bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human cytomegalovirus glycoprotein variants governing viral tropism and syncytium formation in epithelial cells and macrophages
Authors: Cimato Giorgia , Zhou Xuan , Brune Wolfram , Frascaroli Giada 
Published: June 2024

ABSTRACT

Human cytomegalovirus (HCMV) displays a broad cell tropism, and the infection of biologically relevant cells such as epithelial, endothelial, and hematopoietic cells supports viral transmission, systemic spread, and pathogenesis in the human host. HCMV strains differ in their ability to infect and replicate in these cell types, but the genetic basis of these differences has remained incompletely understood. In this study, we investigated HCMV strain VR1814, which is highly infectious for epithelial cells and macrophages and induces cell-cell fusion in both cell types. A VR1814-derived bacterial artificial chromosome (BAC) clone, FIX-BAC, was generated many years ago but has fallen out of favor because of its modest infectivity. By sequence comparison and genetic engineering of FIX, we demonstrate that the high infectivity of VR1814 and its ability to induce syncytium formation in epithelial cells and macrophages depends on VR1814-specific variants of the envelope glycoproteins gB, UL128, and UL130. We also show that UL130-neutralizing antibodies inhibit syncytium formation, and a FIX-specific mutation in UL130 is responsible for its low infectivity by reducing the amount of the pentameric glycoprotein complex in viral particles. Moreover, we found that a VR1814-specific mutation in US28 further increases viral infectivity in macrophages, possibly by promoting lytic rather than latent infection of these cells. Our findings show that variants of gB and the pentameric complex are major determinants of infectivity and syncytium formation in epithelial cells and macrophages. Furthermore, the VR1814-adjusted FIX strains can serve as valuable tools to study HCMV infection of myeloid cells.

IMPORTANCE
Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients and the leading cause of congenital infections. HCMV infects various cell types, including epithelial cells and macrophages, and some strains induce the fusion of neighboring cells, leading to the formation of large multinucleated cells called syncytia. This process may limit the exposure of the virus to host immune factors and affect pathogenicity. However, the reason why some HCMV strains exhibit a broader cell tropism and why some induce cell fusion more than others is not well understood. We compared two closely related HCMV strains and provided evidence that small differences in viral envelope glycoproteins can massively increase or decrease the virus infectivity and its ability to induce syncytium formation. The results of the study suggest that natural strain variations may influence HCMV infection and pathogenesis in humans.
Sensorineural hearing impairment among preterm children: a Norwegian population-based study
Authors: Hemmingsen Dagny , Moster Dag , Engdahl Bo Lars , Klingenberg Claus 
Published: June 2024

ObjectiveTo investigate the risk for sensorineural hearing impairment (SNHI) in preterm infants, and to what extent the risk is attributed to perinatal morbidities and therapies.DesignPopulation-based cohort study using data from several nationwide registries.SettingNorwegian birth cohort 1999–2014, with data on SNHI until 2019.Participants60 023 live-born preterm infants, divided in moderate-late preterm (MLP) infants (32–36 weeks), very preterm (VP) infants (28–31 weeks) and extremely preterm (EP) infants (22–27 weeks), and a reference group with all 869 797 term-born infants from the study period.Main outcome measuresSNHI defined by selected ICD-10 codes, recorded during minimum 5-year observation period after birth.ResultsThe overall SNHI prevalence in the preterm cohort was 1.4% compared with 0.7% in the reference group. The adjusted risk ratios (95% CIs) for SNHI were 1.7 (1.5–1.8) in MLP infants, 3.3 (2.8–3.9) in VP infants and 7.6 (6.3–9.1) in EP infants. Among EP infants, decreasing gestational age was associated with a steep increase in the risk ratio of SNHI reaching 14.8 (7.7–28.7) if born at 22–23 weeks gestation. Among the VP and MLP infants, mechanical ventilation and antibiotic therapy had strongest association with increased risk of SNHI, but infants not receiving these therapies remained at increased risk. Among EP infants intracranial haemorrhage increased the already high risk for SNHI. We found no signs of delayed or late-onset SNHI in preterm infants.ConclusionPreterm birth is an independent risk factor for SNHI. Invasive therapies and comorbidities increase the risk, predominantly in infants born after 28 weeks gestation.
Association between metformin use with circumpapillary retinal nerve fibre layer thickness and capillary vessel density in glaucoma
Authors: Nishida Takashi , Moghimi Sasan , Gunasegaran Gopikasree , Walker Evan , Wu Jo-Hsuan , Rahmatnejad Kamran , Zangwill Linda M , Baxter Sally L , Weinreb Robert N 
Published: June 2024

Background/aims
To investigate the association between use of metformin and circumpapillary retinal nerve fibre layer (cpRNFL) thickness, as well as whole image capillary density (wiCD), in patients with glaucoma.

