (S1), 5-week post-vaccination (S2) from vaccinates, and a third (S3) (at 10 weeks) from vaccinates who received a booster. Seropositivity was defined as an OD450 nm value ≥0.5 for one or both antigens. Mixed-effects ordered logistic regression analysis was used to identify factors associated with a suspect seropositive and seropositive value on the combined Antigen A and Antigen C iELISA. Post hoc pairwise comparisons of linear predictive margins were used to assess the differences in OD450 at a specific time between Antigens A and C. RESULTS: Nineteen of 25 (76%) vaccinates were seropositive at S2 compared to 1 of 26 (4%) non-vaccinates. When adjusted for sample number, vaccinates were more likely to be seropositive or suspect than non-vaccinates (OR 14; P = .02, 95% CI 1.62-122.03). The OD450 value was significantly larger for Antigen C than Antigen A for vaccinates (P < .001; 95% CI 0.13-0.26) when normalised by age, sex and breed. MAIN LIMITATIONS: Guttural pouch sampling for S. equi in seroconverted horses was unavailable. CONCLUSIONS: With a high rate of seroconversion to both antigens, the use of the dual antigen iELISA is not recommended in populations vaccinated with Pinnacle® IN.

In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications.

The human adenovirus phylogenetic tree is split across seven species (A-G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of pre-existing immunity detected across screened populations. However, many aspects of the basic virology of species D-such as their cellular tropism, receptor usage, and in vivo biodistribution profile-remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49)-a relatively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry, but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting, whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells, and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen, whilst avoiding liver interactions, such as intravascular vaccine applications.

Antimicrobial prescribing patterns in equine ambulatory practice.

Antimicrobial resistance is one of the most important public health risks facing our world today. Antimicrobials are commonly prescribed in equine veterinary medicine, but limited information exists documenting their use in practice. The goal of this study was to investigate antimicrobial prescription patterns in regards to prescription frequency, duration, drug class, clinician and affected body system in an equine ambulatory setting via retrospective analysis of billing and electronic medical records. Risk factors associated with antimicrobial prescription including the nature of the visit, submission of a culture, body system affected and clinician were assessed using multivariable regression. We found that antimicrobials were prescribed in 8.5 % of visits with a median number of 3.5 (IQR 0.8-12.2) animal-defined daily doses (ADD), defined as the number of daily doses of all antimicrobials prescribed to a patient at a single visit. Aminoglycosides were the most common class of antimicrobials prescribed and trimethoprim sulfamethoxazole was the most common drug prescribed overall. Amikacin was primarily used for patients presenting with musculoskeletal signs, and the median number of ADDs for visits where amikacin was prescribed was 1 (IQR 0.9-1.9), while the median number of antimicrobial ADDs for all other visits was 4.4 (IQR 0-14.1). Statistically significant differences in antimicrobial use patterns existed across clinicians, months, years and affected body systems. Horses presenting with ocular (OR 1199; 95 % CI 204-7,037; p < 0.001) and integumentary (OR 365; 95 % CI 87.2-1532; p < 0.001) signs were most likely to be prescribed an antimicrobial. Emergency visits (OR 5.61; 95 % CI 3.19-9.89; p < 0.001) and submission of a bacterial culture (OR 3.58; 95 % CI 2.11-6.09; p < 0.001) were associated with an increased likelihood of an antimicrobial prescription. This observational study was the first to quantitatively characterize antimicrobial use patterns in equine ambulatory practice in the United States, which is an important step needed to determine appropriateness of use and develop and evaluate antimicrobial stewardship guidelines.

Differences in the genome, methylome, and transcriptome do not differentiate isolates of Streptococcus equi subsp. equi from horses with acute clinical signs from isolates of inapparent carriers.

Streptococcus equi subsp. equi (SEE) is a host-restricted bacterium that causes the common infectious upper respiratory disease known as strangles in horses. Perpetuation of SEE infection appears attributable to inapparent carrier horses because it neither persists long-term in the environment nor infects other host mammals or vectors, and infection results in short-lived immunity. Whether pathogen factors enable SEE to remain in horses without causing clinical signs remains poorly understood. Thus, our objective was to use next-generation sequencing technologies to characterize the genome, methylome, and transcriptome of isolates of SEE from horses with acute clinical strangles and inapparent carrier horses-including isolates recovered from individual horses sampled repeatedly-to assess pathogen-associated changes that might reflect specific adaptions of SEE to the host that contribute to inapparent carriage. The accessory genome elements and methylome of SEE isolates from Sweden and Pennsylvania revealed no significant or consistent differences between acute clinical and inapparent carrier isolates of SEE. RNA sequencing of SEE isolates from Pennsylvania demonstrated no genes that were differentially expressed between acute clinical and inapparent carrier isolates of SEE. The absence of specific, consistent changes in the accessory genomes, methylomes, and transcriptomes of acute clinical and inapparent carrier isolates of SEE indicates that adaptations of SEE to the host are unlikely to explain the carrier state of SEE. Efforts to understand the carrier state of SEE should instead focus on host factors.

