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Abstract This prospective cohort study reports aneuploidy score by mFast-SeqS as a strong prognostic marker in MBC patients. mFAST-SeqS is an affordable and easily implementable method for the assessment of total ctDNA levels and, as such, provides an alternative prognostic tool. One mixed cohort (cohort A, n = 45) starting any type of treatment in any line of therapy and one larger cohort (cohort B, n = 129) consisting of patients starting aromatase inhibitors (AI) as first-line therapy were used. mFAST-SeqS was performed using plasma of blood in which CTCs (CellSearch) were enumerated. The resulting aneuploidy score was correlated with categorized CTC count and associated with outcome. The aneuploidy score was significantly correlated with CTC count, but discordance was observed in 31.6% when applying cut-offs of 5. In both cohorts, aneuploidy score was a significant prognostic marker for both PFS and OS. In the Cox regression models, the HR for aneuploidy score for PFS was 2.52 (95% CI: 1.56–4.07), and the HR for OS was 2.37 (95% CI: 1.36–4.14). Results presented here warrant further investigations into the clinical utility of this marker in MBC patients.

Abstract Retinitis pigmentosa (RP) defines a group of hereditary progressive rod-cone degenerations that exhibit a common phenotype caused by variants in over 70 genes. While most variants in the dehydrodolichyl diphosphate synthase (DHDDS) gene result in syndromic abnormalities, some variants cause non-syndromic RP (RP59). DHDDS encodes one subunit of the enzyme cis-prenyltransferase (CPT), which is required for the synthesis of dolichol (Dol), that is a necessary protein glycosylation cofactor. We previously reported the creation and initial characterization of a knock-in (KI) mouse model harboring the most prevalent RP59-associated DHDDS variant (K42E) to understand how defects in DHDDS lead to retina-specific pathology. This model exhibited no profound retinal degeneration, nor protein N-glycosylation defects. Here, we report that the Dol isoprenylogue species in retina, liver, and brain of the K42E mouse model are statistically shorter than in the corresponding tissues of age-matched controls, as reported in blood and urine of RP59 patients. Retinal transcriptome analysis demonstrated elevation of many genes encoding proteins involved in synaptogenesis and synaptic function. Quantitative retinal cell layer thickness measurements demonstrated a significant reduction in the inner nuclear layer (INL) and total retinal thickness (TRT) beginning at postnatal (PN) ∼2 months, progressively increasing to PN 18-mo. Histological analysis revealed cell loss in the INL, outer plexiform layer (OPL) disruption, and ectopic localization of outer nuclear layer (ONL) nuclei into the OPL of K42E mutant retinas, relative to controls. Electroretinograms (ERGs) of mutant mice exhibited reduced b-wave amplitudes beginning at PN 1-mo, progressively declining through PN 18-mo, without appreciable a-wave attenuation, relative to controls. Our results suggest that the underlying cause of DHDDS K42E variant driven RP59 retinal pathology is defective synaptic transmission from outer to inner retina.

ObjectiveWhether patients with acute stroke and large vessel occlusion (LVO) benefit from prehospital identification and diversion by emergency medical services (EMS) to an endovascular stroke therapy (EST)-capable center is controversial. We sought to estimate the accuracy of field-based identification of potential EST candidates in a hypothetical best-of-all-worlds situation.MethodsIn Kaiser Permanente Northern California, all acute stroke patients arriving at its 21 stroke centers between 7:00 am and midnight from January 2016 to December 2019 were evaluated by teleneurologists on arrival. Initial National Institutes of Health Stroke Scale (NIHSS) score, presence of LVO, and referral for EST were obtained from standardized teleneurology notes. Factors associated with LVO were evaluated using generalized estimating equations accounting for clustering by facility.ResultsAmong 13,377 patients brought in by EMS with potential stroke, 7168 (53.6%) were not candidates for acute stroke interventions. Of the remaining 6089 cases, 2,573 (42.3%) had an NIHSS score >10, the cutoff with a higher association for LVO. Only 703 patients (27.3% with NIHSS score >10) were ultimately diagnosed with LVO and referred for EST. Across all NIHSS scores, only 884 (6.6%) suspected acute stroke patients had LVO and EST referral.ConclusionsEven if field-based tools were as accurate as NIHSS scoring and predictions by stroke neurologists, only about 1 in 4 acute stroke patients diverted to EST-capable centers would benefit by receiving EST. Depending on geography and stroke center performance on door-to-needle time, many systems may be better served by focusing on expediting evaluation, treatment with intravenous thrombolysis, and transfer to EST-capable centers.

