bluuebunny/crossref_metadata_2025 huggingface dataset:
Uptake of breast cancer screening practices in low- and middle-income countries: a systematic review and meta-analysis
Authors: Ebrahimoghli Reza , Aghaei Mir Hossein , Azami-Aghdash Saber , Houssami Nehmat
Published: August 2024

Background

Breast cancer is the most prevalent cancer worldwide and the leading cause of cancer mortality in women. Uptake of breast cancer screening and early-detection practices in low- and middle-income countries (LMIC) has not been synthesized. We aimed to systematically quantify uptake of breast cancer screening in LMIC.

Methods

We performed a systematic review and meta-analysis of observational population-based studies that reported the uptake of screening or early-detection practices. We searched the PubMed, Scopus, Embase, and Web of Knowledge databases to January 2024. We pooled data using random-effects meta-analysis and explored heterogeneity using subgroup analyses.

Results

We included 174 population-based studies encompassing more than 78 million women. Pooled prevalence of self-reported uptake of screening mammography was 22.7% (95% confidence interval = 18.6% to 27.2%), of self-reports of having had a clinical breast examination for screening was 23.1% (95% confidence interval = 19.5% to 27.0%), and of self-reported regular breast self-examination (relevant for breast awareness in LMIC) was 14.6% (95% confidence interval = 11.6% to 17.9%). Uptake of breast cancer screening practices was lowest in Africa and low- and lower-middle income countries. Uptake of breast cancer screening practices remained stable over time or decreased slightly. Women who lived in rural area, were single, had lower income levels, had low educational attainment, were unemployed, were uninsured, and had no family history of breast cancer were generally least likely to self-report uptake of breast cancer screening.

Conclusion

This meta-analysis identified concerningly low uptake of breast cancer screening practices in LMIC. Governments should prioritize developing context-appropriate strategies to address this low uptake to support population-level stage shifting of breast cancer in LMIC.
Adopting the 2023 CDC Early Testing for Perinatal Hepatitis C: Call to Action for Pediatric Primary Care Providers
Authors: Saleh Ezzeldin , Rodriguez Marcela
Published: August 2024

In the United States, the burden of hepatitis C virus (HCV) infection is disproportionately high among young adults including pregnant persons, resulting in increased infections among children as perinatal transmission remains the main route of HCV infection in children. Hence, in 2020, the Centers for Disease Control and Prevention (CDC) recommended universal HCV screening during each pregnancy. HCV infection in infancy is usually asymptomatic, so the diagnosis entirely relies on testing of perinatally exposed infants which, historically, included anti-HCV antibody testing at ≥18 months of age. However, nation-wide perinatal HCV testing rates have been suboptimal with significant loss to follow-up. To address this problem, in 2023, the CDC introduced early single HCV RNA testing at 2–6 months of age with an alternative for HCV RNA testing up to 17 months of age if not previously tested. The high sensitivity and specificity of the HCV real-time PCR laid the grounds for this policy shift. In this review, we highlight how these new CDC recommendations will enhance testing of infants and children and ultimately contribute to overall HCV elimination efforts. We also emphasize the role of all pediatric providers and obstetricians in implementing these new guidelines. Additionally, we offer our perspective and practical advice for testing of perinatally exposed infants and children. Currently, curative oral antivirals for HCV-infection treatment are approved for children ≥3 years of age. As pediatricians, advocating for children’s wellness, it is our utmost duty to ensure that every child exposed to perinatal hepatitis C has been tested, diagnosed, linked to care, treated, and achieved cure.
Homonymous hemianopia following yellow fever vaccination: a case of acute disseminated encephalomyelitis
Authors: Hensel Carla A , Jackson Justin D
Published: August 2024

A 42-year-old Caucasian man developed left homonymous hemianopia 16 days after receipt of a live-attenuated 17D-204 yellow fever virus vaccine. MRI imaging of the brain revealed right occipital and left parieto-occipital lesions with marked hyperintensity consistent with demyelination, and a diagnosis of yellow fever vaccine-associated acute disseminated encephalomyelitis was made.
Excitation of CO molecules in diffuse gas over cosmic history
Authors: Klimenko V V , Balashev S A , Noterdaeme P , Srianand R , Ivanchik A V
Published: August 2024

We studied the physical conditions in the local interstellar medium (ISM) and at high redshift by fitting observed column densities of CO and H2 rotational levels and C i fine-structure levels using photodissociation models calculated with the Meudon PDR code. We analysed CO absorption systems in 28 sight lines in the local ISM and seven damped Lyman-α absorption systems at high redshift, covering $N({\rm H_2})=10^{19}\!-\!10^{21.5}\,{\rm cm}^{-2}$ and $N({\rm CO})=10^{13}\!-\!10^{18}\,{\rm cm}^{-2}$. We constructed a method to accurately calculate CO excitation, incorporating the effects of photon trapping. Our findings indicate that in the local ISM, CO excitation is primarily driven by collisions and excitation due to the CMB radiation. We demonstrated that an increase in CO excitation observed near $N({\rm CO})\simeq 10^{15}~{\rm cm^{-2}}$, is attributed to an increase in gas densities from ${\simeq}100\,{\rm cm}^{-3}$ to ${\simeq}300\!-\!1000\,{\rm cm}^{-3}$. CO absorption systems in the local ISM are characterized by a gas number density of about 10–1000 cm−3, a kinetic temperature of 10–100 K, and an intensity of external UV field ranging from 0.1 to 10 units of Mathis field. Compared to the average gas probed by C i absorption, the gas detected in CO is denser and colder, while the external UV field remains nearly constant. We observed a negative correlation between the kinetic temperature and both N(CO) and N(H2), with power-law slopes of $-0.21\pm 0.02$ and $-0.65\pm 0.05$, respectively. At the same time, the gas number density exhibits a positive correlation with N(CO) and N(H2) with slopes of $0.38\pm 0.02$ and $1.15\pm 0.05$, respectively.
An ALMA survey of submillimetre galaxies in the Extended Chandra Deep Field South: an unbiased study of SMG environments measured with narrow-band imaging
Authors: Cornish Thomas M , Wardlow Julie , Wade Heather , Sobral David , Brandt William N , Cox Pierre , Dannerbauer Helmut , Decarli Roberto , Gullberg Bitten , Knudsen Kirsten , Stott John , Swinbank Mark , Walter Fabian , van der Werf Paul
Published: August 2024

