bluuebunny/crossref_metadata_2025 huggingface dataset:
High sensitivity C-reactive protein and glycated hemoglobin levels as dominant predictors of all-cause dementia: a nationwide population-based cohort study
Authors: Fan Yen-Chun , Chou Chia-Chi , Bintoro Bagas Suryo , Chien Kuo-Liong , Bai Chyi-Huey
Published: February 2022

Background

Chronic inflammation might play a major role in the pathogenesis linking diabetes mellitus (DM) to cognition. In addition, DM might be the main driver of dementia risk. The purpose of the present study was to evaluate whether inflammation, glycation, or both are associated with the risk of developing all-cause dementia (ACD).

Methods

A nationwide population-based cohort study was conducted with 4113 participants. The data were obtained from the Taiwanese Survey on Prevalence of Hypertension, Hyperglycemia, and Hyperlipidemia (TwSHHH) in 2007, which was linked with the Taiwan National Health Insurance Research Database (NHIRD). The markers of inflammation, expressed as hs-CRP, and glycation, presented as HbA1c, were measured. High levels of hs-CRP and HbA1c were defined as values greater than or equal to the 66th percentile. Developed ACD was identified based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes.

Results

During 32,926.90 person-years, 106 individuals developed ACD in up to 8 years of follow-up. The study participants were separated into four categories by the top tertiles of hs-CRP and HbA1c based on the 66th percentile: high levels of both hs-CRP and HbA1c, only high levels of hs-CRP, only high levels of HbA1c, and non-high levels of hs-CRP nor HbA1c. Those who with a high level of only hs-CRP had the higher hazard for developing ACD (adjusted HR = 2.58; 95% CI = 1.29 ~ 5.17; P = 0.007), followed by the group with a high level of only HbA1c (adjusted HR = 2.52; 95% CI = 1.34 ~ 4.74; P = 0.004) and the group with high levels of both hs-CRP and HbA1c (adjusted HR = 2.36; 95% CI = 1.20 ~ 4.62; P = 0.012). Among those aged less than 65 years, hs-CRP was the only significant predictor of ACD risk (P = 0.046), whereas it did not yield any significant result in the elderly.

Conclusions

A higher risk of developing ACD was found not only in patients with high levels of inflammation but also high levels of glycated hemoglobin. Future studies should focus on the clinical implementation of hs-CRP or HbA1c to monitor cognitive deficits.
Genetic mutation profiles and immune microenvironment analysis of pulmonary enteric adenocarcinoma
Authors: Xie Min , Chen Dong , Li Yong , Liu Xiansheng , Kuang Dong , Li Xiaochen
Published: February 2022

Background

Pulmonary enteric adenocarcinoma (PEAC) has distinctive clinical outcomes, radiographic, pathological and molecular characteristics. The prognosis of patients with PEAC was poor. However, molecular profiles and therapeutic biomarkers of PEAC remain elusive.

Methods

In the present study, the hospitalized patients with PEAC admitted to Tongji Hospital in Wuhan from January 1, 2014 to November 20, 2020 were retrospectively enrolled and followed until December 10, 2020. Comprehensive genomic profiling of tumor tissue from the PEAC patients were performed and compared with lung adenocarcinoma, colorectal cancer and metastatic colorectal carcinoma. Tumor immune microenvironment analysis were evaluated.

Results

There were 10 patients with PEAC enrolled. 70% of patients were male and the median age of onset was 63 years (interquartile range, 55–72). There were six early-stage patients (Stage IA to IIB) and four stage IV patients. Molecular analysis revealed the most common gene mutations included TP53 (57%, 4/7) and KRAS (57%, 4/7) mutations. There were 40% mutations occurred in genes encoding receptor tyrosine kinases (RTKs). 100% of patients (8/8) were microsatellite stability (MSS). The median level of TMB was 6.0 (interquartile range, 4.5–7.0) mutations/Mb. Three of 10 patients showed low PD-L1 expression (tumor proportion score < 10%) and the others were PD-L1 negative. A small subset of CD8+, CD3+, CD68+ T cells were observed and were mainly distributed in the cancer stroma.

Conclusion

This study demonstrated that PEAC was characterized by low-frequency RTK gene mutation, high KRAS mutation, low PD-L1 expression, low TMB, and low CD8+ T cells infiltration.
Morphological diversity of the tricuspid posterior leaflet affects surgical complexity for control of tricuspid regurgitation
Authors: Kawase Takumi , Takahashi Yosuke , Nishiya Kenta , Kishimoto Noriaki , Yamane Kokoro , Sakon Yoshito , Morisaki Akimasa , Fujii Hiromichi , Shibata Toshihiko
Published: February 2022

Objective

We investigated the effect of morphological diversity of the tricuspid valve with multiple posterior leaflets on the technical outcomes of tricuspid valve repair.

Methods

From April 2016 to November 2020, 141 patients were diagnosed with secondary tricuspid regurgitation associated with left heart disease and underwent tricuspid valve repair. We retrospectively analyzed the clinical and echocardiographic data of patients who underwent both preoperative and postoperative transthoracic echocardiography. We divided the patients into two groups according to the surgical technique used to treat tricuspid regurgitation: ring annuloplasty alone (Group 1, n = 109) or additional approximation of leaflet edges (edge-to-edge repair) with ring annuloplasty (Group 2, n = 32). We measured the morphological diversity of the tricuspid valve during the operation in all patients.

