bluuebunny/crossref_metadata_2025 huggingface dataset:
O214: The tumour immune microenvironment and its response to exercise during treatment for Oesophagogastric cancer
Authors: Casey Patrick , Tarazi Munir , Powell Arfon , Baker Alexander , Ashton Garry , Valpione Sara , Redfern Jennifer , McGrath Stephen , Sultan Javed
Published: March 2024

Introduction

Pre-clinical studies suggest that exercise during cancer treatment may enhance tumour regression and promote an anti-tumorigenic immune microenvironment. Considering the evolution of immunotherapy in oesophagogastric cancer, further understanding of the host-tumour immune response to exercise therapy is of significant interest.

Methods

Using multiplex immunofluorescence, resection specimens of 30 patients with oesophageal adenocarcinoma were labelled for CD3, CD4, CD8, PD-1, PD-L1, FOXP3, CD68, and PanCK to characterise tumour and peri-tumoral immune infiltrate. All patients received the same neoadjuvant chemotherapy prior to oesophagectomy. 14 patients who engaged with a structured prehabilitation exercise program (mixed aerobic and resistance training twice-weekly) were case-matched with 16 control patients who did not.

Results

The prehabilitation group had a significant increase (per mm2 ) in cytotoxic T-cells (99.4 vs 13.8, p=0.003). There was also a significant increase in immune suppressive macrophages, exhausted T-helper and cytotoxic T-cells. The only significant change in the peritumoural sections was an increase in exhausted CD8 cytotoxic-T cells in the prehabilitation group (3.3 vs 1.4, p=0.043). There was no difference in the number of Treg or T-helper cells within, or around the tumour sections.

Conclusions

This study is the ‘first-in-man’ to show that exercise prehabilitation during chemotherapy impacts on the tumour immune microenvironment in patients with oesophageal adenocarcinoma. Exercise results in an increased abundance of both anti-tumorigenic and immunosuppressive cell types. These finding warrant further investigation, especially in the context of modern immunotherapy treatments, to understand the clinical impact that exercise oncology has on tumour regression.
O84: A systematic review of pancreaticoduodenectomy for pancreatic cancer in randomised control trials to examine variations in operative technique
Authors: Malik Abdullah , Karki Bishow , Mahendran Balaji , Shrikhande Shailesh , Moir John , Smith Andrew , Blencowe Natalie , Pathak Samir
Published: March 2024

Background

Pancreatoduodenectomy (PD) is a complex surgical intervention comprising multiple components which, when delivered differently, can impact outcomes, introduce bias into randomised controlled trials (RCTs) and impair accurate interpretation of results. This study aimed to systematically explore and summarise variation in PD description and standardisation amongst contemporary RCTs in pancreas surgery.

Methods

Systematic literature searches for RCTs of PD were undertaken from 2020 to 2023. RCTs including robotic PD, or other types of pancreas resection (e.g. total, distal), were excluded. An established methodological framework was used to deconstruct the technical aspects of PD were deconstructed into constituent components (pre-operative considerations, before skin incision, incision, dissection, resection, haemostasis, reconstruction, insertion of adjuncts, closure and after closure). Trial reports and protocols were scrutinised to examine whether the components/steps were described, and whether (and how) adherence was assessed.

Results

Of 83 screened articles, 29 RCTs were included, reporting on 3440 patients across 16 countries (1 trial compared pre-operative interventions, 18 trials compared intra-operative interventions, and 10 trials compared post-operative interventions). Forty-one PD steps were identified. No studies described all steps and five did not describe any. Fifteen component parts were described in one RCT. Only three RCTs reported that delivery of PD was recorded and assessed, using intra-operative photographs in all cases.

Conclusions

In a contemporary series of RCTs evaluating PD, descriptions of the procedure were inadequate. Clear descriptions of PD using pre-existing methodological frameworks in future trials are warranted to improve outcomes, decrease bias and facilitate cross-RCT comparisons in systematic reviews.
O172: Donor blood tests and pancreas outcome in simultaneous pancreas kidney transplantation, a national cohort study
Authors: Ho Ning Xuan , Tingle Samuel James , Malik Abdullah K , Thompson Emily R , Amer Aimen , Pandanaboyana Sanjay , Wilson Colin H , White Steve
Published: March 2024

Introduction

Simultaneous pancreas-kidney (SPK) transplantation improves quality of life in people with diabetes and end-stage renal disease, and limits the progression of diabetes related complications. Many surgeons are reluctant to accept the pancreas of a donor with raised amylase, due to concern of potentially inferior outcomes. We aim to ascertain whether donor amylase and liver blood tests (a marker of visceral ischaemic injury) predict pancreas transplant outcome.

Methods

This retrospective cohort study used the NHS registry on adult SPK transplantation (2016-2021). Adjusted regressions models assessed the effect of donor amylase and liver blood tests on pancreas transplant outcome.

Results

857 SPK recipients were included (619 following brainstem death, 238 following circulatory death). Peak donor amylase ranged from 8-3300U/L (median=70). Donor peak amylase had no significant impact on pancreas graft survival when adjusting for multiple confounders (aHR=0.944, 95% CI=0.754-1.81). Median peak alanine transaminase and aspartate transaminase was 67U/L and 72U/L (range 8-5930 and 0-7910U/L). Neither of these influenced pancreas graft survival in multivariable models (aHR=0.967, 95% CI=0.848-1.102 and aHR=0.908, 95% CI=0.771-1.070, respectively). Restricted cubic splines were used to assess the relationship between donor blood tests and pancreas graft survival without assuming linear relationships; these confirmed neither amylase, nor transaminases, significantly impact on pancreas transplant outcome.

