bluuebunny/crossref_metadata_2025 huggingface dataset:
Preclinical efficacy and pharmacokinetics of an RNA-encoded T cell–engaging bispecific antibody targeting human claudin 6
Authors: Stadler Christiane R. , Ellinghaus Ursula , Fischer Leyla , Bähr-Mahmud Hayat , Rao Martin , Lindemann Claudia , Chaturvedi Anuhar , Scharf Caroline , Biermann Imke , Hebich Bernhard , Malz Alexandra , Beresin Georg , Falck Georg , Häcker Aline , Houben Astrid , Erdeljan Michael , Wolf Kristina , Kullmann Maximilian , Chang Philip , Türeci Özlem , Şahin Uğur
Published: May 2024

We present the preclinical pharmacology of BNT142, a lipid nanoparticle (LNP)–formulated RNA (RNA-LNP) encoding a T cell–engaging bispecific antibody that monovalently binds the T cell marker CD3 and bivalently binds claudin 6 (CLDN6), an oncofetal antigen that is absent from normal adult tissue but expressed on various solid tumors. Upon BNT142 RNA-LNP delivery in cell culture, mice, and cynomolgus monkeys, RNA is translated, followed by self-assembly into and secretion of the functional bispecific antibody RiboMab02.1. In vitro, RiboMab02.1 mediated CLDN6 target cell–specific activation and proliferation of T cells, and potent target cell killing. In mice and cynomolgus monkeys, intravenously administered BNT142 RNA-LNP maintained therapeutic serum concentrations of the encoded antibody. Concentrations of RNA-encoded RiboMab02.1 were maintained longer in circulation in mice than concentrations of directly injected, sequence-identical protein. Weekly injections of mice with BNT142 RNA-LNP in the 0.1- to 1-μg dose range were sufficient to eliminate CLDN6-positive subcutaneous human xenograft tumors and increase survival over controls. Tumor regression was associated with an influx of T cells and depletion of CLDN6-positive cells. BNT142 induced only transient and low cytokine production in CLDN6-positive tumor-bearing mice humanized with peripheral blood mononuclear cells (PBMCs). No signs of adverse effects from BNT142 RNA-LNP administration were observed in mice or cynomolgus monkeys. On the basis of these and other findings, a phase 1/2 first-in-human clinical trial has been initiated to assess the safety and preliminary efficacy of BNT142 RNA-LNP in patients with CLDN6-positive advanced solid tumors (NCT05262530).
Ursoricin, a bacteriocin of
Streptococcus ursoris
, has potent activity against methicillin-resistant
Staphylococcus aureus
and vancomycin-resistant enterococci
Authors: Wang Chutian , Le Mi Nguyen-Tra , Kawada-Matsuo Miki , Hisatsune Junzo , Sugawara Yo , Arai Chika , Nakanishi Jun , Takeda Katsuhiro , Shiba Hideki , Sugai Motoyuki , Komatsuzawa Hitoshi
Published: May 2024

The emergence of drug-resistant bacteria, particularly methicillin-resistant
Staphylococcus aureus
(MRSA) and vancomycin-resistant enterococci (VRE), has increased the need to discover novel antimicrobial agents that are effective against these species. Here, we describe the identification and purification of the mutacin BHT-B-like gene locus and bacteriocin peptide from
Streptococcus ursoris
, which is closely related to
Streptococcus ratti
; hence, we named this bacteriocin ursoricin. Ursoricin is a cationic, chromosome-encoded peptide that has potent antimicrobial effects against Gram-positive pathogens, including MRSA and VRE, with minimum inhibitory concentrations in the micromolar range. Ursoricin also inhibits the biofilm formation of high biofilm-forming
S. aureus
. Antibacterial activity was retained after treatment at 100°C for 60 min at a pH range of 3–9 and was partially reduced by treatment with proteinase K for 2 h (63% residual activity). The potent anti-MRSA, anti-VRE, and antibiofilm effects of ursoricin suggest that it is a possible candidate for the treatment of MRSA, VRE, and biofilm-associated infections.

IMPORTANCE

The emergence of multidrug-resistant bacteria worldwide has posed a significant public health threat and economic burdens that make the identification and development of novel antimicrobial agents urgent. Bacteriocins are promising new agents that exhibit antibacterial activity against a wide range of human pathogens. In this study, we report that the bacteriocin produced by
Streptococcus ursoris
showed good antibacterial activity against a wide range of
Staphylococcus aureus
and enterococcus strains, particularly methicillin-resistant
Staphylococcus aureus
, vancomycin-resistant enterococci, and high biofilm-forming
S. aureus
. Interestingly, this bacteriocin had a stronger effect on
S. aureus
than on
Staphylococcus epidermidis
, which is a major commensal bacterium in human skin; this result is important when considering the disturbance of bacterial flora, especially on the skin, mediated by the application of antibacterial agents.
AcMNPV P74 is cleaved at R325 and R334 by proteinases of both OB and BBMV to expose a potential fusion peptide for oral infection
Authors: Li Zhuorui , Zhang Nan , Zhang Tao , Wang Zhiying , Li Jiang , Wang Manli , Hu Zhihong , Wang Xi
Published: May 2024

