Use of letermovir for cytomegalovirus primary prophylaxis in lung transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) is a driver of negative outcomes after lung transplant (LTX) and primary prophylaxis (PPX) with valganciclovir (VGC) is standard-of-care. VGC is associated with myelosuppression, prompting interest in letermovir (LTV). METHODS: Adults receiving LTX between April 1, 2015, and July 30, 2022, at our institution were evaluated. Patients were excluded if low CMV risk (D-/R-), survived <90 days post-LTX, or transferred care before PPX withdrawal. Primary outcomes were leukopenia (white blood cell count [WBC] ≤ 3.0 × 109/L), severe leukopenia (WBC ≤ 2.0 × 109/L), and neutropenia (absolute neutrophil count ≤ 1500 cells/µL) requiring granulocyte-colony stimulating factor (GCSF) on PPX. Secondary outcomes included breakthrough CMV infection and post-PPX CMV infection. RESULTS: 204 patients met inclusion criteria: 175 patients on VGC and 29 patients on LTV (after VGC conversion). Most patients received bilateral LTX (62.7%) with non-lymphocyte-depleting induction (96.6%) and moderate-risk serostatus (D+/R+, 48.5%). Patients transitioned from VGC to LTV after a mean of 178 days (SD 80.8 days) post-transplant. Patients on VGC experienced significantly more leukopenia (82.3% vs. 58.6%, p = 0.008), severe leukopenia (57.1% vs. 31.0%, p = 0.016), and neutropenia requiring GCSF (70.9% vs. 51.7%, p = 0.048). Breakthrough (5.7% vs. 3.4%, p = 0.955) and post-PPX (24.6% vs. 37.9%, p = 0.199) infections were similar. A subgroup analysis of patients with high-risk serostatus showed similar trends, though did not reach statistical significance. CONCLUSIONS: In this single-center study, the incidence of leukopenia and neutropenia requiring GCSF were reduced with LTV compared to VGC. Breakthrough and post-PPX infections were not significantly different. This evidence suggests that LTV has comparable efficacy with reduced myelosuppression compared to VGC in LTX recipients, and may be an appropriate alternative for PPX.

Do professionalism, leadership, and resilience combine for professional identity formation? Evidence from confirmatory factor analysis.

Introduction: Professional identity formation (PIF) is an ongoing, self-reflective process involving habits of thinking, feeling and acting like a physician and is an integral component of medical education. While qualitative work has suggested that PIF is informed by professionalism, resilience, and leadership, there is a dearth of quantitative work in this area. Multiple methods build rigor and the present study aimed to quantitatively assess the relative psychometric contributions of professionalism, resilience, and leadership constructs to informing PIF, using a latent factor analysis approach. Methods: We analyzed data from the PILLAR study, which is an online cross-sectional assessment of a pre-clinical cohort of medical students in the RCSI University of Medicine and Health Sciences, Dublin, using established and validated quantitative measures in each area of interest: PIF, professionalism, leadership and resilience. A total of 76 items, combining four validated scales, along with a selection of demographic questions, were used. The hypothesis that PIF is informed by, and correlates with, professionalism, resilience and leadership was examined by conducting a confirmatory factor analysis of a proposed three-factor higher-order model. Model estimation used Maximum Likelihood Method (MLM) with geomin rotation. The hypothesized (measurement) model was examined against an alternative (saturated) model, as well as a three-factor model. Results: Latent variable analysis from 1,311 students demonstrated that a three-factor higher-order model best fit the data; suggesting PIF is informed by professionalism, resilience, and leadership, and that these constructs are statistically distinct and account for differential aspects of PIF. This higher-order model of PIF outperformed both the saturated model and the three-factor model. The analysis of which component may be the most or least influential was inconclusive, and the overall model was not influenced by year of training. Discussion: Building upon existing conceptual contentions, our study is the first to quantitatively support the contribution of professionalism, resilience, and leadership to the development of professional identity, and to delineate the inter-relationships between PIF and these constructs. This information can be used by medical educators when designing curricula and educational strategies intended to enhance PIF. Future work should seek to assess the influence of these constructs longitudinally.

Risk factors for severe COVID-19 disease increase SARS-CoV-2 infectivity of endothelial cells and pericytes.

