bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exhaled Mycobacterium tuberculosis predicts incident infection in household contacts
Authors: Williams CML , Muhammad A , Sambou B , Bojang A , Jobe A , Daffeh G , Owolabi O , Pan D , Pareek M , Barer MR , Sutherland JS , Haldar P 
Published: November 2021

AbstractBackgroundHalting transmission of Mycobacterium tuberculosis (Mtb) by identifying infectious individuals early is key to eradicating Tuberculosis (TB). Here we evaluate face mask sampling as a tool for stratifying infection risk in household contacts of pulmonary TB (pTB).MethodsForty-six sputum positive pTB patients in The Gambia (Aug 2016-Nov 2017) consented to mask sampling prior to commencing treatment. Incident Mtb infection was defined in their 181 household contacts as QuantiFERON (QFT) conversion or an increase in Interferon-ƴ release of ≥ 1IU/ml, 6 months after index diagnosis. Multilevel mixed-effects logistical regression analysis with cluster adjustment by household was used to identify predictors of incident infection.FindingsMtb was detected in 91% of pTB mask samples with high variation in IS6110 copies (5.3 ×102 to 1.2 ×107). A high mask Mtb level (≥20,000 IS6110 copies) was observed in 45% of cases and independently associated with increased likelihood of incident Mtb infection in contacts (AOR (95%CI) 3.20 (1.26 - 8.12), p=0.01), compared with cases having low/negative mask Mtb levels. Mask Mtb level was a better predictor of incident Mtb infection than sputum bacillary load, chest radiographic characteristics or sleeping proximity.InterpretationMask sampling offers a highly sensitive and non-invasive tool to support both diagnosis of pTB and stratification of individuals who are most infectious. Our findings have the potential to revolutionise contact screening strategies and outbreak management in high TB burden settings and is of urgent public health importance.
Surgical Outcomes of Myelomeningocele Repair: a 20-Year Experience from a Single Center in a Middle-Income Country
Authors: Zoghi Sina , Feili Maryam , Mosayebi Mohammad Amin , Afifi Mohammad Amin , Feili Afrooz , Masoudi Mohammad Sadegh , Taheri Reza 
Published: November 2021

AbstractObjectiveSpina bifida primarily affects people of low and middle socioeconomic status. Herein, we describe the outcome of myelomeningocele surgical management in Iran and predictors of its postoperative complications and mortality.MethodsThis retrospective chart review studies the children who underwent surgical management for myelomeningocele in Shiraz, Fars province, Iran, from May 2001 to September 2020. To this end, we investigated mortality and 30-day complications and the factors that determined the operation’s outcome.Results256 patients were enrolled. The median age at the operation was roughly eight days (IQR: 7). The most common site of involvement of Myelomeningocele (MMC) was Lumbosacral (86%, n = 204). At the evaluation conducted prior to operation, CSF leaking was observed in 7% (n=16) of the patients. Postoperatively, 5.7% of the patients were expired in the 30 days following the operation (n = 14), while 24% needed readmission (n = 47). The most common complications leading to readmission included wound dehiscence (n = 10, 42%) and wound purulence (n = 6, 25%). No variable was significantly associated with postoperative complication except for the site of the lesion (p-value = 0.035) and the presence of the lipid content in the defect (p-value = 0.044).ConclusionsMost patients born with MMC are referred for the neurosurgical evaluation following their birth; however, as results show there is much left to be desired compared with the 48h recommended by The Congress of Neurological Surgeons. Here, we concluded that presence of lipid compartment in the lesion and the site of the lesion are the two factor that were associated with the rate of mortality. However, further investigation into preoperative interventions and risk factors to mitigate risk of postoperational complications and mortality is highly encouraged. We highly advocate for the investigation and dissemination of the outcome of the conventional surgical management of MMC in financially restrained areas; because they can show the limitation these settings are confronted with (that are in a way unique to them and different from the resourceful settings) and provide a model for other similar areas with limited suitable care.
A connectivity signature for glioblastoma
Authors: Hai Ling , Hoffmann Dirk C , Mandelbaum Henriette , Xie Ruifan , Ito Jakob , Jung Erik , Weil Sophie , Sievers Philipp , Venkataramani Varun , Azorin Daniel Dominguez , Ernst Kati , Reibold Denise , Will Rainer , Suvà Mario L. , Herold-Mende Christel , Sahm Felix , Winkler Frank , Schlesner Matthias , Wick Wolfgang , Kessler Tobias 
Published: November 2021