Conclusions

Donor amylase and transaminases do not predict transplant outcomes. Therefore, raised donor amylase or transaminases should not be considered a barrier to organ utilisation. The use of pancreas grafts from donors with hyperamylasaemia is a safe, immediate, and simple approach to expand the donor pool.
O182: Tag localisation vs wire localisation: which is the more effective technique for localising non palpable breast lesions?
Authors: Hamza Eman , Duke Deirdre , Nimhuircheartaigh Neasa , O’Brein Aoife , Hegarty Aisling , Hassett Caoimhe , Crilly Emily , Patterson Rory , Singh Sneha , Hill Arnold
Published: March 2024

Introduction

Following the expansion of breast screening programmes, non-palpable lesions comprise a challenge for accurate localisation. Placement of wires has been the historic gold standard of care. We aimed to compare wire-guided localisation (WGL) to radiofrequency identification system (RFID) LOCalizer(Hologic) with regards to resection margins and complications.

Methods

Data was collected retrospectively on patients who underwent breast conserving surgery for malignancy following localisation with LOCalizer RFID system or wire, in Beaumont Breast Centre, from January 2018 to March 2023. Lesion type, size, specimen weight, resection margins and complications were recorded and analysed.

Results

690 were included in the study. 391 (57%) had a pre-operative diagnosis of malignancy: 88 in RFID tag guided localisation (TGL), 129 in mammogram wire guided localisation (MG-WGL) and 174 in ultrasound (US-WGL). The remaining had therapeutic excisional biopsy in which 18 (6%) were upgraded to in situ or invasive. Positive surgical margins were; US-WGL was 24% (43), MG-WGL was 23% (34) and TGL was 12% (11). Average tumour size was: 20.3mm US-WGL, 13.0mm MG-WGL, 18.3mm TGL. Average specimen weight for malignant cases were 33.8g US-WGL, 43.5g MG-WGL and 40.7g TGL. No significant complications were recorded in either group, however, a second localisation procedure was required for 14 patients in the TGL group and 10 patients in the WGL group.

Conclusion

TGL is a safe and effective alternative technique which allows greater flexibility in scheduling and increased efficiency. It has a learning curve which accounts for the slightly higher complication rate identified.
O180: An In Vitro Cell Model to Assess the Effects of Complement Inhibition on Ischemia-Reperfusion Injury in Cholangiocytes
Authors: Hulme Callum , Mahendran Balaji , Malik Abdullah , Wilson Colin , Thompson Emily , Sheerin Neil , Ali Simi , Palmer Jeremy , Bates Lucy , Hand Rebecca
Published: March 2024

Background

Liver transplantation is the definitive procedure for end-stage liver failure but is limited by a shortage of viable donor organs. IRI is an unavoidable consequence of transplantation, triggering damage via several pathways, including complement activation. Development of an in vitro cell model of IRI with addition of complement allows analysis of cholangiocyte cellular stress response and whether this response can be attenuated by eculizumab, a complement inhibitor.

Methods

H69 cholangiocytes were subject to anoxic incubation for 4 hours and subsequent normoxia for 24 hours, before addition of complement to the system. Complement was provided from perfusate taken from liver normothermic machine perfusion (NMP). Analysis of cellular response was then carried out at different stages of simulated IRI.

Results

Eculizumab-treated perfusate significantly increased cell proliferation compared to untreated perfusate (p<0.0001). Addition of complement to the model increased cellular oxidative stress and inflammation. Eculizumab-treated perfusate significantly decreased production of GDF15 (p<0.0001), an oxidative stress marker, in cholangiocytes. Despite a significant increase, compared to the normoxic control, IL-10 and IL-8 production showed no significant difference between cells treated with control NMP perfusate or eculizumab-treated perfusate. VEGF gene expression was upregulated in the context of eculizumab-treated perfusate.

Conclusion

The in vitro model successfully simulates IRI and addition of perfusate leads to increased production of markers of inflammation and oxidative stress. Complement-depleted perfusate significantly reduced GDF15 production, suggesting amelioration of cellular oxidative stress, by eculizumab; however, we cannot conclude with the current data that complement-depleted perfusate attenuates the effects of IRI in this model.
O133: Development and Validation of HAS (Hajibandeh Index, ASA Status, Sarcopenia) - A Novel Model for Predicting Mortality after Emergency Laparotomy
Authors: Saji Alwin Puthiyakunnel , Hughes Ioan , Hajibandeh Shahin , Alessandri Giorgio , Duncan Trish , O’Reilly David , Kumar Nagappan , Hajibandeh Shahab
Published: March 2024

Introduction

Current predictive models for mortality following an emergency laparotomy (EL) have a discrimination power of adequate to strong with none showing excellent discrimination. We aim to develop and validate a predictive model to predict the risk of postoperative mortality after EL considering the following variables: age, age ≥ 80, American Society of Anaesthesiologists (ASA) status, clinical frailty score, sarcopenia, Hajibandeh Index (HI), bowel resection, and intraperitoneal contamination.

Methods

A retrospective cohort study of adult patients who underwent EL due to non-traumatic acute abdominal pathology between 2017 and 2022 was conducted. Multivariable binary logistic regression analysis was used to develop and validate the model via two protocols (Protocol A and B). The model performance was evaluated in terms of ROC curve discrimination, calibration (calibration diagram and Hosmer-Lemeshow test), and classification.