Coronavirus disease 2019 (COVID-19) was initially considered a primarily respiratory disease but is now known to affect other organs including the heart and brain. A major route by which COVID-19 impacts different organs is via the vascular system. We studied the impact of apolipoprotein E (APOE) genotype and inflammation on vascular infectivity by pseudo-typed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses in mouse and human cultured endothelial cells and pericytes. Possessing the APOE4 allele or having existing systemic inflammation is known to enhance the severity of COVID-19. Using targeted replacement human APOE3 and APOE4 mice and inflammation induced by bacterial lipopolysaccharide (LPS), we investigated infection by SARS-CoV-2. Here, we show that infectivity was higher in murine cerebrovascular pericytes compared to endothelial cells and higher in cultures expressing APOE4. Furthermore, increasing the inflammatory state of the cells by prior incubation with LPS increased infectivity into human and mouse pericytes and human endothelial cells. Our findings provide insights into the mechanisms underlying severe COVID-19 infection, highlighting how risk factors such as APOE4 genotype and prior inflammation may exacerbate disease severity by augmenting the virus's ability to infect vascular cells.

A longitudinal analysis of COVID-19 prevention strategies implemented among US K-12 public schools during the 2021-2022 school year.

PURPOSE: Examine how school-based COVID-19 prevention strategy implementation varied over time, including by local characteristics. METHODS: School administrators (n = 335) from a nationally representative sample of K-12 public schools completed four surveys assessing COVID-19 prevention strategies at two-month intervals between October 2021 and June 2022. We calculated weighted prevalence estimates by survey wave. Generalized estimating equations (GEE) were used to model longitudinal changes in strategy implementation, accounting for school and county covariates. RESULTS: Opening doors/windows, daily cleaning, and diagnostic testing were reported by ≥ 50 % of schools at each survey wave. Several strategies were consistently implemented across the 2021-2022 school year (i.e., daily cleaning, opening doors and windows, diagnostic testing) while other strategies increased initially and then declined (i.e., contact tracing, screening testing, on-campus vaccination) or declined consistently throughout the school year (i.e., mask requirement, classroom distancing, quarantine). Although longitudinal changes in strategy implementation did not vary by school characteristics, strategy implementation varied by urban-rural classification and school level throughout the school year. CONCLUSIONS: Strategies that were consistently implemented throughout the school year were also reported by a majority of schools, speaking toward their feasibility for school-based infection control and prevention and potential utility in future public health emergencies.

The Masquerading Myocarditis: A Case of Late Recurrence of Acute Myocarditis Presenting as "Peripartum Cardiomyopathy".

Myocarditis is a potentially fatal medical condition with varied etiologies. Peripartum cardiomyopathy (PPCM) refers to systolic dysfunction occurring toward the end of pregnancy or in the months following delivery; it is a diagnosis of exclusion. We present a patient with chest pain, bipedal edema, markedly elevated troponins, electrocardiogram (EKG) findings that were concerning for myocardial infarction, and a significantly reduced left ventricular ejection fraction (LVEF) on the echocardiogram. The patient's presentation in the postpartum period closely resembled peripartum cardiomyopathy and presented a peculiar diagnostic challenge to our team. The right diagnosis was possible with cardiac magnetic resonance imaging, which revealed late gadolinium enhancement. Additionally, the patient had positive Coxsackie B5 and Epstein Bar virus serologies. While the clinical course of the disease is often benign, it could rapidly deteriorate, so early recognition and diagnosis are important to ensure patients receive adequate therapeutic support.

Receipt of and Satisfaction with School-based and Virtual Special Education Supports and Therapeutic Services During the COVID-19 Pandemic.

The COVID-19 pandemic impacted school-based delivery of special educational supports and therapeutic services. This study describes student receipt of school-based supports/services and parent satisfaction by instruction modalities during the 2020-2021 academic year in the United States. Data were collected through the COVID Experiences Survey from parents of children ages 5-12 years, administered using NORC's AmeriSpeak panel. Most parents reported satisfaction with supports (88.4%) and services (93.2%). Dissatisfaction with special education supports and therapeutic services was more common among parents whose children received supports/services virtually than in person (special educational supports: aOR=12.00, 95% CI [1.49-96.89], p=0.020; therapeutic services: aOR=15.76, 95% CI [1.01-245.40], p=0.049). These findings suggest opportunities to improve design and delivery of online special education supports and therapeutic services as well as emergency preparedness by considering the needs of students with disabilities and their families.