Methods
This cross-sectional study included patients with glaucoma suspect or primary open-angle glaucoma (POAG) underwent optical coherence tomography angiography imaging. Use and duration of antidiabetic medications were assessed at the time of imaging. Multivariable linear mixed-effect modelling was used to estimate the effect of diabetes medication on wiCD and cpRNFL while controlling for covariates including age, race, body mass index, diagnosis, 24–2 visual field mean deviation, and intraocular pressure, average signal strength index as well as any variables that showed a p &0.1 in the univariable analysis.

Results
A total of 577 eyes (330 POAG and 247 glaucoma suspect) of 346 patients were included. Sixty-five patients (23%) had diabetes, of whom 55 (78.5%) used metformin, and 17 (26.2%) used insulin. After adjusting for covariates, the association between metformin use and wiCD (1.56 (95% CI 0.40 to 2.71); p=0.008), duration of metformin use and wiCD (0.12 (95% CI 0.02 to 0.22) per 1 year longer; p=0.037), and metformin use and cpRNFL thickness (5.17 (95% CI 1.24 to 9.10) µm; p=0.010) had statistically significant associations in each model.

Conclusions
Metformin use was associated with higher wiCD and thicker cpRNFL. These findings indicate a potential association, underscoring the need for longitudinal studies to determine if metformin plays a role in the retinal conditions of patients with glaucoma.

Trial registration number

NCT00221897
Approaching the SDG targets with sustained political commitment: drivers of the notable decline in maternal and neonatal mortality in Morocco
Authors: Elomrani Sanae , Bezad Rachid , De Brouwere Vincent , Campbell Oona Maeve Renee , L Lange Isabelle , Oswald William Edward , Assarag Bouchra 
Published: June 2024

BackgroundBetween 2000 and 2017/2018, Morocco reduced its maternal mortality ratio by 68% and its neonatal mortality rate by 52%—a higher improvement than other North African countries. We conducted the Exemplars in Maternal and Neonatal Health study to systematically and comprehensively research factors associated with this rapid reduction in mortality over the past two decades.MethodsThe study was conducted from September 2020 to December 2021 using mixed methods, including: literature, database and document reviews, quantitative analyses of national data sets and qualitative key-informant interviews at national and district levels. Analyses were based on a conceptual framework of drivers of health and survival of mothers and neonates.ResultsA favourable political and economic environment, and a high political commitment encouraged prioritisation of maternal and neonatal health (MNH) by aligning evidence-based policy and technical approaches. Five main factors accounted for Morocco’s success: (1) continuous increases in antenatal care and institutional delivery and reductions socioeconomically-based inequalities in MNH service usage; (2) health-system strengthening by expanding the network of health facilities, with increased uptake of facility birthing, scale-up of the production of midwives, reductions in financial barriers and, later in the process, attention to improving the quality of care; (3) improved underlying health status of women and changes in reproductive patterns; (4) a supportive policy and infrastructure environment; and 5) increased education and autonomy of women.ConclusionOur study provides evidence that supportive changes in Morocco’s policy environment for maternal health, backed by greater political will and increased resources, significantly contributed to the dramatic progress in reducing maternal and neonatal mortality. While these efforts were successful in improving MNH in Morocco, several implementation challenges still require special attention and renewed political attention is needed.
Learning from success: the main drivers of the maternal and newborn health transition in seven positive-outlier countries and implications for future policies and programmes
Authors: Campbell Oona Maeve Renee , Amouzou Agbessi , Blumenberg Cauane , Boerma Ties 
Published: June 2024

