bluuebunny/crossref_metadata_2025 huggingface dataset:
Acetyl-CoA carboxylase 1 controls a lipid droplet–peroxisome axis and is a vulnerability of endocrine-resistant ER
+
breast cancer
Authors: Bacci Marina , Lorito Nicla , Smiriglia Alfredo , Subbiani Angela , Bonechi Francesca , Comito Giuseppina , Morriset Ludivine , El Botty Rania , Benelli Matteo , López-Velazco Joanna I. , Caffarel Maria M. , Urruticoechea Ander , Sflomos George , Malorni Luca , Corsini Michela , Ippolito Luigi , Giannoni Elisa , Meattini Icro , Matafora Vittoria , Havas Kristina , Bachi Angela , Chiarugi Paola , Marangoni Elisabetta , Morandi Andrea
Published: February 2024

Targeting aromatase deprives ER
+
breast cancers of estrogens and is an effective therapeutic approach for these tumors. However, drug resistance is an unmet clinical need. Lipidomic analysis of long-term estrogen-deprived (LTED) ER
+
breast cancer cells, a model of aromatase inhibitor resistance, revealed enhanced intracellular lipid storage. Functional metabolic analysis showed that lipid droplets together with peroxisomes, which we showed to be enriched and active in the LTED cells, controlled redox homeostasis and conferred metabolic adaptability to the resistant tumors. This reprogramming was controlled by acetyl-CoA-carboxylase-1 (ACC1), whose targeting selectively impaired LTED survival. However, the addition of branched- and very long–chain fatty acids reverted ACC1 inhibition, a process that was mediated by peroxisome function and redox homeostasis. The therapeutic relevance of these findings was validated in aromatase inhibitor–treated patient-derived samples. Last, targeting ACC1 reduced tumor growth of resistant patient-derived xenografts, thus identifying a targetable hub to combat the acquisition of estrogen independence in ER
+
breast cancers.
APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model
Authors: Jiang Shihe , Li Xindi , Li Yan , Chang Zhilin , Yuan Meng , Zhang Ying , Zhu Huimin , Xiu Yuwen , Cong Hengri , Yin Linlin , Yu Zhen-Wei , Fan Junwan , He Wenyan , Shi Kaibin , Tian De-Cai , Zhang Jing , Verkhratsky Alexei , Jin Wei-Na , Shi Fu-Dong
Published: February 2024

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)–rich ADEVs in patients with AQP4-Abs–positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE
130–149
attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor–related protein 1 (LRP1) could block the restorative effects of APOE
130–149
administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE
−/−
mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.
Enterohemorrhagic
Escherichia coli
effector EspF triggers oxidative DNA lesions in intestinal epithelial cells
Authors: Fang Yuting , Fu Muqing , Li Xinyue , Zhang Bao , Wan Chengsong
Published: February 2024

Attaching/effacing (A/E) pathogens induce DNA damage and colorectal cancer by injecting effector proteins into host cells via the type III secretion system (T3SS). EspF is one of the T3SS-dependent effector proteins exclusive to A/E pathogens, which include enterohemorrhagic
Escherichia coli
. The role of EspF in the induction of double-strand breaks (DSBs) and the phosphorylation of the repair protein SMC1 has been demonstrated previously. However, the process of damage accumulation and DSB formation has remained enigmatic, and the damage response is not well understood. Here, we first showed a compensatory increase in the mismatch repair proteins MutS homolog 2 (MSH2) and MSH6, as well as poly(ADP-ribose) polymerase 1, followed by a dramatic decrease, threatening cell survival in the presence of EspF. Flow cytometry revealed that EspF arrested the cell cycle at the G2/M phase to facilitate DNA repair. Subsequently, 8-oxoguanine (8-oxoG) lesions, a marker of oxidative damage, were assayed by ELISA and immunofluorescence, which revealed the accumulation of 8-oxoG from the cytosol to the nucleus. Furthermore, the status of single-stranded DNA (ssDNA) and DSBs was confirmed. We observed that EspF accelerated the course of DNA lesions, including 8-oxoG and unrepaired ssDNA, which were converted into DSBs; this was accompanied by the phosphorylation of replication protein A 32 in repair-defective cells. Collectively, these findings reveal that EspF triggers various types of oxidative DNA lesions with impairment of the DNA damage response and may result in genomic instability and cell death, offering novel insight into the tumorigenic potential of EspF.

IMPORTANCE

Oxidative DNA lesions play causative roles in colitis-associated colon cancer. Accumulating evidence shows strong links between attaching/effacing (A/E) pathogens and colorectal cancer (CRC). EspF is one of many effector proteins exclusive to A/E pathogens with defined roles in the induction of oxidative stress, double-strand breaks (DSBs), and repair dysregulation. Here, we found that EspF promotes reactive oxygen species generation and 8-oxoguanine (8-oxoG) lesions when the repair system is activated, contributing to sustained cell survival. However, infected cells exposed to EspF presented 8-oxoG, which results in DSBs and ssDNA accumulation when the cell cycle is arrested at the G2/M phase and the repair system is defective or saturated by DNA lesions. In addition, we found that EspF could intensify the accumulation of nuclear DNA lesions through oxidative and replication stress. Overall, our work highlights the involvement of EspF in DNA lesions and DNA damage response, providing a novel avenue by which A/E pathogens may contribute to CRC.
Revised whole genome and DNA methylome of
Mycobacterium marinum
type strain ATCC 927
T
Authors: Savijoki Kirsi , Deptula Paulina , Roberts Richard J. , Hammarén Milka , Yli-Kauhaluoma Jari , Varmanen Pekka , Parikka Mataleena
Published: February 2024