Disparities in behaviors and experiences among transgender and cisgender high school students - 18 U.S. states, 2021.

PURPOSE: Transgender youth (those whose gender identity differs from their sex assigned at birth) experience stigma and discrimination that can place them at increased risk for poor health outcomes compared with cisgender youth (those whose gender identity aligns with their sex assigned at birth). Limited population-based data exist on disparities among transgender and cisgender youth. METHODS: We examined differences in experiences of violence, substance use, mental health, suicide, sexual behavior, unstable housing, parental monitoring, and school connectedness among 98,174 transgender and cisgender high school students using data from 18 states that included an item to assess transgender identity on their 2021 Youth Risk Behavior Survey. RESULTS: Overall, 2.9% of students identified as transgender and 2.6% questioned whether they were transgender. Among transgender students, 71.5% reported that their mental health was not good, 32.3% had attempted suicide, and 29.0% experienced sexual violence. Transgender students were more likely than cisgender students to report experiences of violence, substance use, poor mental health, suicide risk, some sexual risk behaviors, and unstable housing, and were less likely to report feeling connected to others at school. CONCLUSIONS: Interventions that can address the causes of these adverse outcomes and promote the health and wellbeing of transgender youths are warranted.

Key informant views on potential acceptability and feasibility of long-acting antiretroviral treatment for HIV in Kenya.

BACKGROUND: In 2020, 14% of diagnosed persons living with HIV (PLWH) in Kenya were not taking antiretroviral therapy (ART), and 19% of those on ART had unsuppressed viral loads. Long-acting antiretroviral therapy (LA-ART) may increase viral suppression by promoting ART uptake and adherence. We conducted key informant (KI) interviews with HIV experts in Kenya to identify product and delivery attributes related to the acceptability and feasibility of providing LA-ART to PLWH in Kenya. METHODS: Interviews were conducted via Zoom on potential LA-ART options including intra-muscular (IM) injections, subcutaneous (SC) injections, implants, and LA oral pills. KI were asked to discuss the products they were most and least excited about, as well as barriers and facilitators to LA-ART roll-out. In addition, they were asked about potential delivery locations for LA-ART products such as homes, pharmacies, and clinics. Interviews were recorded and transcribed, and data were analyzed using a combination of inductive and deductive coding. RESULTS: Twelve KI (5 women, 7 men) participated between December 2021 and February 2022. Overall, participants reported that LA-ART would be acceptable and preferable to PLWH because of fatigue with daily oral pills. They viewed IM injections and LA oral pills as the most exciting options to ease pill burden and improve adherence. KI felt that populations who could benefit most were adolescents in boarding schools and stigmatized populations such as sex workers. SC injections and implants were less favored, as they would require new training initiatives for patients or healthcare workers on administration. In addition, SC injections would require refrigeration and needle disposal after use. Some KI thought patients, especially men, might worry that IM injections and implants would impact fertility, given their role in family planning. Pharmacies were perceived by most KI as suboptimal delivery locations; however, given ongoing work in Kenya to include pharmacies in antiretroviral delivery, they recommended asking patients their views. CONCLUSION: There is interest and support for LA-ART in Kenya, especially IM injections and LA oral pills. Identifying patient preferences for modes and delivery locations and addressing misconceptions about specific products as they become available will be important before wide-scale implementation.

A complex receptor locus confers responsiveness to necrosis and ethylene-inducing like peptides in Brassica napus.