AbstractTumor cell extensions called tumor microtubes (TMs) in glioma resemble neurites during neurodevelopment and connect glioma cells to a network that has considerable relevance for tumor progression and therapy resistance. The determination of interconnectivity in individual tumors has been challenging and the impact of tumor cell connectivity on patient survival remained unresolved so far. Here, a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells was established and clinically validated. Thirty-four of 40 connectivity genes were related to neurogenesis, neural tube development or glioma progression, including the TM-network-relevant GAP43 gene. Astrocytic-like and mesenchymal-like GB cells had the highest connectivity signature scores in scRNA-Seq data of patient-derived xenografts and patient samples. In 230 human GBs, high connectivity correlated with the mesenchymal expression subtype, TP53 wildtype, and with dismal patient survival. CHI3L1 was identified as a robust molecular marker of connectivity. Thus, the connectivity signature allows novel insights into brain tumor biology, provides a proof-of-principle that tumor cell connectivity is relevant for patients’ prognosis, and serves as a robust biomarker that can be used for future clinical trials.Statement of significanceIntegration of GB cells into functional networks drives tumor progression and resistance. Here, we established and validated a novel connectivity gene expression signature of single GB cells and whole tumors that can be easily applied to clinical and preclinical samples. It is shown that connectivity is determining prognosis combining molecular, functional and clinical insights into the disease.
Changes in transmission of Enterovirus D68 (EV-D68) in England inferred from seroprevalence data
Authors: Pons-Salort Margarita , Lambert Ben , Kamau Everlyn , Pebody Richard , Harvala Heli , Simmonds Peter , Grassly Nicholas C 
Published: November 2021

AbstractThe factors leading to the global emergence of enterovirus D68 (EV-D68) in 2014 as a cause of acute flaccid myelitis (AFM) in children are unknown. To investigate potential changes in virus transmissibility or population susceptibility, we measured the seroprevalence of EV-D68-specific neutralising antibodies in serum samples collected in England in 2006, 2011 and 2017. Using catalytic mathematical models, we estimate an approximately two-fold increase in the basic reproduction number over the 10-year study period, coinciding with the emergence of clade B around 2009. Despite such increase in transmission, the virus was already widely circulating before the AFM outbreaks and the increase of infections by age cannot explain the observed number of AFM cases. Therefore, the acquisition of or an increase in neuropathogenicity would be additionally required to explain the emergence of outbreaks of AFM. Our results provide evidence that changes in enterovirus phenotypes cause major changes in disease epidemiology.
Cumulative incidence of SARS-CoV-2 and associated risk factors among healthcare workers in the Eastern Cape, South Africa
Authors: Stead David , Adeniyi Oladele Vincent , Singata-Madliki Mandisa , Abrahams Shareef , Batting Joanne , Jelliman Eloise , Parrish Andrew 
Published: November 2021