Mycobacterium marinum
, a slow-growing Actinobacterium, typically induces tuberculosis-like disease in fish. Here, we report a new reference sequence for
M. marinum
ATCC 927
T
, along with its DNA methylome. This aims to maximize the research potential of this type strain and facilitates investigations into the pathomechanisms of human tuberculosis.
The complete genome of
Vibrio
sp. 16 unveils two circular chromosomes and a distinctive 46-kb plasmid
Authors: Wu Xiaofen , Segall Anca M. , Giglione Carmela , Meinnel Thierry
Published: February 2024

The entire 4.6-Mb genome of
Vibrio
sp. 16, encoding 4,270 genes, best matches with
Vibrio rotiferianus
. A 46-kb plasmid (pVDT1), alongside two circular chromosomes, showcases
parAB
/
repB
partition genes and three toxin/antitoxin systems potentially linked to phage infection.
Liver sinusoidal cells eliminate blood-borne phage K1F
Authors: Sánchez Romano Javier , Simón-Santamaría Jaione , McCourt Peter , Smedsrød Bård , Mortensen Kim Erlend , Sagona Antonia P. , Sørensen Karen Kristine , Larsen Anett Kristin
Published: February 2024

Phage treatment has regained attention due to an increase in multiresistant bacteria. For phage therapy to be successful, phages must reach their target bacteria in sufficiently high numbers. Blood-borne phages are believed to be captured by macrophages in the liver and spleen. Since liver sinusoids also consist of specialized scavenger liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs), this study investigated the contribution of both cell types in the elimination of
Escherichia coli
phage K1Fg10b::gfp (K1F
gfp
) in mice. Circulatory half-life, organ, and hepatocellular distribution of K1F
gfp
were determined following intravenous administration. Internalization of K1F
gfp
and effects of phage opsonization on uptake were explored using primary mouse and human LSEC and KC cultures. When inoculated with 10
7
virions, >95% of the total K1F
gfp
load was eliminated from the blood within 20 min, and 94% of the total retrieved K1F
gfp
was localized to the liver. Higher doses resulted in slower elimination, possibly reflecting temporary saturation of liver scavenging capacity. Phage DNA was detected in both cell types, with a KC:LSEC ratio of 12:1 per population following cell isolation. Opsonization with plasma proteins increased time-dependent cellular uptake in both LSECs and KCs
in vitro
. Internalized phages were rapidly transported along the endocytic pathway to lysosomal compartments. Reduced viability of intracellular K1F
gfp
corroborated inactivation following endocytosis. This study is the first to identify phage distribution in the liver at the hepatocellular level, confirming clearance of K1F
gfp
performed mostly by KCs with a significant uptake also in LSECs.

IMPORTANCE

Faced with the increasing amounts of bacteria with multidrug antimicrobial resistance, phage therapy has regained attention as a possible treatment option. The phage field has recently experienced an emergence in commercial interest as research has identified new and more efficient ways of identifying and matching phages against resistant superbugs. Currently, phages are unapproved drugs in most parts of the world. For phages to reach broad clinical use, they must be shown to be clinically safe and useful. The results presented herein contribute to increased knowledge about the pharmacokinetics of the T7-like phage K1F in the mammalian system. The cell types of the liver that are responsible for rapid phage blood clearance are identified. Our results highlight the need for more research about appropriate dose regimens when phage therapy is delivered intravenously and advise essential knowledge about cell systems that should be investigated further for detailed phage pharmacodynamics.
Vero cell-adapted SARS-CoV-2 strain shows increased viral growth through furin-mediated efficient spike cleavage
Authors: Minami Shohei , Kotaki Tomohiro , Sakai Yusuke , Okamura Shinya , Torii Shiho , Ono Chikako , Motooka Daisuke , Hamajima Rina , Nouda Ryotaro , Nurdin Jeffery A. , Yamasaki Moeko , Kanai Yuta , Ebina Hirotaka , Maeda Yusuke , Okamoto Toru , Tachibana Taro , Matsuura Yoshiharu , Kobayashi Takeshi
Published: February 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes several host proteases to cleave the spike (S) protein to enter host cells. SARS-CoV-2 S protein is cleaved into S1 and S2 subunits by furin, which is closely involved in the pathogenicity of SARS-CoV-2. However, the effects of the modulated protease cleavage activity due to S protein mutations on viral replication and pathogenesis remain unclear. Herein, we serially passaged two SARS-CoV-2 strains in Vero cells and characterized the cell-adapted SARS-CoV-2 strains
in vitro
and
in vivo
. The adapted strains showed high viral growth, effective S1/S2 cleavage of the S protein, and low pathogenicity compared with the wild-type strain. Furthermore, the viral growth and S1/S2 cleavage were enhanced by the combination of the Δ68–76 and H655Y mutations using recombinant SARS-CoV-2 strains generated by the circular polymerase extension reaction. The recombinant SARS-CoV-2 strain, which contained the mutation of the adapted strain, showed increased susceptibility to the furin inhibitor, suggesting that the adapted SARS-CoV-2 strain utilized furin more effectively than the wild-type strain. Pathogenicity was attenuated by infection with effectively cleaved recombinant SARS-CoV-2 strains, suggesting that the excessive cleavage of the S proteins decreases virulence. Finally, the high-growth-adapted SARS-CoV-2 strain could be used as the seed for a low-cost inactivated vaccine; immunization with this vaccine can effectively protect the host from SARS-CoV-2 variants. Our findings provide novel insights into the growth and pathogenicity of SARS-CoV-2 in the evolution of cell-cell transmission.