Results

The preoperative tricuspid regurgitation score was higher in Group 2 than in Group 1 (2.1 ± 0.78 vs. 1.6 ± 0.7, respectively; p = 0.0046), and Group 2 contained more patients with two posterior leaflets than Group 1 [20 (63%) vs. 36 (33%), respectively; p = 0.003]. The univariate and multivariate logistic regression analyses showed that the presence of two posterior leaflets was an independent risk factor for additional procedures during tricuspid valve repair (odds ratio, 2.6; 95% confidence interval, 1.1–6.1; p = 0.033).

Conclusions

Additional procedures to reduce tricuspid regurgitation were required more frequently in patients with two posterior leaflets of the tricuspid valve. The morphological diversity of two posterior leaflets is a potential risk factor for a more complicated tricuspid repair.
Challenges and improvement needs in the care of patients with central diabetes insipidus
Authors: Teare H. , Argente J. , Dattani M. , Leger J. , Maghnie M. , Sherlock M. , Ali G.-C. , Francombe J. , Marjanovic S.
Published: February 2022

Central diabetes insipidus (CDI) is a rare condition, with significant impact on patient health and well-being. It is a chronic condition which usually requires meticulous long-term care. It can affect both children and adults. There is limited literature considering the needs and challenges inherent in providing high quality care to patients with CDI, across the care pathway. This paper seeks to address this gap by providing a unique and well-rounded understanding of clinical and healthcare systems-related challenges. It draws on insights from the literature, from direct clinical experience contributed by five clinicians as co-authors (providing insights from France, Ireland, Italy, Spain and the United Kingdom), and from patient perspectives provided through interviews with patient representatives from three patient organisations. We identify clinical challenges related to the diagnosis of CDI, including differentiating between other similar conditions and determining the underlying aetiology. Treatment is challenging, given the need to tailor medication to each patient’s needs and ongoing management is required to ensure that patients continue to respond adequately to treatment. Ongoing support is required when patients switch between formulations. We also identify healthcare systems challenges related to limited awareness of CDI amongst primary care physicians and general paediatricians, and the need for highly skilled specialist care and appropriate workforce capacity. There is also a significant need for raising awareness and for the education of both healthcare professionals and patients about different aspects of CDI, with the aim of supporting improved care and effective patient engagement with healthcare professionals. We reflect on this information and highlight improvement opportunities. These relate to developing guidance to support patients, carers, primary care physicians and general paediatricians to identify clinical features earlier, and to consider CDI as a possible diagnosis when a patient presents with suggestive symptoms.
Risk factors for pregnancy-related clinical outcome in myasthenia gravis: a systemic review and meta-analysis
Authors: Su Manqiqige , Liu Xiaoqing , Wang Liang , Song Jie , Zhou Zhirui , Luo Sushan , Zhao Chongbo
Published: February 2022

Objective

Myasthenia gravis (MG) is an autoimmune disorder that frequently affects females at reproductive age. Herein, we aimed to assess the associations of clinical factors with pregnancy-related outcome in MG.

Methods

We searched PubMed and EMBASE for case–control and cohort studies that reported the MG status during or after pregnancy and relevant clinical variables. The data was extracted in proportions and odds ratios (ORs) with 95% confidence intervals (CIs) in subsequent meta-analysis.

Results

Fifteen eligible articles reporting on 734 pregnancies with 193 worsening and 51 improved episodes were included out of 1765 records. The estimated worsening proportions in total, antepartum and postpartum periods were 0.36 (95% CI 0.25–0.40), 0.23 (95% CI 0.14–0.34) and 0.11 (95% CI 0.04–0.22) respectively. The proportion of pregnancy-related improvement in enrolled patients was 0.28 (95% CI 0.17–0.40), with 0.07 (95% CI 0.00–0.28) during pregnancy and 0.14 (95% CI 0.02–0.34) after pregnancy. No significant associations were disclosed between the clinical factors and MG worsening. Thymectomy before delivery is a strong predictor for MG improvement in postpartum period (OR 4.85, 95% CI 1.88–12.50, p = 0.001).

Conclusion

The total proportion of pregnancy-related MG worsening and improvement in MG was 0.36 (95% CI 0.25–0.40) and 0.28 (95% CI 0.17–0.40), respectively. Thymectomy before the delivery may aid in clinical improvements associated with pregnancy. Future prospective cohort studies are required to determine more relevant factors.
Assessing the role of blood pressure in amyotrophic lateral sclerosis: a Mendelian randomization study
Authors: Xia Kailin , Zhang Linjing , Tang Lu , Huang Tao , Fan Dongsheng
Published: February 2022

Background

Observational studies have suggested a close but controversial relationship between blood pressure (BP) and amyotrophic lateral sclerosis (ALS). It remains unclear whether this association is causal. The authors employed a bidirectional two-sample Mendelian randomization (MR) approach to evaluate the causal relationship between BP and ALS. Genetic proxies for systolic blood pressure (SBP), diastolic blood pressure (DBP), antihypertensive drugs (AHDs), ALS, and their corresponding genome-wide association study (GWAS) summary datasets were obtained from the most recent studies with the largest sample sizes. The inverse variance weighted (IVW) method was adopted as the main approach to examine the effect of BP on ALS and four other MR methods were used for sensitivity analyses. To exclude the interference between SBP and DBP, a multivariable MR approach was used.

Results

We found that genetically determined increased DBP was a protective factor for ALS (OR = 0.978, 95% CI 0.960–0.996, P = 0.017) and that increased SBP was an independent risk factor for ALS (OR = 1.014, 95% CI 1.003–1.025, P = 0.015), which is supported by sensitivity analyses. The use of calcium channel blocker (CCB) showed a causal relationship with ALS (OR = 0.985, 95% CI 0.971–1.000, P = 0.049). No evidence was revealed that ALS caused changes in BP.