Submillimetre galaxies (SMGs) are some of the most extreme star-forming systems in the Universe, whose place in the framework of galaxy evolution is as yet uncertain. It has been hypothesized that SMGs are progenitors of local early-type galaxies, requiring that SMGs generally reside in galaxy cluster progenitors at high redshift. We test this hypothesis and explore SMG environments using a narrow-band VLT/HAWK-I+GRAAL study of H $\alpha$ and [O iii] emitters around an unbiased sample of three ALMA-identified and spectroscopically confirmed SMGs at $z \sim 2.3$ and $\sim 3.3$, where these SMGs were selected solely on spectroscopic redshift. Comparing with blank-field observations at similar epochs, we find that one of the three SMGs lies in an overdensity of emission-line sources on the $\sim 4$ Mpc scale of the HAWK-I field of view, with overdensity parameter $\delta _{g} = 2.6^{+1.4}_{-1.2}$. A second SMG is significantly overdense only on $\lesssim 1.6$ Mpc scales and the final SMG is consistent with residing in a blank field environment. The total masses of the two overdensities are estimated to be $\log (M_{h}/{\rm M}_{\odot }) =$ 12.1–14.4, leading to present-day masses of $\log (M_{h,z=0}/{\rm M}_{\odot }) =$ 12.9–15.9. These results imply that SMGs occupy a range of environments, from overdense protoclusters or protogroups to the blank field, suggesting that while some SMGs are strong candidates for the progenitors of massive elliptical galaxies in clusters, this may not be their only possible evolutionary pathway.
The TRAPUM Large Magellanic Cloud pulsar survey with MeerKAT – I. Survey set-up and first seven pulsar discoveries
Authors: Prayag V , Levin L , Geyer M , Stappers B W , Carli E , Barr E D , Breton R P , Buchner S , Burgay M , Kramer M , Possenti A , Krishnan V Venkatraman , Venter C , Behrend J , Chen W , Horn D M , Padmanabh P V , Ridolfi A
Published: August 2024

The Large Magellanic Cloud (LMC) presents a unique environment for pulsar population studies due to its distinct star formation characteristics and proximity to the Milky Way. As part of the TRAPUM (TRAnsients and PUlsars with MeerKAT) Large Survey Project, we are using the core array of the MeerKAT radio telescope (MeerKAT) to conduct a targeted search of the LMC for radio pulsars at L-band frequencies, 856–1712 MHz. The excellent sensitivity of MeerKAT, coupled with a 2-h integration time, makes the survey 3 times more sensitive than previous LMC radio pulsar surveys. We report the results from the initial four survey pointings which have resulted in the discovery of seven new radio pulsars, increasing the LMC radio pulsar population by 30 per cent. The pulse periods of these new pulsars range from 278 to 1690 ms, and the highest dispersion measure is 254.20 $\mathrm{ pc} \, \mathrm{ cm}^{-3}$. We searched for, but did not find any significant pulsed radio emission in a beam centred on the SN 1987A remnant, establishing an upper limit of 6.3 $\mu \mathrm{ Jy}$ on its minimum flux density at 1400 MHz.
Closed, Closing, and Close to Closure: The Nineteenth-Century “Closing Theme” Problem as Exemplified in Mendelssohn’s Sonata Practice
Authors: Taylor Benedict
Published: August 2024

There is little theoretical consensus on what constitutes a closing theme in a sonata-form exposition. William Caplin’s formal-functional theory essentially rejects the notion, while conversely it is upheld in James Hepokoski and Warren Darcy’s sonata theory. For them, a “C-theme” is defined contextually, as occurring after a decisive cadence. Yet there appear to be exceptions to this rule, more prevalent in the nineteenth century, which concern “apparent C-zones in the absence of an EEC,” or “Sc themes,” in which rhetorical factors override the lack of preceding cadential closure. This concession opens up a theoretical minefield that has until now been barely explored; nevertheless, it speaks to a genuine feature of nineteenth-century sonata practice.