Baculoviruses enter insect midgut epithelial cells via a set of occlusion-derived virion (ODV) envelope proteins called
per os
infectivity factors (PIFs). P74 of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV), which was the first identified PIF, is cleaved by an endogenous proteinase embedded within the occlusion body during
per os
infection, but the target site(s) and function of the cleavage have not yet been ascertained. Here, based on bioinformatics analyses, we report that cleavage was predicted at an arginine and lysine-rich region in the middle of P74. A series of recombinant viruses with site-directed mutants in this region of P74 were generated. R325 or R334 was identified as primary cleavage site. In addition, we showed that P74 is also cleaved by brush border membrane vesicles (BBMV) of the host insect at R325 or R334, instead of R195, R196, and R199, as previously reported. Simultaneous mutations in R195, R196, and R199 lead to instability of P74 during ODV release. Bioassays showed that mutations at both R325 and R334 significantly affected oral infectivity. Taken together, our data show that both R325 and R334 of AcMNPV P74 are the primary cleavage site for both occlusion body endogenous proteinase and BBMV proteinase during ODV release and are critical for oral infection.

IMPORTANCE

Cleavage of viral envelope proteins is usually an important trigger for viral entry into host cells. Baculoviruses are insect-specific viruses that infect host insects via the oral route. P74, a
per os
infectivity factor of baculoviruses, is cleaved during viral entry. However, the function and precise cleavage sites of P74 remain unknown. In this study, we found that R325 or R334 between the N- and C-conserved domains of P74 was the primary cleavage site by proteinase either from the occlusion body or host midgut. The biological significance of cleavage seems to be the release of the potential fusion peptide at the N-terminus of the cleaved C-terminal P74. Our results shed light on the cleavage model of P74 and imply its role in membrane fusion in baculovirus
per os
infection.
Acute peripartum pancreatitis complicating seronegative antiphospholipid antibody syndrome in pregnancy
Authors: Zimmer Zoe , Hill Rebecca , Fratto Victoria , Lutgendorf Monica A
Published: May 2024

Antiphospholipid antibody syndrome is an autoimmune condition with clinical manifestations of vascular thrombosis and adverse pregnancy outcomes including recurrent miscarriage, fetal loss, growth restriction and pre-eclampsia with persistent antiphospholipid antibodies on laboratory examination. Treatment is targeted at preventing recurrent thrombosis and improving pregnancy outcomes. Commonly, treatment includes aspirin and anticoagulation, however, newer immunomodulatory treatments may also improve outcomes. The case describes a patient with a history of multiple miscarriages and pregnancy losses, fetal growth restriction and pre-eclampsia, and pulmonary embolism. Because of her significant adverse pregnancy outcomes, she was treated with certolizumab with a successful delivery at 33 weeks and 6 days. She also developed acute pancreatitis in the postpartum period. This is a rare condition, affecting 1–14/10 000 births. The pancreatitis resolved with conservative management, and she had an uncomplicated interval cholecystectomy.
Consensus methods in patellofemoral pain: how rigorous are they? A scoping review
Authors: Blazey Paul , Scott Alex , Ardern Clare L , Davis Jennifer C , Whittaker Jackie L , Losciale Justin M , Khan Karim M
Published: May 2024

Objective

Clinicians treating patients with patellofemoral pain (PFP) rely on consensus statements to make the best practice recommendations in the absence of definitive evidence on how to manage PFP. However, the methods used to generate and assess agreement for these recommendations have not been examined. Our objective was to map the methods used to generate consensus-based recommendations for PFP and apply four novel questions to assess the rigour of consensus development.

Design

Scoping review.

Data sources

We searched Medline, SPORTDiscus, CINAHL and Embase from inception to May 2022 to identify consensus-derived statements or practice guidelines on PFP. The Joanna Briggs Institute Manual for Evidence Synthesis was followed to map the existing evidence. We measured the consensus methods based on four sets of questions addressing the panel composition, application of the consensus method chosen, agreement process and the use of evidence mapping.

Eligibility criteria

All consensus statements or clinical guidelines on PFP were considered.

Results

Twenty-two PFP consensus statements were identified. Panel composition: 3 of the 22 (14%) consensus groups reported the panellists’ experience, 2 (9%) defined a desired level of expertise, 10 (45%) reported panellist sex and only 2 (9%) included a patient. Consensus method: 7 of 22 (32%) reported using an established method of consensus measurement/development. Agreement process: 10 of 22 (45%) reported their consensus threshold and 2 (9%) acknowledged dissenting opinions among the panel. Evidence mapping: 6 of 22 (27%) reported using systematic methods to identify relevant evidence gaps.

Conclusions

PFP consensus panels have lacked diversity and excluded key partners including patients. Consensus statements on PFP frequently fail to use recognised consensus methods, rarely describe how ‘agreement’ was defined or measured and often neglect to use systematic methods to identify evidence gaps.
Prospective associations between breast feeding, metabolic health, inflammation and bone density in women with prior gestational diabetes mellitus
Authors: Hebeisen Ines , Gonzalez Rodriguez Elena , Arhab Amar , Gross Justine , Schenk Sybille , Gilbert Leah , Benhalima Katrien , Horsch Antje , Quansah Dan Yedu , Puder Jardena J
Published: May 2024

Introduction

The aim of the study is to investigate prospective associations between breastfeeding and metabolic outcomes, inflammation, and bone density in women with prior gestational diabetes mellitus (GDM).