Conclusions

This study provides genetic support for a causal effect of BP and ALS that increased DBP has a protective effect on ALS, and increased SBP is a risk factor for ALS, which may be related to sympathetic excitability. Blood pressure management is essential in ALS, and CCB may be a promising candidate.
Is it possible to implement a rare disease case-finding tool in primary care? A UK-based pilot study
Authors: Buendia Orlando , Shankar Sneha , Mahon Hadley , Toal Connor , Menzies Lara , Ravichandran Pradeep , Roper Jane , Takhar Jag , Benfredj Rudy , Evans Will
Published: February 2022

Introduction

This study implemented MendelScan, a primary care rare disease case-finding tool, into a UK National Health Service population. Rare disease diagnosis is challenging due to disease complexity and low physician awareness. The 2021 UK Rare Diseases Framework highlights as a key priority the need for faster diagnosis to improve clinical outcomes.

Methods and results

A UK primary care locality with 68,705 patients was examined. MendelScan encodes diagnostic/screening criteria for multiple rare diseases, mapping clinical terms to appropriate SNOMED CT codes (UK primary care standardised clinical terminology) to create digital algorithms. These algorithms were applied to a pseudo-anonymised structured data extract of the electronic health records (EHR) in this locality to "flag" at-risk patients who may require further evaluation. All flagged patients then underwent internal clinical review (a doctor reviewing each EHR flagged by the algorithm, removing all cases with a clear diagnosis/diagnoses that explains the clinical features that led to the patient being flagged); for those that passed this review, a report was returned to their GP. 55 of 76 disease criteria flagged at least one patient. 227 (0.33%) of the total 68,705 of EHR were flagged; 18 EHR were already diagnosed with the disease (the highlighted EHR had a diagnostic code for the same RD it was screened for, e.g. Behcet’s disease algorithm identifying an EHR with a SNOMED CT code Behcet's disease). 75/227 (33%) EHR passed our internal review. Thirty-six reports were returned to the GP. Feedback was available for 28/36 of the reports sent. GP categorised nine reports as "Reasonable possible diagnosis" (advance for investigation), six reports as "diagnosis has already been excluded", ten reports as "patient has a clear alternative aetiology", and three reports as "Other" (patient left study locality, unable to re-identify accurately). All the 9 cases considered as "reasonable possible diagnosis" had further evaluation.

Conclusions

This pilot demonstrates that implementing such a tool is feasible at a population level. The case-finding tool identified credible cases which were subsequently referred for further investigation. Future work includes performance-based validation studies of diagnostic algorithms and the scalability of the tool.
Long-term clinical efficacy of topical treatment with recombinant human nerve growth factor in neurotrophic keratopathy: a novel cure for a rare degenerative corneal disease?
Authors: Bruscolini Alice , Marenco Marco , Albanese Giuseppe Maria , Lambiase Alessandro , Sacchetti Marta
Published: February 2022

Background

Neurotrophic keratopathy (NK) is a rare, degenerative ocular disease characterized by reduction or loss of corneal sensitivity and development of non-healing corneal epithelial defects and ulcers. Cenegermin, a recombinant human nerve growth factor (rhNGF) eye drop solution, is the first drug approved for the treatment of NK. The aim of our study is to evaluate the long-term efficacy of this innovative topical treatment in patients with NK.

Methods

Retrospective, consecutive, observational case series study from a single-center setting (Department of Sense Organs, University Sapienza of Rome, Rome, Italy). 18 patients with diagnosis of stage 2 or 3 NK, treated with Cenegermin 20 mcg/ml eye drops were followed for up to 48 months. Recurrence of lesion during follow-up was evaluated at 12, 24, 36, and 48 months. In addition, corneal sensitivity, Schirmer tear test, and visual acuity (VA) were recorded at baseline, end of treatment, and at 12, 24, 36, and 48 months.

Results

Three patients experienced recurrence of persistent epithelial defects (PEDs) within 12 months and one patient experienced recurrence of a corneal ulcer within 36 months. Corneal sensitivity was significantly improved at all timepoints (P < 0.05). Significant improvements in visual acuity and tear production were seen at the completion of treatment as well as at 12, 24, and 36 months (P < 0.05) when compared to baseline.

Conclusions

A single 8-week treatment regimen of Cenegermin eye drops has clinical efficacy that can persist for up to 48 months. The long-term clinical utility of treatment with Cenegermin for NK was demonstrated through the low rate of lesion recurrence along with improvements in corneal sensitivity and tear production.
Long non-coding RNA OIP5-AS1 suppresses microRNA-92a to augment proliferation and metastasis of ovarian cancer cells through upregulating ITGA6
Authors: Wang Yujue , Li Lingling , Zhang Xun , Zhao Xiaolan
Published: February 2022

Objective

Recently, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been identified as essential biomarkers during development of malignancies. This study was performed to study the roles of lncRNA opa-interacting protein 5 antisense transcript 1 (OIP5-AS1) and miR-92a in ovarian cancer (OC).

Methods

OIP5-AS1, miR-92a and integrin alpha 6 (ITGA6) expression in OC tissues and cells was assessed. The screened OC cells were respectively with OIP5-AS1-, miR-92a- and ITGA6-related vectors or oligonucleotides . The viability, migration, invasion and apoptosis of the cells were determined and the levels of epithelial-mesenchymal transition (EMT)-related proteins were also measured. The interactions between OIP5-AS1 and miR-92a, and between miR-92a and ITGA6 were confirmed.