Currently, about 8% of deaths worldwide are maternal or neonatal deaths, or stillbirths. Maternal and neonatal mortality have been a focus of the Millenium Development Goals and the Sustainable Development Goals, and mortality levels have improved since the 1990s. We aim to answer two questions: What were the key drivers of maternal and neonatal mortality reductions seen in seven positive-outlier countries from 2000 to the present? How generalisable are the findings?We identified positive-outlier countries with respect to maternal and neonatal mortality reduction since 2000. We selected seven, and synthesised experience to assess the contribution of the health sector to the mortality reduction, including the roles of access, uptake and quality of services, and of health system strengthening. We explored the wider context by examining the contribution of fertility declines, and the roles of socioeconomic and human development, particularly as they affected service use, the health system and fertility. We analysed government levers, namely policies and programmes implemented, investments in data and evidence, and political commitment and financing, and we examined international inputs. We contextualised these within a mortality transition framework.We found that strategies evolved over time as the contacts women and neonates had with health services increased. The seven countries tended to align with global recommendations but could be distinguished in that they moved progressively towards implementing their goals and in scaling-up services, rather than merely adopting policies. Strategies differed by phase in the transition framework—one size did not fit all.
Does proactive care in care homes improve survival? A quality improvement project
Authors: Attwood David , Hope Suzy V , Spicer Stuart G , Gordon Adam L , Boorer James , Ellis Wendy , Earley Michelle , Denovan Jillian , Hart Gerard , Williams Maria , Burdett Nicholas , Lemon Melissa 
Published: June 2024

BackgroundNHS England’s ‘Enhanced Health in Care Homes’ specification aims to make the healthcare of care home residents more proactive. Primary care networks (PCNs) are contracted to provide this, but approaches vary widely: challenges include frailty identification, multidisciplinary team (MDT) capability/capacity and how the process is structured and delivered.AimTo determine whether a proactive healthcare model could improve healthcare outcomes for care home residents.Design and settingQuality improvement project involving 429 residents in 40 care homes in a non-randomised crossover cohort design. The headline outcome was 2-year survival.MethodAll care home residents had healthcare coordinated by the PCN’s Older Peoples’ Hub. A daily MDT managed the urgent healthcare needs of residents. Proactive healthcare, comprising information technology-assisted comprehensive geriatric assessment (i-CGA) and advanced care planning (ACP), were completed by residents, with prioritisation based on clinical needs.Time-dependent Cox regression analysis was used with patients divided into two groups:Control group: received routine and urgent (reactive) care only.Intervention group: additional proactive i-CGA and ACP.ResultsBy 2 years, control group survival was 8.6% (n=108), compared with 48.1% in the intervention group (n=321), p<0.001. This represented a 39.6% absolute risk reduction in mortality, 70.2% relative risk reduction and the number needed to treat of 2.5, with little changes when adjusting for confounding variables.ConclusionA PCN with an MDT-hub offering additional proactive care (with an i-CGA and ACP) in addition to routine and urgent/reactive care may improve the 2-year survival in older people compared with urgent/reactive care alone.
Comparing acceptance of smoking cessation and smoke-free home intervention offers and associated factors among people with low income in the USA: baseline results of a randomised controlled trial
Authors: McQueen Amy , Wolff Jennifer , Grimes Lauren , Teshome Enguday , Garg Rachel , Thompson Tess , Carpenter Kelly , Kegler Michelle C , Kreuter Matthew W 
Published: June 2024

IntroductionState tobacco quitlines are the most commonly available smoking cessation programmes; however, they have low reach and typically only enrol people who are ready to quit in the next 30 days. Expanding quitline services may increase the total number of people engaged in tobacco control efforts and the number who eventually quit. In this randomised controlled trial, we offered both arms a tobacco quitline intervention. In arm 2, if they declined the quitline, we then offered a smoke-free home (SFH) intervention. We examined the number of participants who accepted each intervention offer at baseline and whether acceptance varied by participant characteristics.MethodsWe recruited 1982 people who called 211, a social services helpline for social needs; mean age=50, 68% female; 45% white, 41% black and 14% other race/ethnicity; 68% reported an annual household income <US$20 000.ResultsIn each arm, 59.7% of participants accepted the quitline offer. In arm 2, among those who declined the quitline offer, 53.1% accepted the SFH intervention offer. Thus, an additional 212 (21.4% of all arm 2 participants) people who smoke engaged in tobacco control programmes than would have with standard practice alone (quitline only). Acceptance differed by participant characteristics: males were less likely than females to accept either offer. Whites were less likely, and older adults and those with greater nicotine dependence were more likely, to accept the quitline offer.ConclusionsProactive approaches identified many low-income people who smoke and offering an SFH intervention retained many more of them in tobacco control efforts. Future trial results will assess intervention engagement and effects on cessation.Trial registration numberClinicalTrials.gov identifierNCT04311983.
Risk of colorectal neoplasia after removal of conventional adenomas and serrated polyps: a comprehensive evaluation of risk factors and surveillance use
Authors: Polychronidis Georgios , He Ming-Ming , Vithayathil Mathew , Knudsen Markus D , Wang Kai , Song Mingyang 
Published: June 2024