IMPORTANCE

The efficacy of the S protein cleavage generally differs among the SARS-CoV-2 variants, resulting in distinct viral characteristics. The relationship between a mutation and the entry of SARS-CoV-2 into host cells remains unclear. In this study, we analyzed the sequence of high-growth Vero cell-adapted SARS-CoV-2 and factors determining the enhancement of the growth of the adapted virus and confirmed the characteristics of the adapted strain by analyzing the recombinant SARS-CoV-2 strain. We successfully identified mutations Δ68-76 and H655Y, which enhance viral growth and the S protein cleavage by furin. Using recombinant viruses enabled us to conduct a virus challenge experiment
in vivo
. The pathogenicity of SARS-CoV-2 introduced with the mutations Δ68-76, H655Y, P812L, and Q853L was attenuated in hamsters, indicating the possibility of the attenuation of excessive cleaved SARS-CoV-2. These findings provide novel insights into the infectivity and pathogenesis of SARS-CoV-2 strains, thereby significantly contributing to the field of virology.
Genomic epidemiology of the primary methicillin-resistant
Staphylococcus aureus
clones causing invasive infections in Paraguayan children
Authors: Guillén Rosa , Salinas Claudia , Mendoza-Álvarez Alejandro , Rubio Rodríguez Luis A. , Díaz-de Usera Ana , Lorenzo-Salazar José M. , González-Montelongo Rafaela , Flores Carlos , Rodríguez Fátima
Published: February 2024

Methicillin-resistant
Staphylococcus aureus
(MRSA) is one of the major human pathogens. It could carry numerous resistance genes and virulence factors in its genome, some of which are related to the severity of the infection. An observational, descriptive, cross-sectional study was designed to molecularly analyze MRSA isolates that cause invasive infections in Paraguayan children from 2009 to 2013. Ten representative MRSA isolates of the main clonal complex identified were analyzed with short-read paired-end sequencing and assessed for the virulome, resistome, and phylogenetic relationships. All the genetically linked MRSA isolates were recovered from diverse clinical sources, patients, and hospitals at broad gap periods. The pan-genomic analysis of these clones revealed three major and different clonal complexes (CC30, CC5, and CC8), each composed of clones closely related to each other. The CC30 genomes prove to be a successful clone, strongly installed and disseminated throughout our country, and closely related to other CC30 public genomes from the region and the world. The CC5 shows the highest genetic variability, and the CC8 carried the complete arginine catabolic mobile element (ACME), closely related to the USA300-NAE-ACME+, identified as the major cause of CA-MRSA infections in North America. Multiple virulence and resistance genes were identified for the first time in this study, highlighting the complex virulence profiles of MRSA circulating in the country. This study opens a wide range of new possibilities for future projects and trials to improve the existing knowledge on the epidemiology of MRSA circulating in Paraguay.

IMPORTANCE

The increasing prevalence of methicillin-resistant
Staphylococcus aureus
(MRSA) is a public health problem worldwide. The most frequent MRSA clones identified in Paraguay in previous studies (including community and hospital acquired) were the Pediatric (CC5-ST5-IV), the Cordobes-Chilean (CC5-ST5-I), the SouthWest Pacific (CC30-ST30-IV), and the Brazilian (CC8-ST239-III) clones. In this study, the pan-genomic analysis of the most representative MRSA clones circulating in invasive infection in Paraguayan children over the years 2009–2013, such as the CC30-ST30-IV, CC5-ST5-IV, and CC8-ST8-IV, was carried out to evaluate their genetic diversity, their repertoire of virulence factors, and antimicrobial resistance determinants. This revealed multiple virulence and resistance genes, highlighting the complex virulence profiles of MRSA circulating in Paraguay. Our work is the first genomic study of MRSA in Paraguay and will contribute to the development of genomic surveillance in the region and our understanding of the global epidemiology of this pathogen.
Characterization of a neutralizing antibody that recognizes a loop region adjacent to the receptor-binding interface of the SARS-CoV-2 spike receptor-binding domain
Authors: Anzai Itsuki , Fujita Junso , Ono Chikako , Kosaka Yoichiro , Miyamoto Yuki , Shichinohe Shintaro , Takada Kosuke , Torii Shiho , Taguwa Shuhei , Suzuki Koichiro , Makino Fumiaki , Kajita Tadahiro , Inoue Tsuyoshi , Namba Keiichi , Watanabe Tokiko , Matsuura Yoshiharu
Published: February 2024

Although the global crisis caused by the coronavirus disease 2019 (COVID-19) pandemic is over, the global epidemic of the disease continues. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of COVID-19, initiates infection via the binding of the receptor-binding domain (RBD) of its spike protein to the human angiotensin-converting enzyme II (ACE2) receptor, and this interaction has been the primary target for the development of COVID-19 therapeutics. Here, we identified neutralizing antibodies against SARS-CoV-2 by screening mouse monoclonal antibodies and characterized an antibody, CSW1-1805, that targets a narrow region at the RBD ridge of the spike protein. CSW1-1805 neutralized several variants
in vitro
and completely protected mice from SARS-CoV-2 infection. Cryo-EM and biochemical analyses revealed that this antibody recognizes the loop region adjacent to the ACE2-binding interface with the RBD in both a receptor-inaccessible “down” state and a receptor-accessible “up” state and could stabilize the RBD conformation in the up-state. CSW1-1805 also showed different binding orientations and complementarity determining region properties compared to other RBD ridge-targeting antibodies with similar binding epitopes. It is important to continuously characterize neutralizing antibodies to address new variants that continue to emerge. Our characterization of this antibody that recognizes the RBD ridge of the spike protein will aid in the development of future neutralizing antibodies.

