bluuebunny/crossref_metadata_2025 huggingface dataset:
Neoadjuvant rituximab modulates the tumor immune environment in patients with high risk prostate cancer
Authors: Ryan Stephen T. , Zhang Jing , Burner Danielle N. , Liss Michael , Pittman Emily , Muldong Michelle , Shabaik Ahmed , Woo Jason , Basler Nicole , Cunha Jonathan , Shalapour Shabnam , Estrada Monica V. , Karin Michael , Messer Karen , Howell Stephen , Kane Christopher J. , Jamieson Christina A. M.
Published: May 2020

Background

Immunotherapeutic regulation of the tumor microenvironment in prostate cancer patients is not understood. Most antibody immunotherapies have not succeeded in prostate cancer. We showed previously that high-risk PCa patients have a higher density of tumor infiltrating B-cells in prostatectomy specimens. In mouse models, anti-CD20 antibody ablation of B-cells delayed PCa regrowth post-treatment. We sought to determine whether neoadjuvant anti-CD20 immunotherapy with rituximab could reduce CD20+ B cell infiltration of prostate tumors in patients.

Methods

An open label, single arm clinical trial enrolled eight high-risk PCa patients to receive one cycle of neoadjuvant rituximab prior to prostatectomy. Eleven clinical specimens with similar characteristics were selected as controls. Treated and control samples were concurrently stained for CD20 and digitally scanned in a blinded fashion. A new method of digital image quantification of lymphocytes was applied to prostatectomy sections of treated and control cases. CD20 density was quantified by a deconvolution algorithm in pathologist-marked tumor and adjacent regions. Statistical significance was assessed by one sided Welch’s t-test, at 0.05 level using a gatekeeper strategy. Secondary outcomes included CD3+ T-cell and PD-L1 densities.

Results

Mean CD20 density in the tumor regions of the treated group was significantly lower than the control group (p = 0.02). Mean CD3 density in the tumors was significantly decreased in the treated group (p = 0.01). CD20, CD3 and PD-L1 staining primarily occurred in tertiary lymphoid structures (TLS). Neoadjuvant rituximab was well-tolerated and decreased B-cell and T-cell density within high-risk PCa tumors compared to controls.

Conclusions

This is the first study to treat patients prior to surgical prostate removal with an immunotherapy that targets B-cells. Rituximab treatment reduced tumor infiltrating B and T-cell density especially in TLSs, thus, demonstrating inter-dependence between B- and T-cells in prostate cancer and that Rituximab can modify the immune environment in prostate tumors. Future studies will determine who may benefit from using rituximab to improve their immune response against prostate cancer.

Trial registration NCT01804712, March 5th, 2013 https://clinicaltrials.gov/ct2/show/NCT01804712?cond=NCT01804712&draw=2&rank=1
ProBDNF promotes sepsis-associated encephalopathy in mice by dampening the immune activity of meningeal CD4+ T cells
Authors: Luo Ru-Yi , Luo Cong , Zhong Feng , Shen Wei-Yun , Li Hui , Hu Zhao-Lan , Dai Ru-Ping
Published: May 2020

Background

Sepsis-associated encephalopathy (SAE) increases the mortality of septic patients, but its mechanism remains unclear. The present study aimed to investigate the roles of T lymphocytes, proBDNF, and their interaction in the pathogenesis of SAE.

Methods

Fear conditioning tests were conducted for cognitive assessment in the lipopolysaccharide (LPS, 5 mg kg−1)-induced septic mice. Meninges and peripheral blood were harvested for flow cytometry or qPCR. FTY720 and monoclonal anti-proBDNF antibody (McAb-proB) were used to investigate the effect of lymphocyte depletion and blocking proBDNF on the impaired cognitive functions in the septic mice.

Results

In the septic mice, cognitive function was impaired, the percentage of CD4+T cells were decreased in the meninges (P= 0.0021) and circulation (P= 0.0222), and pro-inflammatory cytokines were upregulated, but the anti-inflammatory cytokines interleukin (IL)-4 (P< 0.0001) and IL-13 (P= 0.0350) were downregulated in the meninges. Lymphocyte depletion by intragastrically treated FTY720 (1 mg kg−1) for 1 week ameliorated LPS-induced learning deficit. In addition, proBDNF was increased in the meningeal (P= 0.0042) and peripheral (P= 0.0090) CD4+T cells. Intraperitoneal injection of McAb-proB (100 μg) before LPS treatment significantly alleviated cognitive dysfunction, inhibited the downregulation of meningeal (P= 0.0264) and peripheral (P= 0.0080) CD4+T cells, and normalized the gene expression of cytokines in the meninges. However, intra-cerebroventricular McAb-proB injection (1 μg) did not have such effect. Finally, exogenous proBDNF downregulated the percentage of CD4+T cells in cultured splenocytes from septic mice (P= 0.0021).