Brassica crops are susceptible to diseases which can be mitigated by breeding for resistance. MAMPs (microbe-associated molecular patterns) are conserved molecules of pathogens that elicit host defences known as pattern-triggered immunity (PTI). Necrosis and Ethylene-inducing peptide 1-like proteins (NLPs) are MAMPs found in a wide range of phytopathogens. We studied the response to BcNEP2, a representative NLP from Botrytis cinerea, and showed that it contributes to disease resistance in Brassica napus. To map regions conferring NLP response, we used the production of reactive oxygen species (ROS) induced during PTI across a population of diverse B. napus accessions for associative transcriptomics (AT), and bulk segregant analysis (BSA) on DNA pools created from a cross of NLP-responsive and non-responsive lines. In silico mapping with AT identified two peaks for NLP responsiveness on chromosomes A04 and C05 whereas the BSA identified one peak on A04. BSA delimited the region for NLP-responsiveness to 3 Mbp, containing ~245 genes on the Darmor-bzh reference genome and four co-segregating KASP markers were identified. The same pipeline with the ZS11 genome confirmed the highest-associated region on chromosome A04. Comparative BLAST analysis revealed unannotated clusters of receptor-like protein (RLP) homologues on ZS11 chromosome A04. However, no specific RLP homologue conferring NLP response could be identified. Our results also suggest that BR-SIGNALLING KINASE1 may be involved with modulating the NLP response. Overall, we demonstrate that responsiveness to NLP contributes to disease resistance in B. napus and define the associated genomic location. These results can have practical application in crop improvement.

Distinct neurochemical influences on fMRI response polarity in the striatum.

The striatum, known as the input nucleus of the basal ganglia, is extensively studied for its diverse behavioral roles. However, the relationship between its neuronal and vascular activity, vital for interpreting functional magnetic resonance imaging (fMRI) signals, has not received comprehensive examination within the striatum. Here, we demonstrate that optogenetic stimulation of dorsal striatal neurons or their afferents from various cortical and subcortical regions induces negative striatal fMRI responses in rats, manifesting as vasoconstriction. These responses occur even with heightened striatal neuronal activity, confirmed by electrophysiology and fiber-photometry. In parallel, midbrain dopaminergic neuron optogenetic modulation, coupled with electrochemical measurements, establishes a link between striatal vasodilation and dopamine release. Intriguingly, in vivo intra-striatal pharmacological manipulations during optogenetic stimulation highlight a critical role of opioidergic signaling in generating striatal vasoconstriction. This observation is substantiated by detecting striatal vasoconstriction in brain slices after synthetic opioid application. In humans, manipulations aimed at increasing striatal neuronal activity likewise elicit negative striatal fMRI responses. Our results emphasize the necessity of considering vasoactive neurotransmission alongside neuronal activity when interpreting fMRI signal.

Information about life expectancy related to obesity is most important to cat owners when deciding whether to act on a veterinarian's weight loss recommendation.

OBJECTIVE: To determine the relative importance of information communicated to cat owners during veterinarian-client obesity-related conversations. SAMPLE: Cat owner participants recruited via snowball sampling. METHODS: A cross-sectional online questionnaire was distributed to cat owners who owned cats of any weight status. A discrete choice experiment design was used to determine the relative importance of obesity-related attributes to cat owners when receiving information from a veterinarian. RESULTS: A total of 1,095 questionnaires were analyzed. Participating cat owners resided primarily in Canada and the US. Impact on life expectancy was the most important attribute that would encourage participants to pursue weight management for a cat with obesity (relative importance, 32.66%), followed by change to cost of food (20.40%), future quality of life (20.38%), future mobility (14.40%), and risk of developing diabetes (12.15%). CLINICAL RELEVANCE: Findings suggest that cat owners consider the impact on life expectancy to be most important when considering whether to follow a veterinarian's recommendation for their cat to lose weight. When veterinary professionals are communicating about obesity in practice, there is the potential to increase owner engagement in weight management efforts for cats by emphasizing the obesity-related information owners prefer to receive.

Impact on life expectancy was the most important information to clients when considering whether to take action for an overweight or obese dog.