IMPORTANCE

SARS-CoV-2 cell entry is initiated by the interaction of the viral spike protein with the host cell receptor. Therefore, mechanistic findings regarding receptor recognition by the spike protein help uncover the molecular mechanism of SARS-CoV-2 infection and guide neutralizing antibody development. Here, we characterized a SARS-CoV-2 neutralizing antibody that recognizes an epitope, a loop region adjacent to the receptor-binding interface, that may be involved in the conformational transition of the receptor-binding domain (RBD) of the spike protein from a receptor-inaccessible “down” state into a receptor-accessible “up” state, and also stabilizes the RBD in the up-state. Our mechanistic findings provide new insights into SARS-CoV-2 receptor recognition and guidance for neutralizing antibody development.
Transdermal administration of farnesol-ethosomes enhances the treatment of cutaneous candidiasis induced by
Candida albicans
in mice
Authors: Shen Ting , Tian Baocheng , Liu Wei , Yang Xuesong , Sheng Qi , Li Mengxin , Wang Haiyan , Wang Xiuwen , Zhou Huihui , Han Yanchun , Ding Chen , Sai Sixiang
Published: February 2024

Cutaneous candidiasis, caused by
Candida albicans
, is a severe and frustrating condition, and finding effective treatments can be challenging. Therefore, the development of farnesol-loaded nanoparticles is an exciting breakthrough. Ethosomes are a novel transdermal drug delivery carrier that incorporates a certain concentration (10–45%) of alcohols into lipid vesicles, resulting in improved permeability and encapsulation rates compared to conventional liposomes. Farnesol is a quorum-sensing molecule involved in morphogenesis regulation in
C. albicans
, and these ethosomes offer a promising new approach to treating this common fungal infection. This study develops the formulation of farnesol-loaded ethosomes (farnesol-ethosomes) and assesses applications in treating cutaneous candidiasis induced by
C. albicans in vitro
and
in vivo
. Farnesol-ethosomes were successfully developed by ethanol injection method. Therapeutic properties of farnesol-ethosomes, such as particle size, zeta potential, and morphology, were well characterized. According to the results, farnesol-ethosomes demonstrated an increased inhibition effect on cells’ growth and biofilm formation in
C. albicans
. In Animal infection models, treating farnesol-ethosomes by transdermal administration effectively relieved symptoms caused by cutaneous candidiasis and reduced fungal burdens in quantity. We also observed that ethosomes significantly enhanced drug delivery efficacy
in vitro
and
in vivo
. These results indicate that farnesol-ethosomes can provide future promising roles in curing cutaneous candidiasis.

IMPORTANCE

Cutaneous candidiasis attributed to
Candida
infection is a prevalent condition that impacts individuals of all age groups. As a type of microbial community, biofilms confer benefits to host infections and mitigate the clinical effects of antifungal treatments. In
C. albicans
, the yeast-to-hypha transition and biofilm formation are effectively suppressed by farnesol through its modulation of multiple signaling pathway. However, the characteristics of farnesol such as hydrophobicity, volatility, degradability, and instability in various conditions can impose limitations on its effectiveness. Nanotechnology holds the potential to enhance the efficiency and utilization of this molecule. Treatment of farnesol-ethosomes by transdermal administration demonstrated a very remarkable therapeutic effect against
C. albicans
in infection model of cutaneous candidiasis in mice. Many patients suffering fungal skin infection will benefit from this study.
Hyper-enrichment of gold via quartz fracturing and growth of polymetallic melt droplets
Authors: Jian Wei , Mao Jingwen , Lehmann Bernd , Cook Nigel J. , Li Jiankang , Song Shiwei , Zhu Lei
Published: February 2024

Gold precipitation in hydrothermal systems is traditionally attributed to supersaturation of gold due to decreasing gold complex stability triggered by changes in physicochemical conditions of the ore fluid. However, ultrahigh-grade gold veins in orogenic (shear zone related) gold deposits can contain kilograms per tonne of gold or more, in marked contrast to the typically very low gold concentrations (tens of parts per billion) in fluid. The gold mineral assemblage is commonly restricted to native gold and/or Au-(Ag)-tellurides and occurs in micro-fractures of sheared quartz veins. Textural and compositional characterization of such assemblages, coupled with hydrothermal diamond anvil cell experiments and heating-freezing experiments, provides evidence for an alternative ultrahigh-grade gold enrichment mechanism via growth of polymetallic melt droplets induced by quartz fracturing. We propose that polymetallic melt droplets of Au-Ag-Te-Bi–rich composition form through adsorption-reduction of metal complexes on fractured quartz surfaces, where surface silanol groups and hydrogen serve as reductants. The melt droplets subsequently grow by catalyzing reduction of metal complexes and absorbing metals from fluids percolating in the fractured quartz network. The mobile and reactive polymetallic melt droplets can repeatedly react with the fluid on protracted quartz fracturing and efficiently continue to scavenge gold from multiple pulses of gold-undersaturated ore fluids.
Association between the frailty index and readmission risk in hospitalised elderly Chinese patients: a retrospective cohort study
Authors: Wang Lina , Zhang Xiaolin , Liu Xinmin
Published: February 2024

Objectives

Frailty is a common and important concern of the ageing population. This study examined the association between the frailty index and negative outcomes of hospitalised elderly Chinese patients.