Background and purposeShelter-in-place (SIP) orders implemented to mitigate severe acute respiratory syndrome coronavirus 2 spread may inadvertently discourage patient care-seeking behavior for critical conditions like acute ischemic stroke. We aimed to compare temporal trends in volume of acute stroke alerts, patient characteristics, telestroke care, and short-term outcomes pre- and post-SIP orders.MethodsWe conducted a cohort study in 21 stroke centers of an integrated healthcare system serving 4.4+ million members across Northern California. We included adult patients who presented with suspected acute stroke and were evaluated by telestroke between January 1, 2019, and May 9, 2020. SIP orders announced the week of March 15, 2020, created pre (January 1, 2019, to March 14, 2020) and post (March 15, 2020, to May 9, 2020) cohort for comparison. Main outcomes were stroke alert volumes and inpatient mortality for stroke.ResultsStroke alert weekly volume post-SIP (mean, 98 [95% CI, 92-104]) decreased significantly compared with pre-SIP (mean, 132 [95% CI, 130-136]; P

This study's goal was to compare aspects related to academic persistence of two groups of college students with non-visible disabilities: 110 Canadian two and four-year college students--55 with mental health related disabilities and 55 with Specific Learning Disorder (LD). Results show that students with mental health related disabilities were less likely to intend to graduate than students with LD. Students with mental health disabilities were also older, more likely to be female, to have worse personal circumstances and to feel more socially isolated on campus. They were also less likely to be enrolled in their first choice program or to be registered for campus disability related services than students with LD. Different variables predicted intention to graduate for the two groups. This is a key finding in helping students in these two groups successfully graduate, as they may have different academic, social, personal and accommodation needs. Recommendations are made about how to intervene to improve the academic persistence of students with mental health related disabilities. These include minimizing the fear of stigmatization and adopting a model where accommodations are based on students' unique needs rather than their diagnoses.

Background Clinical risk factors, a single blood pressure (BP) measurement, current biomarkers, and biophysical parameters can effectively identify risk of early‐onset preeclampsia but have limited ability to predict later‐onset preeclampsia and gestational hypertension. Clinical BP patterns hold promise to improve early risk stratification for hypertensive disorders of pregnancy. Methods and Results After excluding preexisting hypertension, heart, kidney, or liver disease, or prior preeclampsia, the retrospective cohort (n=249 892) all had systolic BP

Melanin is a dark color pigment biosynthesized naturally in most living organisms. Fungal melanin is a major putative virulence factor of Mucorales fungi that allows intracellular persistence by inducing phagosome maturation arrest. Recently, it has been shown that the black pigments of Rhizopus delemar is of eumelanin type, that requires the involvement of tyrosinase (a copper-dependent enzyme) in its biosynthesis. Herein, we have developed a series of compounds (UOSC-1-14) to selectively target Rhizopus melanin and explored this mechanism therapeutically. The compounds were designed based on the scaffold of the natural product, cuminaldehyde, identified from plant sources and has been shown to develop non-selective inhibition of melanin production. While all synthesized compounds showed significant inhibition of Rhizopus melanin production and limited toxicity to mammalian cells, only four compounds (UOSC-1, 2, 13, and 14) were selected as promising candidates based on their selective inhibition to fungal melanin. The activity of compound UOSC-2 was comparable to the positive control kojic acid. The selected candidates showed significant inhibition of Rhizopus melanin but not human melanin by targeting the fungal tyrosinase, and with an IC50 that are 9 times lower than the reference standard, kojic acid. Furthermore, the produced white spores were phagocytized easily and cleared faster from the lungs of infected immunocompetent mice and from the human macrophages when compared with wild-type spores. Collectively, the results suggested that the newly designed derivatives, particularly UOSC-2 can serve as promising candidate to overcome persistence mechanisms of fungal melanin production and hence make them accessible to host defenses.

AimThe aim of this study was to develop a nanofiber-based dressing capable of local sustained delivery of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) and augmenting human CAMP induction.Materials & methodsNanofibrous wound dressings containing 1,25(OH)2D3 were successfully prepared by electrospinning, which were examined in vitro, in vivo and ex vivo.Results1,25(OH)2D3 was successfully loaded into nanofibers with encapsulation efficiency larger than 90%. 1,25(OH)2D3 showed a sustained release from nanofibers over 4 weeks. Treatment of U937 and HaCaT cells with 1,25(OH)2D3-loaded poly(ϵ-caprolactone) nanofibers significantly induced hCAP18/LL37 expression in monocytes and keratinocytes, skin wounds of humanized transgenic mice and artificial wounds of human skin explants.Conclusion1,25(OH)2D3 containing nanofibrous dressings could enhance innate immunity by inducing antimicrobial peptide production.