Conclusion

Upregulated proBDNF in immune system promoted the pathogenesis of SAE through downregulating the circulating CD4+T cells, limiting its infiltration into the meninges and perturbing the meningeal pro-/anti-inflammatory homeostasis.
Genetic profiling of patients with adenoid cystic carcinoma of the Bartholin’s glands reveals potential new routes for targeted therapies: a case report
Authors: Nakamura Kohei , Aimono Eriko , Tanishima Shigeki , Nomura Hidetaka , Imai Mitsuho , Hayashi Hideyuki , Nishihara Hiroshi
Published: May 2020

Background

Bartholin gland carcinomas (BGCs) are rare tumor types, for which no molecular analyses including genomic sequencing have been reported to date. Adenoid cystic carcinomas (ACCs) of the Bartholin’s glands are an atypical histological type of BGC, and currently nothing is known regarding their genetic profiles or similarity to ACC carcinogenesis in other organs including the salivary glands, thereby limiting possible therapeutic options using precision medicine.

Case presentation

We used targeted gene sequencing to analyze the occurrence of 160 cancer-related genes in two patients with BG-ACC. KRAS and KDM6A mutations were detected in tumor samples collected from each patient. No KRAS mutations have been previously reported in salivary gland ACCs, indicating that the carcinogenesis of BG-ACC differs from that of the salivary gland ACCs. KDM6A mutations are often reported in salivary gland ACCs and facilitate novel gene-targeted therapy, including the use of BET and HDAC inhibitors.

Conclusions

A better understanding of the underlying genetic mechanisms will help to clarify the carcinogenesis of BG-ACC. In turn, this will enable treatment with novel targeting agents, as well as the initial exploration of gene-based precision oncological therapies, which aim to improve treatment outcomes for patients with this disease.
The Glycosylphosphatidylinositol biosynthesis pathway in human diseases
Authors: Wu Tenghui , Yin Fei , Guang Shiqi , He Fang , Yang Li , Peng Jing
Published: May 2020

Glycosylphosphatidylinositol biosynthesis defects cause rare genetic disorders characterised by developmental delay/intellectual disability, seizures, dysmorphic features, and diverse congenital anomalies associated with a wide range of additional features (hypotonia, hearing loss, elevated alkaline phosphatase, and several other features). Glycosylphosphatidylinositol functions as an anchor to link cell membranes and protein. These proteins function as enzymes, adhesion molecules, complement regulators, or co-receptors in signal transduction pathways. Biallelic variants involved in the glycosylphosphatidylinositol anchored proteins biosynthetic pathway are responsible for a growing number of disorders, including multiple congenital anomalies-hypotonia-seizures syndrome; hyperphosphatasia with mental retardation syndrome/Mabry syndrome; coloboma, congenital heart disease, ichthyosiform dermatosis, mental retardation, and ear anomalies/epilepsy syndrome; and early infantile epileptic encephalopathy-55. This review focuses on the current understanding of Glycosylphosphatidylinositol biosynthesis defects and the associated genes to further understand its wide phenotype spectrum.
Ulam’s stability for some linear conformable fractional differential equations
Authors: Wang Sen , Jiang Wei , Sheng Jiale , Li Rui
Published: May 2020

In this paper, by introducing the concepts of Ulam type stability for ODEs into the equations involving conformable fractional derivative, we utilize the technique of conformable fractional Laplace transform to investigate the Ulam–Hyers and Ulam–Hyers–Rassias stability for several kinds of linear differential equations in the frame of conformable fractional derivative.
A fractional derivative with two singular kernels and application to a heat conduction problem
Authors: Baleanu Dumitru , Jleli Mohamed , Kumar Sunil , Samet Bessem
Published: May 2020

In this article, we suggest a new notion of fractional derivative involving two singular kernels. Some properties related to this new operator are established and some examples are provided. We also present some applications to fractional differential equations and propose a numerical algorithm based on a Picard iteration for approximating the solutions. Finally, an application to a heat conduction problem is given.
Impact of trade liberalisation on formal–informal interlinkages in India: does sectoral labour mobility matter?
Authors: Kundu Anirban
Published: May 2020

Existing study argues that labour market flexibility accompanied by trade liberalisation helped in building complementary relationship between formal and informal sectors in India. However, no direct relation is established between the labour market flexibility and trade liberalisation with respect to inter- and intra-sectoral movement of labour. The present study enquires whether the extent of labour mobility between and within formal–informal sectors affects the formal–informal growth linkages due to the tariff cut on traded goods, as a part of trade liberalisation in India. The findings based on static CGE analysis indicate that in absence of labour market segmentation (i.e. in absence of both wage rigidity and skill specificity) with full mobility of labour, formal sector growth is higher vis-à-vis the growth of those activities under segmented labour market with full mobility of labour. Amongst growing informal sector activities, output growth is lower in absence of segmented labour market with full mobility of labour. Finally, restricted labour mobility leads to largest expansion of formal activities, but further exacerbates the growth of informal activities. The study reveals that improvement in functional income distribution is mixed across households, depending on the degree of labour mobility, which implies labour market adjustment is costly due to structural reforms, that pitches for government intervention.
Consumers’ preference and willingness to pay for enriched snack product traits in Shashamane and Hawassa cities, Ethiopia
Authors: Ahmed Jemal , Tefera Tewodros , Kassie Girma T.
Published: May 2020