Results

1043 patients were included (statistical power = 94%). Multivariable analysis kept HI (Protocol-A: P=0.0004; Protocol-B: P=0.0017), ASA status (Protocol-A: P=0.0068; Protocol-B: P=0.0007), and sarcopenia (Protocol-A: P<0.0001; Protocol-B: P<0.0001) as final predictors of 30-day mortality in both protocols; hence the model was called HAS (HI, ASA status, sarcopenia). The HAS demonstrated excellent discrimination (AUC: 0.96, P<0.0001), excellent calibration (P<0.0001), and excellent classification (95%) via both protocols. The performance of HAS was significantly better than NELA score (AUC: 0.96 vs 0.86, P<0.0001).

Conclusions

The HAS is the first model demonstrating excellent discrimination, calibration, and classification in predicting the risk of 30-day mortality following EL. The HAS model seems promising and is worth attention for external validation using HAS Emergency Laparotomy calculator.
O117: Comparing the effect of using Virtual reality versus Simulation, to manage an acute surgical scenario, on academic buoyancy
Authors: Tran Mi-Tra , Ahmad Manal , Patel Kirtan , Argyriou Orestis , Davies Alun , Shalhoub Joseph
Published: March 2024

Background

Simulation is regularly used in surgical training to allow trainees to practice skills safely. Virtual reality (VR) is a recent simulation modality which offers immersive computer-generated medical and surgical training scenarios. Much of trainee performance can be hindered by stress, self-consciousness, performance anxiety, fear of criticism and self-perceived poor task execution. Academic buoyancy is a learner’s ability to successfully deal with short-term, minor academic setbacks, such as poor grades and exam pressures, and having academic buoyancy can translate into long-term academic resilience. We aimed to compare academic buoyancy between junior doctors after managing an acute surgical scenario using VR and mannequin-based simulation.

Method

Eighteen junior doctor volunteers (Foundation and Core Trainee Year 1) were recruited, with ten participants randomly allocated to VR and eight to mannequin-based Simulation. Participants assessed and managed a 15-minute pneumothorax scenario. The academic buoyancy scale (ABS), which consists of four questions on a self-rated 7-point Likert scale, was used to measure pre-session and post-session academic buoyancy.

Results

ABS scores increased for both study groups, although this was only statistically significant for VR participants (p≤0.01), suggesting that VR may provide a more comfortable environment for trainees to hone their clinical skills. VR participants also had higher overall simulation scores than mannequin-based simulation participants, however no correlation was found between ABS scores and overall simulation scores.

Conclusion

VR as a simulation modality benefits by improving short-term markers of confidence. Future research should establish whether spaced VR teaching sessions translate into improved long-term markers of resilience.
O71: Sentinel Lymph Node Biopsy in Elderly Patients with Early ER+ Breast Cancer: A Systematic Review of the Literature
Authors: Alrawashdeh Maen , Daly Gordon , Dowling Gavin , Reid Susan , Calpin Gavin , Kilkenny Conor , Hill Arnold
Published: March 2024

Purpose

In 2016, the Choosing Wisely guidelines recommended that women over 70 years of age with Oestrogen Receptor positive (ER+), HER2-negative (HER2-), early-stage (T1, T2), clinically node-negative (cN0) invasive breast cancer (BC) should not routinely undergo sentinel lymph node biopsy (SLNB). The aim of this systematic review is to analyse subsequent literature on the influence of SLNB on management and outcomes.

Methods

An electronic search of Medline (OVID), EMBASE and Cochrane Reviews was conducted Studies comparing SLNB vs. no SLNB were included. 4 studies were eligible for final inclusion. Overall survival (OS), breast cancer-specific survival (BCSS) and influence on adjuvant therapy decisions were analysed.

Results

Chagpar et al. found SLNB was independently associated with significantly better OS (HR=0.633) in 157,584 patients and better BCSS (HR=0.452) in a subset of 116,059 patients compared to no SLNB. In 24,995 patients, Xu et al. found better OS in those who received SLNB (HR= 0.585) and better BCSS (HR=0.864) vs. those who did not. Castelo et al. performed 2 studies: the first included 126,047 patients, worse BCSS was observed in the no-SLNB group (sub-distribution HR=1.17); the second included 6,286 patients, both worse OS (adjusted HR=1.22), and BCSS (adjusted HR=1.08) were also associated with not receiving SLNB.

Conclusion

Better OS and BCSS were seen in patients who received SLNB vs. no SLNB despite adjusting for confounders across these studies. While some selection bias may have influenced results, clinicians should remain cautious in omitting SLNB in this cohort.
O168: Impact of donor transaminases on liver transplant utilisation and unnecessary organ discard: national registry cohort study
Authors: Dobbins Joseph , Tingle Samuel , Mehew Jennifer , Thompson Emily , Kourounis Georgios , McPherson Stuart , White Steven , Wilson Colin
Published: March 2024

Background

Donor liver transaminases (ALT and AST) have been used to decline livers for transplant, despite evidence that they do not influence transplant outcomes. This study assesses the effect that raised donor transaminases currently have on the unnecessary decline of livers.

Methods

This retrospective cohort study used the National Health Service registry on adult liver transplantation (2016-2019). Logistic regression models were built to assess the impact of donor transaminases on the utilisation of organs donated following brain stem death (DBD) and circulatory death (DCD). A further model was used to predict the impact on liver decline if raised donor ALT was not used to make utilisation decisions.

