bluuebunny/crossref_metadata_2025 huggingface dataset:
Forage lignocellulose is an important factor in driving the seasonal dynamics of rumen anaerobic fungi in grazing yak and cattle
Authors: Liang Zeyi , Zhang Jianbo , Ahmad Anum Ali , Han Jianlin , Gharechahi Javad , Du Mei , Zheng Juanshan , Wang Peng , Yan Ping , Salekdeh Ghasem Hosseini , Ding Xuezhi
Published: September 2023

Anaerobic fungi (AF) inhabit the gastrointestinal tract of ruminants and play an important role in the degradation of fiber feed. However, limited knowledge is available on seasonal dynamics and inter-species differences in rumen AF community in yak and cattle under natural grazing systems. Using the random forests model, the null model, and structural equation model, we investigated the seasonal dynamics and key driving factors of fiber-associated rumen AF in grazing yak and cattle throughout the year on the Qinghai-Tibet Plateau (QTP). We found that the richness and diversity of rumen AF of grazing yak and cattle in cold season were significantly higher than those in warm season (
P
< 0.05). We identified 12 rumen AF genera, among which ,
Cyllamyces
, and
Orpinomyces
were predominant in the rumen of both grazing yak and cattle. LEfSe and random forest analysis showed that
Feramyces
,
Tahromyces
, and
Buwchfawromyces
were important seasonal indicator of rumen AF in grazing yak (
P
< 0.05), and
Caecomyces
,
Cyllamyces
, and
Piromyces
in grazing cattle (
P
< 0.05). Null model analysis revealed that the dynamic changes of rumen AF community structure were mainly affected by deterministic factors. Notably, mantel test and structural equation model revealed that forage physical-chemical properties, including dry matter (DM), neutral detergent fiber (NDF), and hemicellulose contents (HC) were the key factors driving the seasonal variations of the rumen AF community (
P
< 0.05). The results revealed that forage lignocellulose was probably an important factor affecting the seasonal dynamics and inter-species differences of the rumen AF community under natural grazing conditions.

IMPORTANCE

The seasonal dynamics of rumen anaerobic fungi in nature grazing yak and cattle were determined during cold and warm seasons based on pasture nutritional quality and environmental data sets. The main driving factors of anaerobic fungi in yak and cattle rumen were explored by combining random forest and structural equation models. In addition, the dynamic differences in the composition of the anaerobic fungi community in the yak and cattle in different seasons were characterized. It was found that some rumen anaerobic fungi have contributed to high fiber degradation rate in yak. These novel findings improve our understanding of the association of environmental and dietary seasonal variations with anaerobic fungal community, facilitating yak adaptation to high altitude.
Design combinations of evolved phage and antibiotic for antibacterial guided by analyzing the phage resistance of poorly antimicrobial phage
Authors: Xu Zhenhe , Ding Zihan , Shi Lijia , Xie YuZhen , Zhang Yuanxing , Sao Shuai , Wang Qiyao , Liu Qin
Published: September 2023

Although antibiotics are the primary method against bacterial infections, the rapid emergence of antibiotic resistance has forced interest in alternative antimicrobial strategies. Phage has been considered a new biological antimicrobial agent due to its high effectiveness in treating bacterial infections. However, the applications of phage therapy have been limited by the quick development of phage-resistant bacteria. Therefore, more effective phage treatment strategies need to be explored guided by characterizing phage-resistant mutants. In this study,
Pseudomonas plecoglossicida
phage vB_PpS_SYP was isolated from the sewage but exhibited weak antibacterial activity caused by phage-resistant bacteria. Phage-resistant mutants were isolated and their whole genomes were analyzed for differences. The results showed that mutations in glycosyltransferase family 1 (
GT-1
) and hypothetical outer membrane protein (
homP
) led to bacterial phage resistance. The
GT-1
mutants had lower biofilm biomass and higher antibiotic sensitivity than wild-type strain. Phage SYP evolved a broader host range and improved antimicrobial efficacy to infect
homP
mutants. Therefore, we designed a strategy for combined antibiotic and evolved phage inhibition driven by the two phage-resistant mutants. The results showed that the combination was more effective against bacteria than either antibiotics or phage alone. Our findings presented a novel approach to utilizing poorly antimicrobial phages by characterizing their phage-resistant mutants, with the potential to be expanded to include phage therapy for a variety of pathogens.

IMPORTANCE

The rapid emergence of antibiotic resistance renews interest in phage therapy. However, the lack of efficient phages against bacteria and the emergence of phage resistance impaired the efficiency of phage therapy. In this study, the isolated
Pseudomonas plecoglossicida
phage exhibited poor antibacterial capacity and was not available for phage therapy. Analysis of phage-resistant mutants guided the design of antibacterial strategies for the combination of antibiotics with evolved phages. The combination has a good antibacterial effect compared to the original phage. Our findings facilitate ideas for the development of antimicrobial-incapable phage, which have the potential to be applied to the phage treatment of other pathogens.
Advance care planning in perinatal settings: national survey of implementation using Normalisation Process Theory
Authors: Shaw Karen L , Spry J , Cummins Carole , Ewer Andrew K , Kilby Mark D , Mancini Alexandra
Published: September 2023

Background

Perinatal advance care planning (PnACP) is a process of formal decision-making to help families plan for their baby’s care when recognised that they may have a life-limiting condition. While PnACP is recommended in policy, there is a lack of evidence to support implementation and development in the perinatal setting.