En ce 21e siècle, le cancer est une maladie qui suscite particulièrement l’attention en raison de sa complexité ainsi que des impacts physiques, émotionnels et financiers sur notre vie. L’attention portée à la recherche et les investissements dans le traitement contre le cancer en font la maladie la plus étudiée dans les essais cliniques à l’échelle mondiale. Les infirmières de recherche clinique font partie de l’équipe de recherche en oncologie et sont un élément fondamental de réussite des essais. Leurs relations directes avec les participants d’une étude de recherche sont essentielles pour les activités des essais cliniques en première ligne. De façon générale, l’afflux et la complexité des essais cliniques en oncologie ont transformé la pratique infirmière en oncologie et ont mené à la création de la sous-spécialité unique qu’est l’infirmière de recherche clinique en oncologie. La présente revue exploratoire s’est penchée sur le rôle et la pratique futurs de l’infirmière de recherche clinique.

In the 21st century, cancer is a disease that captures much of our attention for its complexity, and its physical, emotional, and financial impacts on one’s life. Research attention and investment in cancer management has made it the most studied disease in clinical trials globally. Clinical trials nurses are part of the oncology research team and a fundamental factor in trial success. Their direct relationship with research subjects is the key connection in the operation of clinical trials at the front line. The influx and complexity of oncology clinical trials has transformed both oncology nursing practice in general and led to the development of the unique subspecialty of the oncology clinical trials nurse. This scoping review investigated the role and future practice of the clinical trials nurse.

Abstract Wolbachia, cytoplasmically inherited endosymbionts of arthropods, are known to hijack their host reproduction in various ways to increase their own vertical transmission. This may lead to the selective sweep of associated mitochondria, which can have a large impact on the evolution of mitochondrial lineages. In Japan, two different Wolbacahia strains (wCI and wFem) are found in two sister species of pierid butterflies, Eurema mandarina and Eurema hecabe. In both species, females infected with wCI (C females) produce offspring with a nearly 1:1 sex ratio, while females infected with both wCI and wFem (CF females) produce all‐female offspring. Previous studies have suggested the historical occurrence of hybrid introgression in C individuals between the two species. Furthermore, hybrid introgression in CF individuals is suggested by the distinct mitochondrial lineages between C females and CF females of E. mandarina. In this study, we performed phylogenetic analyses based on nuclear DNA and mitochondrial DNA markers of E. hecabe with previously published data on E. mandarina. We found that the nuclear DNA of this species significantly diverged from that of E. mandarina. By contrast, mitochondrial DNA haplotypes comprised two clades, mostly reflecting Wolbachia infection status rather than the individual species. Collectively, our results support the previously suggested occurrence of two independent historical events wherein the cytoplasms of CF females and C females moved between E. hecabe and E. mandarina through hybrid introgression.

Abstract Objective In insects, closely related species are often difficult or impossible to distinguish solely by morphological traits. Mitochondrial DNA (mtDNA) markers are often useful and reliable for distinguishing closely related species. However, useful mtDNA markers can be unavailable, particularly when such species pairs experienced hybrid introgression in the past. Although polymorphic nuclear DNA markers would be necessary to distinguish such species pairs, recombination, multiple copies, and slower mutation rates of the nuclear DNA compared with those of mtDNA often make it challenging. The objective of this study was to develop a multiplex polymerase chain reaction that can reliably amplify and distinguish the Tpi sequences of Eurema mandarina and Eurema hecabe. Results We successfully analyzed the nucleotide sequences of the Z chromosome-linked triose phosphate isomerase (Tpi) gene to develop a multiplex polymerase chain reaction (PCR) that amplified ca. 120-bp products for E. mandarina and ca. 375-bp products for E. hecabe. We suggest that multiplex PCR using Tpi with appropriately designed primers can be used to accurately and reliably distinguish between other closely related Lepidoptera species.