This article examines the use of apparently rhetorical C themes in a precedential situation in the first half of the nineteenth century, taking the sonata expositions of Felix Mendelssohn as a case study. Mendelssohn’s music highlights this issue particularly well owing to his customary avoidance of cadential closure and regular recourse to primary-theme material toward the end of an exposition. Combining form-functional and sonata-theoretical perspectives, I identify in his music a characteristic structure whereby the functions formerly reserved for a single theme are expanded to encompass what would have formed multiple themes in the late eighteenth century. Moreover, the P-based closing idea generally functions as a large-scale cadential phrase in an enormous sentence initiated by the secondary theme, thus highlighting a latent terminological ambiguity over whether the word “closing” indicates “already closed” or “in the process of closing.” I argue for the need to refine existing terminology in order to distinguish between these two meanings when applied to the nineteenth-century repertory.
Induction of bacterial expression at the mRNA level by light
Authors: Ranzani Américo T , Buchholz Konrad , Blackholm Marius , Kopkin Hayat , Möglich Andreas
Published: August 2024

Vital organismal processes, including development, differentiation and adaptation, involve altered gene expression. Although expression is frequently controlled at the transcriptional stage, various regulation mechanisms operate at downstream levels. Here, we leverage the photoreceptor NmPAL to optogenetically induce RNA refolding and the translation of bacterial mRNAs. Blue-light-triggered NmPAL binding disrupts a cis-repressed mRNA state, thereby relieves obstruction of translation initiation, and upregulates gene expression. Iterative probing and optimization of the circuit, dubbed riboptoregulator, enhanced induction to 30-fold. Given action at the mRNA level, the riboptoregulator can differentially regulate individual structural genes within polycistronic operons. Moreover, it is orthogonal to and can be wed with other gene-regulatory circuits for nuanced and more stringent gene-expression control. We thus advance the pAurora2 circuit that combines transcriptional and translational mechanisms to optogenetically increase bacterial gene expression by >1000-fold. The riboptoregulator strategy stands to upgrade numerous regulatory circuits and widely applies to expression control in microbial biotechnology, synthetic biology and materials science.
Protocol and rationale for a randomized controlled SGLT2 inhibitor trial in paediatric and young adult populations with chronic kidney disease: DOUBLE PRO-TECT Alport
Authors: Gross Oliver , Boeckhaus Jan , Weber Lutz T , Heerspink Hiddo J L , Simon James F , Ahmed Rees , Gerst Christoph , Duerr Ulrike , Walker Florian , Tostmann Ralf , Helm Jürgen , Asendorf Thomas , Friede Tim ,   for the study group of the German Society of Pediatric Nephrology, Boeckhaus Jan , Weber Lutz T , Heerspink Hiddo J L , Simon James F , Ahmed Rees , Gerst Christoph , Duerr Ulrike , Walker Florian , Tostmann Ralf , Helm Jürgen , Asendorf Thomas , Friede Tim
Published: August 2024

Background

Clinical trials have demonstrated positive cardiovascular and kidney outcomes of sodium–glucose co-transporter 2 (SGLT2) inhibitors in adult patients with diabetic and other chronic kidney diseases (CKDs). Whether benefits extend to children, teenagers and young adults with early-stage CKD is unknown. For this reason, the DOUBLE PRO-TECT Alport trial (NCT05944016) will study the progression of albuminuria in young patients with Alport syndrome (AS), the most common hereditary CKD, to assess the safety and efficacy of the SGLT2 inhibitor dapagliflozin. Patients living with AS and chronically elevated albuminuria have a high risk of kidney failure before the age of 50 years.

Methods

DOUBLE PRO-TECT Alport is a multicentre, randomized, double-blind, placebo-controlled trial. Participants (ages 10–39 years) must have a diagnosis of AS by genetic testing or kidney biopsy, be on a stable (>3 months) maximum tolerated dose of a renin–angiotensin system inhibitor and have a urinary albumin:creatinine ratio (UACR) of >300 mg/g (paediatric) or >500 mg/g (adult).

Eligible participants will be randomly assigned at a 2:1 ratio to 48 weeks of treatment with dapaglifozin 10 mg/day or matched placebo. Most participants are expected to be children with a normal estimated glomerular filtration rate (eGFR). In addition to safety, the primary (change in UACR from baseline to week 48) and key secondary (eGFR change from baseline to week 52) efficacy outcomes will be analysed with a mixed model repeated measures approach. Efficacy analyses will be performed primarily in the full analysis set according to the intention-to-treat principle. A sensitivity analysis will be performed using reference-based multiple imputation.

Conclusion

DOUBLE PRO-TECT Alport will assess whether SGLT2 inhibitors can safely reduce the UACR change from baseline as a marker for progression of CKD in young patients living with AS.
Intensive pediatric chemotherapy regimen (PNET HR+5) in adult high-risk medulloblastoma and pineoblastoma patients
Authors: Larrouquere Louis , Dufour Christelle , Faure-Conter Cécile , Alapetite Claire , Meyronet David , Bolle Stéphanie , Bonneville-Levard Alice , Sunyach Marie-Pierre , Laurence Valérie , Frappaz Didier
Published: August 2024

Background

High-risk medulloblastoma (HRMB) is rare in adults. The 5-year overall survival rate is less than 60%. We present here a retrospective analysis of adults treated with an intensive pediatric chemo-radiotherapy regimen PNET HR + 5: NCT00936156.

Methods

Eighteen patients over the age of 20 (range, 20–33 years) with HRMB (n = 13), pinealoblastoma (n = 4), and central nervous system embryonal tumor (n = 1) were treated with 2 courses of carboplatin-etoposide followed by 2 courses of high-dose thiotepa (HDT) with autologous hematopoietic stem-cell rescue. A craniospinal irradiation (CSI; 36 Gy craniospinal axis then a boost of 18 Gy to the primary tumor site) was then initiated within 150 days of surgery, completed with 6 cycles of temozolomide; the axis irradiation was not mandatory for non-metastatic pinealoblastoma.

