Development of CMX001 for the Treatment of Poxvirus Infections

CMX001 (phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl] ester) is a lipid conjugate of the acyclic nucleotide phosphonate, cidofovir (CDV). CMX001 is currently in Phase II clinical trials for the prophylaxis of human cytomegalovirus infection and under development using the Animal Rule for smallpox infection. It has proven effective in reduction of morbidity and mortality in animal models of human smallpox, even after the onset of lesions and other clinical signs of disease. CMX001 and CDV are active against all five families of double-stranded DNA (dsDNA) viruses that cause human morbidity and mortality, including orthopoxviruses such as variola virus, the cause of human smallpox. However, the clinical utility of CDV is limited by the requirement for intravenous dosing and a high incidence of acute kidney toxicity. The risk of nephrotoxicity necessitates pre-hydration and probenecid administration in a health care facility, further complicating high volume CDV use in an emergency situation. Compared with CDV, CMX001 has a number of advantages for treatment of smallpox in an emergency including greater potency in vitro against all dsDNA viruses that cause human disease, a high genetic barrier to resistance, convenient oral administration as a tablet or liquid, and no evidence to date of nephrotoxicity in either animals or humans. The apparent lack of nephrotoxicity observed with CMX001 in vivo is because it is not a substrate for the human organic anion transporters that actively secrete CDV into kidney cells. The ability to test the safety and efficacy of CMX001 in patients with life-threatening dsDNA virus infections which share many basic traits with variola is a major advantage in the development of this antiviral for a smallpox indication

'I don't think I ever had food poisoning' : A practice-based approach to understanding foodborne disease that originates in the home

© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Food stored, prepared, cooked and eaten at home contributes to foodborne disease which, globally, presents a significant public health burden. The aim of the study reported here was to investigate, analyse and interpret domestic kitchen practices in order to provide fresh insight about how the domestic setting might influence food safety. Using current theories of practice meant the research, which drew on qualitative and ethnographic methods, could investigate people and material things in the domestic kitchen setting whilst taking account of people's actions, values, experiences and beliefs. Data from 20 UK households revealed the extent to which kitchens are used for a range of nonfood related activities and the ways that foodwork extends beyond the boundaries of the kitchen. The youngest children, the oldest adults and the family pets all had agency in the kitchen, which has implications for preventing foodborne disease. What was observed, filmed and photographed was not a single practice but a series of entangled encounters and actions embedded and repeated, often inconsistently, by the individuals involved. Households derived logics and principles about foodwork that represented rules of thumb about 'how things are done' that included using the senses and experiential knowledge when judging whether food is safe to eat. Overall, food safety was subsumed within the practice of 'being' a household and living everyday life in the kitchen. Current theories of practice are an effective way of understanding foodborne disease and offer a novel approach to exploring food safety in the home.Peer reviewedFinal Published versio

The Vehicle, Spring 1974

Table of Contents PhotoJim Painterpage 1 Six Poems of the LandRay Schmuddepage 5 At Last to Find FreedomJann Briesacherpage 7 The Last IrisMarjorie Thoelepage 9 (Untitled)Melinda E. Recordpage 10 MenJan Schroederpage 10 ImpressionsJudy Bardpage 11 ScaredAnita Surpage 11 Loved and LostJan Schroederpage 12 Dripped-Over WaxAnita Surpage 13 The Crowded RoomWilliam E. Uteschpage 14 A River in IllinoisJames Jonespage 14 Sneeze SeasonDarlene A. Moorepage 14 ChangesMark Chianakaspage 15 PhotoJim Painterpage 16 Wedding VowsJann Briesacherpage 17 PhotoJim Painterpage 18 PhotoJim Painterpage 19 PhotoJim Painterpage 20 PhotoJim Painterpage 21 PhotoJim Painterpage 22 PhotoLarry Smyserpage 23 From Outside ColoradoRay Schmuddepage 24 Dairy QueenGayle Gleichmanpage 26 With Sunstreaks in our HairNancy Broom Brownpage 33 PhotoJim Painterpage 34 Water\u27s EdgeMarjorie Thoelepage 35 My 665th Illusion of SanityGordon Glessnerpage 36 Is it my turn to do the laundry again??? Jann Briesacherpage 38 TV Teachingbobbdoddpage 39 GuidanceWendy Diane Wielandpage 40 PhotoJim Painterpage 41 RaindropsJane Ann Beerspage 42 WaitingJan Schroederpage 42 To JonJudy Bardpage 43 One Autumn Day in 1971E. Christmanpage 43 More Surely Than Picture AlbumsMarjorie Thoelepage 44 WingspanningNancy Broom Brownpage 45 ReligionMelinda E. Recordpage 45 Rosalie StevensonMark Holleypage 46 PhotoJim Painterpage 47 WhiteShirley A. Rardinpage 48 The Beginning of a Perfect DayShirley A. Rardinpage 49 PhotoMichael Chenpage 50 Rosethorn Wall of June 17bobbdoddpage 51 ManJan Schroederpage 51 HaikuJudy Bardpage 51 You know it leaves me emptyJames Osbornepage 52 For JesseJames Osbornepage 52 EndingsMark Chianakaspage 53 ConfusionGary L. Owenspage 53 PhotoMichael Chenpage 54 PoemsJann Briesacherpage 54 Journey of just oneNancy Broom Brownpage 55 Blackbirds in IllinoisJames Jonespage 56 PoemsJann Briesacherpage 56 PhotoMichael Chenpage 57 I am a poemDarlene A. Moorepage 57 A Glimpse of ParadiseJann Briesacherpage 57 PhotoJim Painterpage 58 PoemSheila Marie Foorpage 59 In my windowBarbara S. Meyerpage 59 Section 4., Draft 3bobbdoddpage 60 PhotoJim Painterpage 61 PoemJann Briesacherpage 61 PhotoGary Deanpage 62 I amWilliam E. Uteschpage 62 To a tank-car in IllinoisJames Jonespage 63 PoemJane Ann Beerspage 63 PoemsJann Briesacherpage 63 Editor\u27s Pagepage 64https://thekeep.eiu.edu/vehicle/1031/thumbnail.jp