BackgroundSurveillance colonoscopy after polyp removal is recommended to prevent subsequent colorectal cancer (CRC). It is known that advanced adenomas have a substantially higher risk than non-advanced ones, but optimal intervals for surveillance remain unclear.DesignWe prospectively followed 156 699 participants who had undergone a colonoscopy from 2007 to 2017 in a large integrated healthcare system. Using multivariable Cox proportional hazards regression we estimated the subsequent risk of CRC and high-risk polyps, respectively, according to index colonoscopy polyps, colonoscopy quality measures, patient characteristics and the use of surveillance colonoscopy.ResultsAfter a median follow-up of 5.3 years, we documented 309 CRC and 3053 high-risk polyp cases. Compared with participants with no polyps at index colonoscopy, those with high-risk adenomas and high-risk serrated polyps had a consistently higher risk of CRC during follow-up, with the highest risk observed at 3 years after polypectomy (multivariable HR 5.44 (95% CI 3.56 to 8.29) and 8.35 (95% CI 4.20 to 16.59), respectively). Recurrence of high-risk polyps showed a similar risk distribution. The use of surveillance colonoscopy was associated with lower risk of CRC, with an HR of 0.61 (95% CI 0.39 to 0.98) among patients with high-risk polyps and 0.57 (95% CI 0.35 to 0.92) among low-risk polyps. Among 1548 patients who had high-risk polyps at both index and surveillance colonoscopies, 65% had their index polyps in the proximal colon and 30% had index and interval polyps in the same segments.ConclusionPatients with high-risk polyp findings were at higher risk of subsequent CRC and high-risk polyps and may benefit from early surveillance within 3 years. The subsite distribution of the index and recurrent high-risk polyps suggests the contribution of incomplete resection and missed lesions to the development of interval neoplasia.
Targeting the oncogenic m6A demethylase FTO suppresses tumourigenesis and potentiates immune response in hepatocellular carcinoma
Authors: Chen Ao , Zhang Vanilla Xin , Zhang Qingyang , Sze Karen Man-Fong , Tian Lu , Huang Hongyang , Wang Xia , Lee Eva , Lu Jingyi , Lyu Xueying , Lee Man-Fong Joyce , Wong Chun Ming , Ho Daniel Wai-Hung , Ng Irene Oi-Lin 
Published: June 2024

ObjectiveFat mass and obesity-associated protein (FTO), an eraser ofN6-methyadenosine (m6A), plays oncogenic roles in various cancers. However, its role in hepatocellular carcinoma (HCC) is unclear. Furthermore, small extracellular vesicles (sEVs, or exosomes) are critical mediators of tumourigenesis and metastasis, but the relationship between FTO-mediated m6A modification and sEVs in HCC is unknown.DesignThe functions and mechanisms of FTO and glycoprotein non-metastatic melanoma protein B (GPNMB) in HCC progression were investigated in vitro and in vivo. Neutralising antibody of syndecan-4 (SDC4) was used to assess the significance of sEV-GPNMB. FTO inhibitor CS2 was used to examine the effects on anti-PD-1 and sorafenib treatment.ResultsFTO expression was upregulated in patient HCC tumours. Functionally, FTO promoted HCC cell proliferation, migration and invasion in vitro, and tumour growth and metastasis in vivo. FTO knockdown enhanced the activation and recruitment of tumour-infiltrating CD8+T cells. Furthermore, we identified GPNMB to be a downstream target of FTO, which reduced the m6A abundance of GPNMB, hence, stabilising it from degradation by YTHN6-methyladenosine RNA binding protein F2. Of note, GPNMB was packaged into sEVs derived from HCC cells and bound to the surface receptor SDC4 of CD8+T cells, resulting in the inhibition of CD8+T cell activation. A potential FTO inhibitor, CS2, suppresses the oncogenic functions of HCC cells and enhances the sensitivity of anti-PD-1 and sorafenib treatment.ConclusionTargeting the FTO/m6A/GPNMB axis could significantly suppress tumour growth and metastasis, and enhance immune activation, highlighting the potential of targeting FTO signalling with effective inhibitors for HCC therapy.
ALK-rearranged mesenchymal neoplasms: a clinicopathological and molecular study of eight additional cases of an emerging group of tyrosine kinase fusion mesenchymal tumours
Authors: Zhao Ming , Song Jing , Yin Xiaona , Xu Jiayun , Teng Xiaodong , Wang Jian 
Published: June 2024