Respiratory Distress in the Adult and Foal.

Respiratory distress in the horse and foal is an emergency. Managing equine respiratory distress in the field starts with appropriate assessment of the patient to determine whether the breathing obstruction stems from the upper or lower respiratory tract or is nonrespiratory in origin. From a thorough, but efficient, physical examination to point-of-care ultrasound and endoscopy, the veterinarian has many tools in the field to help diagnose the patient.

Detection of Streptococcus equi subsp. equi in guttural pouch lavage samples using a loop-mediated isothermal nucleic acid amplification microfluidic device.

BACKGROUND: Rapid point-of-care (POC) detection of Streptococcus equi subsp. equi (S. equi) would theoretically reduce the spread of strangles by identifying index and carrier horses. HYPOTHESIS: That the eqbE isothermal amplification (LAMP) assay, and the same eqbE LAMP assay tested in a microfluidic device format, are comparable to a triplex real-time quantitative polymerase chain reaction (qPCR) assay that is commonly used in diagnostic labs. SAMPLES: Sixty-eight guttural pouch lavage (GPL) specimens from horses recovering from strangles. METHODS: Guttural pouch lavage specimens were tested for S. equi retrospectively using the benchtop eqbE LAMP, the eqbE LAMP microfluidic device, and compared to the triplex qPCR, that detects 2 S. equi-specific genes, eqbE and SEQ2190, as the reference standard using the receiver operating characteristic area under the curve (ROC). RESULTS: The 27/68 specimens were positive by benchtop eqbE LAMP, 31/64 by eqbE LAMP microfluidic device, and 12/67 by triplex qPCR. Using the triplex PCR as the reference, the benchtop eqbE LAMP showed excellent discrimination (ROC Area = 0.813, 95% confidence interval [CI] = 0.711-0.915) as did the LAMP microfluidic device (ROC Area = 0.811, 95% CI = 0.529-0.782). There was no significant difference between the benchtop LAMP and LAMP microfluidic device (ROC Area 0.813 ± 0.055 vs 0.811 ± 0.034, P = .97). CONCLUSIONS: The eqbE LAMP microfluidic device detected S. equi in GPL specimens from convalescent horses. This assay shows potential for development as a POC device for rapid, sensitive, accurate, and cost-efficient detection of S. equi.

Lack of Association Between Barometric Pressure and Incidence of Colic in Equine Academic Ambulatory Practice.

Anecdotal accounts correlate equine colic onset to changing weather conditions; however, atmospheric effects on colic have not been studied extensively. We hypothesized that changes in barometric pressure would increase the likelihood of a colic diagnosis compared with other noncolic sick events. Multivariable logistic regression analysis was used to look for associations between colic diagnosis and barometric pressure. The University of Pennsylvania Field Service electronic medical records were searched by identifiable examination type via billing procedure codes collecting 3,108 emergent and nonemergent medical events along with corresponding weather data from the National Weather Service from January 1, 2005, through January 1, 2017. Barometric pressure values and changes were not found to be statistically associated with a diagnosis of colic (P = .1). Horses that did not survive were almost 12 times more likely to have a diagnosis of colic (odds ratio [OR]: 11.97; P < .0001). Horses with disease recurrence were 30% more likely to have a diagnosis of colic (OR: 1.29; P = .006). The likelihood of colic diagnosis increased with increasing latitude (OR: 2.43; P = .04). Horses were more likely to be diagnosed with colic in the fall (OR: 1.72; P < .0001), spring (OR: 1.29; P = .04), and summer (OR: 1.85; P < .0001), compared with winter. Stallions were 48% less likely to colic compared with mares (OR: 0.52; P = .016) and Quarter Horses were 32% less likely to colic compared with Thoroughbreds and Arabians (OR: 0.68; P = .047). This study provided evidence that changes in barometric pressure were not a contributing risk factor for colic, although seasons with changing weather and latitude may play a role.

Cathelicidins and the Onset of Labour.

