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New SARS-CoV-2 variants causing COVID-19 are a major risk to public health worldwide due to the potential for phenotypic change and increases in pathogenicity, transmissibility and/or vaccine escape. Recognising signatures of new variants in terms of replacing growth and severity are key to informing the public health response. To assess this, we aimed to investigate key time periods in the course of infection, hospitalisation and death, by variant. We linked datasets on contact tracing (Contact Tracing Advisory Service), testing (the Second-Generation Surveillance System) and hospitalisation (the Admitted Patient Care dataset) for the entire length of contact tracing in the England – from March 2020 to March 2022. We modelled, for England, time delay distributions using a Bayesian doubly interval censored modelling approach for the SARS-CoV-2 variants Alpha, Delta, Delta Plus (AY.4.2), Omicron BA.1 and Omicron BA.2. This was conducted for the incubation period, the time from infection to hospitalisation and hospitalisation to death. We further modelled the growth of novel variant replacement using a generalised additive model with a negative binomial error structure and the relationship between incubation period length and the risk of a fatality using a Bernoulli generalised linear model with a logit link. The mean incubation periods for each variant were: Alpha 4.19 (95% credible interval (CrI) 4.13–4.26) days; Delta 3.87 (95% CrI 3.82–3.93) days; Delta Plus 3.92 (95% CrI 3.87–3.98) days; Omicron BA.1 3.67 (95% CrI 3.61–3.72) days and Omicron BA.2 3.48 (95% CrI 3.43–3.53) days. The mean time from infection to hospitalisation was for Alpha 11.31 (95% CrI 11.20–11.41) days, Delta 10.36 (95% CrI 10.26–10.45) days and Omicron BA.1 11.54 (95% CrI 11.38–11.70) days. The mean time from hospitalisation to death was, for Alpha 14.31 (95% CrI 14.00–14.62) days; Delta 12.81 (95% CrI 12.62–13.00) days and Omicron BA.2 16.02 (95% CrI 15.46–16.60) days. The 95th percentile of the incubation periods were: Alpha 11.19 (95% CrI 10.92–11.48) days; Delta 9.97 (95% CrI 9.73–10.21) days; Delta Plus 9.99 (95% CrI 9.78–10.24) days; Omicron BA.1 9.45 (95% CrI 9.23–9.67) days and Omicron BA.2 8.83 (95% CrI 8.62–9.05) days. Shorter incubation periods were associated with greater fatality risk when adjusted for age, sex, variant, vaccination status, vaccination manufacturer and time since last dose with an odds ratio of 0.83 (95% confidence interval 0.82–0.83) (P value < 0.05). Variants of SARS-CoV-2 that have replaced previously dominant variants have had shorter incubation periods. Conversely co-existing variants have had very similar and non-distinct incubation period distributions. Shorter incubation periods reflect generation time advantage, with a reduction in the time to the peak infectious period, and may be a significant factor in novel variant replacing growth. Shorter times for admission to hospital and death were associated with variant severity – the most severe variant, Delta, led to significantly earlier hospitalisation, and death. These measures are likely important for future risk assessment of new variants, and their potential impact on population health.
Diagnosis, treatment, and prevention of vector-borne disease (VBD) in pets is one cornerstone of companion animal practices. Veterinarians are facing new challenges associated with the emergence, reemergence, and rising incidence of VBD, including heartworm disease, Lyme disease, anaplasmosis, and ehrlichiosis. Increases in the observed prevalence of these diseases have been attributed to a multitude of factors, including diagnostic tests with improved sensitivity, expanded annual testing practices, climatologic and ecological changes enhancing vector survival and expansion, emergence or recognition of novel pathogens, and increased movement of pets as travel companions. Veterinarians have the additional responsibility of providing information about zoonotic pathogen transmission from pets, especially to vulnerable human populations: the immunocompromised, children, and the elderly. Hindering efforts to protect pets and people is the dynamic and ever-changing nature of VBD prevalence and distribution. To address this deficit in understanding, the Companion Animal Parasite Council (CAPC) began efforts to annually forecast VBD prevalence in 2011. These forecasts provide veterinarians and pet owners with expected disease prevalence in advance of potential changes. This review summarizes the fidelity of VBD forecasts and illustrates the practical use of CAPC pathogen prevalence maps and forecast data in the practice of veterinary medicine and client education.