Design

Retrospective cohort study.

Setting

Geriatrics Department of Peking University First Hospital.

Participants

470 hospitalised elderly patients.

Main outcomes and measures

Frailty was measured using a 30-item deficit-accumulation frailty index. The outcomes were the hospitalisation duration and readmission.

Results

The frailty index was available for 470 patients: 72 (15.32%) were categorised as robust, 272 (57.87%) as prefrail and 126 (26.81%) as frail. The frail group had a longer hospital stay than the robust and prefrail groups. After adjustment for age, sex and cause of hospitalisation at baseline, frailty remained a strong independent risk factor for all-cause readmission and cardiocerebrovascular disease readmission (HR 2.41, 95% CI 1.49 to 3.91, p<0.001; HR 4.92, 95% CI 1.47 to 6.31, p<0.001, respectively).

Conclusions

The frailty index predicted a longer length of stay and higher all-cause and cardiocerebrovascular disease readmission risk in hospitalised elderly patients.
Effectiveness of a Regenerative Epithelial Suspension (RES), on the pigmentation of split-thickness skin graft donor sites in children: the dRESsing pilot randomised controlled trial protocol
Authors: Bairagi Anjana , Tyack Zephanie , Kimble Roy M , McPhail Steven M , McBride Craig Antony , Patel Bhaveshkumar , Vagenas Dimitrios , Dettrick Zoe , Griffin Bronwyn
Published: February 2024

Background

Paediatric donor site wounds are often complicated by dyspigmentation following a split-thickness skin graft. These easily identifiable scars can potentially never return to normal pigmentation. A Regenerative Epidermal Suspension (RES) has been shown to improve pigmentation in patients with vitiligo, and in adult patients following a burn injury. Very little is known regarding the efficacy of RES for the management of donor site scars in children.

Methods and analysis

A pilot randomised controlled trial of 40 children allocated to two groups (RES or no RES) standard dressing applied to donor site wounds will be conducted. All children aged 16 years or younger requiring a split thickness skin graft will be screened for eligibility. The primary outcome is donor site scar pigmentation 12 months after skin grafting. Secondary outcomes include re-epithelialisation time, pain, itch, dressing application ease, treatment satisfaction, scar thickness and health-related quality of life. Commencing 7 days after the skin graft, the dressing will be changed every 3–5 days until the donor site is ≥ 95% re-epithelialised. Data will be collected at each dressing change and 3, 6 and 12 months post skin graft.

Ethics and dissemination

Ethics approval was confirmed on 11 February 2019 by the study site Human Research Ethics Committee (HREC) (HREC/18/QCHQ/45807). Study findings will be published in peer-reviewed journals and presented at national and international conferences. This study was prospectively registered on the Australian New Zealand Clinical Trials Registry (available athttps://anzctr.org.au/ACTRN12620000227998.aspx).

Trial registration number

Australian New Zealand Clinical Trials Registry [Available athttps://anzctr.org.au/ACTRN12620000227998.aspx]
Lived experiences of people living with HIV and hypertension or diabetes access to care in Ethiopia: a phenomenological study
Authors: Badacho Abebe Sorsa , Mahomed Ozayr Haroon
Published: February 2024

Background

People living with HIV (PLWH) are more likely to develop hypertension and diabetes than people without HIV. Previous studies have shown that HIV stigma, discrimination and exclusion make it difficult for PLWH to access care for hypertension and diabetes.

Objectives

This study aimed to explore the lived experiences of PLWH with comorbid hypertension or diabetes to access hypertension and diabetes care in southern Ethiopia.

Design

We conducted a qualitative study using a semistructured interview guide for an in-depth, in-person interview.

Settings

From 5 August to 25 September 2022, PLWH with comorbid hypertension or diabetes were purposefully selected from five primary healthcare (PHC) facilities in the Wolaita zone of southern Ethiopia.

Participants

A total of 14 PLWH with comorbid hypertension or diabetes who were receiving antiretroviral therapy from PHC were interviewed. Among them, 10 were women, and 4 were men.

Methods

In-person, in-depth interviews were conducted. Qualitative data analysis software (NVivo V.12) was used to assist with the data organisation, and Colaizzi’s (1978) inductive thematic analyses were conducted to explore key concepts.

Result

This study yielded two main themes: Theme 1: barriers to accessing care as individual barriers to access (low awareness of non-communicable diseases, misperceptions, lack of health insurance and cost of treatment); healthcare system barriers (shortage of supplies, drugs and equipment; long wait times; lack of integrated services; absence of routine screening and lack of respect from providers); community barriers (lack of support from families, friends and the community) and stigma and discrimination access to hypertension and diabetes. Theme 2: accessibility facilitators (support from family, friends and organisations; health insurance coverage).