OBJECTIVE: To determine dog owner preferences for information communicated during veterinarian-client obesity-related conversations within companion animal practice. SAMPLE: Dog owners recruited using snowball sampling. METHODS: A cross-sectional online questionnaire was distributed to dog owners. A discrete choice experiment was used to determine the relative importance, to participating dog owners, of information about selected weight-related attributes that would encourage them to pursue weight management for a dog when diagnosed as overweight by a veterinarian. RESULTS: A total of 1,108 surveys were analyzed, with most participating dog owners residing in Canada. The most important weight-related attribute was life expectancy (relative importance, 28.56%), followed by the timeline for developing arthritis (19.24%), future quality of life (18.91%), change to cost of food (18.90%), and future mobility (14.34%). CLINICAL RELEVANCE: Results suggest that dog owners may consider information relating to an extension of their dog's life as the most important aspect of an obesity-related veterinary recommendation. By integrating dog owner preferences into discussions between clients and veterinary professionals about obesity, there is the potential to encourage more clients to engage in weight management efforts for their overweight or obese dog.

Barriers and Facilitators to Screening for Kidney Disease Among Older Adults with Hypertension and Diabetes in Mbarara Southwestern Uganda: Healthcare Providers' Perspective.

Background: Screening for kidney disease (KD) among high-risk patients (patients with hypertension or diabetes) allows early diagnosis, intervention and delayed progression of the disease. In low- and middle-income countries (LMIC), KD screening is still sub-optimal. This study explored the healthcare providers' perceived barriers and facilitators to KD screening among older adults with hypertension and diabetes in Mbarara southwestern Uganda. Methods: This was a descriptive qualitative study among healthcare providers caring for older adults with diabetes mellitus and hypertension at Mbarara Regional Referral Hospital (MRRH) in southwestern Uganda. In-depth interviews were conducted using a semi-structured interview guide. Interviews were audio-recorded, transcribed verbatim, and thematically analyzed to develop themes of barriers and facilitators. Results: We conducted 30 in-depth interviews among healthcare providers. Barriers to screening for kidney disease included patient related factors according to healthcare providers (financial hardships, poor health seeking behavior, limited knowledge and awareness), healthcare factors (work overload, ineffective patient healthcare provider communication) and system/policy related factors (lack of laboratory supplies, lack of guidelines and poor medical record keeping and documentation). With respect to facilitators, we found formation of peer support groups, effective team, and continuous medical education (CME). Conclusion: Healthcare providers encounter substantial but modifiable barriers in screening older adults for KD. The identification of barriers and facilitators in timely KD detection gives us an outlook of the problem in Uganda and leads for proposals of action. Interventions that address these barriers and promote facilitators may improve the healthcare provider's effectiveness and capacity to care including screening for patients at risk of KD.

Assessing the quality of drinking water from selected water sources in Mbarara city, South-western Uganda.

This study assessed the physical, chemical, and microbiological quality with emphasis on risk score, source apportionment, geochemistry, feacal coliforms and water quality index of drinking water from selected water sources. A cross-sectional study was conducted in six villages in Mbarara city, south-western Uganda. Each selected source was inspected using a WHO-adopted sanitary inspection questionnaire. Each source's risk score was calculated. Thirty-seven samples were taken from one borehole, nine open dug wells, four rain harvest tanks, and twenty-three taps. The values for apparent color and phosphate were higher than the permissible level as set by the World Health Organization and Ugandan standards (US EAS 12). The isolated organisms were Klebsiella spp. (8.11%), Citrobacter divergens (62.16%), Citrobacter fluendii (2.7%), E. coli (35.14%), Enterobacter aerogenes (8.11%), Enterobacter agglomerus (5.4%), Proteus spp. (2.7%), Enterobacter cloacae (13.5%), and Proteus mirabilis (2.7%). Twelve water sources (32.4%) had water that was unfit for human consumption that was unfit for human consumption (Grade E), Five sources (13.5%) had water that had a very poor index (Grade D), nine (24.3%) had water of poor index (Grade C), eight (21.6%) had water of good water index (Grade B), and only three (8.1%) had water of excellent water quality index (Grade A). The piper trilinear revealed that the dominant water type of the area were Mgso4 and Caso4 type. Gibbs plot represents precipitation dominance. PCA for source apportionment showed that well, tap and borehole water account for the highest variations in the quality of drinking water. These results suggest that drinking water from sources in Mbarara city is not suitable for direct human consumption without treatment. We recommend necessary improvements in water treatment, distribution, and maintenance of all the available water sources in Mbarara City, South Western Uganda.

Pathogen lifestyle determines host genetic signature of quantitative disease resistance loci in oilseed rape (Brassica napus).

