bluuebunny/crossref_metadata_2025 huggingface dataset:
358 Surgical Management of Spinal Cord Injuries: An Overview of Controversies
Authors: Jamal S , Sheeraz A
Published: October 2021

Aim

Spinal Cord Injuries (SCI) are incredibly debilitating injuries associated with significant morbidity and financial burden, with an incidence of 12-16 per million population in the UK. There is currently no cure for SCI, with majority of interventions focusing on primary prevention of SCI or of further damage once SCI is sustained. We present an overview of the role of closed reduction, timing of surgery and role of steroids, and provide an algorithm for management of SCI.

Method

A search was carried out on PubMed, looking at notable reviews, consensus statements and trends in management of spinal cord injuries. This was cross-referenced with the NICE and BOAST guidelines for SCI.

Results

The efficacy of closed reduction in cervical fractures and necessity of pre-reduction MRI is still equivocal and remains a source of major debate amongst spinal surgeons. The timing of surgery remains controversial as studies have not consistently shown improved outcomes with early, aggressive surgery but there have been trends noted in the newer studies with some benefit of early surgery. The use of steroids in acute SCI has fallen out of favour with most guidelines not recommending them due to their equivocal benefit and unequivocal side-effect profile.

Conclusions

Prevention and pre-hospital management are crucial in the management of SCI, along with early spinal alignment restoration, decompression and stabilisation augmented by good long-term rehabilitation measures. There is a need for new randomised controlled trials assessing the role of closed reduction, need for pre-reduction MRI and timing of surgery in SCI.
360 The Impact COVID-19 Has Had on Paediatric Supracondylar Fractures: A Closed Loop Audit Demonstrating How Compliance to BOAST 11 Guidelines Has Changed in An Orthopaedic Department
Authors: Yeoh T , Arslanboga E , Yeoh C
Published: October 2021

Aim

Supracondylar fractures of the humerus in the paediatric patient is a common orthopaedic injury. Resultantly, strict guidelines were created by the British Orthopaedic Association of Standards in Trauma 11 (BOAST 11). In 2020, the COVID-19 pandemic, drastically affected the way medicine was practised. This audit aims to highlight, the extent to which compliance with BOAST 11 changed.

Method

Children with a supracondylar fracture of the humerus (Gartland 2 or 3) were included in this study. Standards from BOAST 11 were selected and the orthopaedic department were audited against these over a period of 2 years. After the first audit cycle, an information booklet was created and distributed to all doctors within the department. At the end of 2020, the department was re-audited, comparing pre-COVID results (2019) with COVID results (2020).

Results

Compliance improved within five BOAST 11 domains assessed on re-audit. With significant changes in neurovascular status being appropriately assessed and documented in clerking notes (improvement of 28%); and 2mm k-wire being used and documented in operation notes (improved by 23%). However, significant regression in results in patient’s being operated on within 24hours.

Conclusions

Global improvement of results during the national pandemic in 2020 demonstrates that our department did not compromise patient care despite limited resources but in fact strived for clinical excellence. The reason for a regression in compliance with regards to patients not being operated on within 24hours was likely due to protect paediatric patients from unnecessary stay in hospital, in a strategy to reduce COVID-19 transmission rates.
377 Expanding the Use of Wide-Awake Local Anaesthesia Non-Tourniquet (WALANT) Technique in The Management of Hand Trauma Patients During the COVID 19 Pandemic
Authors: O'Sullivan S , Macfarlane R , Khan K , Horwitz M
Published: October 2021

Aim

COVID19 produced a unique challenge to the management of hand trauma. There was reduced theatre capacity and inpatient beds as staff and resources were lost to make way for the critically unwell1, however the burden of patients (albeit reduced) requiring emergency procedures remained2. During 1stUK peak we adopted a one-stop hand trauma clinic where patients were assessed by senior surgeons and immediately operated on under local anaesthesia with Adrenalin, a model mirrored by other units across the UK during this time3,4. Subsequent to surgery they were either seen on the same day for advice with a hand therapist or booked for immediate hand therapy follow up.