Purpose The aim of this study was to evaluate the choroidal thickness (CT) changes and its effect on the early functional and anatomic outcome in eyes with diabetic macular edema (DME) following intravitreal injection of bevacizumab by using enhanced depth imaging optical coherence tomography. Design This is a prospective interventional study. Patients and methods A total of 40 eyes (of 27 patients) with clinically significant DME were included in the present study. Evaluation of CT at different points before and after three intravitreal injections of bevacizumab was done by using enhanced depth imaging optical coherence tomography. Patients were classified according to the anatomic and functional outcome to responder and nonresponder groups. Results There was a significant decrease in the mean subfoveal CT from 425.47±96.61 to 374.75±99.71 μm following the three intravitreal injections (P

COVID-19 has become a major cause of global mortality and driven massive health and economic disruptions. Mass global vaccination offers the most efficient pathway towards ending the pandemic. The development and deployment of first-generation COVID-19 vaccines, encompassing mRNA or viral vectors, has proceeded at a phenomenal pace. Going forward, nanoparticle-based vaccines which deliver SARS-CoV-2 antigens will play an increasing role in extending or improving vaccination outcomes against COVID-19. At present, over 26 nanoparticle vaccine candidates have advanced into clinical testing, with ∼60 more in pre-clinical development. Here, we discuss the emerging promise of nanotechnology in vaccine design and manufacturing to combat SARS-CoV-2, and highlight opportunities and challenges presented by these novel vaccine platforms.

Retinitis pigmentosa-59 (RP59) is a rare, recessive form of RP, caused by mutations in the gene encoding DHDDS (dehydrodolichyl diphosphate synthase). DHDDS forms a heterotetrameric complex with Nogo-B receptor (NgBR; gene NUS1) to form a cis-prenyltransferase (CPT) enzyme complex, which is required for the synthesis of dolichol, which in turn is required for protein N-glycosylation as well as other glycosylation reactions in eukaryotic cells. Herein, we review the published phenotypic characteristics of RP59 models extant, with an emphasis on their ocular phenotypes, based primarily upon knock-in of known RP59-associated DHDDS mutations as well as cell type- and tissue-specific knockout of DHDDS alleles in mice. We also briefly review findings in RP59 patients with retinal disease and other patients with DHDDS mutations causing epilepsy and other neurologic disease. We discuss these findings in the context of addressing “knowledge gaps” in our current understanding of the underlying pathobiology mechanism of RP59, as well as their potential utility for developing therapeutic interventions to block the onset or to dampen the severity or progression of RP59.

Abstract Objective Whether patients with acute stroke and large vessel occlusion (LVO) benefit from prehospital identification and diversion by emergency medical services (EMS) to an endovascular stroke therapy (EST)‐capable center is controversial. We sought to estimate the accuracy of field‐based identification of potential EST candidates in a hypothetical best‐of‐all‐worlds situation. Methods In Kaiser Permanente Northern California, all acute stroke patients arriving at its 21 stroke centers between 7:00 am and midnight from January 2016 to December 2019 were evaluated by teleneurologists on arrival. Initial National Institutes of Health Stroke Scale (NIHSS) score, presence of LVO, and referral for EST were obtained from standardized teleneurology notes. Factors associated with LVO were evaluated using generalized estimating equations accounting for clustering by facility. Results Among 13,377 patients brought in by EMS with potential stroke, 7168 (53.6%) were not candidates for acute stroke interventions. Of the remaining 6089 cases, 2,573 (42.3%) had an NIHSS score >10, the cutoff with a higher association for LVO. Only 703 patients (27.3% with NIHSS score >10) were ultimately diagnosed with LVO and referred for EST. Across all NIHSS scores, only 884 (6.6%) suspected acute stroke patients had LVO and EST referral. Conclusions Even if field‐based tools were as accurate as NIHSS scoring and predictions by stroke neurologists, only about 1 in 4 acute stroke patients diverted to EST‐capable centers would benefit by receiving EST. Depending on geography and stroke center performance on door‐to‐needle time, many systems may be better served by focusing on expediting evaluation, treatment with intravenous thrombolysis, and transfer to EST‐capable centers.