Research design and methods

We prospectively included 171 women with GDM from the MySweetheart trial. Women were followed during pregnancy (from 24 up to 32 weeks’ gestational age) up to 1 year postpartum. Outcomes included weight, weight retention, body composition, insulin resistance and secretion indices, C reactive protein (CRP), and bone density. We compared differences in the associations between breastfeeding and health outcomes between women who breast fed <6 months vs ≥6 months. Analyses were adjusted for potential medical and sociodemographic confounders.

Results

Breastfeeding initiation was 94.2% (n=161) and mean breastfeeding duration was 6.6 months. Breastfeeding duration was independently associated with lower weight, weight retention, body fat, visceral adipose tissue, lean mass, CRP, insulin resistance (Homeostatic Model Assessment for Insulin Resistance), and insulin secretion (Homeostatic Model Assessment of β-cell index) at 1 year postpartum (all p≤0.04) after adjusting for confounders. Breastfeeding was associated with higher insulin resistance-adjusted insulin secretion (Insulin Secretion-Sensitivity Index-2) in the unadjusted analyses only. There was no association between breastfeeding duration and bone density. Compared with <6 months, breastfeeding duration ≥6 months was associated with lower weight, weight retention, body fat, fat-free mass as well as lower CRP at 1 year postpartum (all p<0.05) after adjusting for confounders.

Conclusions

Longer breastfeeding duration among women with prior GDM was associated with lower insulin resistance, weight, weight retention, body fat and inflammation, but not lower bone density at 1 year postpartum. Breastfeeding for ≥6 months after GDM can help to improve cardiometabolic health outcomes 1 year after delivery.
Hypersexuality in neurological disorders: A systematic review
Authors: Tayim Natalie , Barbosa Pedro , Panicker Jalesh
Published: May 2024

Background

Hypersexuality (HS) accompanying neurological conditions remains poorly characterized despite profound psychosocial impacts.

Objective

We aimed to systematically review the literature on HS in patients with neurological disorders.

Study selection and analysis

We conducted a systematic review to identify studies that reported HS in neurological disorders. HS was defined as a condition characterized by excessive and persistent preoccupation with sexual thoughts, urges, and behaviors that cause significant distress or impairment in personal, social, or occupational functioning. Data on demographics, assessment techniques, associated elements, phenotypic manifestations, and management strategies were also extracted.

Findings

The final analysis included 79 studies on HS, encompassing 32 662 patients across 81 cohorts with neurological disorders. Parkinson's disease was the most frequently studied condition (55.6%), followed by various types of dementia (12.7%). Questionnaires were the most common assessment approach for evaluating HS, although the techniques varied substantially. Alterations in the dopaminergic pathways have emerged as contributing mechanisms based on the effects of medication cessation. However, standardized treatment protocols still need to be improved, with significant heterogeneity in documented approaches. Critical deficiencies include risks of selection bias in participant sampling, uncontrolled residual confounding factors, and lack of blinded evaluations of reported outcomes.

Conclusions and clinical implications

Despite growth in the last decade, research on HS remains limited across neurological conditions, with lingering quality and methodological standardization deficits. Key priorities include advancing assessment tools, elucidating the underlying neurobiology, and formulating management guidelines.

PROSPERO registration number

CRD42017036478.
Anterior Spinal Artery Syndrome After Bronchial Embolization for Hemoptysis: A Case Report and Literature Review
Authors: Ghouri Raza Gulzar , Ali Muhammad Mohsin , Naeem Hamza , Raza Maryam Saleem , Arshad Waqas
Published: May 2024

Background

Bronchial artery embolization (BAE) is the established first-line treatment for patients presenting with massive haemoptysis, a life-threatening condition that can occur because of numerous underlying diseases. BAE is a relatively safe procedure with control of haemorrhage achieved in 77%–90% of cases and rare occurrence of complications. Spinal cord infarction is one such rare complication, which can have severe implications in terms of morbidity.

Case presentations

We present a case of a 70-year-old man who developed paraplegia with loss of pain and temperature sensation as well as sphincteric involvement following BAE for hemoptysis. MRI of the spine was suggestive of an ischaemic event involving anterolateral spinal cord segment T4–T6, so a diagnosis of anterior spinal artery syndrome post BAE was made. The patient was given corticosteroids, dual antiplatelet medications, pregabalin, supportive management and regular physiotherapy. Follow-up of the patient at 3 and 6 months failed to show any significant improvement in neurological function, although the patient did not report problem of significant hemoptysis afterward.

Conclusion

Spinal cord infarct is a rare and disabling complication of BAE despite it being a safe procedure with good long-term outcomes. Detailed knowledge about the anatomy of bronchial arteries and spinal arteries with detailed preprocedure investigations may lower the risk of this disabling complication.
Exploration of understanding of impactibility analysis and application through workshops to inform model design for population health management policy: a qualitative assessment
Authors: Orlowski Andi , Forshaw Rukiye , Humphreys Heather , Ashton Rachel , Cornelius Victoria , Pickles Jason , Snowden Simon , Bottle Alex
Published: May 2024

Objectives

Assess understanding of impactibility modelling definitions, benefits, challenges and approaches.

Design

Qualitative assessment.

Setting

Two workshops were developed. Workshop 1 was to consider impactibility definitions and terminology through moderated open discussion, what the potential pros and cons might be, and what factors would be best to assess. In workshop 2, participants appraised five approaches to impactibility modelling identified in the literature.