AimsMesenchymal neoplasms characterised byALKfusions mainly include inflammatory myofibroblastic tumour (IMT) and epithelioid fibrous histiocytoma (EFH). Most recently,ALK-rearranged mesenchymal tumours that are not IMT or EFH have been reported. Our aim is to further characterise eight such neoplasms, with a detailed clinicopathological, immunohistochemical and molecular analysis.MethodsClinicopathological features were assessed and partner agnostic targeted RNA-sequencing on clinically validated platforms was performed.ResultsThe patients consisted of seven males and one female with a median age of 47 years (28 –59 years). The tumours ranged in size from 2.0 to 10.0 cm (mean=3.0 cm) and involved superficial and deep soft tissue (n=6) and visceral locations (n=2). Of the seven patients with follow-up (9–130 months), two developed distant metastases and five had no disease recurrence or metastasis. The tumours demonstrated diverse architectures and variable cellularity and cellular morphologies. The main constitutive cells appeared in elongated spindled in three, primitive to ovoid in two and round to epithelioid in three cases. We expanded the histopathological spectrum to include mildly to moderately cellular spindled to stellate cells in a multinodular growth in a prominent myxoid and vascularised stroma (n=2). All tumours expressed ALK(D5F3); seven were positive for S100 protein and six were positive for CD34. By fluorescence in situ hybridisation,ALKrearrangement was identified in all eight tumours.ALKfusion partners were identified by RNA-sequencing in all cases, including previously reported:EML4(n=3), DCTN(n=1), CLIP1(n=1) andPLEKHH2(n=1), and also two novel fusion partners:TKT(n=1) andMMP2(n=1).ConclusionsOur study expands the clinicopathological and molecular spectrum ofALK-rearranged mesenchymal neoplasms.
Clinical and safety outcomes of acute stenting plus thrombectomy for carotid tandem lesions with large ischemic core
Authors: Deliktas Yakub , Derraz Imad , Finitsis Stephanos , Caroff Jildaz , Bourcier Romain , Soize Sébastien , Moulin Solène , Richard Sébastien , Marnat Gaultier , Hoferica Matúš , Cognard Christophe , Desilles Jean-Philippe , Anadani Mohammad , Olivot Jean-Marc , Casolla Barbara , Consoli Arturo , Lapergue Bertrand , Gory Benjamin 
Published: June 2024

BackgroundWe evaluated the clinical and safety outcomes of emergent carotid artery stenting (eCAS) plus endovascular thrombectomy (EVT) among patients with anterior tandem lesion (TL) and large ischemic core (LIC).MethodsThis retrospective study included consecutive stroke patients enrolled in the Endovascular Treatment in Ischemic Stroke Registry in France between January 2015 and June 2023. We compared the outcomes of carotid stenting vs no stenting in tandem lesion with pre-treatment LIC (Alberta Stroke Program Early CT Score (ASPECTS) 3–5) and stenting in tandem lesion vs thrombectomy alone for isolated intracranial occlusions with pre-treatment LIC. Primary outcome was a score of 0 to 3 on the modified Rankin scale (mRS) at 90 days. Multivariable mixed-effects logistic regression was performed.ResultsAmong 218 tandem patients with LIC, 55 were treated with eCAS plus EVT. The eCAS group had higher odds of 90-day mRS 0–3 (adjusted Odds Ratio (aOR) 2.40, 95% confidence interval (CI) 1.10 to 5.21; p=0.027). There were no differences in the risk of any intracerebral hemorrhage (OR 1.41, 95% CI 0.69 to 2.86; p=0.346), parenchymal hematoma (aOR 1.216, 95% CI 0.49 to 3.02; p=0.675), symptomatic intracerebral hemorrhage (aOR 1.45, 95% CI 0.60 to 3.48; p=0.409), or 90-day mortality (aOR 0.74, 95% CI 0.33 to 1.68; p=0.472). eCAS was associated with a higher rate of carotid patency at day 1 (aOR 3.54, 95% CI 1.14 to 11.01; p=0.028). Safety outcomes were similar between EVT+eCAS group in TL-LIC and EVT alone group in isolated intracranial occlusions with LIC.ConclusioneCAS appears to be a safe and effective strategy in patients with TL and LIC volume.