Results

OIP5-AS1 and ITGA6 were upregulated while miR-92a was downregulated in OC. Inhibited OIP5-AS1 or downregulated ITGA6 or elevated miR-92a repressed EMT, viability, migration and invasion, and promoted apoptosis of OC cells. OIP5-AS1 as a competing endogenous RNA interacted with miR-92a to regulate ITGA6. These effects that induced by silenced OIP5-AS1 could be reversed by miR-92a inhibition while those that induced by up-regulated miR-92a were reduced by restored ITGA6.

Conclusion

OIP5-AS1 silencing promoted miR-92a to repress proliferation and metastasis of OC cells through inhibiting ITGA6.
Comparative analysis of antibody- and lipid-based multiplexing methods for single-cell RNA-seq
Authors: Mylka Viacheslav , Matetovici Irina , Poovathingal Suresh , Aerts Jeroen , Vandamme Niels , Seurinck Ruth , Verstaen Kevin , Hulselmans Gert , Van den Hoecke Silvie , Scheyltjens Isabelle , Movahedi Kiavash , Wils Hans , Reumers Joke , Van Houdt Jeroen , Aerts Stein , Saeys Yvan
Published: February 2022

Background

Multiplexing of samples in single-cell RNA-seq studies allows a significant reduction of the experimental costs, straightforward identification of doublets, increased cell throughput, and reduction of sample-specific batch effects. Recently published multiplexing techniques using oligo-conjugated antibodies or -lipids allow barcoding sample-specific cells, a process called “hashing.”

Results

Here, we compare the hashing performance of TotalSeq-A and -C antibodies, custom synthesized lipids and MULTI-seq lipid hashes in four cell lines, both for single-cell RNA-seq and single-nucleus RNA-seq. We also compare TotalSeq-B antibodies with CellPlex reagents (10x Genomics) on human PBMCs and TotalSeq-B with different lipids on primary mouse tissues. Hashing efficiency was evaluated using the intrinsic genetic variation of the cell lines and mouse strains. Antibody hashing was further evaluated on clinical samples using PBMCs from healthy and SARS-CoV-2 infected patients, where we demonstrate a more affordable approach for large single-cell sequencing clinical studies, while simultaneously reducing batch effects.

Conclusions

Benchmarking of different hashing strategies and computational pipelines indicates that correct demultiplexing can be achieved with both lipid- and antibody-hashed human cells and nuclei, with MULTISeqDemux as the preferred demultiplexing function and antibody-based hashing as the most efficient protocol on cells. On nuclei datasets, lipid hashing delivers the best results. Lipid hashing also outperforms antibodies on cells isolated from mouse brain. However, antibodies demonstrate better results on tissues like spleen or lung.
Minimising young children’s anxiety through schools (MY-CATS): protocol for a cluster randomised controlled trial to evaluate the effectiveness and cost-effectiveness of an online parent-led intervention compared with usual school practice for young children identified as at risk for anxiety disorders
Authors: Reardon Tessa , Dodd Helen , Hill Claire , Jasper Bec , Lawrence Peter J. , Morgan Fran , Rapee Ronald M. , Ukoumunne Obioha C. , Violato Mara , Davey Emily , Halliday Gemma , Jones Benjamin , Martineau Lindsey , McCall Amy , Niekamp Natascha , Placzek Anna , Potts Ruth , Weisser Tamatha , Creswell Cathy
Published: February 2022

Background

Identifying and supporting young children who are at risk of developing anxiety disorders would benefit children, families, and wider society. Elevated anxiety symptoms, inhibited temperament, and high parental anxiety are established risk factors for later anxiety disorders, but it remains unclear who is most likely to benefit from prevention and early intervention programmes. Delivering an online intervention through schools to parents of young children who have one or more of these risks could maximise reach. The primary aim of this trial is to evaluate the effectiveness and cost-effectiveness of delivering an online parent-led intervention, compared with usual school provision only, for children (aged 4–7) identified as at risk for anxiety disorders on the basis of at least one risk factor. We also aim to identify the characteristics of children who do and do not benefit from intervention and mechanisms of change from the intervention.

Methods

The design will be a parallel group, superiority cluster randomised controlled trial, with schools (clusters) randomised to intervention or usual school practice arms in a 1:1 ratio stratified according to level of deprivation within the school. The study will recruit and randomise at least 60 primary/infant schools in England, and on the basis of recruiting 60 schools, we will recruit 1080 trial participants (540 per arm). Parents of all children (aged 4–7) in sampled Reception, Year 1, and Year 2 classes will be invited to complete screening questionnaires. Children who screen positive on the basis of anxiety symptoms, and/or behavioural inhibition, and/or parent anxiety symptoms will be eligible for the trial. Parents/carers of children in schools allocated to the intervention arm will be offered a brief online intervention; schools in both arms will continue to provide any usual support for children and parents throughout the trial. Assessments will be completed at screening, baseline (before randomisation), 6 weeks, 12 weeks, and 12 months post-randomisation. The primary outcome will be the absence/presence of an anxiety disorder diagnosis at 12 months.

Discussion

The trial will determine if delivering an online intervention for parents of young children at risk of anxiety disorders identified through screening in schools is effective and cost-effective.