Participants

National Health Service (NHS) analysts, policy-makers, academics and members of non-governmental think tank organisations identified through existing networks and via a general announcement on social media. Interested participants could enrol after signing informed consent.

Outcome measures

Descriptive assessment of responses to gain understanding of the concept of impactibility (defining impactibility analysis), the benefits and challenges of using this type of modelling and most relevant approach to building an impactibility model for the NHS.

Results

37 people attended 1 or 2 workshops in small groups (maximum 10 participants): 21 attended both workshops, 6 only workshop 1 and 10 only workshop 2. Discussions in workshop 1 illustrated that impactibility modelling is not clearly understood, with it generally being viewed as a cross-sectional way to identify patients rather than considering patients by iterative follow-up. Recurrent factors arising from workshop 2 were the shortage of benchmarks; incomplete access to/recording of primary care data and social factors (which were seen as important to understanding amenability to treatment); the need for outcome/action suggestions as well as providing the data and the risk of increasing healthcare inequality.

Conclusions

Understanding of impactibility modelling was poor among our workshop attendees, but it is an emerging concept for which few studies have been published. Implementation would require formal planning and training and should be performed by groups with expertise in the procurement and handling of the most relevant health-related real-world data.
Tranquilisers and sedatives misuse and associated factors among adolescents in Estonia: findings from cross-sectional ESPAD surveys, 2003–2019
Authors: Veskimäe Liina , Vorobjov Sigrid , Pärna Kersti
Published: May 2024

Objectives

This study aimed to (1) to describe trends of tranquilliser and sedative (TS) misuse in Estonia during 2003–2019 and (2) to analyse the associations between TS misuse and explanatory factors (perceived access to TS, medical use of TS, family-related, friends-related, school-related factors, risk behaviour and leisure time physical activity).

Design

A cross-sectional study.

Setting

Data were collected from the European School Survey Project on Alcohol and Other Drugs (ESPAD) from 2003 to 2019 in Estonia.

Participants

Estonian schoolchildren aged 15–16 years old (n=11 328), 48.6% were boys.

Outcome measures

Prevalence, crude and adjusted ORs with 95% CIs for TS misuse.

Results

The prevalence of lifetime TS misuse significantly increased from 2003 (5.0% of boys and 12.6% of girls) to 2019 (11.3% and 17.5%, respectively) (p<0.001). Among boys, TS misuse increased significantly among those reporting medical use of TS from 21.1% to 41.4% in 2003–2019 (p=0.006). Medical use of TS multiplied the odds of misuse by 6.89 (95% CI 5.15 to 9.24) for boys and by 4.53 (95% CI 3.58 to 5.73) for girls. Perceived easy access to TS increased the odds of misuse by 6.57 (95% CI 4.13 to 10.46) times for boys and by 4.66 (95% CI 3.25 to 6.70) times for girls. Having many friends who misuse TS increased the odds of misuse by 3.27 (95% CI 2.16 to 4.95) times for boys and by 5.07 (95% CI 3.79 to 6.77) times for girls. Furthermore, higher odds of TS misuse were observed among adolescents who smoked cigarettes and engaged in less sports.

Conclusions

TS misuse prevalence among Estonian adolescents increased significantly from 2003 to 2019. Misuse was strongly associated with medical use, perceived easy access and friends’ TS misuse. These findings emphasise the need for targeted prevention strategies, including improving prescription practices, limiting TS access and promoting healthy behaviours and positive peer relationships among adolescents.
Perceptions and self-management of a healthy diet among middle-aged adults with risk of stroke in North China: a qualitative exploration
Authors: Liu Cui , Chong Mei Chan , Lee Wan Ling , Zhang Hai Yan , Zhang Jin Hua
Published: May 2024

Objective

Although stroke is prevalent among older people, there is a rising incidence among the younger subpopulations, particularly middle-aged adults. A healthy diet is one of the key modifiable factors to primary prevention of stroke among these subpopulations, yet there is limited understanding of the dietary habits among middle agers who have the risk factor(s) but no occurrence of stroke. This study aims to explore the views on perceptions and the self-management of middle-aged adults at risk of stroke on a healthy diet and to identify the enablers and barriers that could inform the future development of dietary interventions.

Design

This study used an interpretive descriptive qualitative design, employing semistructured purposive sampling for focus group discussions. Thematic analysis was conducted on the transcribed interviews and field notes, facilitated by NVivo 12.0 Plus software.

Setting

Community settings in Zhengzhou City, Henan Province.

Participants

Middle-aged adults (aged 45–59) were identified as at risk of stroke due to the presence of one or more modifiable risk factors.

Result

A total of seven focus group discussions were audio recorded. Four main themes emerged, which were: (1) cognitive understanding of a healthy diet; (2) dietary practices; (3) knowledge acquisition and (4) barriers to dietary adherence.