Results

5424 adult livers were offered for transplant, of which 3605 were utilised (2841 DBD, 764 DCD). In multivariable analysis, adjusted for key factors, increasing peak donor ALT independently increased the odds of liver decline (DBD aOR = 1.396, 1.305-1.494, p<0.001, DCD aOR = 1.162, 1.084-1.246, p<0.001). AST was also a significant predictor of liver decline. 18.5% of livers from DBD donors with ALT>40U/L (n=1683) were declined for transplantation. In this group, our model predicted a 48% (38% - 58%) decrease in decline if donor ALT was excluded from these decisions. This represents an additional 37 (30-45) livers every year that could be safely accepted and transplanted.

Conclusions

Raised donor ALT increases the likelihood of liver decline, despite previous evidence that it does not influence transplant outcome. Avoiding donor ALT-based organ decline is an immediate and effective way to expand the donor pool.
O145: Autologous blood transfusion reduces the requirement for perioperative allogeneic blood transfusion in patients undergoing major hepatopancreatobiliary surgery: a retrospective cohort study.
Authors: Lakha Adil , Chadha Radhika , Von-Kier Stephen , Barbosa Antonio , Maher Keith , Pirkl Martin , Stoneham Mark , Silva Michael A , Soonawalla Zahir , Udupa Venkatesha , Reddy Srikanth , Gordon-Weeks Alex
Published: March 2024

Introduction

Major hepatopancreatobiliary surgery is associated with a risk of major blood loss. We aimed to assess whether autologous transfusion of blood salvaged intraoperatively reduced postoperative allogenic transfusion in this patient cohort.

Materials and Methods

In this single-centre study, information from a prospective database of 501 patients undergoing major hepatopancreatobiliary resection (2015–2022) was analysed. Patients who received cell salvage (n=264) were compared with those who did not (n=237). Nonautologous (allogenic) transfusion was assessed from the time of surgery to 5 days postsurgery, and blood loss tolerance was calculated using the Lemmens–Bernstein–Brodosky formula. Multivariate analysis was used to identify factors associated with allogenic blood transfusion avoidance.

Results

32% of lost blood volume was replaced through autologous transfusion in patients receiving cell salvage. Although the cell salvage group experienced significantly higher intraoperative blood loss compared with the noncell salvage group (1360 vs. 971 ml, P=0.0005), they received significantly fewer allogenic red blood cell units (0.92 vs. 1.5 units/patient, P=0.03). Correction of blood loss tolerance in patients undergoing cell salvage was independently associated with avoidance of allogenic transfusion (Odds ratio 0.05 (0.006–0.38) P=0.005). In a subgroup analysis, cell salvage was associated with significant reduction in 30-day mortality in patients undergoing major hepatectomy (1 vs. 6%, P=0.04).

Conclusion

Cell salvage use was associated with reduction in allogenic blood transfusion and a reduction in 30-day mortality in patients undergoing major hepatectomy. Prospective trials are warranted to understand whether the use of cell salvage should be routinely utilised for major hepatectomy.
P106: Continuing the catheter pack quality improvement project
Authors: Moulding Samuel , Melzer Mark , Allchorne Paula , Green James
Published: March 2024

Background

Up to 90,000 patients have a urinary catheter in the community. Although they can be life saving they have been estimated to cost the NHS £1 – 2.5 billion/yr in adverse events. Patient education, as well as ensuring the correct equipment is being used, has been shown to reduce ED attendances and improve patient satisfaction. However, the use of specific “catheter packs” containing replacement equipment and “catheter passports” with information on catheter care is an under researched area.

Methods

We surveyed 175 patients at our TWOC clinic post-intervention.

Results

Only 10/86 patients (11.63%) who did not receive a catheter pack reported having enough supplies. 75/85 patients (88.24%) who received a catheter pack reported having enough supplies (p<0.01). 45/143 patients (31.47%) that were not given a catheter passport reported complications. 5/20 patients (25%) that were given a catheter passport reported complications. In the group who were not given catheter packs the rate was 0.56 ED attendances per patient. The re-attendance rate in those who were given a catheter pack was statistically significantly lower at 0.20 (p<0.01). We have shown that the introduction of catheter packs has increased the number of patients with appropriate levels of home supplies, which corresponded with a reduced ED attendance rate before their TWOC clinic appointment.

Conclusions

Although we have shown a reduction in the number of reported complications in those who were given a catheter passport, our test was underpowered highlighting the need for further research in this area.
P258: Does The Latarjet Procedure For Anterior Shoulder Instability Put Off-Track Lesions Back On Track: A Systematic Review
Authors: Doyle Tom , Toale James , Davey Martin , Hurley Eoghan , Mullett Hannan
Published: March 2024

Introduction

The Latarjet procedure is commonly used in the treatment of shoulder instability for high risk patients. The glenoid track is widened by fixing the coracoid to the anterior glenoid. In the presence of bipolar bone loss there is concern that the Latarjet procedure may not adequately address off-track lessions.The aim of this systematic review to assess whether the Latarjet procedure is sufficient to convert 'off-track' Hill-Sachs lesions back to 'on-track'.

Methods

A systematic review of Pubmed, Embase and the Cochrane Library was performed in October 2023. The primary outcome was the rate of post-operative 'on-track' lesions and of recurrent instability. Changes in glenoid diameter and Hill-Sachs lesion interval were also recorded.

Results

A total of 5 studies were included with 187 patients. Weighted mean age was 29.2 ± 2.2 years old and 90.8% of patients were male. The mean follow-up time was 26.8 months. All patients had off-track Hill-Sachs lesions pre-operatively. 88.6% of cases were converted to on-track lesions. The overall post-operative instability rate was 4.8%. The recurrence rate was significantly greater for off-track lesions (33.3%) than for on-track lesions (4.2%), odds ratio 11.4 (3.5-37.0). The weighted mean post-operative glenoid diameter change was 8.4 ± 5.8mm. The weighted mean Hill-Sachs lesion interval was 25.6 ± 4.5mm.