AbstractObjectivesThis study assesses the cumulative incidence of SARS-CoV-2 infection among healthcare workers (HCWs) during South Africa’s first wave and examines the associated demographic, health-related, and occupational risk factors for infection.MethodsMulti-stage cluster sampling was used in a cross-sectional study to recruit 1,309 HCWs from two academic hospitals in the Eastern Cape, South Africa over six weeks in November and December 2020. Prior test results for SARS-CoV-2 polymerase chain reaction (PCR) and participants’ characteristics were recorded while a blood sample was drawn for detection of IgG antibodies against SARS-CoV-2 nucleocapsid protein. The primary outcome measure was the SARS-CoV-2 cumulative incidence rate, defined as the combined total of positive results for either PCR or IgG antibodies, divided by the total sample. The secondary outcome was significant risk factors associated with infection.ResultsOf the total participants included in the analysis (N=1295), the majority were female (81.5%), of black race (78.7%) and nurses (44.8%). A total of 390 (30.1%) HCWs had a positive SARS-CoV-2 PCR result and SARS-CoV-2 antibodies were detected in 488 (37.7%), yielding a cumulative incidence of 47.2% (n = 611). In the adjusted logistic regression model, being overweight (Adjusted odds ratio (AOR) = 2.15, 95% CI 1.44-3.20), obese (AOR = 1.37, 95% CI 1.02-1.85) and living with HIV (AOR = 1.78, 95% CI 1.38-were independently associated with SARS-CoV-2 infection. There was no significant difference in infection rates between high, medium and low COVID-19 exposure working environments.ConclusionsThe high SARS-CoV-2 cumulative incidence in the cohort was surprising this early in the epidemic and probably related to exposure both in and outside the hospitals. To mitigate the impact of SARS-CoV-2 among HCWs, infection prevention and control (IPC) strategies should target community transmission in addition to screening for HIV and metabolic conditions.Strengths and limitations of this studyThis is a large representative sample of the total workforce of the two hospitals, with a good spectrum of staff category.Combining the historical SARS-CoV-2 PCR results with the Nucleocapsid IgG enabled capturing of some of the asymptomatic and missed SARS-CoV-2 infections.This is one of the first studies to look at SARS-CoV-2 infection risk factors in a high exposure environment in Africa.A limitation is that HIV ELISA and CD4 counts were not tested, but relied on self-report, which may likely underestimate the burden of HIV in the cohort.
Neutralisation of the SARS-CoV-2 Delta sub-lineage AY.4.2 and B.1.617.2 + E484K by BNT162b2 mRNA vaccine-elicited sera
Authors: Lassaunière Ria , Polacek Charlotta , Fonager Jannik , Bennedbæk Marc , Boding Lasse , Rasmussen Morten , Fomsgaard Anders 
Published: November 2021

AbstractSeveral factors may account for the recent increased spread of the SARS-CoV-2 Delta sublineage AY.4.2 in the United Kingdom, Romania, Poland, and Denmark. Here, we evaluate the sensitivity of AY.4.2 to neutralisation by sera from Pfizer/BioNTech (BNT162b2) vaccine recipients. AY.4.2 neutralisation was comparable to other circulating Delta lineages or sublineages. In contrast, the more rare B.1.617.2+E484K variant showed a significant >4-fold reduction in neutralisation that warrants surveillance of strains with the acquired E484K mutation.
Interchromosomal interaction of homologous Stat92E alleles regulates transcriptional switch during stem-cell differentiation
Authors: Antel Matthew , Masoud Madona , Raj Romir , Pan Ziwei , Li Sheng , Mellone Barbara G. , Inaba Mayu 
Published: November 2021

AbstractThe strength of pairing of homologous chromosomes differs in a locus-specific manner and is correlated to gene expression states. However, the functional impact of homolog pairing on local transcriptional activity is still unclear. Drosophila male germline stem cells (GSCs) constantly divide asymmetrically to produce one GSC and one differentiating gonialblast (GB). The GB then enters the differentiation program in which stem cell specific genes are quickly downregulated. Here we demonstrate that a change in local pairing state of the Stat92E locus is required for the downregulation of the Stat92E gene during differentiation. Using OligoPaint fluorescent in situ hybridization (FISH), we show that the interaction between homologous regions of Stat92E is always tight in GSCs and immediately loosened in GBs. When one of the Stat92E locus was absent or relocated to another chromosome, Stat92E did not pair and failed to downregulate, suggesting that the pairing is required for switching of transcriptional activity. The defect in downregulation of Stat92E was also observed upon knockdown of global pairing or anti-pairing factors. Moreover, the Stat92E enhancer element, but not cis-transcription, is required for the change in pairing state, indicating that it is not a consequence of transcriptional changes. GSCs are known to inherit pre-existing histones H3 and H4, while newly synthesized histones are distributed in GBs. When this histone inheritance was compromised, the change in Stat92E pairing did not occur, suggesting that it is an intrinsically programmed process during asymmetric stem cell division. We propose that the change of local pairing state may be a common process to reprogram gene activity during cell-differentiation.
In vitro reconstitution of divisome activation
Authors: Radler Philipp , Baranova Natalia , Caldas Paulo , Sommer Christoph , López-Pelegrín Mar , Michalik David , Loose Martin 
Published: November 2021