Conclusions

The middle-aged adults at risk of stroke were generally aware of the risk and attempted to practise healthy eating. The existing educational programmes on following a healthy diet in the prevention of disease need to be made more comprehensible, accessible and equitable, especially for those from socioeconomically disadvantaged communities.
Modular multimodal hospital-home chain physical activity rehabilitation programme (3M2H-PARP) in liver cancer: a protocol for a randomised controlled trial
Authors: Chen Haiyan , Lu Hanxiao , Zhou Huimin , Wu Bo , Dong Zhixia , Zhang Shuo , Gu Yuanlong , Zhou Guangwen , Xiang Jie , Yang Jun
Published: May 2024

Introduction

Patients with liver cancer are susceptible to experiencing a decline in muscle mass and function, which can lead to physical frailty and have a negative impact on prognosis. However, there is currently a lack of physical activity interventions specifically tailored for these patients. Therefore, we have developed a modular multimodal hospital-home chain physical activity rehabilitation programme (3M2H-PARP) designed specifically for patients with liver cancer undergoing transarterial chemoembolisation (TACE). We aim to validate the effectiveness and feasibility of this programme through a randomised controlled trial (RCT).

Methods and analysis

3M2H-PARP RCT will compare a 12-week, modular, multimodal physical activity rehabilitation programme that includes supervised exercise in a hospital setting and self-management exercise at home. The programmes consist of aerobic, resistance, flexibility and balance exercise modules, and standard survivorship care in a cohort of liver cancer survivors who have undergone TACE. The control group will receive standard care. A total of 152 participants will be randomly assigned to either the 3M2H-PARP group or the control group. Assessments will be conducted at three time points: baseline, after completing the intervention and a 24-week follow-up visit. The following variables will be evaluated: liver frailty index, Functional Assessment of Cancer Therapy-Hepatobiliary subscale, Cancer Fatigue Scale, Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale and physical activity level. After the completion of the training programme, semi-structured interviews will be conducted with participants from the 3M2H-PARP group to investigate the programme’s impact on their overall well-being. SPSS V.26.0 software will be used for statistical analyses.

Ethics and dissemination

Ethical approval has been granted by the Jiangnan University School of Medicine Research Ethics Committee. The findings will be disseminated through publication in a peer-reviewed journal.

Trial registration number

ChiCTR2300076800.
Protocol of a randomised controlled multicentre trial investigating the effectiveness and safety of a wilderness programme on the mental and physical well-being of adolescents and young adults affected by cancer: the WAYA-2 study
Authors: Jong Miek C , Fernee Carina Ribe , Stenling Andreas , Lown E Anne , Berntsen Sveinung , Victorson David E , Jong Mats
Published: May 2024

Introduction

Adolescents and young adults (AYAs) affected by cancer are an understudied group. Effective interventions are needed to support coping with the late effects of cancer, its treatment and to promote quality of life. Nature-based interventions may be promising in support of the self-management and health of AYAs affected by cancer. However, randomised controlled studies (RCTs) on the effectiveness of such interventions are lacking. We performed a first pilot RCT (n=42) that showed that it is feasible and safe to conduct such a study. Here, we propose a full-scale RCT to investigate the effectiveness and safety of a wilderness programme on the mental and physical health of AYAs affected by cancer.

Methods and analysis

Participants are 150 AYAs affected by cancer, aged 16–39 years, who will be randomised to a wilderness (n=75) or a hotel stay (n=75). The wilderness programme is an 8-day intervention including a 6-day wilderness expedition. This is followed 3 months later by a 4-day intervention including a 2-day basecamp. Activities include hiking, backpacking, kayaking, rock climbing, mindfulness and bush-crafting. The comparison group is an 8-day hotel stay followed by a 4-day hotel stay (interventions include two travel days) at the same hotel after 3 months. Primary outcomes are psychological well-being and nature connectedness up to 1 year after the study start. Secondary outcomes are quality of life, physical activity and safety parameters.

Ethics and dissemination

The Swedish Ethical Review Authority approved the study protocol on 27 September 2023 (reference: 2023-05247-01). The recruitment started on 19 February 2024 and the first part is planned to end on 31 December 2027. Study results will be disseminated by means of scientific publications, presentations at conferences, popular articles, interviews, chronicles and books. News items will be spread via social media, websites and newsletters.

Trial registration number

ISRCTN93856392.
Traditional versus progressive robot-assisted gait training in people with multiple sclerosis and severe gait disability: study protocol for the PROGR-EX randomised controlled trial
Authors: Baroni Andrea , Lamberti Nicola , Gandolfi Marialuisa , Rimondini Michela , Bertagnolo Valeria , Grassilli Silvia , Zerbinati Luigi , Manfredini Fabio , Straudi Sofia
Published: May 2024

Gait disorders are the most frequent symptoms associated to multiple sclerosis (MS). Robot-assisted gait training (RAGT) in people with MS (PwMS) has been proposed as a possible effective treatment option for severe motor disability without significant superiority when compared to intensive overground gait training (OGT). Furthermore, RAGT at high intensity may enhance fatigue and spasticity. This study aims to evaluate the effects of a low-intensity RAGT at progressively increasing intensity compared to conventional RAGT and OGT in PwMS and moderate to severe walking impairment. 24 PwMS will be recruited and assigned to one of the three treatment groups: low-intensity RAGT at progressively increasing intensity, conventional RAGT and OGT. All participants will receive 3-weekly treatment sessions of 3 hours each for 4 weeks. In the first 2 hours of treatment, all participants will receive a rehabilitation programme based on stretching exercises, muscle strengthening and educational interventions. During the last hour, subjects will undergo specific gait training according to the assignment group. Outcomes will be assessed before and after treatment and at 3-month follow-up. The primary outcome is walking speed. Secondary outcomes include mobility and balance, psychological measures, muscle oxygen consumption, electrical and haemodynamic brain activity, urinary biomarkers, usability, and acceptability of robotic devices for motor rehabilitation. The results of this study will provide a safe, affordable and non-operator-dependent, intervention for PwMS. Results in terms of functional, psychological, neurophysiological and biological outcomes will confirm our hypothesis. The study’s trial registration number:NCT06381440.
Neutrophil extracellular traps activate hepatic stellate cells and monocytes via NLRP3 sensing in alcohol-induced acceleration of MASH fibrosis
Authors: Babuta Mrigya , Morel Caroline , de Carvalho Ribeiro Marcelle , Calenda Charles , Ortega-Ribera Martí , Thevkar Nagesh Prashanth , Copeland Christopher , Zhuang Yuan , Wang Yanbo , Cho Yeonhee , Joshi Radhika , Brezani Viliam , Hawryluk Danielle , Datta Aditi Ashish , Mehta Jeeval , Nasser Imad , Szabo Gyongyi
Published: May 2024