Conclusion

The Latarjet procedure results in the majority of Hill-Sachs lesions being converted to on-track lesions. However, due to bipolar bone loss approximately 1/9 cases will remain off track. In cases of failure to return on-track, there is an unacceptably high rate of recurrent instability (33.3%).
Altered resting-state brain function in endurance athletes
Authors: Yan Shizhen , Zhao Guang , Zhang Qihan , Liu Liqing , Bai Xuejun , Jin Hua
Published: March 2024

Previous research has confirmed significant differences in regional brain activity and functional connectivity between endurance athletes and non-athletes. However, no studies have investigated the differences in topological efficiency of the brain functional network between endurance athletes and non-athletes. Here, we compared differences in regional activities, functional connectivity, and topological properties to explore the functional basis associated with endurance training. The results showed significant correlations between Regional Homogeneity in the motor cortex, visual cortex, cerebellum, and the training intensity parameters. Alterations in functional connectivity among the motor cortex, visual cortex, cerebellum, and the inferior frontal gyrus and cingulate gyrus were significantly correlated with training intensity parameters. In addition, the graph theoretical analysis results revealed a significant reduction in global efficiency among athletes. This decline is mainly caused by decreased nodal efficiency and nodal local efficiency of the cerebellar regions. Notably, the sensorimotor regions, such as the precentral gyrus and supplementary motor areas, still exhibit increased nodal efficiency and nodal local efficiency. This study not only confirms the improvement of regional activity in brain regions related to endurance training, but also offers novel insights into the mechanisms through which endurance athletes undergo changes in the topological efficiency of the brain functional network.
Hippocampal ripples coincide with “up-state” and spindles in retrosplenial cortex
Authors: Pedrosa Rafael , Nazari Mojtaba , Kergoat Loig , Bernard Christophe , Mohajerani Majid , Stella Federico , Battaglia Francesco
Published: March 2024

During NREM sleep, hippocampal sharp-wave ripple (SWR) events are thought to stabilize memory traces for long-term storage in downstream neocortical structures. Within the neocortex, a set of distributed networks organized around retrosplenial cortex (RS-network) interact preferentially with the hippocampus purportedly to consolidate those traces. Transient bouts of slow oscillations and sleep spindles in this RS-network are often observed around SWRs, suggesting that these two activities are related and that their interplay possibly contributes to memory consolidation. To investigate how SWRs interact with the RS-network and spindles, we combined cortical wide-field voltage imaging, Electrocorticography, and hippocampal LFP recordings in anesthetized and sleeping mice. Here, we show that, during SWR, “up-states” and spindles reliably co-occur in a cortical subnetwork centered around the retrosplenial cortex. Furthermore, retrosplenial transient activations and spindles predict slow gamma oscillations in CA1 during SWRs. Together, our results suggest that retrosplenial–hippocampal interaction may be a critical pathway of information exchange between the cortex and hippocampus.
Associations of hearing loss and structural changes in specific cortical regions: a Mendelian randomization study
Authors: Liu Xiaoduo , Shi Lubo , Li Enze , Jia Shuo
Published: March 2024

Introduction

Previous studies have suggested a correlation between hearing loss (HL) and cortical alterations, but the specific brain regions that may be affected are unknown.

Methods

Genome-wide association study (GWAS) data for 3 subtypes of HL phenotypes, sensorineural hearing loss (SNHL), conductive hearing loss, and mixed hearing loss, were selected as exposures, and GWAS data for brain structure-related traits were selected as outcomes. The inverse variance weighted method was used as the main estimation method.

Results

Negative associations were identified between genetically predicted SNHL and brain morphometric indicators (cortical surface area, cortical thickness, or volume of subcortical structures) in specific brain regions, including the bankssts (β = −0.006 mm, P = 0.016), entorhinal cortex (β = −4.856 mm2, P = 0.029), and hippocampus (β = −24.819 cm3, P = 0.045), as well as in brain regions functionally associated with visual perception, including the pericalcarine (β = −10.009 cm3, P = 0.013).

Conclusion

Adaptive changes and functional remodeling of brain structures occur in patients with genetically predicted HL. Brain regions functionally associated with auditory perception, visual perception, and memory function are the main brain regions vulnerable in HL.
Small nucleolar RNA host gene 18 controls vascular smooth muscle cell contractile phenotype and neointimal hyperplasia
Authors: Niu Kaiyuan , Zhang Chengxin , Yang Mei , Maguire Eithne Margaret , Shi Zhenning , Sun Shasha , Wu Jianping , Liu Chenxin , An Weiwei , Wang Xinxin , Gao Shan , Ge Shenglin , Xiao Qingzhong
Published: March 2024

Aims

Long non-coding RNA (LncRNA) small nucleolar RNA host gene 18 (SNHG18) has been widely implicated in cancers. However, little is known about its functional involvement in vascular diseases. Herein, we attempted to explore a role for SNHG18 in modulating vascular smooth muscle cell (VSMC) contractile phenotype and injury-induced neointima formation.