This study investigated the consumers’ preference and willingness to pay for enriched snack product traits. Using a choice experiment framework, we generated 8400 observations from a random sample of 700 respondents in Shashamanne and Hawassa city administrations. Taste parameters and heterogeneities were estimated using the generalized multinomial logit (G-MNL) model. The results reveal nutrition and/or health claim labeling is the most influential trait on the consumers’ decision to buy enriched snack products followed by mango flavor, sorghum chickpea main ingredient, price, and mixed shape. The WTP estimates show that consumers are willing to pay a premium for nutrition and/or health claim labeling equal to 1.43, 1.6, and 8.03 times higher than for a change in the flavor of the products from tomato to mango, the improvement of main ingredients to sorghum chickpea, and change of the product shape from spherical to mixed shape, respectively. The heterogeneities (variations) around the mean taste parameters were partially explained by sex, family size, and educational levels of the respondents. Generally, the consumers in the study areas prefer buying sorghum chickpea main ingredients, a combination of different shapes (mixed shape), mango flavored, and nutrition and/or health claim-labeled enriched snack products. Therefore, we suggest designing and implementing innovative ways of promoting snack products to urban communities with a deliberate focus on these traits to create a snack with the best combination. Given the high literacy of urban consumers and influential role of nutrition and/or health claim labeling trait on consumers’ decision, the trait-based promotion and marketing of the products constitute the right strategy.
Alternative food shoppers and the “quantity dilemma”: a study on the determinants of their purchases at alternative markets
Authors: Cicatiello Clara
Published: May 2020

Despite the increasing interest around alternative food networks and their huge growth in the last decades, they are still considered a complementary source of provision by most customers. Alternative food shoppers are faced with a “quantity dilemma”, i.e., choosing how much food they want to buy through these channels. This decision affects the importance of alternative food networks in the market and the extent to which they may contribute to the improvement of the food systems’ overall sustainability. Basing on a survey involving 1200 food shoppers interviewed at alternative markets in Italy, this paper studies the factors explaining the quantity of food that customers choose to buy there, with respect to the quantity they purchase through conventional channels. Results show that their motivations to buy at alternative markets are crucial to increase the share of food provisions attained through these channels, especially when quality and environmental motivations are concerned. Another key factor is the type of alternative market where consumers are used to shop at, with box schemes being more likely to represent a main source of food provision for their customers than farmers’ markets and farm shops. A strong effect is played by customers’ loyalty to alternative markets, showing that establishing a long-term relation with producers participating at alternative markets increases the probability of buying more food through these channels. These findings disclose a potential in terms of upscaling of alternative food networks, linked to the identification of the consumers segments that are more likely to use these channels as a main source of food provision, and to the types of business models that can more likely increase the quantity of food purchased.
Laboratory monitoring of rivaroxaban in Chinese patients with deep venous thrombosis: a preliminary study
Authors: Li Ying , Du Liping , Tang Xiaowan , Chen Yuexin , Mei Dan
Published: May 2020

Background

Rivaroxaban, a novel oral anticoagulant drug, is widely used in clinical practice. There is no standardized laboratory monitoring for rivaroxaban, and its plasma concentration in Chinese patients with deep vein thrombosis is unclear. The rivaroxaban concentrations in human plasma and determine the steady-state concentration of rivaroxaban in patients with deep vein thrombosis are needed.

Methods

An ultra-high-performance liquid chromatography with mass spectrometric detection method was developed. Chromatographic separation was performed on a Waters BEH C18 column with isocratic elution using a mobile phase composed of acetonitrile and water. Quantitation of the analytes was performed using positive ionization mode and mass transitions of m/z 437.3 → m/z 145.0 and m/z 440.1 → m/z 145.0 for rivaroxaban and the internal standard, respectively. Blood samples were collected at 0 h and 2 h after patients took rivaroxaban for 7 days or more.

Results

The method was validated over the concentration range of 0.5 ~ 400 ng•mL− 1 with a very low limit of quantification of 0.5 ng·mL− 1, and the intra- and inter-day precision (RSD%) were < 15%. The range of the steady state concentration in patients that took 15 mg rivaroxaban twice daily, 10 mg twice daily, 20 mg once daily, 15 mg once daily, and 10 mg once daily were 168.5 ~ 280.1 ng•mL− 1, 74.2 ~ 271.4 ng•mL− 1, 25.7 ~ 306.8 ng•mL− 1, 24.5 ~ 306.4 ng•mL− 1, and 15.4 ~ 229.2 ng•mL− 1, respectively.

Conclusions

The plasma rivaroxaban concentration in patients who took 10 mg rivaroxaban twice daily fluctuated less than that in patients who took 20 mg rivaroxaban once daily. The plasma concentration can be used for therapeutic drug monitoring for rivaroxaban.
Can we optimise doxorubicin treatment regimens for children with cancer? Pharmacokinetic simulations and a Delphi consensus procedure
Authors: Siebel Christian , Würthwein Gudrun , Lanvers-Kaminsky Claudia , André Nicolas , Berthold Frank , Castelli Ilaria , Chastagner Pascal , Doz François , English Martin , Escherich Gabriele , Frühwald Michael C. , Graf Norbert , Groll Andreas H. , Ruggiero Antonio , Hempel Georg , Boos Joachim
Published: May 2020

Background

Despite its cardiotoxicity doxorubicin is widely used for the treatment of paediatric malignancies. Current treatment regimens appear to be suboptimal as treatment strategies vary and do not follow a clear pharmacological rationale. Standardisation of dosing strategies in particular for infants and younger children is required but is hampered by scarcely defined exposure-response relationships. The aim is to provide a rational dosing concept allowing for a reduction of variability in systemic therapy intensity and subsequently unforeseen side effects.