Results

We observed no progression under chemotherapy and no toxic death. Four patients received only 1 HDT. Two non-metastatic pinaloblastomas received only focal irradiation. One medulloblastoma received only 25 Gy on the axis. 56% (10/18) received 6 cycles of temozolomide. No long-term toxicity was recorded. The median time between surgery and CSI was 175 days (range, 115–250). With a median follow-up of 6.0 years (range, 2.6–9), the progression-free survival and overall survival rates for medulloblastoma were respectively 65% (95% CI: 31%–86%) and 76% (95% CI: 42%–91%) at 5 years.

Conclusions

The PNET HR + 5 regimen showed promising results in an adult population, with a meaningful improvement in progression-free survival and overall survival in patients with HRMB.
Ships of State and Empty Vessels: Critical Reflections on ‘Territorial Status in International Law’
Authors: Green Alex
Published: August 2024

In his recent monograph, Territorial Status in International Law, Jure Vidmar offers ‘a new theory of statehood’ that consolidates his existing work and departs in important ways from legal orthodoxy. As a work of doctrinal law, the text is rigorous; however, its theoretical contribution is somewhat unclear. Vidmar’s central theoretical claim—that the status of individual states is established by discrete norms of customary international law—adds very little to his doctrinal argument. By examining his position, this review article examines what it might mean to provide helpful ‘theories of statehood’. It begins by framing the theoretical challenge posed by such work before setting out some desiderata for theoretical success in this area. Finally, it sketches out a general approach, grounded in Hannah Arendt’s conception of power, which offers a promising means for moving beyond doctrinal description within ‘reconstructive’ international legal theory.
Weaponizing women and gender: Party appeals to women voters ahead of the 2024 UK general election
Authors: Sanders Anna , Gains Francesca
Published: August 2024

Whilst there are significant electoral advantages for political parties to target women’s votes, scholarship on recent electoral appeals questions the quality of gendered policy promises to address deep structural gender inequalities existing within the British state. This article examines British Election Study data to identify women voters’ concerns and explores how the two largest Westminster parties developed appeals to women voters in the build up to the 2024 UK general election through an analysis of leadership speeches to the 2023 party conferences. We find a disconnect between women’s electoral demands to address class-based gender inequalities and party attempts to ‘weaponize’ the woman question around status issues. We conclude by pointing to the enduring nature of gendered inequalities despite the election of a Labour government, which targeted appeals more closely to the class-based concerns of women voters.
Performance of the Fully Equipped Spin Flip Chopper for the Neutron Lifetime Experiment at J-PARC
Authors: Mishima K , Ichikawa G , Fuwa Y , Hasegawa T , Hino M , Hosokawa R , Ino T , Iwashita Y , Kitaguchi M , Matsuzaki S , Mogi T , Okabe H , Oku T , Okudaira T , Seki Y , Shimizu H E , Shimizu H M , Takahashi S , Tanida M , Yamashita S , Yokohashi M , Yoshioka T
Published: August 2024

To solve the “neutron lifetime puzzle,” where measured neutron lifetimes differ depending on the measurement methods, an experiment with a pulsed neutron beam at J-PARC is in progress. In this experiment, neutrons are bunched into 40-cm lengths using a spin flip chopper (SFC), where the statistical sensitivity was limited by the aperture size of the SFC. The SFC comprises three sets of magnetic supermirrors and two resonant spin flippers. In this paper, we discuss an upgrade to enlarge the apertures of the SFC. With this upgrade, the statistics per unit time of the neutron lifetime experiment increased by a factor of 2.8, while maintaining a signal-to-noise ratio of 250–400, which is comparable to the previous one. Consequently, the time required to reach a precision of 1 s in the neutron lifetime experiment was reduced from 590 to 170 days, which is a significant reduction in time. This improvement in the statistics will also contribute to the reduction of systematic uncertainties, such as background evaluation, fostering further advancements in the neutron lifetime experiments at J-PARC.
Moments of the Charge Distribution Observed through Electron Scattering in 3H and 3He
Authors: Hiyama Emiko , Suzuki Toshio
Published: August 2024

The moments of the charge distributions obtained by the sum-of-Gaussians (SOG) analysis of electron-scattering data are examined in $^3$H and $^3$He, together with those obtained by the Fourier–Bessel (FB) analysis. The SOG and FB methods reproduce well the experimental form factors available at present, but provide different charge distributions from each other. As a result, they do not yield the same values of the moments of the charge distribution, although their analyses are called “model-independent.” The moments are sensitive to the tail of the charge distribution. The present experimental data are not enough for SOG and FB analyses to determine with reasonable accuracy the shape of the tails, in a quantum mechanical point of view. New, accurate experimental data at small momentum transfer squared less than 0.1 fm$^{-2}$ are desired.
Who can predict farmers’ choices in risky gambles?
Authors: Schaak Henning , Rommel Jens , Sagebiel Julian , Barreiro-Hurlé Jesus , Bougherara Douadia , Cembalo Luigi , Cerjak Marija , Čop Tajana , Czajkowski Mikołaj , Espinosa-Goded María , Höhler Julia , Lagerkvist Carl-Johan , Rodriguez-Entrena Macario , Tensi Annika , Thoyer Sophie , Tomić Maksan Marina , Vecchio Riccardo , Zagórska Katarzyna
Published: August 2024