Conclusion

PLWH recommended that access to services can be improved by service integration, awareness-raising activities, no user fee charges for hypertension and diabetes care and routine screening.
Impact and cost-effectiveness of SARS-CoV-2 self-testing strategies in schools: a multicountry modelling analysis
Authors: Chevalier Joshua M , Han Alvin X , Hansen Megan A , Klock Ethan , Pandithakoralage Hiromi , Ockhuisen Tom , Girdwood Sarah J , Lekodeba Nkgomeleng A , de Nooy Alexandra , Khan Shaukat , Johnson Cheryl C , Sacks Jilian A , Jenkins Helen E , Russell Colin A , Nichols Brooke E
Published: February 2024

Objectives

To determine the most epidemiologically effective and cost-effective school-based SARS-CoV-2 antigen-detection rapid diagnostic test (Ag-RDT) self-testing strategies among teachers and students.

Design

Mathematical modelling and economic evaluation.

Setting and participants

Simulated school and community populations were parameterised to Brazil, Georgia and Zambia, with SARS-CoV-2 self-testing strategies targeted to teachers and students in primary and secondary schools under varying epidemic conditions.

Interventions

SARS-CoV-2 Ag-RDT self-testing strategies for only teachers or teachers and students—only symptomatically or symptomatically and asymptomatically at 5%, 10%, 40% or 100% of schools at varying frequencies.

Outcome measures

Outcomes were assessed in terms of total infections and symptomatic days among teachers and students, as well as total infections and deaths within the community under the intervention compared with baseline. The incremental cost-effectiveness ratios (ICERs) were calculated for infections prevented among teachers and students.

Results

With respect to both the reduction in infections and total cost, symptomatic testing of all teachers and students appears to be the most cost-effective strategy. Symptomatic testing can prevent up to 69·3%, 64·5% and 75·5% of school infections in Brazil, Georgia and Zambia, respectively, depending on the epidemic conditions, with additional reductions in community infections. ICERs for symptomatic testing range from US$2 to US$19 per additional school infection averted as compared with symptomatic testing of teachers alone.

Conclusions

Symptomatic testing of teachers and students has the potential to cost-effectively reduce a substantial number of school and community infections.
Knowledge, attitudes and practices towards the diagnosis and management of paediatric sepsis among paediatric physicians and nurses: a cross-sectional study of 21 hospitals in Hubei Province, China
Authors: Yue Jing , Zhao Hui , Li Jie , Wu Jiannan , Zheng Ronghao
Published: February 2024

Objectives

To evaluate the knowledge, attitudes and practices towards diagnosing and managing paediatric sepsis among paediatric physicians and nurses.

Design

A cross-sectional, questionnaire-based study.

Setting

21 hospitals in Hubei Province between February 2023 and March 2023.

Participants

Paediatric physicians and nurses.

Interventions

None.

Primary and secondary outcome measures

The questionnaire contained 35 items across four dimensions (demographic information, knowledge, attitude and practice).

Results

The study included 295 participants (173 women). The average knowledge, attitude and practice scores were 10.93±2.61 points (possible range, 0–20 points), 32.22±2.65 points (possible range, 7–35 points) and 36.54±5.24 points (possible range, 9–45 points), respectively. Knowledge had a direct influence on both attitude (β=0.240, 95% CI 0.136 to 0.365, p=0.009) and practice (β=0.278, 95% CI 0.084 to 0.513, p=0.010), which also indirectly influenced practice through attitude (β=0.162, 95% CI 0.078 to 0.290, p=0.007). Attitude directly influenced practice (β=0.677, 95% CI 0.384 to 0.902, p=0.025). A higher attitude score was associated with good practice (OR=1.392; 95% CI 1.231 to 1.576; p<0.001), while not working in a tertiary hospital reduced the odds of good practice (OR=0.443; 95% CI 0.2390.821; p=0.010).

Conclusions

The knowledge regarding paediatric sepsis, especially knowledge about sepsis management, is poor among paediatric physicians and nurses in Hubei Province. The findings of this study may facilitate the development and implementation of training programmes to improve the diagnosis and management of paediatric sepsis.
Trend of cerebral aneurysms over the past two centuries: need for early screening
Authors: Burlakoti Arjun , Kumaratilake Jaliya , Taylor Jamie , Henneberg Maciej
Published: February 2024

Objective

Cerebral aneurysms (CAs) are linked to variations in the cerebral basal arterial network (CBAN). This study aimed to find the optimal age for screening to detect brain arterial variations and predict aneurysms before rupture.

Design

An observational, quantitative and retrospective research.

Setting

The study analysed 1127 cases of CAs published from 1761 to 1938. Additionally, CT angiography images of 173-patients at the Royal Adelaide Hospital (RAH), South Australia between 2011 and 2019 were examined for the presence and the location of aneurysms in CBAN.

Participants

The data were collected from patients at RAH and 407 published sources, including males and females across the entire age range, up to 100 years old.

Outcome measures and results

Data, CAs cases, from 1761 to 1938 included (526 males, 573 females and 28 unknown sexes). The age of these patients varied from 18 months to 89 years (mean age=42, SD=18). Approximately 11.5% of the CAs occurred in patients aged <20 years. Among the 1078 aneurysms whose location was reported, 76% were located in the internal carotid (IC), middle cerebral (MC) and anterior communicating artery complex (AcomAC) regions, while the remaining 24% were in the vertebrobasilar region. Among 173 patients from RAH aged between 18 and 100 years (male=83 and female=90, mean age=60, SD=16), 94% of the CAs were found in the IC, MC and AcomAC regions. The pattern of aneurysm occurrence, as indicated by values at the 25th, 50th and 75th percentiles, along with the minimum and maximum patient ages, has remained consistent from 1761 to 2019.