Methods and results

Analysis of single-cell RNA sequencing and transcriptomic datasets showed decreased levels of SNHG18 in injured and atherosclerotic murine and human arteries, which is positively associated with VSMC contractile genes. SNHG18 was upregulated in VSMCs by TGFβ1 through transcription factors Sp1 and SMAD3. SNHG18 gene gain/loss-of-function studies revealed that VSMC contractile phenotype was positively regulated by SNHG18. Mechanistic studies showed that SNHG18 promotes a contractile VSMC phenotype by up-regulating miR-22-3p. SNHG18 up-regulates miR-22 biogenesis and miR-22-3p production by competitive binding with the A-to-I RNA editing enzyme, adenosine deaminase acting on RNA-2 (ADAR2). Surprisingly, we observed that ADAR2 inhibited miR-22 biogenesis not through increasing A-to-I editing within primary miR-22, but by interfering with the binding of microprocessor complex subunit DGCR8 to primary miR-22. Importantly, perivascular SNHG18 overexpression in the injured vessels dramatically up-regulated the expression levels of miR-22-3p and VSMC contractile genes, and prevented injury-induced neointimal hyperplasia. Such modulatory effects were reverted by miR-22-3p inhibition in the injured arteries. Finally, we observed a similar regulator role for SNHG18 in human VSMCs and a decreased expression level of both SNHG18 and miR-22-3p in diseased human arteries; and we found that the expression level of SNHG18 was positively associated with that of miR-22-3p in both healthy and diseased human arteries.

Conclusion

We demonstrate that SNHG18 is a novel regulator in governing VSMC contractile phenotype and preventing injury-induced neointimal hyperplasia. Our findings have important implications for therapeutic targeting snhg18/miR-22-3p signalling in vascular diseases.
Essential dextrin structure as donor substrate for 4-α-glucanotransferase in glycogen debranching enzyme
Authors: Uno Rentaro , Makino Yasushi , Matsubara Hiroshi
Published: March 2024

Glycogen debranching enzyme is a single polypeptide with distinct catalytic sites for 4-α-glucanotransferase and amylo-α-1,6-glucosidase. To allow phosphorylase to degrade the inner tiers of highly branched glycogen, 4-α-glucanotransferase converts the phosphorylase-limit biantennary branch G-G-G-G-(G-G-G-G↔)G-G- (G: d-glucose, hyphens: α-1,4-linkages; double-headed arrow: α-1,6-linkage) into the G-G-G-G-(G↔)G-G- residue, which is then subjected to amylo-α-1,6-glucosidase to release the remaining G↔ residue. However, while the essential side-chain structure of the 4-α-glucanotransferase donor substrate has been determined to be the G-G-G-G↔ residue (Watanabe, Y., et al. (2008) J. Biochem.143, 435–440), its essential main-chain structure remains to be investigated. In this study, we probed the 4-α-glucanotransferase donor-binding region using novel fluorogenic dextrins Gm-(G4↔)G-Gn-F (F: 1-deoxy-1-[(2-pyridyl)amino]-d-glucitol) and maltohexaose (G6) as the donor and acceptor substrates, respectively. 4-α-Glucanotransferase exhibited maximum activity towards G4-(G4↔)G-F and G4-(G4↔)G-G-F, indicating that recognition of the G4-(G4↔)G-moiety was essential for full enzyme function. Notably, when the 4-α-glucanotransferase activity towards G4-(G4↔)G-G-F was taken as unity, those towards nonbranching dextrins were < 0.001. This indicated that the disproportionation activities towards maltooligosaccharides (Gm) are abnormal behaviours of 4-α-glucanotransferase. Notably, however, these activities have been traditionally measured to identify the 4-α-glucanotransferase mutations causing glycogen storage disease type III. This study provides a basis for more accurate identification.
Discordant responses of bone formation and absorption markers in Japanese infants with vitamin D deficiency: a comprehensive matched case–control study
Authors: Takahashi Keigo , Ikeda Kazushige , Hara-Isono Kaori , Nitta Akihisa , Nagano Nobuhiko , Arimitsu Takeshi
Published: March 2024

Vitamin D deficiency during infancy has been associated with increased bone turnover rate and bone mineral loss. However, few studies have examined bone turnover markers (BTMs) for both bone formation and resorption in infants with vitamin D deficiency. Here, we analyzed serum concentrations of 25OHD, intact parathormone (iPTH), and BTMs including total alkaline phosphatase (ALP), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), and serum type I collagen N-telopeptide (NTx) as well as basic clinical characteristics of 456 infants (626 samples) aged less than 12 mo born at Saitama City Hospital, Japan (latitude 35.9° North) between January 2021 and December 2022. One hundred sixteen infants (147 samples) were classified as having vitamin D deficiency (25OHD < 12.0 ng/mL), and 340 infants (479 samples) had sufficient vitamin D levels (25OHD ≥ 12.0 ng/mL). In addition to 25OHD and ALP, both TRACP-5b and sNTx were measured in 331 infants (418 samples), while 90 infants (105 samples) had only TRACP-5b measured and 101 infants (103 samples) had only sNTx measured. Statistical comparison of 104 subjects each in the vitamin D deficiency and sufficiency groups after matching for the background characteristics revealed that the vitamin D deficiency group had significantly higher levels of ALP and iPTH compared with the sufficiency group (P = <.0001, .0012, respectively). However, no significant differences were found in TRACP-5b and NTx levels between the 2 groups (P = .19, .08, respectively). Our findings suggest discordant responses between bone formation and resorption markers in subclinical vitamin D deficiency during infancy.
Round-up of United States copyright cases 2023
Authors: Macedo Charles R , Goldberg David P , Hart Thomas , Xu Yangfan
Published: March 2024