The Vehicle, Spring 1974

Table of Contents PhotoJim Painterpage 1 Six Poems of the LandRay Schmuddepage 5 At Last to Find FreedomJann Briesacherpage 7 The Last IrisMarjorie Thoelepage 9 (Untitled)Melinda E. Recordpage 10 MenJan Schroederpage 10 ImpressionsJudy Bardpage 11 ScaredAnita Surpage 11 Loved and LostJan Schroederpage 12 Dripped-Over WaxAnita Surpage 13 The Crowded RoomWilliam E. Uteschpage 14 A River in IllinoisJames Jonespage 14 Sneeze SeasonDarlene A. Moorepage 14 ChangesMark Chianakaspage 15 PhotoJim Painterpage 16 Wedding VowsJann Briesacherpage 17 PhotoJim Painterpage 18 PhotoJim Painterpage 19 PhotoJim Painterpage 20 PhotoJim Painterpage 21 PhotoJim Painterpage 22 PhotoLarry Smyserpage 23 From Outside ColoradoRay Schmuddepage 24 Dairy QueenGayle Gleichmanpage 26 With Sunstreaks in our HairNancy Broom Brownpage 33 PhotoJim Painterpage 34 Water\u27s EdgeMarjorie Thoelepage 35 My 665th Illusion of SanityGordon Glessnerpage 36 Is it my turn to do the laundry again??? Jann Briesacherpage 38 TV Teachingbobbdoddpage 39 GuidanceWendy Diane Wielandpage 40 PhotoJim Painterpage 41 RaindropsJane Ann Beerspage 42 WaitingJan Schroederpage 42 To JonJudy Bardpage 43 One Autumn Day in 1971E. Christmanpage 43 More Surely Than Picture AlbumsMarjorie Thoelepage 44 WingspanningNancy Broom Brownpage 45 ReligionMelinda E. Recordpage 45 Rosalie StevensonMark Holleypage 46 PhotoJim Painterpage 47 WhiteShirley A. Rardinpage 48 The Beginning of a Perfect DayShirley A. Rardinpage 49 PhotoMichael Chenpage 50 Rosethorn Wall of June 17bobbdoddpage 51 ManJan Schroederpage 51 HaikuJudy Bardpage 51 You know it leaves me emptyJames Osbornepage 52 For JesseJames Osbornepage 52 EndingsMark Chianakaspage 53 ConfusionGary L. Owenspage 53 PhotoMichael Chenpage 54 PoemsJann Briesacherpage 54 Journey of just oneNancy Broom Brownpage 55 Blackbirds in IllinoisJames Jonespage 56 PoemsJann Briesacherpage 56 PhotoMichael Chenpage 57 I am a poemDarlene A. Moorepage 57 A Glimpse of ParadiseJann Briesacherpage 57 PhotoJim Painterpage 58 PoemSheila Marie Foorpage 59 In my windowBarbara S. Meyerpage 59 Section 4., Draft 3bobbdoddpage 60 PhotoJim Painterpage 61 PoemJann Briesacherpage 61 PhotoGary Deanpage 62 I amWilliam E. Uteschpage 62 To a tank-car in IllinoisJames Jonespage 63 PoemJane Ann Beerspage 63 PoemsJann Briesacherpage 63 Editor\u27s Pagepage 64https://thekeep.eiu.edu/vehicle/1031/thumbnail.jp

Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma : A Study by the Lunenburg Lymphoma Biomarker Consortium