KEY MESSAGE: Using associative transcriptomics, our study identifies genes conferring resistance to four diverse fungal pathogens in crops, emphasizing key genetic determinants of multi-pathogen resistance. Crops are affected by several pathogens, but these are rarely studied in parallel to identify common and unique genetic factors controlling diseases. Broad-spectrum quantitative disease resistance (QDR) is desirable for crop breeding as it confers resistance to several pathogen species. Here, we use associative transcriptomics (AT) to identify candidate gene loci associated with Brassica napus constitutive QDR to four contrasting fungal pathogens: Alternaria brassicicola, Botrytis cinerea, Pyrenopeziza brassicae, and Verticillium longisporum. We did not identify any shared loci associated with broad-spectrum QDR to fungal pathogens with contrasting lifestyles. Instead, we observed QDR dependent on the lifestyle of the pathogen-hemibiotrophic and necrotrophic pathogens had distinct QDR responses and associated loci, including some loci associated with early immunity. Furthermore, we identify a genomic deletion associated with resistance to V. longisporum and potentially broad-spectrum QDR. This is the first time AT has been used for several pathosystems simultaneously to identify host genetic loci involved in broad-spectrum QDR. We highlight constitutive expressed candidate loci for broad-spectrum QDR with no antagonistic effects on susceptibility to the other pathogens studies as candidates for crop breeding. In conclusion, this study represents an advancement in our understanding of broad-spectrum QDR in B. napus and is a significant resource for the scientific community.

Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trial.

ABSTRACT: Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. This phase 3, open-label study evaluated the efficacy and safety of fitusiran prophylaxis in males aged ≥12 years with hemophilia A or B, with or without inhibitors, who received prior bypassing agent (BPA)/clotting factor concentrate (CFC) prophylaxis. Participants continued their prior BPA/CFC prophylaxis for 6 months before switching to once-monthly 80 mg fitusiran prophylaxis for 7 months (onset and efficacy periods). Primary end point was annualized bleeding rate (ABR) in the BPA/CFC prophylaxis and fitusiran efficacy period. Secondary end points included spontaneous ABR (AsBR) and joint ABR (AjBR). Safety and tolerability were assessed. Of 80 enrolled participants, 65 (inhibitor, n = 19; noninhibitor, n = 46) were eligible for ABR analyses. Observed median ABRs were 6.5 (interquartile range [IQR], 2.2-19.6)/4.4 (IQR, 2.2-8.7) with BPA/CFC prophylaxis vs 0.0 (IQR, 0.0-0.0)/0.0 (IQR, 0.0-2.7) in the corresponding fitusiran efficacy period. Estimated mean ABRs were substantially reduced with fitusiran by 79.7% (P = .0021) and 46.4% (P = .0598) vs BPA/CFC prophylaxis, respectively. Forty-one participants (63.1%) experienced 0 treated bleeds with fitusiran vs 11 (16.9%) with BPAs/CFCs. Median AsBR and AjBR were both 2.2 with BPA/CFC prophylaxis and 0.0 in the fitusiran efficacy period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Once-monthly fitusiran prophylaxis significantly reduced bleeding events vs BPA/CFC prophylaxis in PwHA/B, with or without inhibitors, and reported adverse events were generally consistent with previously identified risks of fitusiran. This trial was registered at www.ClinicalTrials.gov as #NCT03549871.

Real-world use of thrombopoietin receptor agonists for the management of immune thrombocytopenia in adult patients in the United Kingdom: Results from the TRAIT study.

Few studies have reported the real-world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO-RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO-RA. A platelet count ≥30 × 109/L was achieved in 89% of patients with the first TPO-RA treatments, while 68% achieved a platelet count ≥100 × 109/L. Treatment-free response (TFR; platelet count ≥30 × 109/L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO-RAs, most of whom achieved platelet counts ≥30 × 109/L with the second TPO-RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO-RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO-RAs had similar efficacy and safety profiles to those reported in clinical studies.

The homeobox transcription factor DUXBL controls exit from totipotency.