Risk is a pervasive factor in agriculture and a subject of great interest to agricultural economists. However, there is a lack of comprehensive understanding of the knowledge held by farm advisors, students, and economists with regards to farmers’ risk preferences. Misconceptions about farmers’ willingness to take risks could lead to misguided advice. This study builds upon a recent multinational endeavor that employed a multiple price list to assess risk preferences among European farmers. We expand this research by gathering predictions for farmers’ risk preferences from 561 farm advisors, students, and economists. Our objectives are threefold: firstly, we explore variations as to how accurately participants can predict risk preferences in different specializations; secondly, we compare the predictive accuracy of different groups of forecasters; and thirdly, we assess whether modifying incentive mechanisms can improve the accuracy of predictions. Whereas our findings reveal substantial variation in individual predictions, the averages closely align with the observed responses of farmers. Notably, the most accurate predictions were provided by a sample of experimental economics researchers. Furthermore,predictions for different production systems exhibit minimal disparities. Introducing incentive schemes, such as a tournament structure, where the best prediction receives a reward, or a high-accuracy system, where randomly selected participants are compensated for the accuracy of their predictions, does not significantly impact accuracy. Further research and exploration are needed to identify the most reliable sources of advice for farmers.
A central role of sulcal width in the associations of sleep duration and depression with cognition in mid to late life
Authors: Faucher Caroline , Borne Léonie , Behler Anna , Paton Bryan , Giorgio Joseph , Fripp Jurgen , Thienel Renate , Lupton Michelle K , Breakspear Michael
Published: August 2024

Study Objectives

Evidence suggests that poor sleep impacts cognition, brain health, and dementia risk but the nature of the association is poorly understood. This study examined how self-reported sleep duration, napping, and subjective depression symptoms are associated with the brain-cognition relationship in older adults, using sulcal width as a measure of relative brain health.

Methods

A canonical partial least squares analysis was used to obtain two composite variables that relate cognition and sulcal width in a cross-sectional study of 137 adults aged 46–72. We used a combination of ANCOVA and path analyses to test the associations of self-reported sleep duration, napping, and subjective depression symptoms with the brain-cognition relationship.

Results

We observed a significant main effect of sleep duration on sulcal width, with participants reporting 7 hours showing narrower sulci than other durations. This effect remained significant after including subjective depression as a covariate, which also had a significant main effect on sulcal width in the model. There was no significant effect of napping on sulcal width. In path analyses where the effects of age, self-reported sleep duration and depression symptoms were investigated together, sulcal width mediated the relationship between age and cognition. We also observed a significant indirect effect of sulci width in the subjective depression-cognition relationship.

Conclusions

Findings suggest that self-reported sleep duration and subjective depression may each be independently associated with brain morphology, which is related to cognitive functions. Results could help inform clinical trials and related intervention studies that aim at delaying cognitive decline in adults at risk of developing dementia.
Scotland in the Forefront of Property Law Reforms in the UK: Potential Implications for the Scottish People
Authors: Okara Goodtime Chimnecherem
Published: August 2024

The Scottish Government has taken steps to revolutionise its body of law on ‘trust and succession’ and housing. The recent Trusts and Succession (Scotland) Act 2024 has severally impacted the issues of appointment and removal of trustees, fiduciary duties of trustees, rights of beneficiaries, and Environmental, Social, and Governance (ESG) investments in Scotland; while the proposed new Housing (Scotland) Bill 2024 has the proclivity of influencing rent, rent control areas, eviction and homelessness in Scotland. Accordingly, this paper focuses on exploring the potential impacts of these legislative reforms on the lives of the Scottish people. Do they ‘make’ or ‘mar’ the proprietary rights of the Scottish people? Are all the provisions useful to Scotland’s rental market? Will the proposed ‘ask and act’ approach address homelessness in Scotland? This paper will also be important to jurisdictions that may intend to modernise their property law and housing regimes.
CTSG polymorphisms in Chinese children with type 1 diabetes mellitus
Authors: Li Jiaci , Zhang Mingying , Zhang Shuyue , Wang Rui , Cai Yingzi , Chen Xiaofang , Dong Yan , Wang Ping , Shu Jianbo , Lv Ling , Cai Chunquan
Published: August 2024

Cathepsin G (CTSG) plays an important role in the regulation of immune processes. Accumulated studies show that CTSG is involved in the onset and development of type 1 diabetes mellitus (T1DM). As the genetic background of T1DM varies widely among populations, we aimed to study the relationship between genetic polymorphisms in CTSG and T1DM susceptibility in Chinese populations. A total of 141 patients with T1DM and 200 healthy controls were enrolled in the study. Serum CTSG expression was detected using enzyme-linked immunosorbent assay (ELISA). Genotyping of two selected single nucleotide polymorphisms (SNPs) (rs2236742 and rs2070697) of CTSG was performed using PCR and Sanger sequencing. CTSG expression in patients with T1DM was significantly higher than in the control group. Alleles C and T of CTSG SNP rs2236742 were increased in T1DM. No significant associations were found for the SNP rs2070697. Our results indicate that the CTSG rs2236742 allele (C/T) is associated with T1DM in Chinese children and may serve as a new biomarker for predicting T1DM susceptibility.
Hemodynamically significant patent ductus arteriosus profile in preterm neonates (26–34 weeks’ gestation) undergoing surfactant replacement therapy in India: a prospective observational study
Authors: Sk Md Habibullah , Singh Prachi , Saha Bijan
Published: August 2024