Conclusion

The distribution pattern of CAs in relation to sex, age and locations in the CBAN, remained steady over the last 260 years resulting in risk of strokes early in life. Therefore, early screening for CBAN segment variations is advised for stroke prevention if possible.
Understanding the role of household hygiene practices and foodborne disease risks in child stunting: a UKRI GCRF Action Against Stunting Hub protocol paper
Authors: Dominguez-Salas Paula , Waddington Hugh Sharma , Grace Delia , Bosire Caroline , Moodley Arshnee , Kulkarni Bharati , Dasi Teena , Banjara Santosh Kumar , Kumar Ramachandrappa Naveen , Fahmida Umi , Htet Min Kyaw , Sudibya Arienta R P , Faye Babacar , Tine Roger C , Heffernan Claire , Saxena Deepak , Dreibelbis Robert , Häsler B
Published: February 2024

Introduction

Environmental hygiene and food safety are important determinants of child stunting. This research aims to explore the relationship between child stunting and household hygiene practices and behaviours, including the availability of water, sanitation and hygiene (WASH) facilities; the use of safe food and good quality drinking water (especially when used for complementary feeding); hygienic practices in food transport, storage and preparation and the control of cross-contamination from animals, their produce and waste.

Methods and analysis

This study is part of a wider observational study which aims to investigate the interdisciplinary factors contributing to child stunting using a ‘whole child’ paradigm. The observational study recruits women during pregnancy in Hyderabad, India, Lombok, Indonesia and Kaffrine, Senegal, and dyads (ie, 500 mother–infant pairs per country) are followed longitudinally up to 24 months after birth. Within the interdisciplinary niche, the study here has developed tools to investigate the potential exposure pathways to environmental pathogen contamination of foods and water. Holistic WASH and food safety data collection tools have been developed to explore exposure pathways at the household level, including: (1) survey questionnaires; (2) spot-checks; (3) biological sampling of drinking water, food and domestic surfaces and (4) direct observation. An integrated analytical approach will be used to triangulate the evidence in order to examine the relationships between child stunting, WASH and food safety behaviours.

Ethics and dissemination

Ethical approval of the study was granted by the ethics committee of the LSHTM, RVC, ILRI, ICMR, IIPHG, SEAMEO-RECFON, University of Cheikh Anta Diop. Findings of the study will be disseminated through publication in peer-reviewed journals, relevant international conferences, public engagement events, and policy-maker and stakeholder events.
Epigenetic studies in children at risk of stunting and their parents in India, Indonesia and Senegal: a UKRI GCRF Action Against Stunting Hub protocol paper
Authors: Ramsteijn Anouschka S , Ndiaye Magatte , Kalashikam Rajender Rao , Htet Min Kyaw , Yadav DM Dinesh , Augustine Little Flower , Zahra Nur L , Djigal Aicha , Yanti Dwi , Angelin Tiffany C , Nurfadilah Mifa , Gorre Manjula , Subrahamanyam Dantham , Vadakattu Sai Santhosh , Munikumar Manne , Horgan Graham W , Fahmida Umi , Faye Babacar , Kulkarni Bharati , Haggarty Paul
Published: February 2024

Introduction

In 2020, an estimated 150 million children under the age of 5 years were stunted. Stunting results from early-life adversity and it is associated with significant physical and cognitive deficit, lifelong socioeconomic disadvantage and reduced life expectancy. There is a need to understand the causes of stunting and its effects in order to develop strategies to avoid it and to mitigate the consequences once stunting has occurred. Epigenetics is an important mechanism through which early-life factors are thought to influence biological function, with long-term consequences. We describe a series of epigenetic studies designed to understand how early-life adversity results in stunting and to inform the development of practical tools such as predictive markers and therapeutic targets. This work is part of the UKRI GCRF Action Against Stunting Hub.

Methods and analysis

The project—in India, Indonesia and Senegal—comprises an observational study of mothers, fathers, and offspring (n=500) spanning the first 1000 days of life, and an intervention study in each country. Epigenetic status (DNA methylation) is determined in saliva from babies collected within 1 month of birth and again at 18 months of age, and from mothers and fathers around the time of birth. Epigenome-wide analysis is carried out using the Illumina EPIC array, augmented by high-definition sequencing approaches. Statistical analysis is carried out at the level of candidate genes/regions, higher dimensional epigenetic states and epigenome-wide association. Data analysis focuses on the determinants of stunting, the effectiveness of interventions, population comparisons and the link between epigenetics and other thematic areas, which include anthropometry, microbiome, gut health, parasitology, cognition, nutrition, food hygiene and water sanitation, food systems and the home environment.

Ethics and dissemination

This study has been approved by the relevant Ethics Committees in Indonesia, India and Senegal, and the UK. Research data will be published and posted in public repositories.
Identification of immune cell markers associated with ulcerative colitis histological disease activity in colonic biopsies
Authors: Lefevre Pavine L C , Wang Zhongya , Teft Wendy , Zou Guangyong , Van Viegen Tanja , Linggi Bryan , Jairath Vipul , Feagan Brian G , Pai Rish K , Vande Casteele Niels
Published: February 2024

Aims

Accurate determination of histological activity in ulcerative colitis (UC) is essential given its diagnostic and prognostic importance. Data on the relationship between histology and immune cell markers are limited. We aimed to evaluate the association between histological disease activity and immune cell marker concentration in colonic biopsies from patients with UC.