Trial registration

ISRCTN 82398107. Prospectively registered on Jan. 14, 2021.
The INVENT COVID trial: a structured protocol for a randomized controlled trial investigating the efficacy and safety of intravenous imatinib mesylate (Impentri®) in subjects with acute respiratory distress syndrome induced by COVID-19
Authors: Atmowihardjo Leila , Schippers Job R. , Bartelink Imke H. , Bet Pierre M. , van Rein Nienke , Purdy Keith , Cavalla David , Comberiati Valérie , McElroy Andrew , Snape Sue D. , Bogaard Harm Jan , Heunks Leo , Juffermans Nicole , Schultz Marcus , Tuinman Pieter R. , Bos Lieuwe D. J. , Aman Jurjan
Published: February 2022

Background

The coronavirus disease 2019 (COVID-19) pandemic has led to a disruptive increase in the number of intensive care unit (ICU) admissions with acute respiratory distress syndrome (ARDS). ARDS is a severe, life-threatening medical condition characterized by widespread inflammation and vascular leak in the lungs. Although there is no proven therapy to reduce pulmonary vascular leak in ARDS, recent studies demonstrated that the tyrosine kinase inhibitor imatinib reinforces the endothelial barrier and prevents vascular leak in inflammatory conditions, while leaving the immune response intact.

Methods

This is a randomized, double-blind, parallel-group, placebo-controlled, multicenter clinical trial of intravenous (IV) imatinib mesylate in 90 mechanically ventilated subjects with COVID-19-induced ARDS. Subjects are 18 years or older, admitted to the ICU for mechanical ventilation, meeting the Berlin criteria for moderate-severe ARDS with a positive polymerase chain reaction test for SARS-CoV2. Participants will be randomized in a 1:1 ratio to either imatinib (as mesylate) 200 mg bis in die (b.i.d.) or placebo IV infusion for 7 days, or until ICU discharge or death. The primary study outcome is the change in Extravascular Lung Water Index (EVLWi) between day 1 and day 4. Secondary outcome parameters include changes in oxygenation and ventilation parameters, duration of invasive mechanical ventilation, number of ventilator-free days during the 28-day study period, length of ICU stay, and mortality during 28 days after randomization. Additional secondary parameters include safety, tolerability, and pharmacokinetics.

Discussion

The current study aims to investigate the efficacy and safety of IV imatinib in mechanically ventilated subjects with COVID-19-related ARDS. We hypothesize that imatinib decreases pulmonary edema, as measured by extravascular lung water using a PiCCO catheter. The reduction in pulmonary edema may reverse hypoxemic respiratory failure and hasten recovery. As pulmonary edema is an important contributor to ARDS, we further hypothesize that imatinib reduces disease severity, reflected by a reduction in 28-day mortality, duration of mechanical ventilation, and ICU length of stay.

Trial status

Protocol version and date: V3.1, 16 April 2021. Recruitment started on 09 March 2021. Estimated recruitment period of approximately 40 weeks.

Trial registration

ClinicalTrials.govNCT04794088. Registered on 11 March 2021.
Evaluation of two evidence-based decision aids for female BRCA1/2 mutation carriers in Germany: study protocol for a randomised controlled parallel-group trial
Authors: Kautz-Freimuth Sibylle , Redaèlli Marcus , Isselhard Anna , Shukri Arim , Vodermaier Andrea , Rhiem Kerstin , Schmutzler Rita , Stock Stephanie
Published: February 2022

Background

Women with BRCA1/2 mutations have a higher risk of developing breast and ovarian cancer compared to women of the general population. Various preventive options are available to deal with the increased risk of developing cancer. These include intensified breast cancer screening and risk-reducing bilateral mastectomy and salpingo-oophorectomy. The choice of a preventive option can lead to increased decisional conflict. To support these women in their decision-making process, two evidence-based decision aids were developed in an upstream research process and adapted to the German healthcare context. These will be evaluated within a randomised controlled trial (RCT) in terms of their effects on decision-making, women’s level of information and psychological outcome variables.

Methods

A sample of 310 women carrying BRCA1/2 mutations (A) without a history of cancer or (B) with a history of unilateral breast cancer who have received post-test genetic counselling will be enrolled. Upon study consent, women will be randomly assigned to either the intervention or the control group. All participants will receive standard care including a physician’s letter summarising the counselling content. After baseline data collection (t0), the intervention group receives the respective decision aid while the control group receives standard care only. The primary outcome variable assessed at a 3-month follow-up (t1) is the change of extent in decisional conflict (measured with the Decisional Conflict Scale). Secondary outcome variables comprise the stage of decision-making, self-reported symptoms of anxiety, depression and stress due to the genetic test result, and knowledge regarding cancer risks and preventive options. At t1, the extent of preparation for decision-making and acceptability of the decision aids will also be examined. Another secondary outcome variable assessed at 6-month follow-up (t2) is the extent of decision regret.

Discussion

These will be the first decision aids available for BRCA1/2 mutation carriers in Germany to be evaluated regarding their effectiveness and acceptability in clinical use within an RCT. Subsequently, they are to be integrated into the care concept of the centres of the German Consortium for Hereditary Breast and Ovarian Cancer and the affiliated breast centres.