Objective

Alcohol use in metabolic dysfunction-associated steatohepatitis (MASH) is associated with an increased risk of fibrosis and liver-related death. Here, we aimed to identify a mechanism through which repeated alcohol binges exacerbate liver injury in a high fat-cholesterol-sugar diet (MASH diet)-induced model of MASH.

Design

C57BL/6 mice received either chow or the MASH diet for 3 months with or without weekly alcohol binges. Neutrophil infiltration, neutrophil extracellular traps (NETs) and fibrosis were evaluated.

Results

We found that alcohol binges in MASH increase liver injury and fibrosis. Liver transcriptomic profiling revealed differential expression of genes involved in extracellular matrix reorganisation, neutrophil activation and inflammation compared with alcohol or the MASH diet alone. Alcohol binges specifically increased NET formation in MASH livers in mice, and NETs were also increased in human livers with MASH plus alcohol use. We discovered that cell-free NETs are sensed via Nod-like receptor protein 3 (NLRP3). Furthermore, we show that cell-free NETs in vitro induce a profibrotic phenotype in hepatic stellate cells (HSCs) and proinflammatory monocytes. In vivo, neutrophil depletion using anti-Ly6G antibody or NET disruption with deoxyribonuclease treatment abrogated monocyte and HSC activation and ameliorated liver damage and fibrosis. In vivo, inhibition of NLRP3 using MCC950 or NLRP3 deficiency attenuated NET formation, liver injury and fibrosis in MASH plus alcohol diet-fed mice (graphical abstract).

Conclusion

Alcohol binges promote liver fibrosis via NET-induced activation of HSCs and monocytes in MASH. Our study highlights the potential of inhibition of NETs and/or NLRP3, as novel therapeutic strategies to combat the profibrotic effects of alcohol in MASH.
Intravital imaging: dynamic insights into liver immunity in health and disease
Authors: Wang Yuting , Heymann Felix , Peiseler Moritz
Published: May 2024

Inflammation is a critical component of most acute and chronic liver diseases. The liver is a unique immunological organ with a dense vascular network, leading to intense crosstalk between tissue-resident immune cells, passenger leucocytes and parenchymal cells. During acute and chronic liver diseases, the multifaceted immune response is involved in disease promoting and repair mechanisms, while upholding core liver immune functions. In recent years, single-cell technologies have unravelled a previously unknown heterogeneity of immune cells, reshaping the complexity of the hepatic immune response. However, inflammation is a dynamic biological process, encompassing various immune cells, orchestrated in temporal and spatial dimensions, and driven by multiorgan signals. Intravital microscopy (IVM) has emerged as a powerful tool to investigate immunity by visualising the dynamic interplay between different immune cells and their surroundings within a near-natural environment. In this review, we summarise the experimental considerations to perform IVM and highlight recent technological developments. Furthermore, we outline the unique contributions of IVM to our understanding of liver immunity. Through the lens of liver disease, we discuss novel immune-mediated disease mechanisms uncovered by imaging-based studies.
First-trimester use of antiseizure medications and the risk of miscarriage: a population-based cohort study
Authors: Forbes Harriet , Madley-Dowd Paul , Ahlqvist Viktor , Campbell Jennifer , Davies Neil M , Liebling Rachel , Lyall Kristen , Newschaffer Craig , Rast Jessica , Tomson Torbjörn , Zhong Caichen , Magnusson Cecilia , Rai Dheeraj , Lee Brian K
Published: May 2024

Background

Antiseizure medications (ASMs) during the first trimester of pregnancy have been associated with an increased risk of miscarriage.

Methods

We carried out a population-based cohort study using routinely collected healthcare data from the UK, 1995–2018. Pregnancies were identified in the Clinical Practice Research Datalink and we estimated the HR of miscarriage associated with prescriptions of ASMs during the first trimester of pregnancy, using Cox regression, adjusting for potential confounders, including ASM indications.

Results

ASMs were prescribed during the first trimester in 7832 (0.8%) of 1 023 787 included pregnancies. 14.5% of pregnancies with first-trimester exposure to ASMs ended in miscarriage, while 12.2% without ASM exposure in the first trimester ended in miscarriage; after adjustment, there was a 1.06-fold relative hazard of miscarriage (95% CI 1.00 to 1.13) in women with first-trimester ASM use. After restricting to women with specific ASM indications, this association was not evident in women with epilepsy (adjusted HR 0.98, 95% CI 0.89 to 1.08), but was observed in women with bipolar or other psychiatric conditions (1.08, 95% CI 1.00 to 1.16) although CIs overlapped. Compared with discontinuation of ASMs prior to pregnancy, there was no evidence of increased risk of miscarriage for first-trimester ASM use in women with bipolar or other psychiatric conditions (1.02, 95% CI 0.87 to 1.20).