Surfactant administration significantly improves respiratory outcomes in preterm infants with respiratory distress syndrome (RDS). However, surfactant administration may lead to hemodynamic alterations, particularly in the heart, affecting the patent ductus arteriosus (PDA), the consequences of which are not fully understood. This prospective observational study took place in an Indian neonatal care unit from July 2019 to November 2020, enrolling preterm neonates (26–34 weeks’ gestation) with RDS needing non-invasive positive pressure ventilation. They were divided into two groups: those who received surfactant while on respiratory support and those who did not. All newborns in the study had an initial echocardiogram within 24 h to detect PDA flow. Subsequent echocardiograms were conducted between 48 and 72 h or earlier based on symptoms. Of 220 infants requiring respiratory support, 84 were enrolled, with 42 in each group. While demographic variables were similar, the surfactant group had a lower median gestational age (29.0 vs. 31.0 weeks). In the surfactant group, a significantly higher percentage of neonates had hemodynamically significant PDA (hsPDA) compared to the non-surfactant group (54.76% vs. 26.19%, P-value = .008). Multiple logistic regression found no significant association between gestation, birth weight, or shock and hsPDA occurrence. Pulmonary hemorrhage occurred more often in the surfactant group. Bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH) > grade 2, and necrotizing enterocolitis (NEC) ≥ grade 2 did not differ significantly between the groups. Surfactant therapy via the less invasive surfactant administration technique was associated with a higher incidence of hsPDA. While surfactant is crucial for neonatal respiratory care, its potential hemodynamic effects, including hsPDA, should be considered.
Adaptation of lot quality assurance sampling to monitor seasonal malaria chemoprevention delivery performance
Authors: Richardson Sol , Ibinaiye Taiwo , Oresanya Olusola , Oguoma Chibuzo , Okoronkwo Chukwu , Shekarau Emanuel , Sprague Daniel , Baker Kevin , de Cola Monica Anna , Roca-Feltrer Arantxa , Nnaji Chuks , Rassi Christian
Published: August 2024

Malaria Consortium supports delivery of seasonal malaria chemoprevention (SMC) to children ages 3–59 months using sulfadoxine–pyrimethamine plus amodiaquine. Lot quality assurance sampling (LQAS) was adapted as a cost-efficient method for end-of-cycle SMC monitoring surveys across supported countries and an implementation challenges reporting system was established in Nigeria. We present a case study of its application in Nasarawa State. LQAS facilitated timely local performance assessment across 16 indicators. Development of new reporting tools has played a key role in stimulating national-level discussions on improvements to SMC supervisory processes and implementer training and provided a framework for engagement with local stakeholders.
The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2
Authors: Suryawanshi Rahul K. , Jaishankar Priyadarshini , Correy Galen J. , Rachman Moira M. , O’Leary Patrick C. , Taha Taha Y. , Zapatero-Belinchón Francisco J. , McCavitt-Malvido Maria , Doruk Yagmur U. , Stevens Maisie G. V. , Diolaiti Morgan E. , Jogalekar Manasi P. , Richards Alicia L. , Montano Mauricio , Rosecrans Julia , Matthay Michael , Togo Takaya , Gonciarz Ryan L. , Gopalkrishnan Saumya , Neitz R. Jeffrey , Krogan Nevan J. , Swaney Danielle L. , Shoichet Brian K. , Ott Melanie , Renslo Adam R. , Ashworth Alan , Fraser James S.
Published: August 2024

SARS-CoV-2 continues to pose a threat to public health. Current therapeutics remain limited to direct acting antivirals that lack distinct mechanisms of action and are already showing signs of viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) that plays an important role in the coronaviral lifecycle by suppressing host innate immune responses. Genetic inactivation of Mac1 abrogates viral replicationin vivoby potentiating host innate immune responses. However, it is unknown whether this can be achieved by pharmacologic inhibition and can therefore be exploited therapeutically. Here we report a potent and selective lead small molecule, AVI-4206, that is effective in anin vivomodel of SARS-CoV-2 infection. Cellular models indicate that AVI-4206 has high target engagement and can weakly inhibit viral replication in a gamma interferon- and Mac1 catalytic activity-dependent manner; a stronger antiviral effect for AVI-4206 is observed in human airway organoids. In an animal model of severe SARS-CoV-2 infection, AVI-4206 reduces viral replication, potentiates innate immune responses, and leads to a survival benefit. Our results provide pharmacological proof of concept that Mac1 is a valid therapeutic target via a novel immune-restoring mechanism that could potentially synergize with existing therapies targeting distinct, essential aspects of the coronaviral life cycle. This approach could be more widely used to target other viral macrodomains to develop antiviral therapeutics beyond COVID-19.
Response diversity increases functional stability but decreases diversity and compositional stability of grassland communities
Authors: Zieschank Vincent , Junker Robert R.
Published: August 2024