Methods

Doxorubicin plasma concentrations in paediatric cancer patients were simulated for different treatment schedules using a population pharmacokinetic model which considers age-dependent differences in doxorubicin clearance. Overall drug exposure and peak concentrations were assessed. Simulation results were used to support a three round Delphi consensus procedure with the aim to clarify the pharmacological goals of doxorubicin dosing in young children. A group of 28 experts representing paediatric trial groups and clinical centres were invited to participate in this process.

Results

Pharmacokinetic simulations illustrated the substantial differences in therapy intensity associated with current dosing strategies. Consensus among the panel members was obtained on a standardised a priori dose adaptation that individualises doxorubicin doses based on age and body surface area targeting uniform drug exposure across children treated with the same protocol. Further, a reduction of peak concentrations in very young children by prolonged infusion was recommended.

Conclusions

An approach to standardise current dose modification schemes in young children is proposed. The consented concept takes individual pharmacokinetic characteristics into account and involves adaptation of both the dose and the infusion duration potentially improving the safety of doxorubicin administration.
Vestibular impact of Friedreich ataxia in early onset patients
Authors: Maudoux A. , Teissier N. , Francois M. , Van Den Abbeele Th. , Alberti C. , Husson I. , Wiener-Vacher S. R.
Published: May 2020

Background

Friedreich ataxia (FRDA) is the most frequent form of inherited ataxias. Vestibular and auditory assessments are not commonly part of the check up for these patients despite hearing and balance complaints. Screening of vestibular and auditory function was performed in a large group of young patients with genetically confirmed FRDA.

Methods

Our study included 43 patients (7–24 years of age). A complete vestibular assessment was performed including the canals function evaluation at 3 head velocities (bithermal caloric test, earth vertical axis rotation (EVAR) and head impulse test (HIT)) and otolith function evaluation (cervical vestibular evoked myogenic potentials). Information regarding the hearing evaluation of the patients were also retrieved including impedance tympanometry, distortion product otoacoustic emissions (DPOAEs), air and bone conduction audiometry and auditory brainstem response (ABR).

Results

Vestibular responses were impaired for canal responses (only at high and middle head velocities) and vestibulospinal otolithic responses. Abnormal neural conduction in the central auditory pathways was frequently observed. Oculomotor abnormalities were frequent, mostly hypermetric saccades and gaze instability. Inhibition of the vestibulo-ocular reflex by fixation was normal.

Conclusions

We show that Friedreich ataxia, even at onset, frequently associate saccadic intrusions, abnormal ABRs and decreased vestibulo-ocular and vestibulospinal responses progressing over time. These sensory impairments combined with ataxia further impair patient’s autonomy. These vestibular, auditory and visual impairments could be used as markers of the severity and progression of the disease. Adding vestibular and auditory testing to Friedreich patient’s evaluation may help physicians improve patient’s management.
Evaluation of the alpha-amylase inhibitory activity of Nepalese medicinal plants used in the treatment of diabetes mellitus
Authors: Khadayat Karan , Marasini Bishnu P. , Gautam Hira , Ghaju Sajani , Parajuli Niranjan
Published: May 2020

Background

α-Amylase catalyses the hydrolysis of starch and ultimately producing glucose. Controlling the catalytic activity of this enzyme reduces glucose production in the postprandial stage, which could be a therapeutic benefit for people with diabetes. This study was conducted to evaluate α-amylase inhibition for utilizing the crude extracts of some medicinal plants traditionally used in Nepal for the treatment of diabetes and its related complications.

Methods

Microtiter plate approach has been used to assess inhibitory activities of in vitro α-amylase of methanolic extracts of thirty-two medicinal plants. A starch tolerance test was used in rats to investigate the in vivo study of the methanolic extract concerning glibenclamide as the positive control.

Results

Acacia catechu,Dioscorea bulbifera, andSwertia chirataexhibited inhibitory activity against α-amylase and with IC50values; 49.9, 296.1, and 413.5 μg/mL, respectively. Kinetics study revealed that all the extracts displayed a mixed type of inhibition pattern, with Kivalues ranging from 26.6–204.2 μg/mL. Free radical scavenging activity was again re-examined and found prominent in extracts ofA. catechu. Likewise,A. catechuandS. chiratashowed significant reduction of blood glucose concentration up to 30 min after oral dose of 250 mg/kg (F (4, 20) = 4.1,p = .048), and (F (4, 20) = 4.1,p = .036), respectively.

Conclusions

Enzymatic assay for α-amylase inhibition using extracts was successfully evaluated. Also, the in-vitro and in-vivo study model revealed that medicinal plants could be a potent source of α-amylase inhibition. So, they could serve as potential candidates for future drug development strategies for curing diabetes with minimal or no adverse side effects.
Description of the puparium and other notes on the morphological and molecular identification of Phthitia empirica (Diptera, Sphaeroceridae) collected from animal carcasses
Authors: Giordani G. , Vanin S.
Published: May 2020

Background

A correct identification of species is fundamental in order to derive all the biological, ecological, and behavioral information useful to reconstruct previous events when insects are used in forensic and funerary archaeological contexts. Little attention was paid in the past to the description of the immature stages of flies, especially of species belonging to family found only occasionally on human cadavers and animal carrion. Sphaeroceridae species belong to this category.