Trial registration {2a}

DRKS DRKS00015823. Retrospectively registered on 14 June 2019
Sterile water injections for relief of labour pain (the SATURN trial): study protocol for a randomised controlled trial
Authors: Lee Nigel , Gao Yu , Mårtensson Lena B. , Callaway Leonie , Barnett Belinda , Kildea Sue
Published: February 2022

Background

Up to 80% of women use some form of pharmacological analgesia during labour and birth. The side effects of pharmacological agents are often incompatible with the concurrent use of non-pharmacological pain relieving strategies, such as water immersion, ambulation and upright positioning, or may have negative effects on both the mother and fetus. Sterile water injections given into the skin of the lumbar region have been demonstrated to reduce back pain during labour. However, the injections given for back pain have no effect on abdominal contraction pain. The analgesic efficacy of sterile water injections for abdominal pain during childbirth is unknown. The injections cause an immediate, brief but significant pain that deters some women from using the procedure. This study aims to investigate the use of water injections given intradermally into the abdomen to relieve labour contraction pain. A vapocoolant spray will be applied to the skin immediately prior to the injections to reduce the injection pain.

Methods

In this pragmatic, placebo controlled trial 154 low-risk women in labour at term with a labour pain score ≥ 60 on a 100 millimitre visual analogue scale (VAS) will be randomly allocated to receive either six injections of sterile water or a sodium chloride 0.9% solution as a placebo (0.1–.0.3 ml per injection). Three injections are given along the midline from the fundus to the supra-pubis and three laterally across the supra-pubis. The primary outcome will be the difference in VAS score 30 min post injection between groups. Secondary outcomes include VAS score of the injection pain on administration, VAS score of labour pain at 60 and 90 min, maternal and neonatal birth outcomes.

Discussion

Access to effective pain relief during labour is fundamental to respectful and safe maternity care. Pharmacological analgesics should support rather than limit other non-pharmacological strategies. Sterile water injections have the potential to provide an alternative form of labour pain relief that is easy to administer in any labour and birth setting, and compatible with other non-pharmacological choices.

Trial registration

ANZCTR (ACTRN12621001036808) Date submitted: 22/06/2021. Date registered: 05/08/2021. https://www.anzctr.org.au/
Exploiting genomics to mitigate the public health impact of antimicrobial resistance
Authors: Waddington Claire , Carey Megan E. , Boinett Christine J. , Higginson Ellen , Veeraraghavan Balaji , Baker Stephen
Published: February 2022

Antimicrobial resistance (AMR) is a major global public health threat, which has been largely driven by the excessive use of antimicrobials. Control measures are urgently needed to slow the trajectory of AMR but are hampered by an incomplete understanding of the interplay between pathogens, AMR encoding genes, and mobile genetic elements at a microbial level. These factors, combined with the human, animal, and environmental interactions that underlie AMR dissemination at a population level, make for a highly complex landscape. Whole-genome sequencing (WGS) and, more recently, metagenomic analyses have greatly enhanced our understanding of these processes, and these approaches are informing mitigation strategies for how we better understand and control AMR. This review explores how WGS techniques have advanced global, national, and local AMR surveillance, and how this improved understanding is being applied to inform solutions, such as novel diagnostic methods that allow antimicrobial use to be optimised and vaccination strategies for better controlling AMR. We highlight some future opportunities for AMR control informed by genomic sequencing, along with the remaining challenges that must be overcome to fully realise the potential of WGS approaches for international AMR control.
The effect of 24-week belimumab treatment withdrawal followed by treatment restart in patients with SLE: an open-label, non-randomised 52-week study
Authors: Bae Sang-Cheol , Bass Damon L. , Chu Myron , Curtis Paula , Dimelow Richard , Harvey Laurence , Ji Beulah , Kurrasch Regina , Muzaffar Saima , Punwaney Raj , Roth David A. , Song Yeong-Wook , Xie Wendy , Zhang Fengchun
Published: February 2022

Background

Treatment goals for patients with systemic lupus erythematosus (SLE) include minimising disease activity and reducing the risk of flares. Although belimumab is effective at reducing disease activity and risk of severe flares, it was previously unknown what the clinical effects were upon treatment discontinuation. The objective of this study was to assess the impact of temporary withdrawal of intravenous (IV) belimumab in patients with SLE.

Methods

This multicentre, open-label, non-randomised, 52-week study (GSK Study BEL116027; NCT02119156) recruited patients with SLE and stable low disease activity, of whom those on belimumab 10 mg/kg IV plus standard therapy either discontinued belimumab for 24 weeks and then restarted belimumab 10 mg/kg IV every 4 weeks (q4w) for 28 weeks (treatment holiday [TH] group), or continued on belimumab 10 mg/kg IV plus standard therapy q4w for 52 weeks (treatment continuation [TC] group). The primary endpoint was median time to first Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) Flare Index flare. Secondary and other endpoints included rate of any flare, time to severe flare, time to renal flare and rebound (SELENA-SLEDAI score exceeding parent study baseline). Data on rebound phenomenon in patients with any disease level of SLE who had permanently withdrawn from further belimumab treatment (long-term discontinuation group [LTD]) were also assessed. Safety was assessed.

Results

The primary endpoint was not evaluable in the TH (n = 12) and TC (n = 29) groups as fewer than half of patients flared. Unadjusted flare rates per patient-year were 1.0 during treatment discontinuation and 0.3 during treatment restart (0.6 overall) in the TH group and 0.6 in the TC group; there were no severe or renal flares. No TH patients rebounded; 2 (6.9%) TC patients rebounded; 2 (5.1%) patients in the LTD group rebounded. There were no new safety signals.

Conclusions

Twenty-four-week belimumab discontinuation did not appear to increase the risk of flares or rebound in patients with low SLE disease activity; flare rates were low in both groups. Further studies may help to fully determine the effect of belimumab discontinuation.