The US Supreme Court and lower court provided further guidance on fair use defense. The US Copyright Office provided guidance on AI as an author. The Court of Appeals provided guidance on substantial similiarty, server test, abstraction-filtration-comparison, and discovery rule.
Overexpressing GLUTAMINE SYNTHETASE 1;2 maintains carbon and nitrogen balance under high-ammonium conditions and results in increased tolerance to ammonium toxicity in hybrid poplar
Authors: Leng Xue , Wang Hanzeng , Cao Lina , Chang Ruhui , Zhang Shuang , Xu Caifeng , Yu Jiajie , Xu Xiuyue , Qu Chunpu , Xu Zhiru , Liu Guanjun
Published: March 2024

The glutamine synthetase/glutamic acid synthetase (GS/GOGAT) cycle plays important roles in N metabolism, growth, development, and stress resistance in plants. Excess ammonium (NH4+) restricts growth, but GS can help to alleviate its toxicity. In this study, the 84K model clone of hybrid poplar (Populus alba × P. tremula var. glandulosa), which has reduced biomass accumulation and leaf chlorosis under high-NH4+ stress, showed less severe symptoms in transgenic lines overexpressing GLUTAMINE SYNTHETASE 1;2 (GS1;2-OE), and more severe symptoms in RNAi lines (GS1;2-RNAi). Compared with the wild type, the GS1;2-OE lines had increased GS and GOGAT activities and higher contents of free amino acids, soluble proteins, total N, and chlorophyll under high-NH4+ stress, whilst the antioxidant and NH4+ assimilation capacities of the GS1;2-RNAi lines were decreased. The total C content and C/N ratio in roots and leaves of the overexpression lines were higher under stress, and there were increased contents of various amino acids and sugar alcohols, and reduced contents of carbohydrates in the roots. Under high-NH4+ stress, genes related to amino acid biosynthesis, sucrose and starch degradation, galactose metabolism, and the antioxidant system were significantly up-regulated in the roots of the overexpression lines. Thus, overexpression of GS1;2 affected the carbon and amino acid metabolism pathways under high-NH4+ stress to help maintain the balance between C and N metabolism and alleviate the symptoms of toxicity. Modification of the GS/GOGAT cycle by genetic engineering is therefore a potential strategy for improving the NH4+ tolerance of cultivated trees.
The beneficial rhizobacterium Bacillus velezensis SQR9 regulates plant nitrogen uptake via an endogenous signaling pathway
Authors: Chen Yu , Li Yucong , Fu Yansong , Jia Letian , Li Lun , Xu Zhihui , Zhang Nan , Liu Yunpeng , Fan Xiaorong , Xuan Wei , Xu Guohua , Zhang Ruifu
Published: March 2024

Nitrogen fertilizer is widely used in agriculture to boost crop yields. Plant growth-promoting rhizobacteria (PGPRs) can increase plant nitrogen use efficiency through nitrogen fixation and organic nitrogen mineralization. However, it is not known whether they can activate plant nitrogen uptake. In this study, we investigated the effects of volatile compounds (VCs) emitted by the PGPR strain Bacillus velezensis SQR9 on plant nitrogen uptake. Strain SQR9 VCs promoted nitrogen accumulation in both rice and Arabidopsis. In addition, isotope labeling experiments showed that strain SQR9 VCs promoted the absorption of nitrate and ammonium. Several key nitrogen-uptake genes were up-regulated by strain SQR9 VCs, such as AtNRT2.1 in Arabidopsis and OsNAR2.1, OsNRT2.3a, and OsAMT1 family members in rice, and the deletion of these genes compromised the promoting effect of strain SQR9 VCs on plant nitrogen absorption. Furthermore, calcium and the transcription factor NIN-LIKE PROTEIN 7 play an important role in nitrate uptake promoted by strain SQR9 VCs. Taken together, our results indicate that PGPRs can promote nitrogen uptake through regulating plant endogenous signaling and nitrogen transport pathways.
Identification and characterization of two O-methyltransferases involved in biosynthesis of methylated 2-(2-phenethyl)chromones in agarwood
Authors: Wu Wenli , Yan Tingting , Sun Xiaochen , Wilson Iain , Li Gaiyun , Hong Zhou , Shao Fenjuan , Qiu Deyou
Published: March 2024

The 2-(2-phenethyl)chromones (PECs) are the signature constituents responsible for the fragrance and pharmacological properties of agarwood. O-Methyltransferases (OMTs) are necessary for the biosynthesis of methylated PECs, but there is little known about OMTs in Aquilaria sinensis. In this study, we identified 29 OMT genes from the A. sinensis genome. Expression analysis showed they were differentially expressed in different tissues and responded to drill wounding. Comprehensive analysis of the gene expression and methylated PEC content revealed that AsOMT2, AsOMT8, AsOMT11, AsOMT16, and AsOMT28 could potentially be involved in methylated PECs biosynthesis. In vitro enzyme assays and functional analysis in Nicotiana benthamiana demonstrated that AsOMT11 and AsOMT16 could methylate 6-hydroxy-2-(2-phenylethyl)chromone to form 6-methoxy-2-(2-phenylethyl)chromone. A transient overexpression experiment in the variety ‘Qi-Nan’ revealed that AsOMT11 and AsOMT16 could significantly promote the accumulation of three major methylated PECs. Our results provide candidate genes for the mass production of methylated PECs using synthetic biology.
Probiotics in autism spectrum disorders: a systematic review of clinical studies and future directions
Authors: Barba-Vila Olga , García-Mieres Helena , Ramos Belén
Published: March 2024

Context

It is hypothesized that gut dysbiosis, a typical feature of patients with autism spectrum disorder (ASD), could be involved in the origin of this neurodevelopmental disorder. Therefore, the use of probiotics to restore gastrointestinal (GI) equilibrium might be a promising therapeutic strategy due to its capacity to balance the gut-brain axis and behavioral responses.