Results

In this work, adult and puparia of Phthitia empirica (Hutton, 1901) are illustrated and described. In addition, some observations about the molecular identification of this species are presented and discussed.

Conclusions

This work will allow the identification of puparia of this species providing additional tools in forensic entomological investigation. More in general, the effort of producing morphological descriptions and molecular information of species of potential forensic interest clearly implements the possibility to provide a deeper understanding of the peri- and post-mortem events in violent crimes.
Clues For Genetic Anticipation In Multiple Endocrine Neoplasia Type 1
Authors: van den Broek Medard F M , van Nesselrooij Bernadette P M , Pieterman Carolina R C , Verrijn Stuart Annemarie A , van de Ven Annenienke C , de Herder Wouter W , Dekkers Olaf M , Drent Madeleine L , Havekes Bas , Kerstens Michiel N , Bisschop Peter H , Valk Gerlof D
Published: May 2020

Context

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disease caused by the loss of function of the MEN1 gene, a tumor-suppressor gene that encodes the protein menin. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumors (dpNET), pituitary tumors (PIT), adrenal adenomas, and bronchopulmonary (bp-NET), thymic, and gastric neuroendocrine tumors. More insight into factors influencing the age-related penetrance of MEN1 manifestations could provide clues for more personalized screening programs.

Objective

To investigate whether genetic anticipation plays a role in the largest known MEN1 families in the Netherlands.

Methods

All Dutch MEN1 families with ≥ 10 affected members in ≥ 2 successive generations were identified. Age at detection of the different MEN1-related manifestations were compared among generations using regression analyses adjusted for competing risks. To correct for the beneficial effect of being under surveillance, manifestations occurring during surveillance were also separately compared.

Results

A total of 152 MEN1 patients from 10 families were included. A significantly decreased age at detection of pHPT, dpNET, PIT, and bp-NET was found in successive generations (P < 0.0001). Adjusted analyses led to the same results.

Conclusions

These results suggest the presence of genetic anticipation. However, due to a risk of residual bias, the results must be interpreted with caution. After independent validation in other cohorts and further translational research investigating the molecular mechanisms explaining this phenomenon in MEN1, the results might add to future, more personalized, screening protocols and earlier screening for future generations of MEN1 patients.
Equitable Pandemic Preparedness and Rapid Response: Lessons from COVID-19 for Pandemic Health Equity
Authors: Alberti Philip M. , Lantz Paula M. , Wilkins Consuelo H.
Published: May 2020

The novel coronavirus pandemic has set in high relief the entrenched health, social, racial, political, and economic inequities within American society as the incidence of severe morbidity and mortality from the disease caused by the virus appears to be much greater in black and other racial/ethnic minority populations, within homeless and incarcerated populations, and in lower-income communities in general. The reality is that the United States is ill equipped to realize health equity in prevention and control efforts for any type of health outcome, including an infectious disease pandemic. In this article, the authors address an important question: When new waves of the current pandemic emerge, or another novel pandemic emerges, how can the United States be better prepared and also ensure a rapid response that reduces rather than exacerbates social and health inequities? The authors argue for a health equity framework to pandemic preparedness that is grounded in meaningful community engagement and that, while recognizing the fundamental causes of social and health inequity, has a clear focus on upstream and midstream preparedness and downstream rapid response efforts that put social and health equity at the forefront.
Federalism Complicates the Response to the COVID-19 Health and Economic Crisis: What Can Be Done?
Authors: Huberfeld Nicole , Gordon Sarah H. , Jones David K.
Published: May 2020

Federalism has complicated the US response to the novel coronavirus. States' actions to address the pandemic have varied widely, and federal and state officials have provided conflicting messages. This fragmented approach has surely cost time and lives. Federalism will shape the long-term health and economic impacts of COVID-19, including plans for the future, for at least two reasons: First, federalism exacerbates inequities, as some states have a history of underinvesting in social programs, especially in certain communities. Second, many of the states with the deepest needs are poorly equipped to respond to emergencies due to low taxes and distrust of government, leading to inadequate infrastructure. These dynamics are not new, but they have been laid bare by this crisis. What can policy makers do to address the inequities in health and economic outcomes that federalism intensifies? The first section of this article offers a case study of the Mississippi Delta to illustrate the role of federalism in perpetuating the connection between place, health, and economics. The second section examines challenges that safety net programs will face when moving beyond the acute phase of COVID-19. The final section explores near-, middle-, and long-term policy options to mitigate federalism's harmful side effects.
The Emergence of COVID-19 in the US: A Public Health and Political Communication Crisis
Authors: Gollust Sarah E. , Nagler Rebekah H. , Fowler Erika Franklin
Published: May 2020

The coronavirus public health crisis is also a political-communication and health-communication crisis. In this article, the authors describe the key communication-related phenomena and evidence of concerning effects manifested in the United States during the initial response to the pandemic. The authors outline the conditions of communication about coronavirus that contribute to deleterious outcomes, including partisan cueing, conflicting science, downplayed threats, emotional arousal, fragmented media, and Trump's messaging. The authors suggest these have contributed to divergent responses by media sources, partisan leaders, and the public alike, leading to different attitudes and beliefs as well as varying protective actions taken by members of the public to reduce their risk. In turn, these divergent communication phenomena will likely amplify geographic variation in and inequities with COVID-19 disease outcomes. The authors conclude with some suggestions for future research, particularly surrounding communication about health inequity and strategies for reducing partisan divergence in views of public health issues in the future.
The extracellular matrix in development
Authors: Walma David A. Cruz , Yamada Kenneth M.
Published: May 2020