PURPOSE: MYC rearrangement (MYC-R) occurs in approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and has been associated with poor prognosis in many studies. The impact of MYC-R on prognosis may be influenced by the MYC partner gene (immunoglobulin [IG] or a non-IG gene). We evaluated a large cohort of patients through the Lunenburg Lymphoma Biomarker Consortium to validate the prognostic significance of MYC-R (single-, double-, and triple-hit status) in DLBCL within the context of the MYC partner gene. METHODS: The study cohort included patients with histologically confirmed DLBCL morphology derived from large prospective trials and patient registries in Europe and North America who were uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or the like. Fluorescence in situ hybridization for the MYC, BCL2, BCL6, and IG heavy and light chain loci was used, and results were correlated with clinical outcomes. RESULTS: A total of 5,117 patients were identified of whom 2,383 (47%) had biopsy material available to assess for MYC-R. MYC-R was present in 264 (11%) of 2,383 patients and was associated with a significantly shorter progression-free and overall survival, with a strong time-dependent effect within the first 24 months after diagnosis. The adverse prognostic impact of MYC-R was only evident in patients with a concurrent rearrangement of BCL2 and/or BCL6 and an IG partner (hazard ratio, 2.4; 95% CI, 1.6 to 3.6; P < .001). CONCLUSION: The negative prognostic impact of MYC-R in DLBCL is largely observed in patients with MYC double hit/triple-hit disease in which MYC is translocated to an IG partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further

Pharmacokinetics of ss-d-N4-Hydroxycytidine, the Parent Nucleoside of Prodrug Molnupiravir, in Nonplasma Compartments of Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection

ß-d-N4-hydroxycytidine (NHC), the parent nucleoside of molnupiravir, a COVID-19 antiviral, was quantified at sites of SARS-CoV-2 transmission in twelve patients enrolled in AGILE CST-2 (NCT04746183). Saliva, nasal and tear concentrations were 3, 21 and 22% that of plasma. Saliva and nasal NHC concentrations were significantly correlated with plasma (p&amp;lt;0.0001)

Genome-wide association study of endometrial cancer in E2C2

Endometrial cancer (EC), a neoplasm of the uterine epithelial lining, is the most common gynecological malignancy in developed countries and the fourth most common cancer among US women. Women with a family history of EC have an increased risk for the disease, suggesting that inherited genetic factors play a role. We conducted a two-stage genome-wide association study of Type I EC. Stage 1 included 5,472 women (2,695 cases and 2,777 controls) of European ancestry from seven studies. We selected independent single-nucleotide polymorphisms (SNPs) that displayed the most significant associations with EC in Stage 1 for replication among 17,948 women (4,382 cases and 13,566 controls) in a multiethnic population (African America, Asian, Latina, Hawaiian and European ancestry), from nine studies. Although no novel variants reached genome-wide significance, we replicated previously identified associations with genetic markers near the HNF1B locus. Our findings suggest that larger studies with specific tumor classification are necessary to identify novel genetic polymorphisms associated with EC susceptibility. Electronic supplementary material The online version of this article (doi:10.1007/s00439-013-1369-1) contains supplementary material, which is available to authorized users

A Phase 2a clinical trial of Molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus

Molnupiravir (800 mg dose) accelerated SARS-CoV-2 RNA clearance in patients with COVID-19 compared to placebo

Infectious Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Virus in Symptomatic Coronavirus Disease 2019 (COVID-19) Outpatients: Host, Disease, and Viral Correlates

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectious virus isolation in outpatients with coronavirus disease 2019 (COVID-19) has been associated with viral RNA levels and symptom duration, little is known about the host, disease, and viral determinants of infectious virus detection.COVID-19 adult outpatients were enrolled within 7 days of symptom onset. Clinical symptoms were recorded via patient diary. Nasopharyngeal swabs were collected to quantitate SARS-CoV-2 RNA by reverse transcriptase polymerase chain reaction and for infectious virus isolation in Vero E6-cells. SARS-CoV-2 antibodies were measured in serum using a validated ELISA assay.Among 204 participants with mild-to-moderate symptomatic COVID-19, the median nasopharyngeal viral RNA was 6.5 (interquartile range [IQR] 4.7–7.6 log10 copies/mL), and 26% had detectable SARS-CoV-2 antibodies (immunoglobulin (Ig)A, IgM, IgG, and/or total Ig) at baseline. Infectious virus was recovered in 7% of participants with SARS-CoV-2 antibodies compared to 58% of participants without antibodies (prevalence ratio [PR] = 0.12, 95% confidence interval [CI]: .04, .36; P = .00016). Infectious virus isolation was also associated with higher levels of viral RNA (mean RNA difference +2.6 log10, 95% CI: 2.2, 3.0; P < .0001) and fewer days since symptom onset (PR = 0.79, 95% CI: .71, .88 per day; P < .0001).The presence of SARS-CoV-2 antibodies is strongly associated with clearance of infectious virus. Seropositivity and viral RNA levels are likely more reliable markers of infectious virus clearance than subjective measure of COVID-19 symptom duration. Virus-targeted treatment and prevention strategies should be administered as early as possible and ideally before seroconversion.NCT04405570