Preterm birth, defined as delivery before 37 weeks of gestation, is the leading cause of neonatal mortality and morbidity. Infection and inflammation are frequent antecedents of spontaneous preterm birth. Cathelicidin, an antimicrobial host defence peptide, is induced by infection and inflammation and although expressed in the reproductive tract and fetal tissues, its role in the pathogenesis of spontaneous preterm birth is unknown. Here we demonstrate that cathelicidin expression is increased at RNA and protein level in the mouse uterus in a model of inflammation-induced labour, where ultrasound guided intrauterine injection of lipopolysaccharide (LPS) at E17 stimulates preterm delivery within 24 hours. Cathelicidin-deficient (Camp-/-) mice are less susceptible to preterm delivery than wild type mice following intrauterine injection of 1 µg of LPS, and this is accompanied by a decrease in circulating IL-6, an inflammatory mediator implicated in the onset of labour. We also show that the proportion of cathelicidin expressing cells in the myometrium is higher in samples obtained from women in labour at term than pre-labour. Together, these data suggest that cathelicidin has roles in mediating pro-inflammatory responses in a murine model of inflammation-induced labour, and in human term labour.

Evaluating implementation supports delivered within problem-solving consultation.

Teachers participating in problem-solving consultation often struggle to maintain adequate treatment fidelity, which is necessary to improve student outcomes. Low levels of treatment fidelity may result from implementation barriers, such as intervention compatibility, implementer skill, and implementer motivation. This study involves the evaluation of five implementation supports designed to address implementation barriers (i.e., Implementation Planning, Role Play, Participant Modeling, Raising Awareness, Motivational Consulting) within problem-solving consultation. Across 14 randomized individual single-case AB intervention designs, we evaluated the impact of these implementation supports on teacher treatment fidelity of classroom management plans and class-wide academic engagement and disruptive behavior. Visual analysis, descriptive statistics, and randomization test analyses suggest that these implementation supports have the potential to be broadly effective in improving teachers' fidelity and student outcomes. Teachers required a different number of supports to increase fidelity levels and rated the implementation supports positively. Implications of the study's findings are described.

Repurposing simvastatin as a therapy for preterm labor: evidence from preclinical models.

Preterm birth (PTB), the leading cause of neonatal morbidity and mortality, urgently requires novel therapeutic agents. Spontaneous PTB, resulting from preterm labor, is commonly caused by intrauterine infection/inflammation. Statins are well-established, cholesterol-lowering drugs that can reduce inflammation and inhibit vascular smooth muscle contraction. We show that simvastatin reduced the incidence of PTB in a validated intrauterine LPS-induced PTB mouse model, decreased uterine proinflammatory mRNA concentrations (IL-6, Cxcl1, and Ccl2), and reduced serum IL-6 concentration. In human myometrial cells, simvastatin reduced proinflammatory mediator mRNA and protein expression (IL-6 and IL-8) and increased anti-inflammatory cytokine mRNA expression (IL-10 and IL-13). Critically, simvastatin inhibited myometrial cell contraction, basally and during inflammation, and reduced phosphorylated myosin light chain concentration. Supplementation with mevalonate and geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, abolished these anticontractile effects, indicating that the Rho/Rho-associated protein kinase pathway is critically involved. Thus, simvastatin reduces PTB incidence in mice, inhibits myometrial contractions, and exhibits key anti-inflammatory effects, providing a rationale for investigation into the repurposing of statins to treat preterm labor in women.-Boyle, A. K., Rinaldi, S. F., Rossi, A. G., Saunders, P. T. K., Norman, J. E. Repurposing simvastatin as a therapy for preterm labor: evidence from preclinical models.

Factors associated with prolonged treatment days, increased veterinary visits and complications in horses with subsolar abscesses.

There is a lack of epidemiological studies about equine subsolar (hoof) abscesses even though they are among one of the most common causes of acute, severe lameness. The goals of this study were to (1) describe the equine subsolar abscess patient population of the University of Pennsylvania's New Bolton Center's Field Service and (2) to determine the factors that are associated with increased veterinary visits, prolonged treatment and complications. Descriptive statistics were performed on data collected from 160 cases of equine subsolar abscess. Inferential statistics were performed on a subset of those cases. No significant results were identified in relation to an increased number of veterinary visits. Poisson regression of days of treatment revealed that abscesses diagnosed in the summer (incidence rate ratio (IRR)=9.42, P<0.001) and abscesses found at the coronary band (IRR=3.21, P<0.001) were more likely to be treated for longer. Presence of a draining tract (IRR=0.73, P=0.017) and a higher lameness (IRR=0.30, P=0.01 for grade 3, IRR=0.1, P<0.001 for grades 4 and 5) score at presentation resulted in shortened treatment times. Abscesses affecting multiple portions of the digit were associated with an increased chance of complication. The study presented here is the first retrospective study on subsolar abscesses to the authors' knowledge.