As the crucial non-cellular component of tissues, the extracellular matrix (ECM) provides both physical support and signaling regulation to cells. Some ECM molecules provide a fibrillar environment around cells, while others provide a sheet-like basement membrane scaffold beneath epithelial cells. In this Review, we focus on recent studies investigating the mechanical, biophysical and signaling cues provided to developing tissues by different types of ECM in a variety of developing organisms. In addition, we discuss how the ECM helps to regulate tissue morphology during embryonic development by governing key elements of cell shape, adhesion, migration and differentiation.
Canonical Notch signaling controls the early thymic epithelial progenitor cell state and emergence of the medullary epithelial lineage in fetal thymus development
Authors: Liu Dong , Kousa Anastasia I. , O'Neill Kathy E. , Rouse Paul , Popis Martyna , Farley Alison M. , Tomlinson Simon R. , Ulyanchenko Svetlana , Guillemot Francois , Seymour Philip A. , Jørgensen Mette C. , Serup Palle , Koch Ute , Radtke Freddy , Blackburn C. Clare
Published: May 2020

Thymus function depends on the epithelial compartment of the thymic stroma. Cortical thymic epithelial cells (cTECs) regulate T cell lineage commitment and positive selection, while medullary (m) TECs impose central tolerance on the T cell repertoire. During thymus organogenesis, these functionally distinct sub-lineages are thought to arise from a common thymic epithelial progenitor cell (TEPC). The mechanisms controlling cTEC and mTEC production from the common TEPC are not however understood. Here, we show that emergence of the earliest mTEC lineage-restricted progenitors requires active NOTCH signaling in progenitor TEC and that, once specified, further mTEC development is NOTCH-independent. In addition, we demonstrate that persistent NOTCH activity favors maintenance of undifferentiated TEPC at the expense of cTEC differentiation. Finally, we uncover a cross-regulatory relationship between NOTCH and FOXN1, a master regulator of TEC differentiation. These data establish NOTCH as a potent regulator of TEPC and mTEC fate during fetal thymus development and are thus of high relevance to strategies aimed at generating/regenerating functional thymic tissue in vitro and in vivo.
The mevalonate pathway is a critical regulator of tendon cell specification
Authors: Chen Jessica W. , Niu Xubo , King Matthew J. , Noedl Marie-Therese , Tabin Clifford J. , Galloway Jenna L.
Published: May 2020

Tendons and ligaments are critical components of the musculoskeletal system, yet the pathways specifying this lineage remain poorly defined. Through a screen of known bioactive chemicals in zebrafish, we identified a new pathway regulating tendon cell induction. We established that statin, through inhibition of the mevalonate pathway, causes an expansion of the tendon progenitor population. Co-expression and live imaging studies indicate that the expansion does not involve an increase in cell proliferation, but rather results from re-specification of cells from the neural crest-derived sox10+/sox9a+ skeletal lineage. The effect on tendon cell expansion is specific to the geranylgeranylation branch of the mevalonate pathway and mediated by inhibition of Rac activity. This work establishes a novel role for the mevalonate pathway and Rac activity in regulating specification of the tendon lineage.
Chemokine receptors coordinately regulate macrophage dynamics and mammary gland development
Authors: Wilson Gillian J. , Fukuoka Ayumi , Love Samantha R. , Kim Jiwon , Pingen Marieke , Hayes Alan J. , Graham Gerard J.
Published: May 2020

Macrophages are key regulators of developmental processes, including those involved in mammary gland development. We previously demonstrated that the atypical chemokine receptor, ACKR2, contributes to control of ductal epithelial branching in the developing mammary gland by regulating macrophage dynamics. ACKR2 is a chemokine-scavenging receptor, which mediates its effects through collaboration with inflammatory chemokine receptors (iCCRs). Here we reveal reciprocal regulation of branching morphogenesis in the mammary gland, whereby stromal ACKR2 modulates levels of the shared ligand CCL7 to control the movement of a key population of CCR1-expressing macrophages to the ductal epithelium. In addition, estrogen, which is essential for ductal elongation during puberty, upregulates CCR1 expression on macrophages. The age at which girls develop breasts is decreasing, which raises the risk of diseases including breast cancer. This study presents a previously unknown mechanism controlling the rate of mammary gland development during puberty and highlights potential therapeutic targets.
Opposing effects of an F-box protein and the HSP90 chaperone network on microtubule stability and neurite growth in Caenorhabditis elegans
Authors: Zheng Chaogu , Atlas Emily , Lee Ho Ming Terence , Jao Susan Laura Javier , Nguyen Ken C. Q. , Hall David H. , Chalfie Martin
Published: May 2020