Objective

To conduct an online survey of UK and Ireland perinatal providers to examine how PnACP is operationalised in current practice.

Methods

A secure online questionnaire was developed to collect data on (1) ‘what’ is being implemented, (2) the ‘processes’ being used, (3) perceived impact and (4) unmet support needs. Data were analysed using basic descriptive statistics, thematic analysis and through a conceptual lens of Normalisation Process Theory.

Results

Questionnaires were completed by 108 health professionals working in 108 maternity and neonatal services, representing 90 organisations across the UK and Ireland. This revealed many resources and examples of good practice to support PnACP. However, there was wide variation in how PnACP was conceptualised and implemented. Existing frameworks, pathways and planning tools are not routinely embedded into care, and respondents identified many barriers that negatively impact the quality of care. They called for better integration of palliative care principles into acute settings and more investment in staff training to support families at existentially difficult times.

Conclusions

Priorities for additional perinatal service development include greater sharing of best practice and effective strategies to target the unique challenges of PnACP, such as time-sensitive collaborative working and decision-making in the face of high uncertainty.
Risk factors for neonatal mortality: an observational cohort study in Sarlahi district of rural southern Nepal
Authors: Yan Tingting , Mullany Luke C , Subedi Seema , Hazel Elizabeth A , Khatry Subarna K , Mohan Diwakar , Zeger Scott , Tielsch James M , LeClerq Steven C , Katz Joanne
Published: September 2023

Objectives

To assess the association between maternal characteristics, adverse birth outcomes (small-for-gestational-age (SGA) and/or preterm) and neonatal mortality in rural Nepal.

Design

This is a secondary observational analysis to identify risk factors for neonatal mortality, using data from a randomised trial to assess the impact of newborn massage with different oils on neonatal mortality in Sarlahi district, Nepal.

Setting

Rural Sarlahi district, Nepal.

Participants

40 119 pregnant women enrolled from 9 September 2010 to 16 January 2017.

Main outcome

The outcome variable is neonatal death. Cox regression was used to estimate adjusted Hazard Ratios (aHRs) to assess the association between adverse birth outcomes and neonatal mortality.

Results

There were 32 004 live births and 998 neonatal deaths. SGA and/or preterm birth was strongly associated with increased neonatal mortality: SGA and preterm (aHR: 7.09, 95% CI: (4.44 to 11.31)), SGA and term/post-term (aHR: 2.12, 95% CI: (1.58 to 2.86)), appropriate-for-gestational-age/large-for-gestational-age and preterm (aHR: 3.23, 95% CI: (2.30 to 4.54)). Neonatal mortality was increased with a history of prior child deaths (aHR: 1.53, 95% CI: (1.24 to 1.87)), being a twin or triplet (aHR: 5.64, 95% CI: (4.25 to 7.48)), births at health posts/clinics or in hospital (aHR: 1.34, 95% CI: (1.13 to 1.58)) and on the way to facilities or outdoors (aHR: 2.26, 95% CI: (1.57 to 3.26)). Risk was lower with increasing maternal height from <145 cm to 145–150 cm (aHR: 0.78, 95% CI: (0.65 to 0.94)) to ≥150 cm (aHR: 0.57, 95% CI: (0.47 to 0.68)), four or more antenatal care (ANC) visits (aHR: 0.67, 95% CI: (0.53 to 0.86)) and education >5 years (aHR: 0.75, 95% CI: (0.62 to 0.92)).

Conclusion

SGA and/or preterm birth are strongly associated with increased neonatal mortality. To reduce neonatal mortality, interventions that prevent SGA and preterm births by promoting ANC and facility delivery, and care of high-risk infants after birth should be tested.

Trial registration number

NCT01177111.
Blended intervention based on acceptance and commitment therapy for informal caregivers of people with dementia (ACT-IC): protocol of a mixed-methods feasibility study
Authors: Atefi Golnaz L , van Knippenberg Rosalia J M , Bartels Sara Laureen , Verhey Frans R J , de Vugt Marjolein E
Published: September 2023

Introduction

Numerous caregiver support programmes have shown promise in promoting the mental health of informal caregivers of people with dementia (PwD). However, there is still a lack of evidence-based interventions tailored to the specific needs of this population. This mixed-methods study aims to evaluate the feasibility, acceptability and preliminary efficacy of a blended intervention based on acceptance and commitment therapy (ACT) for informal caregivers of PwD, leading to a better understanding of intervention refinements for future controlled trials.

Methods and analysis

This study includes an uncontrolled pre–post intervention pilot study. A total of 30 informal caregivers of PwD will be recruited through memory clinics and social media platforms in the Netherlands. The ACT for informal caregiver (ACT-IC) intervention will be delivered over a 9-week period and consists of a collaborative goal-setting session, nine online ACT modules, nine telephone-based motivational coaching sessions and 6 monthly booster sessions following the main intervention period. Feasibility and acceptability will be assessed using attrition rate, adherence to and engagement with the intervention, proportion of missing data and semistructured interviews. Preliminary efficacy will be assessed with retrospective measures of depression, anxiety, stress, sense of competence, burden and self-efficacy at baseline, postintervention, at 3-month and 6-month follow-ups.