Trial registration

ClinicalTrials.gov, NCT02119156. Registered on April 21, 2014.
Increased oxidative stress contributes to impaired peripheral CD56dimCD57+ NK cells from patients with systemic lupus erythematosus
Authors: Lu Zhimin , Tian Yao , Bai Ziran , Liu Jiaqing , Zhang Yan , Qi Jingjing , Jin Minli , Zhu Jie , Li Xia
Published: February 2022

Background

Systemic lupus erythematosus (SLE) is characterized by loss of immune tolerance and imbalance of immune cell subsets. Natural killer (NK) cells contribute to regulate both the innate and adaptive immune response. In this study, we aimed to detect alterations of peripheral NK cells and explore intrinsic mechanisms involving in NK cell abnormality in SLE.

Methods

Blood samples from healthy controls (HCs) and patients with SLE and rheumatoid arthritis (RA) were collected. The NK count, NK subsets (CD56bright, CD56dimCD57−, and CD56dimCD57+), phenotypes, and apoptosis were evaluated with flow cytometer. Mitochondrial reactive oxygen species (mtROS) and total ROS levels were detected with MitoSOX Red and DCFH-DA staining respectively. Published data (GSE63829 and GSE23695) from Gene Expression Omnibus (GEO) was analyzed by Gene Set Enrichment Analysis (GSEA).

Results

Total peripheral NK count was down-regulated in untreated SLE patients in comparison to that in untreated RA patients and HCs. SLE patients exhibited a selective reduction in peripheral CD56dimCD57+ NK cell proportion, which was negatively associated with disease activity and positively correlated with levels of complement(C)3 and C4. Compared with HCs, peripheral CD56dimCD57+ NK cells from SLE patients exhibited altered phenotypes, increased endogenous apoptosis and higher levels of mtROS and ROS. In addition, when treated with hydrogen peroxide (H2O2), peripheral CD56dimCD57+ NK cell subset was more prone to undergo apoptosis than CD56dimCD57− NK cells. Furthermore, this NK cell subset from SLE patients exhibited impaired cytotoxicity in response to activated CD4+ T cells in vitro.

Conclusion

Our study demonstrated a selective loss of mature CD56dimCD57+ NK cell subset in SLE patients, which may caused by preferential apoptosis of this subset under increased oxidative stress in SLE. The attenuated in vitro cytotoxicity of CD56dimCD57+ NK cells may contribute to the impaired ability of eliminating pathogenic CD4+ T cells in SLE.
Prediction of flare following remission and treatment withdrawal in early rheumatoid arthritis: post hoc analysis of a phase IIIb trial with abatacept
Authors: Ahmad Harris A. , Baker Joshua F. , Conaghan Philip G. , Emery Paul , Huizinga Thomas W. J. , Elbez Yedid , Banerjee Subhashis , Østergaard Mikkel
Published: February 2022

Background

Drug-free remission is a desirable goal in rheumatoid arthritis (RA) for both patients and clinicians. The aim of this post hoc analysis was to investigate whether clinical and magnetic resonance imaging (MRI) variables in patients with early RA who achieved remission with methotrexate and/or abatacept at 12 months could predict disease flare following treatment withdrawal.

Methods

In the AVERT study of abatacept in early RA, patients with low disease activity at month 12 entered a 12-month period with all treatment discontinued (withdrawal, WD). This post hoc analysis assessed predictors of disease flare at WD+6months (mo) and WD+12mo of patients with Disease Activity Score in 28 joints (DAS28)-defined remission (DAS28[C-reactive protein (CRP)] <2.6) at withdrawal using univariate and multivariable regression models. Predictors investigated included the Health Assessment Questionnaire–Disability Index (HAQ-DI), pain, Patient Global Assessment; MRI synovitis, erosion, bone edema, and combined (synovitis + bone edema) inflammation scores.

Results

Remission was achieved by 172 patients; 100 (58%) and 113 (66%) patients had experienced a flare at WD+6mo and WD+12mo, respectively. In univariate analyses, higher HAQ-DI and MRI synovitis, erosion, bone edema, and combined inflammation scores at WD were identified as potential predictors of flare (P ≤ 0.01). In multivariable analysis, high scores at WD for HAQ-DI and MRI erosion were confirmed as independent predictors of flare at WD+6mo and WD+12mo (P < 0.01).

Conclusion

In patients with early RA achieving clinical remission, patient function (HAQ-DI), and MRI measures of bone damage (erosion) predicted disease flare 6 and 12 months after treatment withdrawal. These variables may help identify patients with early RA in clinical remission as candidates for successful treatment withdrawal.

Trial registration

ClinicalTrials.gov, NCT01142726 (date of registration: June 11, 2010)
A comprehensive profile of chemokines in the peripheral blood and vascular tissue of patients with Takayasu arteritis
Authors: Kong Xiufang , Wu Sifan , Dai Xiaojuan , Yu Wensu , Wang Jinghua , Sun Ying , Ji Zongfei , Ma Lingying , Dai Xiaomin , Chen Huiyong , Ma Lili , Jiang Lindi
Published: February 2022

Background

Takayasu arteritis (TAK) is a chronic granulomatous large vessel vasculitis with multiple immune cells involved. Chemokines play critical roles in recruitment and activation of immune cells. This study aimed to investigate chemokine profile in the peripheral blood and vascular tissue of patients with TAK.

Methods

A total of 58 patients with TAK and 53 healthy controls were enrolled. Chemokine array assay was performed in five patients with TAK and three controls. Chemokines with higher levels were preliminarily validated in 20 patients and controls. The validated chemokines were further confirmed in another group of samples with 25 patients and 25 controls. Their expression and distribution were also examined in vascular tissue from 8 patients and 5 controls. Correlations between these chemokines and peripheral immune cells, cytokines, and disease activity parameters were analyzed. Their serum changes were also investigated in these 45 patients after glucocorticoids and immunosuppressive treatment.