AbstractBacterial cell division is coordinated by the Z-ring, a cytoskeletal structure of treadmilling filaments of FtsZ and their membrane anchors, FtsA and ZipA. For divisome maturation and initiation of constriction, the widely conserved actin-homolog FtsA plays a central role, as it links downstream cell division proteins in the membrane to the Z-ring in the cytoplasm. According to the current model, FtsA initiates cell constriction by switching from an inactive polymeric conformation to an active monomeric form, which then stabilizes the Z-ring and recruits downstream proteins such as FtsN. However, direct biochemical evidence for this mechanism is missing so far. Here, we used biochemical reconstitution experiments in combination with quantitative fluorescence microscopy to study the mechanism of divisome activation in vitro. By comparing the properties of wildtype FtsA and FtsA R286W, a gain-of-function mutant thought to mimic its active state, we found that active FtsA outperforms the wildtype protein in replicating FtsZ treadmilling dynamics, filament stabilization and FtsN recruitment. We could attribute these differences to a faster membrane exchange of FtsA R286W as well as its higher packing density below FtsZ filaments. Using FRET microscopy, we also show that binding of FtsN does not compete with, but promotes FtsA self-interaction. Together, our findings shed new light on the assembly and activation of the bacterial cell division machinery and the mechanism of how FtsA initiates cell constriction.
CRISPR-Cas9 mediated nuclear transport and genomic integration of nanostructured genes in human primary cells
Authors: Lin-Shiao Enrique , Pfeifer Wolfgang G. , Shy Brian R. , Doost Mohammad Saffari , Chen Evelyn , Vykunta Vivasvan S. , Hamilton Jennifer R. , Stahl Elizabeth C. , Lopez Diana M. , Espinoza Cindy R. Sandoval , Dejanov Alexander E. , Lew Rachel J. , Poirer Michael G. , Marson Alexander , Castro Carlos E. , Doudna Jennifer A. 
Published: November 2021

AbstractDNA nanostructures are a promising tool for delivery of a variety of molecular payloads to cells. DNA origami structures, where 1000’s of bases are folded into a compact nanostructure, present an attractive approach to package genes; however, effective delivery of genetic material into cell nuclei has remained a critical challenge. Here we describe the use of DNA nanostructures encoding an intact human gene and a fluorescent-protein encoding gene as compact templates for gene integration by CRISPR-mediated homology-directed repair (HDR). Our design includes CRISPR-Cas9 ribonucleoprotein (RNP) binding sites on the DNA nanostructures to increase shuttling of structures into the nucleus. We demonstrate efficient shuttling and genomic integration of DNA nanostructures using transfection and electroporation. These nanostructured templates display lower toxicity and higher insertion efficiency compared to unstructured double-stranded DNA (dsDNA) templates in human primary cells. Furthermore, our study validates virus-like particles (VLPs) as an efficient method of DNA nanostructure delivery, opening the possibility of delivering DNA nanostructures in vivo to specific cell types. Together these results provide new approaches to gene delivery with DNA nanostructures and establish their use as large HDR templates, exploiting both their design features and their ability to encode genetic information. This work also opens a door to translate other DNA nanodevice functions, such as measuring biophysical properties, into cell nuclei.Teaser SentenceCRISPR-Cas9 mediates nuclear transport and integration of nanostructured genes in human primary cells
Central and peripheral delivery of AAV9-SMN target different pathomechanisms in a mouse model of spinal muscular atrophy
Authors: Reilly Aoife , Deguise Marc-Olivier , Beauvais Ariane , Yaworski Rebecca , Thebault Simon , Tessier Daniel R. , Tabard-Cossa Vincent , Hensel Niko , Schneider Bernard L. , Kothary Rashmi 
Published: November 2021