Ethics and dissemination

The Medical Ethical Committee from the Maastricht academic hospital and Maastricht University approved the study. The findings of this study will be shared with healthcare professionals, researchers and public audience through various channels, including scientific publications, conference presentations, online forums and community outreach programmes.

Trial registration number

NCT05064969.
Exploring the development of a framework of social accountability standards for healthcare service delivery: a qualitative multipart, multimethods process
Authors: Anawati Alex , Cameron Erin , Harvey Jacqueline
Published: September 2023

Objectives

Social accountability is an equity-oriented health policy strategy that requires institutions to focus on local population needs. This strategy is well established in health professional education, but there is limited understanding of its application in healthcare service delivery. Building on what is known in the education setting, this study aimed to explore the development of a framework of comprehensive, evidence-based social accountability standards for healthcare service delivery institutions.

Design

This qualitative, multipart, multimethods study consisted of a modified Delphi process guided by an evidence-based social accountability tool for health professional education and complementary methods including developmental evaluation and a review of select literature to capture emerging evidence and contextual relevance.

Setting

The study took place in Northern Ontario, Canada at a medical school and a tertiary, regional academic health sciences centre that are both grounded in social accountability.

Participants

Eight expert participants from diverse, multidisciplinary backgrounds, including a patient advocate, were purposefully recruited from both institutions, enrolled and seven completed the study.

Main outcome

The resulting framework of social accountability standards is organised into 4 major sections that capture broad and critical concepts; 17 key component reflective questions that address key themes; 39 aspirations that describe objective standards and 197 indicators linked to specific expectations.

Results

Three modified Delphi rounds were completed producing a framework of consensus derived standards. Developmental evaluation helped identify facilitators, barriers and provided real-time feedback to the study’s processes and content. The literature reviewed identified 10 new concepts and 43 amendments.

Conclusion

This study highlights the development of a comprehensive, evidence-based framework of social accountability standards for healthcare service delivery institutions. Future studies will aim to evaluate the application of these standards to guide equity-oriented social accountability health policy strategies in healthcare service delivery.
Effect of exoskeleton robot-assisted training on gait function in chronic stroke survivors: a systematic review of randomised controlled trials
Authors: Yang Jinchao , Gong Yu , Yu Lei , Peng Laiying , Cui Yuanfen , Huang Hailong
Published: September 2023

Objectives

Numbers of research have reported the usage of robot-assisted gait training for walking restoration post-stroke. However, no consistent conclusion has been reached yet about the efficacy of exoskeleton robot-assisted training (ERAT) on gait function of stroke survivors, especially during the chronic period. We conducted a systematic review to investigate the efficacy of ERAT on gait function for chronic stroke survivors.

Design

This review followed the Participant, Intervention, Comparison and Outcome principle.

Data sources

PubMed, Cochrane Library, Web of Science, Embase and Cumulative Index to Nursing and Allied Health Literature databases were systematically searched until December 2022.

Eligibility criteria

Only randomised controlled trials (RCTs) were included and these RCTs took patients who had a chronic stroke as participants, exoskeleton robot-assisted gait training as intervention, regular rehabilitation therapy as comparison and gait-related functional assessments as outcomes.

Data extraction and synthesis

Data extraction and synthesis used the reporting checklist for systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The risk of bias and methodological quality of included studies were evaluated by two independent investigators under the guidance of Cochrane risk of bias.

Results

Out of 278 studies, a total of 10 studies (n=323, mean age 57.6 years, 63.2% males) were identified in this systematic review. According to the Cochrane risk of bias, the quality of these studies was assessed as low risk. Six studies reported favourable effects of ERAT on gait function involving gait performance, balance function and physical endurance, and the ERAT group was significantly superior when compared with the control group. In contrast, the other four trials showed equal or negative effects of ERAT considering different study designs. All the included studies did not claim any serious adverse events.

Conclusion

ERAT could be an efficient intervention to improve gait function for individuals who had a chronic stroke. However, more rigorously designed trials are required to draw more solid evidence.

PROSPERO registration number

CRD42023410796.
Protocol for a 2-year longitudinal study of eating disturbances, mental health problems and overuse injuries in rock climbers (CLIMB)
Authors: Edlund Klara , Nigicser Isabel , Sansone Mikael , Identeg Fredrik , Hedelin Henrik , Forsberg Niklas , Tranaeus Ulrika
Published: September 2023

Introduction

Rock climbing is a rapidly growing sport in which performance may be affected by participant’s weight and leanness, and there may be pressure on athletes with respect to their eating behaviour and body weight. However, there is sparse research performed on climbers, constituting a knowledge gap which the present study aims to fill. The primary outcomes of the study are to examine disordered eating and overuse injuries in rock climbers. Secondary variables are body image, indicators of relative energy deficiency, mental health problems, compulsive training, perfectionism, sleep quality and bone density.

Method and analysis

This prospective longitudinal study aims to recruit Swedish competitive rock climbers (>13 years) via the Swedish Climbing Federation. A non-athlete control group will be recruited via social media (n=equal of the climbing group). Data will be collected using streamlined validated web-based questionnaires with three follow-ups over 2 years. Inclusion criteria for rock climbers will be a minimum advanced level according to International Rock-Climbing Research Association. The non-athlete control group is matched for age and gender. Exclusion criteria are having competed at an elite level in any sport as well as training more often than twice per week. Statistical analyses will include multinominal logistic regression, multivariate analysis of variance (MANOVA) and structural equation modelling (SEM). We will assess effect measure modification when relevant and conduct sensitivity analyses to assess the impact of lost to follow-up.