Molecular chaperones often work collaboratively with the ubiquitination-proteasome system (UPS) to facilitate the degradation of misfolded proteins, which typically safeguards cellular differentiation and protects cells from stress. In this study, however, we report that the Hsp70/Hsp90 chaperone machinery and an F-box protein, MEC-15, have opposing effects on neuronal differentiation and that the chaperones negatively regulate neuronal morphogenesis and functions. Using the touch receptor neurons (TRNs) of Caenorhabditis elegans, we find that mec-15(-) mutants display defects in microtubule formation, neurite growth, synaptic development, and neuronal functions, and these defects can be rescued by the loss of Hsp70/Hsp90 chaperones and cochaperones. MEC-15 likely functions in a SCF complex to degrade DLK-1, which is an Hsp90 client protein stabilized by the chaperones. The abundance of DLK-1, and likely other Hsp90 substrates, is fine-tuned by the antagonism between MEC-15 and chaperones; this antagonism regulates TRN development as well as synaptic functions of GABAergic motor neurons. Therefore, a balance between UPS and chaperones tightly controls neuronal differentiation.
Is the Cure Worse than the Disease? Unintended Effects of Payment Reform in a Quantity-Based Transfer Program
Authors: Meckel Katherine
Published: May 2020

Quantity vouchers are used in redistributive programs to shield participants from price variation and alter their consumption patterns. However, because participants are insensitive to prices, vendors of program goods are incentivized to price discriminate between program and non-program customers. I study these trade-offs in the context of a reform to reduce price discrimination in the Supplemental Nutrition Program for Women, Infants, and Children (WIC), which provides a quantity voucher for nutritious foods to low-income mothers and children. The reform caused vendors to drop out, reducing program take-up. In addition, smaller vendors increased prices charged to non-WIC shoppers by 6.4 percent. (JEL H75, I18, I32, I38, J13, J16)
Radiobiologically derived biphasic fractionation schemes to overcome the effects of tumour hypoxia
Authors: Joseph Nuradh , Kirkby Norman F. , Hoskin Peter J , West Catharine M L , Choudhury Ananya , Dale Roger G.
Published: May 2020

Objective:

As a fractionated course of radiotherapy proceeds tumour shrinkage leads to resolution of hypoxia and the initiation of accelerated proliferation of radioresistant cancer cells with better repair capacity. We hypothesise that, in tumours with significant hypoxia, improved tumour control could be achieved with biphasic fractionation schedules that either use acceleration after 3–4 weeks of conventional radiotherapy or deliver a higher proportional dose towards the end of a course of treatment. We conducted a modelling study based on the concept of biological effective dose (BED) comparing such novel regimens with conventional fractionation.

Methods:

The comparator conventional fractionation schedule 70 Gy in 35 fractions delivered over 7 weeks was tested against the following novel regimens, both of which were designed to be isoeffective in terms of late normal tissue toxicity.

40 Gy in 20 fractions over 4 weeks followed by 22.32 Gy in 6 consecutive daily fractions (delayed acceleration)

30.4 Gy in 27 fractions over 4 weeks followed by 40 Gy in 15 fractions over 3 weeks (temporal dose redistribution)

The delayed acceleration regimen is exactly identical to that of the comparator schedule over the first 28 days and the BED gains with the novel schedule are achieved during the second phase of treatment when reoxygenation is complete. For the temporal redistribution regimen, it was assumed that the reoxygenation fraction progressively increases during the first 4 weeks of treatment and an iterative approach was used to calculate the final tumour BED for varying hypoxic fractions.

Results:

Novel fractionation with delayed acceleration or temporal fractionation results in tumour BED gains equivalent to 3.5–8 Gy when delivered in 2 Gy fractions.

Conclusion:

In hypoxic tumours, novel fractionation strategies result in significantly higher tumour BED in comparison to conventional fractionation.

Advances in knowledge:

We demonstrate that novel biphasic fractionation regimens could overcome the effects of tumour hypoxia resulting in biological dose escalation.
A simple model for calculating relative biological effectiveness of X-rays and gamma radiation in cell survival
Authors: Vassiliev Oleg N. , Peterson Christine B. , Grosshans David R. , Mohan Radhe
Published: May 2020

Objectives:

The relative biological effectiveness (RBE) of X-rays and γ radiation increases substantially with decreasing beam energy. This trend affects the efficacy of medical applications of this type of radiation. This study was designed to develop a model based on a survey of experimental data that can reliably predict this trend.

Methods:

In our model, parameters α and β of a cell survival curve are simple functions of the frequency-average linear energy transfer (LF) of delta electrons. The choice of these functions was guided by a microdosimetry-based model. We calculated LF by using an innovative algorithm in which LF is associated with only those electrons that reach a sensitive-to-radiation volume (SV) within the cell. We determined model parameters by fitting the model to 139 measured (α,β) pairs.

Results:

We tested nine versions of the model. The best agreement was achieved with α and β being linear functions of LF .The estimated SV diameter was 0.1–1 µm. We also found that α, β, and the α/β ratio increased with increasing LF .

Conclusions:

By combining an innovative method for calculating LF with a microdosimetric model, we developed a model that is consistent with extensive experimental data involving photon energies from 0.27 keV to 1.25 MeV.

Advances in knowledge:

We have developed a photon RBE model applicable to an energy range from ultra-soft X-rays to megaelectron volt γ radiation, including high-dose levels where the RBE cannot be calculated as the ratio of α values. In this model, the ionization density represented by LF determines the RBE for a given photon spectrum.
Undergraduate medical education: a national survey of consultant radiologists
Authors: Chew C , O’Dwyer PJ
Published: May 2020

Objective:

Rising clinical demand and changes to Radiologists’ job plans mean it is becoming ever more difficult for Radiologists to teach medical students.