OBJECTIVES/SPECIFIC AIMS: Pancreatic ductal adenocarcinoma (PDA) has a dismal 5-year survival rate of 9%, making this disease one of the deadliest human malignancies (https://seer.cancer.gov/). Primary barriers to the treatment of pancreatic cancer include extensive stromal interactions and sustained immune suppression. Aberrant Hedgehog (HH) pathway activity is a hallmark of pancreatic tumorigenesis. Tumor-derived HH ligands signal in a paracrine fashion to the surrounding stroma to influence tumor growth. Expression of HH ligands increases during PDA progression, and previous work has shown that genetic deletion of Sonic HH (Shh) from the epithelium of mice with pancreatic tumors results in increased Indian HH (Ihh) expression. This research aims to investigate the translational impact of changes in immune infiltration following deletion of IHH in a preclinical mouse model of pancreatic cancer. METHODS/STUDY POPULATION: Ihh was deleted in tumor cells lines (IhhKO) derived from a genetically engineered mouse model of pancreatic cancer (LSL-KrasG12D/+;LSL-TrpR270H;P48-Cre), using CRISPR/Cas-9 gene editing to assess the role of Ihh in the tumor microenvironment. The level of HH signaling was determined using tumor cell co-cultures with Gli1lacZ fibroblasts (derived from mice with a lacZ reporter allele knocked into the Gli1 locus), in which Beta Galactosidase activity serves as a readout for HH signaling. WT and IhhKO tumor cells were orthotopically transplanted into the pancreas of syngeneic C57BL/6 mice. Human pancreas samples were obtained from surgical resection of pancreatic adenocarcinoma, or fine needle biopsy procedure (FNB). Immune profiling of mouse and human pancreatic tumors was performed using Cytometry Time-of-Flight analysis (CyTOF), and tumor composition was analyzed by single-cell RNA sequencing (scRNA seq). In vitro cultures with pancreatic fibroblasts treated with either WT or IhhKO tumor cell conditioned media (CM) were cultured with bone-marrow derived macrophages to assess tumor crosstalk. RESULTS/ANTICIPATED RESULTS: Tumor cells lacking Ihh were generated through CRISPR/Cas-9 deletion, and this was confirmed by qRT-PCR. Co-culture of IhhKO tumor cells with Gli1lacZ fibroblasts results in decreased Gli1 expression both in vitro and in vivo. Immune profiling revealed that tumors lacking Ihh have significantly fewer tumor associated macrophages (CD11b+/F4/80+/CD206+), resulting in decreased presence of immunosuppressive factors such as arginase 1 and PDL1. Immune phenotyping of human pancreatic tissues revealed similar populations of immunosuppressive myeloid cells present in tumors. In vitro co-cultures demonstrated that, in the presence of bone-marrow derived macrophages, immunosuppressive IL-6 production was reduced in pancreatic fibroblasts cultured with IhhKO-CM, as compared to fibroblasts cultured with WT-CM, providing mechanistic insight into the in vivo phenotype observed. Further, scRNA seq analysis suggests that modulation of HH signaling in the tumor microenvironment alters chemokine and immunomodulatory signaling pathways driven by fibroblasts in the pancreatic tumor microenvironment. DISCUSSION/SIGNIFICANCE OF IMPACT: HH signaling in pancreatic fibroblasts contributes to the establishment of an immune suppressive environment in pancreatic cancer. Combining methods to target HH signaling and immune checkpoint therapy has translational potential in treating pancreatic cancer patients.
The aim of this study was to perform a systematic review and meta-analysis of the diagnostic accuracy of a point-of-care ultrasound exam for undifferentiated shock in patients presenting to the emergency department.
Ovid MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, and research meeting abstracts were searched from 1966 to June 2018 for relevant studies. QUADAS-2 was used to assess study quality, and meta-analysis was conducted to pool performance data of individual categories of shock.
A total of 5,097 non-duplicated studies were identified, of which 58 underwent full-text review; 4 were included for analysis. Study quality by QUADAS-2 was considered overall a low risk of bias. Pooled positive likelihood ratio values ranged from 8.25 (95% CI 3.29 to 20.69) for hypovolemic shock to 40.54 (95% CI 12.06 to 136.28) for obstructive shock. Pooled negative likelihood ratio values ranged from 0.13 (95% CI 0.04 to 0.48) for obstructive shock to 0.32 (95% CI 0.16 to 0.62) for mixed-etiology shock.
The rapid ultrasound for shock and hypotension (RUSH) exam performs better when used to rule in causes of shock, rather than to definitively exclude specific etiologies. The negative likelihood ratios of the exam by subtype suggest that it most accurately rules out obstructive shock.
The years between 1258 and 67 comprise one of the most influential periods in the Middle Ages in England. This turbulent decade witnessed a bitter power struggle between King Henry III and his baronsover who should control the government of the realm. Before England eventually descended into civil war, a significant proportion of the baronage had attempted to transform its governance by imposingon the crown a programme of legislative and administrative reform far more radical and wide-ranging than Magna Carta in 1215. Constituting a critical stage in the development of parliament, the reformist movement would remain unsurpassed in its radicalism until the upheavals of the seventeenth century. Simon de Montfort, the baronial champion, became the first leader of a political movement to seize power and govern in the king's name. The essays collected here offer the most recent research into and ideas on this pivotal period. Several contributions focus upon the roles played in the political struggle by particular sections of thirteenth-century society, including the Midland knights and their political allegiances, aristocratic women, and the merchant elite in London. The events themselves constitute the second major theme of this volume, with subjects such as the secret revolution of 1258, Henry III's recovery of power in 1261, and the little studied maritime theatre during the civil wars of 1263-7 being considered.
Adrian Jobson is an Associate Lecturer at Canterbury Christ Church University.
Contributors: Sophie Ambler, Nick Barratt, David Carpenter, Peter Coss, Mario Fernandes, Andrew H. Hershey, Adrian Jobson, Lars Kjaer, John A. McEwan, Tony Moore, Fergus Oakes, H.W. Ridgeway, Christopher David Tilley, Benjamin L. Wild, Louise J. Wilkinson.
Several lines of evidence suggest that the neuropeptide oxytocin (OT) may be involved in the pathophysiology of obsessive-compulsive behavior in humans and repetitive grooming behavior in animals. Trichotillomania (TTM), which is characterized by chronic hair pulling, may be conceptualized as a disorder of pathologic grooming. To investigate the role of OT in TTM, the cerebrospinal fluid (CSF) levels of OT in nine women with TTM and nine healthy female controls were measured. Early findings from this ongoing study fail to demonstrate a significant difference in CSF OT levels between women with TTM and healthy female controls.