Results

Patients and controls were age and sex-matched. Twelve higher chemokines and 4 lower chemokines were found based on the chemokine array. After validation, increase of 5 chemokines were confirmed in patients with TAK, including CCL22, RANTES, CXCL16, CXCL11, and IL-16. Their expressions were also increased in vascular tissue of patients with TAK. In addition, levels of RANTES and IL-16 were positively correlated with peripheral CD3+CD4+T cell numbers. Close localization of CCL22, CXCL11, or IL-16 with inflammatory cells was also observed in TAK vascular tissue. No correlations were found between these chemokines and cytokines (IL-6, IL-17, IFN-γ) or inflammatory parameters (ESR, CRP). No differences were observed regarding with these chemokines between active and inactive patients. After treatment, increase of CCL22 and decrease of RANTES and CXCL16 were found, while no changes were showed in levels of CXCL11 and IL-16.

Conclusions

CCL22, RANTES, CXCL16, CXCL11, and IL-16 were identified as the major chemokines involved in the recruitment of immune cells in the vascular tissue of patients with TAK. Additionally, the persistently high levels of CCL22, CXCL11, and IL-16 observed after treatment indicate their role in vascular chronic inflammation or fibrosis and demonstrate the need for developing more efficacious treatment options.
Migrators within migrators: exploring transposable element dynamics in the monarch butterfly, Danaus plexippus
Authors: Baril Tobias , Hayward Alexander
Published: February 2022

Background

Lepidoptera (butterflies and moths) are an important model system in ecology and evolution. A high-quality chromosomal genome assembly is available for the monarch butterfly (Danaus plexippus), but it lacks an in-depth transposable element (TE) annotation, presenting an opportunity to explore monarch TE dynamics and the impact of TEs on shaping the monarch genome.

Results

We find 6.21% of the monarch genome is comprised of TEs, a reduction of 6.85% compared to the original TE annotation performed on the draft genome assembly. Monarch TE content is low compared to two closely related species with available genomes,Danaus chrysippus(33.97% TE) andDanaus melanippus(11.87% TE). The biggest TE contributions to genome size in the monarch are LINEs andPenelope-like elements, and three newly identified families,r2-hero_dPle(LINE),penelope-1_dPle(Penelope-like), andhase2-1_dPle(SINE), collectively contribute 34.92% of total TE content. We find evidence of recent TE activity, with two novel Tc1 families rapidly expanding over recent timescales (tc1-1_dPle,tc1-2_dPle). LINE fragments show signatures of genomic deletions indicating a high rate of TE turnover. We investigate associations between TEs and wing colouration and immune genes and identify a three-fold increase in TE content around immune genes compared to other host genes.

Conclusions

We provide a detailed TE annotation and analysis for the monarch genome, revealing a considerably smaller TE contribution to genome content compared to two closely relatedDanausspecies with available genome assemblies. We identify highly successful novel DNA TE families rapidly expanding over recent timescales, and ongoing signatures of both TE expansion and removal highlight the dynamic nature of repeat content in the monarch genome. Our findings also suggest that insect immune genes are promising candidates for future interrogation of TE-mediated host adaptation.
Heterochrony and repurposing in the evolution of gymnosperm seed dispersal units
Authors: San Martin Juca A. B. , Pozner Raúl E. , Di Stilio Verónica S.
Published: February 2022

Background

Plant dispersal units, or diaspores, allow the colonization of new environments expanding geographic range and promoting gene flow. Two broad categories of diaspores found in seed plants are dry and fleshy, associated with abiotic and biotic dispersal agents, respectively. Anatomy and developmental genetics of fleshy angiosperm fruits is advanced in contrast to the knowledge gap for analogous fleshy structures in gymnosperm diaspores. Improved understanding of the structural basis of modified accessory organs that aid in seed dispersal will enable future work on the underlying genetics, contributing to hypotheses on the origin of angiosperm fruits. To generate a structural framework for the development and evolution of gymnosperm fleshy diaspores, we studied the anatomy and histochemistry of Ephedra (Gnetales) seed cone bracts, the modified leaves surrounding the reproductive organs. We took an ontogenetic approach, comparing and contrasting the anatomy and histology of fleshy and papery-winged seed cone bracts, and their respective pollen cone bracts and leaves in four species from the South American clade.

Results

Seed bract fleshiness in Ephedra derives from mucilage accumulated in chlorenchyma cells, also found in the reduced young leaves before they reach their mature, dry stage. Cellulosic fibers, an infrequent cell type in gymnosperms, were found in Ephedra, where they presumably function as a source of supplementary apoplastic water in fleshy seed cone bracts. Papery-winged bract development more closely resembles that of leaves, with chlorenchyma mucilage cells turning into tanniniferous cells early on, and hyaline margins further extending into “wings”.

Conclusions

We propose an evolutionary developmental model whereby fleshy and papery-winged bracts develop from an early-stage anatomy shared with leaves that differs at the pollination stage. The ancestral fleshy bract state may represent a novel differentiation program built upon young leaf anatomy, while the derived dry, papery-winged state is likely built upon an existing differentiation pattern found in mature vegetative leaves. This model for the evolution of cone bract morphology in South American Ephedra hence involves a novel differentiation program repurposed from leaves combined with changes in the timing of leaf differentiation, or heterochrony, that can further be tested in other gymnosperms with fleshy diaspores.