The insurance hypothesis of biodiversity assumes that ecosystem stability rises with increasing biodiversity because functionally redundant species respond differently to environmental changes, allowing some species to compensate for the loss of others. We tested this hypothesis by combining extensive field data and a common garden experiment where sods originating from different regions were subjected to land-use treatments. Based on plant species-specific performance-environment relationships with abundance as performance proxy and land-use intensity as environmental variable, we calculated response dissimilarity of species-pairs. The resulting dissimilarity matrix was used to calculate response diversity (functional dispersion) of grass sods before and after land-use treatments. Our results showed that high land-use intensity decreased response diversity of plant communities both in the field as well as in the common garden. Response diversity in grass sods increased functional stability but decreased stability in terms of species diversity and composition as communities with high response diversity lost species without replacement in response to experimental land-use change, while those with low response diversity showed species turnover. We conclude that response diversity is an important component of biodiversity and discuss future research directions to refine and generalize the concept of response diversity and its role in ecosystem stability.
Complex genetic determination of male-fertility restoration in the gynodioecious snailPhysa acuta
Authors: Skarlou Elpida , Laugier Fanny , Béthune Kévin , Chenin Timothée , Donnay Jean-Marc , Froissard Céline , David Patrice
Published: August 2024

Male fertility in plants is often controlled by the interaction between mitochondrial and nuclear genes. Some mitotypes confer cytoplasmic male sterility (CMS), making the individual male-sterile, unless the nuclear background contains alleles called restorers, that suppress the effects of CMS and restore the hermaphroditic condition. Restorers in cultivated crops are often alleles with strong and dominant effect, but in wild plants, data often suggest more complex systems. Here, we characterized the inheritance and specificity of restoration in a new CMS model, the freshwater snailPhysa acuta. We explored two different populations (i) a naive population i.e., without contact CMS in the past 80 generations, (ii) a non-naive population, where CMS is present and largely restored. We found that restoration potential was indeed heritable in both contexts and specific to a CMS type. However our results suggest that restoration of male fertility could be of a different nature depending on population history: in naïve populations not coevolved with CMS the background variation may include alleles that happen to act as weak quantitative modifiers of the penetrance of CMS, while in populations coevolved with CMS, selection may have favored, when such variants were available, the emergence of strong alleles with a dominant effect.
Alterations of the skeletal muscle nuclear proteome after acute exercise reveals a post-transcriptional influence
Authors: Martin Ryan A. , Viggars Mark R. , Sanford James A. , Taylor Zane W. , Hansen Joshua R. , Clair Geremy C. , Adkins Joshua N. , Douglas Collin M. , Esser Karyn A.
Published: August 2024

Exercise is firmly established as a key contributor to overall well-being and is frequently employed as a therapeutic approach to mitigate various health conditions. One pivotal aspect of the impact of exercise lies in the systemic transcriptional response, which underpins its beneficial adaptations. While extensive research has been devoted to understanding the transcriptional response to exercise, our knowledge of the protein constituents of nuclear processes that accompany gene expression in skeletal muscle remains largely elusive. We hypothesize that alterations in the nuclear proteome following exercise hold vital clues for comprehending the transcriptional regulation and other related nuclear functions. We isolated skeletal muscle nuclei from C57BL/6 mice both sedentary control and one-hour post 30-minute treadmill running, to gain insights into the nuclear proteome after exercise. A substantial number of the 2,323 proteins identified, were related to nuclear functions. For instance, we found 59 proteins linked to nucleocytoplasmic transport were higher in sedentary mice compared to exercise, hinting at an exercise-induced modulation to nuclear trafficking. Furthermore, 135 proteins exhibited increased abundance after exercise (FDR < 0.1) while 89 proteins decreased, with the most prominent changes in proteins linked to mRNA processing and splicing. Super resolution microscopy further highlights potential localization change in mRNA processing proteins post-exercise, further suggesting changes in nuclear transport dynamics. Nonetheless, our data provide important considerations for the study of the nuclear proteome and supports a paradigm through which exercise downregulated mRNA processing and splicing, offering valuable insights into the broader landscape of the impact from acute exercise.

New & Noteworthy

Exercise plays a crucial role in promoting muscle health, but our understanding of nuclear proteins orchestrating exercise responses is limited. Isolation of skeletal muscle nuclei coupled with mass spectrometry enhanced the identification of nuclear proteins. This approach was used to investigate the effects of acute exercise, revealing changes in the muscle nuclear proteome 1-hour post-exercise, including proteins linked to post-transcriptional processing and splicing. Our findings offer insights into the exercise-induced changes within muscle nuclear proteins.
Interactions between neutrophils and macrophages harboring gram-negative bacteria promote obesity-associated breast cancer
Authors: Takle Sina T. , Grøndal Sturla Magnus , Lien Martin E. , Lianto Priscilia , Deng Wei , Lillestøl Reidun Kristine , Lønning Per , Lorens James B. , Knappskog Stian , Halberg Nils
Published: August 2024

Obesity promotes a more aggressive breast cancer phenotype. Through spatial and single-cell-based analysis of hormone receptor-negative breast cancers, we identify a subset of tumor-associated neutrophils (TANs) positive for granzyme B (GZMB) enriched in the tumor microenvironment of obese patients. In breast tumors evolved in obese environments, TANs are in proximity of M2 polarized macrophages containing lipopolysaccharides (LPS) from gram-negative bacteria. Pyroptosis of macrophages releases bacterial LPS, activating local GZMB+TANs. This induces release of the S100 family member S100A8 that promotes tumor progression. In sum, we describe an obesity associated cellular network of cancer cells, neutrophils and M2 polarized macrophages that promotes tumor growth.
Analytical Validation of a Circulating Tumor DNA Assay using PhasED-Seq Technology for Detecting Residual Disease in B-Cell Malignancies
Authors: Boehm Nina , Close Sandra , Kurtz David M. , Hockett Richard D. , Hyland Laura
Published: August 2024

Background

Circulating tumor DNA (ctDNA) is a non-invasive biomarker that can be used as a tool to detect minimal residual disease (MRD). MRD can provide important prognostic information in diffuse large B-cell lymphomas (DLBCL). Here, we present an MRD assay with an improved detection method for ctDNA, Phased Variant Enrichment and Detection Sequencing (PhasED-Seq) which leverages phased variants (PVs) to detect ctDNA.