Ethics and dissemination

The Rock-Climbers’ Longitudinal attitudes towards Injuries, Mental health and Body image study, CLIMB, was approved by the Swedish ethics authority (2021-05557-01). Results will be disseminated through peer-reviewed research papers, reports, research conferences, student theses and stakeholder communications.

Trial registration number

NCT05587270.
Use of virtual reality in port implantation to reduce perioperative anxiety and pain: protocol for a randomised controlled pilot trial at a single German university hospital (VIP-trial; DRKS00028508)
Authors: Graf Sandra , Feldmann Hannah , Hunold Lisa S , Steinkraus Kira C , Nasir Nadir , Michalski Christoph W , Dörr-Harim Colette , Hüttner Felix J
Published: September 2023

Introduction

Intravenous access port implantation is commonly performed under local anaesthesia, which offers advantages such as increased patient satisfaction and resource savings compared with general anaesthesia. However, patients may experience increased perioperative stress and anxiety in the operating room setting without general anaesthesia. Virtual reality (VR) distraction or hypnosis during surgery under local anaesthesia may help patients to auditorily and visually separate from their real environment and engage with a virtual environment through hypnorelaxing guidance. Previous studies suggested that VR hypnosedation may reduce the use of sedatives or general anaesthesia, and may offer additional benefits such as reducing postoperative pain and nausea, and promoting faster patient discharge.

Methods and analysis

The VIP trial is a randomised controlled pilot trial comparing the usage of VR during port implantation with the current standard of care (local anaesthesia and analgosedation if needed). A total of 120 adult patients are included after screening for eligibility and obtaining informed consent. Patients are randomised preoperatively in a 1:1 ratio to the trial groups. The main outcomes are change of perioperative anxiety and pain. Further outcomes include patient satisfaction and tolerability, perioperative analgesia and sedation, occurrence of postoperative nausea, vomiting and VR sickness symptoms, surgeon’s satisfaction, procedure duration, postoperative complications until postoperative day 30 and patient willingness to hypothetically undergo port implantation again under the same conditions.

Ethics and dissemination

The VIP trial has been approved by the Ethics Committee of the Medical Faculty of Ulm University (reference number 03/22). If the intervention demonstrates that VR can effectively reduce perioperative anxiety and pain, it may become a novel standard of care to minimise the need for analgosedation or general anaesthesia in port implantation procedures and improve patient outcomes. The results will be submitted to a peer-reviewed journal in the field and will be presented at applicable conferences to ensure rigorous evaluation and access for the academic community.

Trial registration number

German Clinical Trials Register: DRKS00028508; registration date 15 March 2022; Universal Trial Number: U1111-1275-4995.
Effects of intravenous sivelestat sodium on prevention of acute respiratory distress syndrome in patients with sepsis: study protocol for a double-blind multicentre randomised controlled trial
Authors: Ma Shaolei , Li Cong , Gao Zhiwei , Xie Jianfeng , Qiu Haibo , Yang Yi , Liu Ling
Published: September 2023

Introduction

Sepsis is one of the most common risk factors for acute respiratory distress syndrome (ARDS). Neutrophil elastase (NE) is believed to be an important mediator of ARDS. When sepsis occurs, a large number of inflammatory factors are activated and released, which makes neutrophils migrate into the lung, eventually leading to the occurrence of ARDS. Sivelestat sodium is an NE inhibitor that can inhibit the inflammatory reaction during systemic inflammatory response syndrome and alleviate lung injury. Therefore, we hypothesise that intravenous sivelestat sodium may prevent the occurrence of ARDS in patients with sepsis.

Methods and analysis

This is a prospective, investigator-initiated, double-blind, adaptive, multicentre, randomised, controlled clinical trial with an adaptive ‘sample size re-estimation’ design. Patients meeting the inclusion criteria who were transferred into the intensive care unit will be randomly assigned to receive sivelestat sodium or placebo for up to 7 days. The primary outcome is the development of ARDS within 7 days after randomisation. A total of 238 patients will be recruited based on a 15% decrease in the incidence of ARDS in the intervention group in this study. A predefined interim analysis will be performed to ensure that the calculation is reasonable after reaching 50% (120) of the planned sample size.

Ethics and dissemination

The study protocol was approved by the Ethics Committee of ZhongDa Hospital affiliated to Southeast University (identifier: Clinical Ethical Approval No. 2021ZDSYLL153-P03). Results will be submitted for publication in peer-reviewed journals and presented at relevant conferences and meetings.

Trial registration number

NCT04973670.
Time to recovery and its predictors among under five children in outpatient therapeutic feeding programme in Borena zone, Southern Ethiopia: a retrospective cohort study
Authors: Kitesa Gutu Yonas , Berhe Trhas Tadesse , Tedla Getachew Weldeyohannes , Sahile Addisu Tadesse , Abegaz Kedir Hussein , Shama Adisu Tafari
Published: September 2023

Objectives

This study aimed to assess the time to recovery and its predictors among 6–59 months aged children treated at an outpatient therapeutic feeding programme in Borena zone.

Design

A retrospective cohort study.

Setting

Facility based; 23 treatment sites included in this study.