Method

A retrospective review of 158 cases operated on over a 4-month COVID19 period compared to the same 4-month period 1 year previously. Indications for surgery and type of anaesthesia were recorded. Follow up and complication rates were reviewed for the COVID19 patients.

Results

There were similarities in the demographic of patients across both cohorts and in mechanism of injury, with trauma the highest indication for surgery. The comparable data sets showed only 21% of patients treated used WALANT pre-COVID19 versus 100% of patient during COVID19.

Conclusions

WALANT is a viable model by which to perform emergency hand trauma surgery in a low cost and low resource setting. Previously this model was not utilised to full effect in our hospital. The results demonstrate the adaptability of WALANT in an adverse and dynamic situation, such as COVID19, thus highlighting benefits to patient care and service provision.
537 Open vs Closed Pilon Fractures: Comparison of Management, Outcomes, and Complications
Authors: Lu V , Zhang J , Thahir A , Lim J A , Krkovic M
Published: October 2021

Aim

Despite the low incidence of pilon fractures, their high impact nature presents difficulties in surgical management/recovery. Current literature is varied, with no universal treatment algorithm. We aim to highlight differences in treatment, outcomes, complications between open and closed pilon fractures.

Method

This retrospective study was conducted at a major trauma centre, including patients over 5-year period. 135 patients were included (open:48, closed:87). Primary outcome was AOFAS score at 3-, 6- and 12-months post-injury. Secondary outcomes include time to partial weight-bear (PWB) and full weight-bear (FWB), bone union time, follow-up time. Post-operative complications were collected.

Results

Open fractures had lower AOFAS score 3 months post-injury, longer bone union time, and time to FWB. For both open and closed fractures, compared to ORIF patients, those treated with fine wire fixator (FWF) had lower AOFAS scores 3- and 6-months post-injury. Closed fracture patients treated with ORIF had shorter bone union time, time to PWB and FWB. Patients with AO/OTA 43A fractures needed shorter time to PWB and FWB than those with 43C fractures. Common complications (closed:open) were superficial infection (22%:54%), post-traumatic arthritis (25%:16%), non-union (11%:24%).

Conclusions

Open fractures, with more extensive soft tissue damage, were likely more suited for FWF, rather than ORIF (18% of open vs 72% of closed were treated with ORIF). Due to greater associated trauma, more frequent complications, and delayed definitive fixation, open fractures had lower AOFAS scores. Nevertheless, use of staged approach involving temporary external fixation, followed with ORIF or FWF achieved low complication rates and good functional recovery.
New insights into ribosomal DNA variation in apomictic and sexualTaraxacum(Asteraceae)
Authors: Macháčková Petra , Majeský Ľuboš , Hroneš Michal , Bílková Lucie , Hřibová Eva , Vašut Radim J
Published: October 2021

Apomictic genera have a complex evolutionary history, including reticulate hybridization, polyploidization and variation in reproduction modes. Restrictions of functional meiosis in polyploid apomictic taxa considerably hamper gene conversion, leaving footprints of past hybridization events in their genomes, which are masked by the homogenization of tandemly organized arrays of nuclear ribosomal DNA in sexual species. Dandelions (Taraxacum) have a highly complex reticulate evolutionary history. Detailed knowledge remains hazy; earlier investigations of rDNA sequences have uncovered the complex pattern derived from evolution but without direct evidence for any particular processes. We investigated the position and number of 45S and 5S rDNA loci in 38 Taraxacum taxa (covering different reproduction modes, geographical regions and putative phylogenetic groups) using fluorescent in situ hybridization (FISH) and measured genome size and GC content. The ITS1-5.8S-ITS2 regions of four sexual and five apomictic taxa were sequenced to investigate inter- and intra-individual variation. Most species considerably differ in the chromosome positions of loci and karyotype patterns, but mostly share the same number of studied loci (45S:5S) in a 1:2 ratio per haploid genome (x = 8), with six exceptions (up to a 4:2 ratio). Genome size (2C) varies sixfold and with GC content partly distinguishes major evolutionary groups. Sexual taxa show limited variation in sequenced regions (with two to eight variants), but apomictic taxa vary significantly (with 20–36 variants). Extensive reticulate evolution in Taraxacum and subsequent phenomena such as genome repatterning and non-effective concerted evolution are probably the cause of the dynamic nature of Taraxacum karyotypes and the large variation in genome size and rDNA sequences.
Regional differences in BDNF expression and behavior as a function of sex and enrichment type: oxytocin matters
Authors: Faraji Jamshid , Lotfi Hamid , Moharrerie Alireza , Jafari S Yaghoob , Soltanpour Nasrin , Tamannaiee Rosa , Marjani Kameran , Roudaki Shabnam , Naseri Farhad , Moeeini Reza , Metz Gerlinde A S
Published: October 2021