Methods

Sigmoid colon biopsies from 20 patients with UC were retrospectively assessed using the Robarts Histopathology Index (RHI). Targeted mass spectrometry determined the concentration of 18 immune cell markers (cluster of differentiation (CD) 4, CD8, CD19, CD20, CD40, CD56, CD68, CD103, forkhead box p3 (FOXP3), human leucocyte antigen, DR alpha chain (HLA-DRA), interleukin 10 (IL-10), IL-23 subunit alpha (IL-23A), IL-23 receptor (IL-23R), IL-2 receptor alpha chain (IL-2RA), Ki67, lymphocyte-activation gene 3 (LAG-3), programmed cell death protein 1 (PD-1) and PD ligand 1 (PD-L1)). The association between RHI score and immune cell marker concentration was quantified using Spearman’s rank correlation coefficient (ρ) and related 95% CIs.

Results

Fourteen of the 18 immune cell marker proteins were detected, with tissue concentration ranging from 0.003 to 11.53 fmol/µg. The overall RHI score was positively correlated with CD19, CD20, CD40, FOXP3, LAG-3, PD-1 and PD-L1 concentration (ρ=0.596–0.799) and negatively correlated with CD56 concentration (ρ=−0.460). There was no significant association between RHI score and CD4, CD8, CD68, CD103, HLA-DRA or Ki67 concentration.

Conclusions

This study provides insight into the correlation between immune cell marker expression and histological disease activity and the possible molecular and immunological determinants underlying microscopic disease activity in UC.
Gamma delta T cells in acute myeloid leukemia: biology and emerging therapeutic strategies
Authors: Rao Adishwar , Agrawal Akriti , Borthakur Gautam , Battula Venkata Lokesh , Maiti Abhishek
Published: February 2024

γδ T cells play an important role in disease control in acute myeloid leukemia (AML) and have become an emerging area of therapeutic interest. These cells represent a minor population of T lymphocytes with intrinsic abilities to recognize antigens in a major histocompatibility complex-independent manner and functionally straddle the innate and adaptive immunity interface. AML shows high expression of phosphoantigens and UL-16 binding proteins that activate the Vδ2 and Vδ1 subtypes of γδ T cells, respectively, leading to γδ T cell-mediated cytotoxicity. Insights from murine models and clinical data in humans show improved overall survival, leukemia-free survival, reduced risk of relapse, enhanced graft-versus-leukemia effect, and decreased graft-versus-host disease in patients with AML who have higher reconstitution of γδ T cells following allogeneic hematopoietic stem cell transplantation. Clinical trials leveraging γδ T cell biology have used unmodified and modified allogeneic cells as well as bispecific engagers and monoclonal antibodies. In this review, we discuss γδ T cells’ biology, roles in cancer and AML, and mechanisms of immune escape and antileukemia effect; we also discuss recent clinical advances related to γδ T cells in the field of AML therapeutics.
Targeting the activated microenvironment with endosialin (CD248)-directed CAR-T cells ablates perivascular cells to impair tumor growth and metastasis
Authors: Ash Sarah L , Orha Rebecca , Mole Holly , Dinesh-Kumar Meg , Lee Steven P , Turrell Frances K , Isacke Clare M
Published: February 2024

Background

Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack of suitable tumor-specific antigens and the immunosuppressive, desmoplastic tumor microenvironment that impedes CAR-T cell infiltration, activity and persistence. We hypothesized that targeting the endosialin (CD248) receptor, strongly expressed by tumor-associated pericytes and perivascular cancer-associated fibroblasts, would circumvent these challenges and offer an exciting antigen for CAR-T cell therapy due to the close proximity of target cells to the tumor vasculature, the limited endosialin expression in normal tissues and the lack of phenotype observed in endosialin knockout mice.

Methods

We generated endosialin-directed E3K CAR-T cells from three immunocompetent mouse strains, BALB/c, FVB/N and C57BL/6. E3K CAR-T cell composition (CD4+/CD8+ratio), activity in vitro against endosialin+and endosialin–cells, and expansion and activity in vivo in syngeneic tumor models as well as in tumor-naive healthy and wounded mice and tumor-bearing endosialin knockout mice was assessed.

Results

E3K CAR-T cells were active in vitro against both mouse and human endosialin+, but not endosialin–, cells. Adoptively transferred E3K CAR-T cells exhibited no activity in endosialin knockout mice, tumor-naive endosialin wildtype mice or in wound healing models, demonstrating an absence of off-target and on-target/off-tumor activity. By contrast, adoptive transfer of E3K CAR-T cells into BALB/c, FVB/N or C57BL/6 mice bearing syngeneic breast or lung cancer lines depleted target cells in the tumor stroma resulting in increased tumor necrosis, reduced tumor growth and a substantial impairment in metastatic outgrowth.

Conclusions

Together these data highlight endosialin as a viable antigen for CAR-T cell therapy and that targeting stromal cells closely associated with the tumor vasculature avoids CAR-T cells having to navigate the harsh immunosuppressive tumor microenvironment. Further, the ability of E3K CAR-T cells to recognize and target both mouse and human endosialin+cells makes a humanized and optimized E3K CAR a promising candidate for clinical development applicable to a broad range of solid tumor types.