Participants

Among the cohorts of 601 children aged 6–59 months enrolled from July 2019 to June 2021, records of 590 children were selected using systematic random sampling. Transfers and incomplete records were excluded.

Primary and secondary outcome measures

Time to recovery was a main outcome while its predictors were secondary outcomes.

Results

The median recovery time was 49 days (95% CI=49 to 52) with a recovery rate of 79.8% (95% CI=76.4 to 83.0). Absence of comorbidity (adjusted HR, AHR=1.72, 95% CI=1.08 to 2.73), referral way by trained mothers on screening (AHR=1.91, 95% CI=1.25 to 2.91), new admission (AHR=1.59, 95% CI=1.05 to 2.41) and adequate Plumpy’Nut provision (AHR=2.10, 95% CI=1.72 to 2.56) were significantly associated with time to recovery. It is also found that being from a distance ≥30 min to treatment site lowers a chance of recovery by 27% (AHR=0.73, 95% CI=0.60 to 0.89).

Conclusions

The findings showed that a time to recovery was within an acceptable range. Incidence of recovery is enhanced with early case detection, proper management, nearby service, new admissions, provision of adequate Plumpy’Nut and enabling mothers to screen their own children for acute malnutrition. However, we did not observe a statistically significant association among breastfeeding status, type of health facility, wasting type, vaccination and routine medications. Service providers should improve adherence to treatment protocols, defaulter tracing, community outreach and timely case identification.
JAK inhibitors for inflammatory bowel disease: recent advances
Authors: Honap Sailish , Agorogianni Alexandra , Colwill Michael J , Mehta Sonia Kalyanji , Donovan Fiona , Pollok Richard , Poullis Andrew , Patel Kamal
Published: September 2023

Inflammatory bowel disease (IBD) commonly requires immunosuppressive treatments to induce and maintain durable remission. Janus kinase inhibitors (JAKis) are a novel group of orally administered, small molecule drugs that work by attenuating multiple cytokine signalling pathways to mediate dysregulated immune responses involved in the pathogenesis of IBD. Tofacitinib, filgotinib and upadacitinib have demonstrated efficacy against placebo and are licensed for the treatment of moderate to severe ulcerative colitis; upadacitinib is the only JAKi also currently approved for the treatment of Crohn’s disease. Safety concerns stratified by age have led to class-wide regulatory restrictions for JAKi use across all inflammatory diseases. It is important for gastroenterologists managing patients with IBD to be aware of the key pivotal trial outcomes, to identify appropriate patients in whom to commence a JAKi, and to understand the safety considerations and ways to mitigate these risks in the patients they treat. This review provides a contemporaneous overview of this emerging therapeutic class and provides a practical guide for healthcare practitioners for initiating and monitoring JAKi in IBD.
Enhanced antitumour immunity following neoadjuvant chemoradiotherapy mediates a favourable prognosis in women with resected pancreatic cancer
Authors: van Eijck Casper W F , Mustafa Dana A M , Vadgama Disha , de Miranda Noel F C C , Groot Koerkamp Bas , van Tienhoven Geertjan , van der Burg Sjoerd H , Malats Núria , van Eijck Casper H J
Published: September 2023

Background

This study investigates sex disparities in clinical outcomes and tumour immune profiles in patients with pancreatic ductal adenocarcinoma (PDAC) who underwent upfront resection or resection preceded by gemcitabine-based neoadjuvant chemoradiotherapy (nCRT).

Methods

Patients originated from the PREOPANC randomised controlled trial. Upfront surgery was performed in 82 patients, and 66 received nCRT before resection. The impact of sex on overall survival (OS) was investigated using Cox proportional hazards models. The immunological landscape within the tumour microenvironment (TME) was mapped using transcriptomic and spatial proteomic profiling.

Results

The 5-year OS rate differed between the sexes following resection preceded by nCRT, with 43% for women compared with 22% for men. In multivariate analysis, the female sex was a favourable independent prognostic factor for OS only in the nCRT group (HR 0.19; 95% CI 0.07 to 0.52). Multivariate heterogeneous treatment effects analysis revealed a significant interaction between sex and treatment, implying increased nCRT efficacy among women with resected PDAC. The TME of women contained fewer protumoural CD163+MRC1+M2 macrophages than that of men after nCRT, as indicated by transcriptomic and validated using spatial proteomic profiling.

Conclusion

PDAC tumours of women are more sensitive to gemcitabine-based nCRT, resulting in longer OS after resection compared with men. This may be due to enhanced immunity impeding the infiltration of protumoral M2 macrophages into the TME. Our findings highlight the importance of considering sex disparities and mitigating immunosuppressive macrophage polarisation for personalised PDAC treatment.
Droplet digital PCR (ddPCR) using FFPE DNA to assess methylation status ofMGMTgene among patients withIDHmutant astrocytoma andIDHwild-type glioblastoma
Authors: Abarna Rajadurai , J Ranjani , chacko Geeta , Pai Rekha
Published: September 2023

MGMTpromoter methylation analysis in formalin-fixed paraffin-embedded (FFPE) tissues can be challenging since the DNA obtained is often fragmented. Bisulfite conversion, which is essential to determine methylation status, further degrades DNA. While conventional methylation-specific PCR (MSP) and pyrosequencing assays have long been used to determine the methylation status ofMGMT, this study was designed to determine the utility of one-tube DNA extraction method coupled with a droplet digital PCR (ddPCR) assay, to study the epigenetic changes in the promoter region of theMGMTgene using DNA obtained from FFPE.