Objective: Early adversity, such as adverse childhood experiences (ACEs), is a risk factor for the development of substance use disorder (SUD). ACEs are associated with earlier initiation of substance use. This study examined the relationship between ACEs and age of initiation of substance use using survival analysis. It is hypothesized that individuals with higher ACEs will have an earlier age of initiation. Method: Participants were recruited from the University of Kentucky's Laboratory for Human Behavioral Pharmacology. Participants were 18 years or older, English speaking, and actively engaged in substance use. Participants were not in substance abuse treatment nor were they seeking treatment. ACE scores were calculated, and age of substance use initiation was recorded. A Cox proportional hazard model was used to examine the effect of ACE score on age of substance use initiation. Results: A total of 107 participants completed the study. An average number of 2.3 ACEs (SD = 2.2) were endorsed with 24% of participants reporting 4 or more ACEs. Higher ACE scores were associated with cigarette smoking and non-medical prescription opioid use onset (hazard ratio (HR) = 1.14, 95% CI=1.02–1.28, p = 0.02, and HR=1.19, 95% CI = 1.04–1.37, p = 0.01, respectively. Conclusions: A significant association was found between higher ACE scores and earlier initiation of cigarette and non-medical prescription opioid use, consistent with prior research. Primary prevention of ACEs, screening for ACEs during childhood, and interventions for ACEs if detected, may help to reduce the risk of substance use/SUD in adulthood. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The GALAD score, a serum biomarker-based model, predicts the likelihood of hepatocellular carcinoma (HCC) in patients with chronic liver disease. We evaluated the performance of the GALAD score compared to that of liver ultrasound in detecting HCC. PATIENTS AND METHODS: This study recruited a group of 136 patients with HCC and a control group of 436 patients with cirrhosis or chronic hepatitis B or hepatitis C. The performance of the GALAD score and ultrasound in detecting HCC in these patients was analyzed using the area under the receiver operating characteristic curve (AUC). The sensitivity and specificity of the optimal GALAD score were compared to those of ultrasound. RESULTS: The AUC of the GALAD score for detecting HCC was 0.940 [95% confidence interval (CI) 0.92-0.96], higher than that of ultrasound [0.939 (0.91-0.96), p < 0.001]. At a threshold of 1.24, the GALAD score had a sensitivity of 91.2% and a specificity of 81.9% for detecting HCC. The AUC of the GALAD score for early HCC detection was 0.75 (95% CI 0.71-0.80, p < 0.001; threshold 1.13, sensitivity 87.5%, specificity 67.8%, p < 0.001). The combination of GALAD and ultrasound (GALADUS score) showed further improvement, achieving an AUC of 0.97 (95% CI 0.96-0.99; cut-off point 1.37, sensitivity 95.6%, specificity 89.2%, p < 0.001). CONCLUSIONS: In our study, the GALADUS score showed improved performance compared to the GALAD score. Therefore, we suggest that the performance of the GALAD score should be reconsidered and that it should be evaluated in combination with ultrasound for HCC detection. [ABSTRACT FROM AUTHOR]

In Egypt, sugar beet (Beta vulgaris L.) has become a major sugar manufacturing plant in latest years. It is recognized that sugar beet damaged by different pathogens, including root rot disease caused by Sclerotium rollsii, in terms of quantity and quality. The aim of the current study was to control the disease of the root rot sugar beet and determine the sucrose content during two successive cropping seasons. Trichoderma harzianum kj831197 produced b- glucanase enzymes that play a key role in fungal disease biocontrol. Twenty two bioactive isolates were tested for the activity of b- glucanases, ten of which are Trichoderma spp strains. Sclerotium rolfsii radial growth has been suppressed with efficiency ranging from 77.77 to 91.11% in dual culture technique. The Vitavax200 fungicide increased control of the disease under greenhouse conditions followed by a combination of b- glucanase enzyme with Trichoderma harzianum kj831197 spore suspension. The use of b- glucanase enzyme mixed with Trichoderma harizianum kj831197 cells leads to an increase above other treatments in the total soluble solid and sucrose content of the sugar beet. Despite the fungicide Vitavax200, the overall soluble solid and sucrose content were significantly affected by disease control but the sugar beets yield was lowered.

Binary expression systems like the LexA-LexAop system provide a powerful experimental tool kit to study gene and tissue function in developmental biology, neurobiology, and physiology. However, the number of well-defined LexA enhancer trap insertions remains limited. In this study, we present the molecular characterization and initial tissue expression analysis of nearly 100 novel StanEx LexA enhancer traps, derived from the StanEx1 index line. This includes 76 insertions into novel, distinct gene loci not previously associated with enhancer traps or targeted LexA constructs. Additionally, our studies revealed evidence for selective transposase-dependent replacement of a previously-undetected KP element on chromosome III within the StanEx1 genetic background during hybrid dysgenesis, suggesting a molecular basis for the over-representation of LexA insertions at the NK7.1 locus in our screen. Production and characterization of novel fly lines were performed by students and teachers in experiment-based genetics classes within a geographically diverse network of public and independent high schools. Thus, unique partnerships between secondary schools and university-based programs have produced and characterized novel genetic and molecular resources in Drosophila for open-source distribution, and provide paradigms for development of science education through experience-based pedagogy.