Objective

To summarize current knowledge on the use of probiotics to treat core clinical ASD symptoms and concomitant GI signs, compare the design of published studies with those of ongoing trials, assess the near future of this field, and provide recommendations for improving novel studies.

Data sources

The literature search was conducted in February 2020 and updated in March 2021, using a broad range of bibliographic and clinical trial–specific databases.

Data extraction

Data were extracted using a standardized form, and articles reporting on 28 clinical studies (already published or still ongoing) were included. The risk of bias in clinical studies was evaluated using the Cochrane Collaboration Risk of Bias Assessment tool for randomized trials and the Risk of Bias in Nonrandomized Studies–Interventions tool for nonrandomized trials.

Results

The results suggest that probiotics improve ASD-like social deficits, GI symptoms, and gut microbiota profile. However, inconsistencies among studies and their methodological limitations make it difficult to draw any conclusions regarding the efficacy of probiotics in ASD. This review provides specific suggestions for future research to improve the quality of the studies.

Conclusions

Although ongoing studies have improved designs, the available knowledge does not permit solid conclusions to be made regarding the efficacy of probiotics in ameliorating the symptoms (psychiatric and/or GI) associated with ASD. Thus, more high-quality research and new approaches are needed to design effective probiotic strategies for ASD.
Innovations in the repayment structure of microcredit contracts
Authors: Barboni Giorgia
Published: March 2024

Microfinance contracts typically require a fixed repayment schedule that, while ensuring repayment discipline, may inhibit entrepreneurship and business growth. In this article, I review the recent developments in the literature studying innovations in the repayment structure of microcredit contracts. Introducing flexible repayment schedules improves business outcomes by allowing microcredit borrowers to increase investment and to respond to income fluctuations to a higher extent. Although financial innovations hold the promise to foster business growth, and evidence suggests that their demand appears concentrated among financially sophisticated borrowers, they are feared to increase credit risk and hence their adoption among microfinance institutions is very limited. I explore potential challenges lenders face in offering these innovations and outline pathways towards a profitable implementation of such contracts.
Frequency and characteristics of severe relapses in giant cell arteritis
Authors: Lozachmeur Nicolas , Dumont Anael , Deshayes Samuel , Boutemy Jonathan , Maigné Gwénola , Martin Silva Nicolas , Nguyen Alexandre , Gallou Sophie , Philip Rémi , Aouba Achille , de Boysson Hubert
Published: March 2024

Objectives

To assess the frequency and characteristics of severe relapse in patients with GCA in a real-life setting.

Methods

In a monocentric database of 530 patients, we retrospectively analysed patients who experienced at least one relapse and distinguished severe from non-severe relapses. Severe relapse was defined by the occurrence of an ischaemic event (ophthalmologic, neurologic, digestive, limb ischaemia), the occurrence of an aortic complication (i.e. new or worsening of aortic dilation, aortic dissection), or new or worsening vascular stenosis.

Results

From the cohort of 530 patients, 242 (45.7%) patients experienced relapse at least once, including 13 (2.5% of the cohort) who experienced severe relapse. Among the 464 recorded relapses, 14 (3% of all relapses) were severe. Severe relapse corresponded to the following vascular events: a peripheral limb ischaemia in six patients, a visual event in three patients (including two acute anterior ischaemic anterior neuropathies), an aortic complication in three patients, a mesenteric ischaemia in one patient and an ischaemic stroke in one patient. When compared with the 229 patients who experienced non-severe relapses, severe relapse patients were younger at diagnosis (P = 0.02), and showed more frequently limb claudication at baseline (P < 0.0001) and fewer GCA-related cranial signs (P < 0.0001). At diagnosis, more large-vessel vasculitis on imaging (82% vs 36%, P = 0.002) were observed in patients with severe relapse. The death rate did not differ between patients with severe and non-severe relapses.

Conclusion

In a real-life setting, relapse affects nearly half of GCA patients, but severe relapse is rare.
Optimal carbon storage during drought
Authors: Stefaniak Elisa Z , Tissue David T , Dewar Roderick C , Medlyn Belinda E
Published: March 2024

Allocation of non-structural carbohydrates to storage allows plants to maintain a carbon pool in anticipation of future stress. However, to do so, plants must forego use of the carbon for growth, creating a trade-off between storage and growth. It is possible that plants actively regulate the storage pool to maximize fitness in a stress-prone environment. Here, we attempt to identify the patterns of growth and storage that would result during drought stress under the hypothesis that plants actively regulate carbon storage. We use optimal control theory to calculate the optimal allocation to storage and utilization of stored carbon over a single drought stress period. We examine two fitness objectives representing alternative life strategies: prioritization of growth and prioritization of storage, as well as the strategies in between these extremes. We find that optimal carbon storage consists of three discrete phases: ‘growth’, ‘storage without growth’ and the ‘stress’ phase where there is no carbon source. This trajectory can be defined by the time point when the plant switches from growth to storage. Growth-prioritizing plants switch later and fully deplete their stored carbon over the stress period, while storage-prioritizing plants either do not grow or switch early in the drought period. The switch time almost always occurs before the soil water is depleted, meaning that growth stops before photosynthesis. We conclude that the common observation of increasing carbon storage during drought could be interpreted as an active process that optimizes plant performance during stress.