The FFPE blocks of 30 (n=30) patients with Central Nervous System (CNS) WHO grade 4 tumours, previously tested by MSP (2011–2021) were retrieved; DNA was extracted using one-tube extraction method and bisulfite converted. All converted samples were analyzed for methylation status of theMGMTpromoter region with a laboratory designed Methylation-Specific ddPCR (MS ddPCR) using degenerate primers and probes that were labelled with FAM or HEX flurocein dye.

Of the 30 cases, 20 cases wereMGMTmethylated and 10 cases were unmethylated by MS ddPCR. The results of MS ddPCR were then compared with those obtained by MSP and found to be concordant in 93.3% (28/30) of the cases and discordant in 2 cases. The Cohen’s kappa coefficient (κ) was 0.84. The sensitivity, specificity, positive predictive value and negative predictive value of the assay in detecting the methylation status was found to be 95%, 90%, 95% and 90%.

The results show that MS ddPCR is a valuable tool to detect the methylation status of MGMT in FFPE with high sensitivity. This method is cost-effective and easy to perform and could be an attractive alternative to the routine method of MSP.
AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival
Authors: Mehra Vedika , Agliardi Giulia , Dias Alves Pinto Juliana , Shafat Manar S , Garai Amaia Cadinanos , Green Louisa , Hotblack Alastair , Arce Vargas Fred , Peggs Karl S , van der Waart Anniek B , Dolstra Harry , Pule Martin A , Roddie Claire
Published: September 2023

Background

AUTO1 is a fast off-rate CD19-targeting chimeric antigen receptor (CAR), which has been successfully tested in adult lymphoblastic leukemia. Tscm/Tcm-enriched CAR-T populations confer the best expansion and persistence, but Tscm/Tcm numbers are poor in heavily pretreated adult patients. To improve this, we evaluate the use of AKT inhibitor (VIII) with the aim of uncoupling T-cell expansion from differentiation, to enrich Tscm/Tcm subsets.

Methods

VIII was incorporated into the AUTO1 manufacturing process based on the semiautomated the CliniMACS Prodigy platform at both small and cGMP scale.

Results

AUTO1 manufactured with VIII showed Tscm/Tcm enrichment, improved expansion and cytotoxicity in vitro and superior antitumor activity in vivo. Further, VIII induced AUTO1 Th1/Th17 skewing, increased polyfunctionality, and conferred a unique metabolic profile and a novel signature for autophagy to support enhanced expansion and cytotoxicity. We show that VIII-cultured AUTO1 products from B-ALL patients on the ALLCAR19 study possess superior phenotype, metabolism, and function than parallel control products and that VIII-based manufacture is scalable to cGMP.

Conclusion

Ultimately, AUTO1 generated with VIII may begin to overcome the product specific factors contributing to CD19+relapse.
Siglec-9+tumor-associated macrophages delineate an immunosuppressive subset with therapeutic vulnerability in patients with high-grade serous ovarian cancer
Authors: Wang Yiying , He Mengdi , Zhang Chen , Cao Kankan , Zhang Guodong , Yang Moran , Huang Yan , Jiang Wei , Liu Haiou
Published: September 2023

Background

The potent immunosuppressive properties of sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on myeloid cells and lymphocytes provide a strong rationale for serving as a therapeutic target. However, the expression profile and critical role of Siglec-9 in high-grade serous ovarian cancer (HGSC) remain obscure. This study aimed to elucidate the prognostic significance of Siglec-9 expression and its predictive value for immunotherapy in HGSC.

Methods

Study enrolled two cohorts, consisting of 120 tumor microarray specimens of HGSC for immunohistochemistry (IHC) and 40 fresh tumor specimens for flow cytometry (FCM). Expression profile of Siglec-9 in immune cells was analyzed by both bioinformatics analysis and FCM. Role of Siglec-9 was studied to identify that Siglec-9+TAMs linked with an immunosuppressive phenotype by IHC and FCM, and block Siglec-9 was sensitive to immunotherapy by ex vivo and in vitro assays.

Results

Siglec-9 is predominantly expressed on tumor-associated macrophages (TAMs). High Siglec-9+TAMs were associated with inferior overall survival (OS). Both tumor-conditioned medium (TCM) and tumor ascites induced enrichment of Siglec-9+TAMs with protumorigenic phenotypes. Siglec-9+TAMs were associated with immunosuppressive tumor microenvironment (TME) characterized by exhausted CD8+T cells and increased immune checkpoint expression. Blockade of Siglec-9 suppressed phosphorylation of the inhibitory phosphatase SHP-1 and repolarized TAMs to antitumorigenic phenotype and retrieved cytotoxic activity of CD8+T cells in vitro and ex vivo. Responders toward antiprogrammed death receptor-1 (anti-PD-1) therapy present more Siglec-9+TAMs than non-responders. Furthermore, blockade Siglec-9 synergized with anti-PD-1 antibody to enhance the cytotoxic activity of CD8+T cells in tissues with higher Siglec-9+TAMs.