The aim of this study was to assess the current role of Radiologists in undergraduate medical education in Scotland.

Methods:

Consultant Radiologists working across all 14 Scottish Health Boards were invited by email to participate in an anonymous short online survey. The survey ran for 6 weeks from November 2019. One reminder email was sent a week before the survey closed.

Results:

102 responses were recorded, representing 34% of the total whole time equivalent Radiologists in Scotland. All agreed Radiology should be taught to medical students. Over 70% (n = 73) taught medical students, most often during supporting professional activity time. 76 percent of Radiologists who did not teach expressed a desire to do so. The most common barrier to teaching was not having enough time in their job plan. Scottish Radiologists delivered a median of 10 h (IQR 0–22) a year of teaching to medical students. Thematic analysis of free comments revealed staffing/time constraints severely limiting ability to teach.

Conclusion:

This is the first national survey to assess the current role of Radiologists in teaching medical students. While most are teaching or want to teach, there is a large drop-off between current Scottish and previously reported UK median teaching hours. Engagement from Universities, Royal College of Radiologists and Health Boards is urgently needed to reverse this trend.

Advances in knowledge:

This is the first national survey into the current role of Radiologists in undergraduate medical education. There is a large drop-off between current Scottish and previously reported UK median teaching hours.
Cardiovascular magnetic resonance and echocardiographic findings of a large thrombosed intramyocardial dissecting hematoma: a case report and a brief review of literature
Authors: Sakrana Amal Abdelsattar , Alzubaidi Shadha A. Ahmed , Shahat Abdulhameed Mohmmed , Mahmoud Abeer Sabri , Naeim Hesham Abdo
Published: May 2020

Intramyocardial dissecting hematoma (IMDH) is an uncommon fatal complication after acute myocardial infarction. It is usually under identified. Transthoracic echocardiography is the first-line modality that can detect IMDH. Cardiac magnetic resonance could confirm the diagnosis. In this paper, we reported a unique partially thrombosed large left ventricle IMDH that mimics thrombosed true aneurysm aiming to highlight the supporting diagnostic transthoracic echocardiography and cardiac magnetic resonance criteria of IMDH.
Fast analysis of scATAC-seq data using a predefined set of genomic regions
Authors: Giansanti Valentina , Tang Ming , Cittaro Davide
Published: May 2020

Background: Analysis of scATAC-seq data has been recently scaled to thousands of cells. While processing of other types of single cell data was boosted by the implementation of alignment-free techniques, pipelines available to process scATAC-seq data still require large computational resources. We propose here an approach based on pseudoalignment, which reduces the execution times and hardware needs at little cost for precision.

Methods: Public data for 10k PBMC were downloaded from 10x Genomics web site. Reads were aligned to various references derived from DNase I Hypersensitive Sites (DHS) using kallisto and quantified with bustools. We compared our results with the ones publicly available derived by cellranger-atac. We subsequently tested our approach on scATAC-seq data for K562 cell line.

Results: We found that kallisto does not introduce biases in quantification of known peaks; cells groups identified are consistent with the ones identified from standard method. We also found that cell identification is robust when analysis is performed using DHS-derived reference in place of de novo identification of ATAC peaks. Lastly, we found that our approach is suitable for reliable quantification of gene activity based on scATAC-seq signal, thus allows for efficient labelling of cell groups based on marker genes.

Conclusions: Analysis of scATAC-seq data by means of kallisto produces results in line with standard pipelines while being considerably faster; using a set of known DHS sites as reference does not affect the ability to characterize the cell populations.
Testing the effect of PAR1 inhibitors on Plasmodium falciparum-induced loss of endothelial cell barrier function
Authors: Storm Janet , Wu Yang , Davies Jill , Moxon Christopher A. , Craig Alister G.
Published: May 2020

Background: Sequestration and cytoadherence of Plasmodium falciparum-infected erythrocytes (IE) to microvascular endothelium alters endothelial barrier function and plays a role in the pathogenesis of severe malaria. Binding of IE is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1) and the PfEMP1 variants that binds to endothelial protein C receptor (EPCR) have, in particular, been associated with the dysregulation of the coagulation/inflammation pathways in endothelial cells. This has prompted speculation about the role of protease-activated receptor-1 (PAR1) activation and signalling in causing endothelial activation and loss of barrier function in cerebral malaria.

Methods: We used a co-culture of primary human brain microvascular endothelial cells (HBMEC) with P. falciparum material, recombinant PfEMP1 or lysates from IE, and measured barrier function by trans endothelial electrical resistance (TEER).  A selection of PAR1 inhibitors was tested for their ability to reverse the P. falciparum and thrombin induced decrease in barrier function.

Results: An initial screen in the presence of recombinant PfEMP1 identified a few inhibitors that were able to reduce the rapid thrombin-induced barrier disruption even when activated protein C (aPC) was unable to do so. However, PAR1 inhibitors did not rescue the barrier dysfunction after co-culture with IE lysate.

Conclusions: The selected PAR1 inhibitors were able to reverse the disruption of barrier function by thrombin but did not reverse the IE lysate induced disruption of barrier function, implicating a different PAR1-independent mechanism.  These findings have implications for the design of adjunct therapies to reduce brain swelling in cerebral malaria.