Conclusion

We found no clear evidence to suggest that first-trimester ASM use increased the risk of miscarriage. Taken together, our analyses suggest that apparent associations between first-trimester ASM use and miscarriage may be the result of confounding by the presence of a bipolar disorder or associated unmeasured variables.
Review of a large trauma registry in Addis Ababa, Ethiopia: insights into prehospital care and provider training for trauma quality improvement
Authors: Starr Nichole , Ayehu Mengistu , Zhuang Alex , Minalu Habtamu Tamiru , Alemu Genet Kifle , Fisseha Samuel , Chekol Sisay , Habtemariam Aklile , Hadis Makida , Alemtsehay Biruh , Mengiste Minale , Kefeni Bori Ashenafi
Published: May 2024

Background

Injury is a major cause of death and disability in Ethiopia. ALERT Hospital, one of only three designated trauma centers in the country, has employed a basic trauma registry since its inception in 2016; however, these data had not been used. In joint efforts with the Federal Ministry of Health, we aimed to understand patient injury characteristics and predictors of mortality, to inform priorities in resource and training investments.

Methods

Data from 12 816 consecutive patients in the first 3 years of the trauma registry were reviewed retrospectively. Modified Early Warning Score was used at triage to indicate injury severity (red=critically injured, green=minor injury). No physiologic data for calculating Injury Severity Scores or in-hospital intervention data were available. Triage groups were compared and multivariate logistic regression conducted to determine predictors of in-emergency department (ED) mortality.

Results

Most patients presented with minor injuries with 64.7% triaged as ‘yellow’ and 16.4% triaged as ‘green’, and most (75.9%) referred from another facility. Of those who were critically injured, only 31.0% arrived by ambulance. Most injuries were soft tissue (51.1%) and fractures (23.0%); when stratified by triage category, most critical (‘red’) patients had sustained head injuries (52.7%). Arrival by ambulance (OR 2.20, p=0.017) and head injury (OR 3.11, p<0.001) were independent predictors of death in the ED.

Conclusion

This study of injured patients presenting to an Ethiopian trauma center is one of the largest to date, highlighting the need for more accessible and streamlined prehospital trauma care. Opportunities for improvement include staff training in initial trauma management and implementation of a more comprehensive trauma registry containing physiologic, intervention, and outcomes data to support a robust quality improvement program. Efforts by the Federal Ministry of Health are ongoing to support these improvements in care.

Level of Evidence

Level 3, observational study
Social determinants of gastrointestinal malformation mortality in Brazil: a national study
Authors: Gerk Ayla , Rosendo Amanda , Telles Luiza , Miranda Arícia Gomes , Carroll Madeleine , Trindade Bruna Oliveira , Motter Sarah Bueno , Freire Esther , Hyman Gabriella , Ferreira Julia , Botelho Fabio , Ferreira Roseanne , Mooney David P , Bustorff-Silva Joaquim
Published: May 2024

Introduction

In Brazil, approximately 5% are born with a congenital disorder, potentially fatal without surgery. This study aims to evaluate the relationship between gastrointestinal congenital malformation (GICM) mortality, health indicators, and socioeconomic factors in Brazil.

Methods

GICM admissions (Q39–Q45) between 2012 and 2019 were collected using national databases. Patient demographics, socioeconomic factors, clinical management, outcomes, and the healthcare workforce density were also accounted for. Pediatric Surgical Workforce density and the number of neonatal intensive care units in a region were extracted from national datasets and combined to create a clinical index termed‘NeoSurg’. Socioeconomic variables were combined to create a socioeconomic index termed‘SocEcon’. Simple linear regression was used to investigate if the temporal changes of both indexes were significant. The correlation between mortality and the different indicators in Brazil was evaluated using Pearson’s correlation coefficient.

Results

Over 8 years, Brazil recorded 12804 GICM admissions. The Southeast led with 6147 cases, followed by the Northeast (2660), South (1727), North (1427), and Midwest (843). The North and Northeast reported the highest mortality, lowest NeoSurg, and SocEcon Index rates. Nevertheless, mortality rates declined across regions from 7.7% (2012) to 3.9% (2019), a 51.7% drop. The North and Midwest experienced the most substantial reductions, at 63% and 75%, respectively. Mortality significantly correlated with the indexes in nearly all regions (p<0.05).