Conclusions

Siglec-9+TAMs may serve as an independent prognostic of poor survival but a predictive biomarker for anti-PD-1/antiprogrammed death ligand-1 immunotherapy in HGSC. In addition, the potential of immunosuppressive Siglec-9+TAMs as a therapeutic target is worth further exploration.
Efficacy, safety, and biomarker analysis of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR-positive HER2-negative metastatic breast cancer: a phase II study (WJOG11418B NEWFLAME trial)
Authors: Masuda Jun , Sakai Hitomi , Tsurutani Junji , Tanabe Yuko , Masuda Norikazu , Iwasa Tsutomu , Takahashi Masato , Futamura Manabu , Matsumoto Koji , Aogi Kenjiro , Iwata Hiroji , Hosonaga Mari , Mukohara Toru , Yoshimura Kiyoshi , Imamura Chiyo K , Miura Sakiko , Yamochi Toshiko , Kawabata Hidetaka , Yasojima Hiroyuki , Tomioka Nobumoto , Yoshimura Kenichi , Takano Toshimi
Published: September 2023

Background

Hormone receptor (HR)-positive breast cancer is a disease for which no immune checkpoint inhibitors have shown promise as effective therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors synergistically increased the effectiveness of antiprogrammed cell death protein-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibodies in preclinical studies.

Methods

This non-randomized, multicohort, phase II study evaluated the efficacy and safety of the anti-PD-1 antibody nivolumab 240 mg administered every 2 weeks in combination with the CDK4/6 inhibitor abemaciclib 150 mg twice daily and either fulvestrant (FUL) or letrozole (LET) as a first-line or second-line treatment for HR-positive HER2-negative metastatic breast cancer. The primary end point was the objective response rate (ORR), and secondary end points were toxicity, progression-free survival, and overall survival. Blood, tissue, and fecal samples were collected at multiple points for correlative studies to evaluate immunity biomarkers.

Results

From June 2019 to early study termination due to safety concerns on July 2020, 17 patients were enrolled (FUL: n=12, LET: n=5). One patient with a prior treatment history in the FUL cohort was excluded. ORRs were 54.5% (6/11) and 40.0% (2/5) in the FUL and LET cohorts, respectively. Treatment-emergent (TE) adverse events (AEs) of grade ≥3 occurred in 11 (92%) and 5 (100%) patients in the FUL and LET cohorts, respectively. The most common grade ≥3 TEAEs were neutropenia (7 (58.3%) and 3 (60.0%) in the FUL and LET cohorts, respectively), followed by alanine aminotransferase elevation (5 (41.6%) and 4 (80.0%)). One treatment-related death from interstitial lung disease occurred in the LET cohort. Ten patients developed liver-related grade ≥3 AEs. Liver biopsy specimens from 3 patients showed hepatitis characterized by focal necrosis with predominant CD8+ lymphocyte infiltration. Marked elevation of tumor necrosis factor-related cytokines and interleukin-11, and a decrease in peripheral regulatory T cells (Tregs), were observed in patients with hepatotoxicity. These findings suggest that treatment-related toxicities were immune-related AEs likely caused by proinflammatory cytokine production and suppression of Treg proliferation due to the addition of abemaciclib to nivolumab therapy.

Conclusions

Although the combination of nivolumab and abemaciclib was active, it caused severe and prolonged immune-related AEs.

Trial registration number

JapicCTI-194782, jRCT2080224706, UMIN000036970.
Cardiovascular events more than 6 months after pregnancy in patients with congenital heart disease
Authors: Schultz Hayley , Sobhani Nasim C , Blissett Sarah , Yogeswaran Vidhushei , Hong Jessica , Harris Ian S , Parikh Nisha , Gonzalez Juan , Agarwal Anushree
Published: September 2023

Objectives

Patients with congenital heart disease (CHD) are increasingly pursuing pregnancy, highlighting the need for data on late cardiovascular events (more than 6 months after delivery). We aimed to determine the incidence of late cardiovascular events in postpartum patients with CHD and evaluate the accuracy of the existing risk scores in predicting these events.

Study design

We identified patients with CHD who delivered between 2008 and 2020 at a tertiary centre and had follow-up data for greater than 6 months post partum. Late cardiovascular events were defined as heart failure, arrhythmia, thromboembolic events, endocarditis, urgent cardiovascular interventions or death. Survival analysis and Cox proportional model were used to estimate the incidence of late cardiovascular events and determine the hazard ratio of factors associated with these events.

Results

Of 117 patients, 19% had 36 late cardiovascular events over a median follow-up of 3.8 years. Annual incidence of any late cardiovascular event was 5.7%. Hazards of late cardiovascular events were significantly higher among those with higher Cardiac Disease in Pregnancy Study (CARPREG) II and Zwangerschap bij Aangeboren HARtAfwijking-Pregnancy in Women With Congenital Heart Disease (ZAHARA) risk scores and among patients with prepregnancy New York Heart Association class≥II. C-statistic to predict the late cardiovascular events was highest for ZAHARA (0.7823), followed by CARPREG II (0.6902) and prepregnancy New York Heart Association class≥ II (0.6677).

Conclusions

Currently available risk tools designed for prognostication during the peripartum period can also be used to determine risks of late maternal cardiovascular events among those with CHD. These findings provide important new information for counselling and risk modification.
Anterior quadratus lumborum block for analgesia after living-donor renal transplantation: a double-blinded randomized controlled trial
Authors: Kim Youngwon , Kim Jin-Tae , Yang Seong-Mi , Kim Won Ho , Han Ahram , Ha Jongwon , Min Sangil , Park Sun-Kyung
Published: September 2023

Introduction

Limited non-opioid analgesic options are available for managing postoperative pain after renal transplantation. We aimed to investigate whether the unilateral anterior quadratus lumborum (QL) block would reduce postoperative opioid consumption after living-donor renal transplantation in the context of multimodal analgesia.