In mice, exit from the totipotent two-cell (2C) stage embryo requires silencing of the 2C-associated transcriptional program. However, the molecular mechanisms involved in this process remain poorly understood. Here we demonstrate that the 2C-specific transcription factor double homeobox protein (DUX) mediates an essential negative feedback loop by inducing the expression of DUXBL to promote this silencing. We show that DUXBL gains accessibility to DUX-bound regions specifically upon DUX expression. Furthermore, we determine that DUXBL interacts with TRIM24 and TRIM33, members of the TRIM superfamily involved in gene silencing, and colocalizes with them in nuclear foci upon DUX expression. Importantly, DUXBL overexpression impairs 2C-associated transcription, whereas Duxbl inactivation in mouse embryonic stem cells increases DUX-dependent induction of the 2C-transcriptional program. Consequently, DUXBL deficiency in embryos results in sustained expression of 2C-associated transcripts leading to early developmental arrest. Our study identifies DUXBL as an essential regulator of totipotency exit enabling the first divergence of cell fates.

Sp1 facilitates continued HSV-1 gene expression in the absence of key viral transactivators.

Productive replication of herpes simplex virus (HSV) relies upon a well-ordered transcriptional cascade flowing from immediate-early (IE) to early (E) to late (L) gene products. While several virus-encoded transcriptional activators are involved in this process, IE and E gene promoters also contain multiple binding sites for the ubiquitously expressed cellular transcription factor Sp1. Sp1 has been previously implicated in activating HSV-1 gene transcription downstream of these sites, but why Sp1-binding sites are maintained in the promoters of genes activated by virus-encoded activators remains unclear. We hypothesized that Sp1 enables continued HSV-1 transcription and replication when viral transactivators are limited. We used a depletion-based approach in human foreskin fibroblasts to investigate the specific contribution of Sp1 to the initiation and progression of the HSV-1 lytic gene cascade. We found that Sp1 increased viral transcript levels, protein expression, and replication following infection with VP16- or ICP0-deficient viruses but had little to no effect on rescued viruses or during wild-type (WT) HSV-1 infection. Moreover, Sp1 promoted WT virus transcription and replication following interferon treatment of fibroblasts and thus may contribute to viral immune evasion. Interestingly, we observed reduced expression of Sp1 and Sp1-family transcription factors in differentiated sensory neurons compared to undifferentiated cells, suggesting that reduced Sp1 levels may also contribute to HSV-1 latent infection. Overall, these findings indicate that Sp1 can promote HSV-1 gene expression in the absence of key viral transactivators; thus, HSV-1 may use Sp1 to maintain its gene expression and replication under adverse conditions.IMPORTANCEHerpes simplex virus (HSV) is a common human pathogen that actively replicates in the epithelia but can persist for the lifetime of the infected host via a stable, latent infection in neurons. A key feature of the HSV replication cycle is a complex transcriptional program in which virus and host-cell factors coordinate to regulate expression of the viral gene products necessary for continued viral replication. Multiple binding sites for the cellular transcription factor Sp1 are located in the promoters of HSV-1 genes, but how Sp1 binding contributes to transcription and replication of wild-type virus is not fully understood. In this study, we identified a specific role for Sp1 in maintaining HSV-1 gene transcription under adverse conditions, as when virus-encoded transcriptional activators were absent or limited. Preservation of Sp1-binding sites in HSV-1 gene promoters may thus benefit the virus as it navigates diverse cell types and host-cell conditions during infection.

What do veterinary professionals and clients want? Using discrete choice methods in veterinary research to determine preferences.

Discrete choice methods (DCMs) are a suite of research techniques for identifying individual preferences using choice information. Widely utilized by other fields yet rarely employed in veterinary research, DCMs have tremendous potential to improve veterinary healthcare by understanding and incorporating owner and veterinary professionals' (encompassing veterinarians, veterinary clinicians, technicians, receptionists, attendants, etc) preferences to optimize the care continuum. DCMs have several advantages over other stated preference methods, such as ranking and ratings, including improved data quality and actionability. However, they are not a panacea, and limitations that may affect DCMs' application to the veterinary field are outlined alongside realistic mitigation strategies. The information provided aims to increase awareness of DCMs and their utility in veterinary research and encourage greater uptake as a more robust method for measuring preferences.