Methods

Plasma samples from non-cancer controls were used to assess assay specificity. A limiting dilution series using DLBCL clinical-contrived samples was performed to assess assay sensitivity and precision. The accuracy of the PhasED-Seq-based assay was assessed using plasma samples from individuals with DLBCL and for whom MRD comparator assay results were also available. All samples were sourced from commercial vendors or academic studies.

Results

The analytical and clinical performance of the MRD assay was evaluated using clinical and clinical-contrived DLBCL samples. The assay’s false positive rate was 0.24% and the background error rate was 1.95E-08. The limit of detection at 95% detection rate (LoD95) at 120 ng was 0.7 parts in 1,000,000 and precision was >96%. Clinical accuracy was 90.62% PPA and 77.78% NPA.

Conclusions

The PhasED-Seq-based MRD assay has strong analytical and clinical performance in B-cell dyscrasias. Through the development of improved ctDNA detection methods such as that presented here, patient outcomes may be improved through the detection of residual disease or early relapse which may be used to guide treatment decisions.

Brief Summary

Here we present the analytical validation of a non-invasive minimal residual disease (MRD) assay which uses Phased Variant Enrichment and Detection Sequencing (PhasED-Seq) to improve the error profile and sensitivity of circulating tumor DNA (ctDNA) detection. The assay’s performance included a false positive rate of 0.24% and a background error rate of 1.95E-08. The limit of detection at 120 ng was 0.7 parts in 1,000,000 (6.61E-07 PVAF) with precision >96%. Positive and negative agreement were 90.62% and 77.78%, respectively. This suggests that the PhasED-Seq-based MRD assay is accurate and reproducible, thus appropriate for clinical use for individuals with B-cell malignancies.
A Literature Review and Pooled Case Analysis of Cardiofaciocutaneous Syndrome to Estimate Cancer Risk
Authors: Bess Jazmyn , Brown Toniya , Bhala Sonia , Faizer Anaqa , Ahmadzada Muzzammil , Livinski Alicia A , Pemov Alex , Kim Jung , Rosenberg Philip S , Ney Gina M , Stewart Douglas R
Published: August 2024

Background

Cardiofaciocutaneous syndrome (CFC) is a rare disorder with multiple congenital anomalies including macrocephaly, failure to thrive, and neurocognitive delay. CFC is part “RASopathy” syndromes caused by pathogenic germline variants inBRAF, KRAS, MAP2K1,andMAP2K2.To estimate cancer risk in CFC we conducted a systematic review using case reports and series.

Methods

We reviewed articles and abstracted CFC cases to form a retrospective cohort based on PRISMA guidelines. Genotype-pphenotype (cancer) correlations, standardized incidence ratios (SIR), cumulative incidence and cause-specific hazard rates for cancer and cancer-free in CFC were calculated.

Results

This study includes 198 publications reporting 690 patients. Only 1.6% (11) had cancer, including acute lymphoblastic leukemia (ALL). Six cancer patients harbored pathogenic variants withinBRAF, MAP2K1, andMAP2K2. Cumulative incidence by age 10 was 5% for cancer or cancer-free death. Hazard Ratio (death) was 1-2% until age 3 and declined thereafter. Significant SIRs were found for all sites (SIR=4.96) and ALL (SIR=24.23).

Conclusions

This is the largest investigation of cancer in CFC to date. Cancer risk in the CFC population is elevated but appears limited to earlier childhood. Modest case and cancer numbers could pose limitations to accurately assess cancer risk in CFC and more studies are needed.

Systematic Review Registration

The review was registered using PROSPERO under the identification tag CRD42023405823 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=405823)
Assessment of genes involved in lysosomal diseases using the ClinGen Clinical Validity framework
Authors: Groopman Emily , Mohan Shruthi , Waddell Amber , Wilke Matheus , Fernandez Raquel , Weaver Meredith , Chen Hongjie , Liu Hongbin , Bali Deeksha , Baudet Heather , Clarke Lorne , Hung Christina , Mao Rong , Pinto e Vairo Filippo , Racacho Lemuel , Yuzyuk Tatiana , Craigen William J , Goldstein Jennifer
Published: August 2024

Lysosomal diseases (LDs) are a heterogeneous group of rare genetic disorders that result in impaired lysosomal function, leading to progressive multiorgan system dysfunction. Accurate diagnosis is paramount to initiating targeted therapies early in the disease process in addition to providing prognostic information and appropriate support for families. In recent years, genomic sequencing technologies have become the first-line approach in the diagnosis of LDs. Understanding the clinical validity of the role of a gene in a disease is critical for the development of genomic technologies, such as which genes to include on next generation sequencing panels, and the interpretation of results from exome and genome sequencing. To this aim, the ClinGen Lysosomal Diseases Gene Curation Expert Panel utilized a semi-quantitative framework incorporating genetic and experimental evidence to assess the clinical validity of the 56 LD-associated genes on the Lysosomal Disease Network's list. Here, we describe the results, and the key themes and challenges encountered.