Methods

Eighty-eight adult patients undergoing living-donor renal transplantation were randomly allocated to receive the unilateral anterior QL block (30 mL of ropivacaine 0.375%) or sham block (normal saline) on the operated side before emergence from anesthesia. All patients received standard multimodal analgesia, including the scheduled administration of acetaminophen and fentanyl via intravenous patient-controlled analgesia. The primary outcome was the total opioid consumption during the first 24 hours after transplantation. The secondary outcomes included pain scores, time to first opioid administration, cutaneous distribution of sensory blockade, motor weakness, nausea/vomiting, quality of recovery scores, time to first ambulation, and length of hospital stay.

Results

The total opioid consumption in the first 24 hours after transplantation did not differ significantly between the intervention and control groups (median (IQR), 160.5 (78–249.8) vs 187.5 (93–309) oral morphine milligram equivalent; median difference (95% CI), −27 (−78 to 24), p=0.29). No differences were observed in the secondary outcomes.

Conclusions

The anterior QL block did not reduce opioid consumption in patients receiving multimodal analgesia after living-donor renal transplantation. Our findings do not support the routine administration of the anterior QL block in this surgical population.

Trial registration number

NCT04908761
.
Fascial plane approach to anesthetizing the radial, median, and ulnar nerves: an educational review
Authors: Moody Alastair E , Miller Sarah T , Tupinio Maegan R , Newberry Cynthia M , Mangleson John , Swenson Jeffrey D
Published: September 2023

Brachial plexus block provides effective anesthesia and analgesia for upper extremity surgery but requires injection of large anesthetic volumes near major vascular structures. Moreover, the extensive motor and sensory loss produced by plexus block often exceeds the neural distribution needed for corresponding surgical procedures.

High-resolution ultrasound facilitates selective nerve blocks at nearly every level of the upper extremity. We present fascial plane injection techniques for selective radial, median, and ulnar nerve blocks. These techniques can be used to match sensory distribution with specific surgical procedures. They are performed using low anesthetic volumes and without proximity to nerves or vascular structures. In this article, fresh cadaver dissections with corresponding ultrasound images are used to demonstrate stepwise fascial plane techniques for the radial, median, and ulnar nerves. These techniques are performed using familiar anatomic landmarks.

Practical applications of these techniques are demonstrated for commonly performed procedures of the upper extremity. Corresponding injection volumes with duration of postoperative analgesia are presented. Selected injections are described for both surgical anesthesia and postoperative analgesia.

Selective fascial plane injections can provide surgical anesthesia and postoperative analgesia in settings that might otherwise require much larger volumes of local anesthetic. These selective nerve blocks can match sensory loss with the anatomic pain distribution in each patient. Reliable techniques for selective nerve blocks of the upper extremity can expand the capabilities for ultrasound-guided regional anesthesia.
Association between obesity and likelihood of remission or low disease activity status in psoriatic arthritis applying index-based and patient-based definitions of remission: a cross-sectional study
Authors: Leung Ying Ying , Eder Lihi , Orbai Ana-Maria , Coates Laura C , de Wit Maarten , Smolen Josef S , Kiltz Uta , Palominos Penélope , Canete Juan D , Scrivo Rossana , Balanescu Andra , Dernis Emanuelle , Meisalu Sandra , Soubrier Martin , Kalyoncu Umut , Gossec Laure
Published: September 2023

Objectives

We aimed to evaluate whether obese patients with psoriatic arthritis (PsA) were less likely to be in remission/low disease activity (LDA).

Methods

We used data from the ReFlaP, an international multi-centre cohort study (NCT03119805), which recruited consecutive adults with definite PsA (disease duration ≥ 2 years) from 14 countries. Demographics, clinical data, comorbidities, and patient-reported outcomes were collected. Remission/LDA was defined as Very Low Disease Activity (VLDA)/minimal disease activity (MDA), Disease Activity in PSoriatic Arthritis (DAPSA) ≤4/≤14, or by patients’ opinion. Obesity was defined as physician-reported and/or body mass index ≥30 kg/m2. We evaluated the association between obesity and the presence of remission/LDA, with adjustment in multivariable regression models.

Results

Among 431 patients (49.3% women), 136 (31.6%) were obese. Obese versus non-obese patients were older, more frequently women, had higher tender joint and enthesitis counts and worse pain, physical function and health-related quality of life. Obese patients were less likely to be in VLDA; DAPSA remission and MDA, with adjusted ORs of 0.31 (95% CI 0.13 to 0.77); 0.39 (95% CI 0.19 to 0.80) and 0.61 (95% CI 0.38 to 0.99), respectively. Rates of DAPSA-LDA and patient-reported remission/LDA were similar for obese and non-obese patients.

Conclusion

PsA patients with comorbid obesity were 2.5–3 folds less likely to be in remission/LDA by composite scores compared with non-obese patients; however, remission/LDA rates were similar based on the patients’ opinion. PsA patients with comorbid obesity may have different disease profiles and require individualised management.