Conclusion

Our study highlights the correlation between social determinants of health and GICM mortality in Brazil, using two novel indexes in the pediatric population. These findings provide an opportunity to rethink and discuss new indicators that could enhance our understanding of our country and could lead to the development of necessary solutions to tackle existing challenges in Brazil and globally.
Polymorphism of a planar neutral radical: magnetic and optical implications
Authors: Borg Genievieve C. , Young Harrison K.S. , Mills Michelle B. , Mastrandrea Jacob W. , Benner Florian , Demir Selvan , Lough Alan J. , Boyle Paul D. , Preuss Kathryn E.
Published: May 2024

The synthesis and characterization of a new paramagnetic ligand, 4-( N′-methyl-2′-benzimidazolyl)-1,2,3,5-dithiadiazolyl (MebimDTDA), is presented. MebimDTDA exhibits polymorphism in the solid state. The red microcrystalline form (Form I-red) is diamagnetic below T = 370 K, consistent with typical multi-center two-electron bonding interactions (i.e., pancake bonds) between planar π-radicals. By contrast, the green–black crystalline form (Form II-green) exhibits paramagnetic properties consistent with the observed unusual crystal packing in which some, but not all, of the radicals are arranged in a typical pancake-bonded geometry. Crystallographic analysis, magnetic data, and computational methods are employed to elucidate the structure-property relationship, with an emphasis on the role of crystal packing.
Interpretable Clusters for Representing Citizens’ Sense of Belonging through Interaction with Cultural Heritage
Authors: Jiménez-Díaz Guillermo , Diaz-Agudo Belen , Emilio Bruni Luis , Kadastik Nele , Follo Anna , Damiano Rossana , Striani Manuel , Sanchez-Martin Angel , Lieto Antonio
Published: May 2024

The EU H2020 project social cohesion, participation, and inclusion through cultural engagement (SPICE) focuses on developing, designing, and implementing new methods and digital tools for citizen curation. This article delineates several software tools developed within the project, presenting innovative approaches to represent and visualize citizens and communities resulting from their engagement with cultural heritage. Aligned with the central tenets of SPICE –particularly the notions of belonging and the interpretation reflection loop– the primary objective is to bolster citizens’ participation and inclusion in fostering social cohesion. This article describes how the SPICE tools can be utilized to guide the processes of interpretation and reflection on cultural heritage artifacts. The Community Model serves as a pivotal component, enabling the modeling of citizens and communities through the utilization of similarity functions for clustering citizens based on perspectives. The clustering algorithm is intricately crafted to generate coherent communities, iterating until all clusters are interpretable using demographic attributes, centroid-based representations, and similarity attributes. Authors posit that this model holds significant value in comprehending and structuring complex data within cultural heritage contexts.

To exemplify our approach, the article examines different attributes of individual citizens and citizen groups in the Galleria Civica d’Arte Moderna e Contemporanea (GAM) case study. Here, perspectives are delineated based on visitors’ demographic attributes and their emotional responses when engaging with artworks. These perspectives are then visualized using the VISIR tool, facilitating the exploration and revelation of connections between citizens and communities, thereby bridging the realms of citizen space and cultural heritage space.
Reassuring, Misleading, Debunking: Comparing Effects of XAI Methods on Human Decisions
Authors: Humer Christina , Hinterreiter Andreas , Leichtmann Benedikt , Mara Martina , Streit Marc
Published: May 2024

Trust calibration is essential in AI-assisted decision-making. If human users understand the rationale on which an AI model has made a prediction, they can decide whether they consider this prediction reasonable. Especially in high-risk tasks such as mushroom hunting (where a wrong decision may be fatal), it is important that users make correct choices to trust or overrule the AI. Various explainable AI (XAI) methods are currently being discussed as potentially useful for facilitating understanding and subsequently calibrating user trust. So far, however, it remains unclear which approaches are most effective. In this article, the effects of XAI methods on human AI-assisted decision-making in the high-risk task of mushroom picking were tested. For that endeavor, the effects of (i) Grad-CAM attributions, (ii) nearest-neighbor examples, and (iii) network-dissection concepts were compared in a between-subjects experiment with

\(N=501\)

participants representing end-users of the system. In general, nearest-neighbor examples improved decision correctness the most. However, varying effects for different task items became apparent. All explanations seemed to be particularly effective when they revealed reasons to (i) doubt a specific AI classification when the AI was wrong and (ii) trust a specific AI classification when the AI was correct. Our results suggest that well-established methods, such as Grad-CAM attribution maps, might not be as beneficial to end users as expected and that XAI techniques for use in real-world scenarios must be chosen carefully.
Effect of Mechanical Pressure on Lifetime, Expansion, and Porosity of Silicon-Dominant Anodes in Laboratory Lithium-Ion Cells
Authors: Friedrich S. , Stojecevic S. , Rapp P. , Helmer S. , Bock M. , Durdel A. , Gasteiger H. A. , Jossen A.
Published: May 2024

The impact of mechanical pressure on electrode stability in full-cells comprising microscale silicon-dominant anodes and NCA cathodes was investigated. We applied different mechanical pressures using spring-compressed T-cells with metallic lithium reference electrodes enabling us to analyze the electrode-specific characteristics. Our investigation covers a wide pressure range from 0.02 MPa (low pressure - LP) to 2.00 MPa (ultra high pressure - UHP) to determine the optimal pressure for cyclic lifetime and energy density. We introduce an experimental methodology considering single-component compression to adjust the cell setup precisely. We characterize the cells using impedance spectroscopy and age them at C/2. In the post-mortem analysis, cross-sections of the aged anodes are measured with scanning electron microscopy. The images are analyzed with regard to electrochemical milling, thickness gain, and porosity decrease by comparing them to the pristine state. The results indicate that cycling at UHP has a detrimental effect on cycle life, being almost two-fold shorter when compared to cycling at normal pressure (NP, 0.20 MPa). Scanning electron microscopy showed a dependency of the thickness and the porosity of the aged silicon anodes on the applied pressure, with coating thickness increasing and porosity decreasing for all pressure settings, and a correlation between thickness and porosity.