The early environment is critical to brain development, but the relative contribution of physical versus social stimulation is unclear. Here, we investigated in male and female rats the response to early physical and social environmental enrichment in relation to oxytocin (OT) and brain-derived neurotrophic factor (BDNF) expression. The findings show that males and females respond differently to prolonged sensorimotor stimulation from postnatal days 21–110 in terms of functional, structural, and molecular changes in the hippocampus versus medial prefrontal cortex (mPFC). Physical enrichment promoted motor and cognitive functions and hippocampal BDNF mRNA and protein expression in both sexes. Combined physical and social enrichment, however, promoted functional and structural gain in females. These changes were accompanied by elevated plasma oxytocin (OT) levels and BDNF mRNA expression in the mPFC, while the hippocampus was not affected. Administration of an OT antagonist in females blocked the beneficial effects of enrichment and led to reduced cortical BDNF signaling. These findings suggest that an OT-based mechanism selectively stimulates a region-specific BDNF response which is dependent on the type of experience.
Primary hyperoxaluria type 1 in developing countries: novel challenges in a new therapeutic era
Authors: Soliman Neveen A , Mabrouk Sameh
Published: October 2021

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inborn error of metabolism characterized by marked hepatic overproduction of oxalate due to deficiency of hepatic peroxisomal alanine-glyoxylate aminotransferase caused by AGXT gene mutation. One major hallmark of PH1 in developed as well as developing countries (DC) is the diagnostic delay. Notably in DC, where the disease is most prevalent and probably underdiagnosed, there are many challenges in PH1 diagnosis and management, with economic constrains and ethical concerns. This has led to the existing gap in the management of PH1 between developed and DC, which is expected to further deepen with the advent of novel therapeutic agents unless appropriate actions are taken. Until recently, treatment possibilities were limited to supportive measures. Thanks to a better understanding of the molecular basis of the disease a number of new therapies are developed, or being developed, leading to profound changes in management strategies. In this review we discuss the current situation of PH1 in DC as well as the accessibility challenges and the advantages of using promising novel therapeutics to bridge the currently existing gap. We also provide an overview of an integrated approach to ensure equitable access of sustainable therapeutics to PH1 patients in DC. This is expected to reduce global PH1 healthcare disparities, improve its standard of care and reduce disability linked to extrarenal complications of PH1 by implementing personalized medicine.
Peripheral blood RNA biomarkers for cardiovascular disease from bench to bedside: a position paper from the EU-CardioRNA COST action CA17129
Authors: Vanhaverbeke Maarten , Attard Ritienne , Bartekova Monika , Ben-Aicha Soumaya , Brandenburger Timo , de Gonzalo-Calvo David , Emanueli Costanza , Farrugia Rosienne , Grillari Johannes , Hackl Matthias , Kalocayova Barbora , Martelli Fabio , Scholz Markus , Wettinger Stephanie Bezzina , Devaux Yvan
Published: October 2021