AbstractSpinal muscular atrophy (SMA) is a neuromuscular disease caused by loss of the SMN1 gene. Although lower motor neurons are a primary target, there is evidence that peripheral organ defects contribute to SMA. Current SMA gene therapy uses a single, high titre intravenous bolus of AAV9-SMN resulting in impressive, yet limited amelioration of the clinical phenotype. However, risks of this treatment include liver toxicity. Intrathecal administration is under clinical trial but was interrupted due to safety concerns in a concomitant animal study. As there is no direct comparison between the different delivery strategies while avoiding high dose toxicity, we injected SMA mice with low dose scAAV9-cba-SMN either intravenously (IV) for peripheral SMN restoration or intracerebroventricularly (ICV) for CNS-focused SMN restoration. Here, IV injections restored SMN in peripheral tissues but not CNS, while ICV injections mildly increased SMN in the periphery and the CNS. Consequently, only ICV treatment rescued motor neuron degeneration. Surprisingly, both treatments resulted in an impressive rescue of survival, weight, motor function, and peripheral phenotypes including liver and pancreas pathology. Our work highlights independent contributions of peripheral organs to SMA pathology and suggests that treatments should not be restricted to the motor neuron.Graphical Abstract
Supply chain resilience and business responses to disruptions of the COVID-19 pandemic
Authors: Ramanathan Usha , Aluko Olu , Ramanathan Ramakrishnan 
Published: November 2021

PurposeAt its peak, the COVID-19 pandemic has created disruption to food supply chains in the UK and for the entire world. Although societal changes created some resilience within the supply chains, high volatility in demand creates supply, logistics and distribution issues. This is reflected in the economic instability of businesses and small and medium enterprises (SMEs). In this paper, the authors explore factors behind this initial disruption in the supply chains and offer suggestions to businesses based on the established practices and theories.Design/methodology/approachThe authors use mixed methods research. First, the authors conducted an exploratory study by collecting data from published online sources. Then, the authors analysed possible scenarios from the available information using regression. The authors then conducted two interviews with UK retail sector representatives. These scenarios have been compared and contrasted to provide decision-making points to businesses and supply chain players to tackle current and any future potential disruptions.FindingsThe findings from the current exploratory study inform the volatility of supply chains. The authors suggested some possible responses from businesses, during and after the pandemic.Originality/valueThe regression model provides a decision-making approach to help supply chain businesses during the pandemic outbreak. Once a complete data set of COVID-19 is available, the authors can create a resilience model that can help businesses and supply chains.
The positive aspects of fire use: a grounded theory of the experiences of non-criminalised fire users
Authors: Horsley Faye K. 
Published: November 2021

PurposePsychological research on fire has focussed primarily on its misuse in the form of arson and firesetting, which reflects a tradition in forensic psychology for focussing on risk and pathological behaviour. However, this is inconsistent with the strengths-based approach because it fails to account for positive aspects of fire and law-abiding/ healthy interactions with fire. This study aims to explore the psychology of non-criminalised forms of fire use. It is predicated on a novel, dimensional, conceptualisation of fire-related behaviour – the continuum of fire use (CoFU; Horsley, 2020, 2021).Design/methodology/approachSemi-structured interviews were conducted with 12 adults who use fire in law-abiding forms. Data were analysed using techniques informed by grounded theory. Steps were taken to ensure reliability and validity, including a Cohen’s Kappa calculation, which indicated an agreement level of 0.8 between two raters.FindingsFour core themes were identified relating to the benefits of fire on psychological well-being, namely, immediate gratification; hope and empowerment; self-concept and emotional security.Research limitations/implicationsDrawing on findings from this study, a theoretical framework of the psychology of non-criminalised fire use is presented. This is a preliminary conceptualisation and more work is needed to address this under-researched topic.Practical implicationsThe findings can inform the work of forensic practitioners. They highlight the importance of considering service users' positive interactions with fire, alongside maladaptive/ criminal use. This has implications for the assessment of fire setters, as well as rehabilitative approaches.Social implicationsIt is argued in this paper that a society-wide approach is key to firesetting reduction. More specifically, findings can inform the development and refinement of early intervention programmes, which focus on supporting young people to develop a healthy relationship with fire.Originality/valueTo the best of the authors’ knowledge, this study is the first to explore the psychology of non-criminalised forms of fire use. It is predicated on a novel, dimensional, conceptualisation of fire-related behaviour – the continuum of fire use (CoFU; Horsley, 2020, 2021a, 2021b).