Despite significant advances in the diagnosis and treatment of cardiovascular diseases, recent calls have emphasized the unmet need to improve precision-based approaches in cardiovascular disease. Although some studies provide preliminary evidence of the diagnostic and prognostic potential of circulating coding and non-coding RNAs, the complex RNA biology and lack of standardization have hampered the translation of these markers into clinical practice. In this position paper of the CardioRNA COST action CA17129, we provide recommendations to standardize the RNA development process in order to catalyse efforts to investigate novel RNAs for clinical use. We list the unmet clinical needs in cardiovascular disease, such as the identification of high-risk patients with ischaemic heart disease or heart failure who require more intensive therapies. The advantages and pitfalls of the different sample types, including RNAs from plasma, extracellular vesicles, and whole blood, are discussed in the sample matrix, together with their respective analytical methods. The effect of patient demographics and highly prevalent comorbidities, such as metabolic disorders, on the expression of the candidate RNA is presented and should be reported in biomarker studies. We discuss the statistical and regulatory aspects to translate a candidate RNA from a research use only assay to an in-vitro diagnostic test for clinical use. Optimal planning of this development track is required, with input from the researcher, statistician, industry, and regulatory partners.
Neutrophil extracellular traps: from physiology to pathology
Authors: Hidalgo Andres , Libby Peter , Soehnlein Oliver , Aramburu Iker Valle , Papayannopoulos Venizelos , Silvestre-Roig Carlos
Published: October 2021

At the frontline of the host defence response, neutrophil antimicrobial functions have adapted to combat infections and injuries of different origins and magnitude. The release of web-like DNA structures named neutrophil extracellular traps (NETs) constitutes an important mechanism by which neutrophils prevent pathogen dissemination or deal with microorganisms of a bigger size. At the same time, nuclear and granule proteins with microbicidal activity bind to these DNA structures promoting the elimination of entrapped pathogens. However, these toxic properties may produce unwanted effects in the host, when neutrophils uncontrollably release NETs upon persistent inflammation. As a consequence, NET accumulation can produce vessel occlusion, tissue damage, and prolonged inflammation associated with the progression and exacerbation of multiple pathologic conditions. This review outlines recent advances in understanding the mechanisms of NET release and functions in sterile disease. We also discuss mechanisms of physiological regulation and the importance of neutrophil heterogeneity in NET formation and composition.
Hypochloraemia following admission to hospital with heart failure is common and associated with an increased risk of readmission or death: a report from OPERA-HF
Authors: Cuthbert J J , Brown O I , Urbinati A , Pan D , Pellicori P , Dobbs K , Bulemfu J , Kazmi S , Sokoreli I , Pauws S C , Riistama J M , Cleland J G F , Clark A L
Published: October 2021

Aims

Hypochloraemia is common in patients hospitalized with heart failure (HF) and associated with a high risk of adverse outcomes during admission and following discharge. We assessed the significance of changes in serum chloride concentrations in relation to serum sodium and bicarbonate concentrations during admission in a cohort of 1002 consecutive patients admitted with HF and enrolled into an observational study based at a single tertiary centre in the UK.

Methods and results

Hypochloraemia (<96 mmol/L), hyponatraemia (<135 mmol/L), and metabolic alkalosis (bicarbonate >32 mmol/L) were defined by local laboratory reference ranges. Outcomes assessed were all-cause mortality, all-cause mortality or all-cause readmission, and all-cause mortality or HF readmission. Cox regression and Kaplan–Meier curves were used to investigate associations with outcome. During a median follow-up of 856 days (interquartile range 272–1416), discharge hypochloraemia, regardless of serum sodium, or bicarbonate levels was associated with greater all-cause mortality [hazard ratio (HR) 1.44, 95% confidence interval (CI) 1.15–1.79; P = 0.001], all-cause mortality or all-cause readmission (HR 1.26, 95% CI 1.04–1.53; P = 0.02), and all-cause mortality or HF readmission (HR 1.41, 95% CI 1.14–1.74; P = 0.002) after multivariable adjustment. Patients with concurrent hypochloraemia and natraemia had lower haemoglobin and haematocrit, suggesting congestion; those with hypochloraemia and normal sodium levels had more metabolic alkalosis, suggesting decongestion.

Conclusion

Hypochloraemia is common at discharge after a hospitalization for HF and is associated with worse outcome subsequently. It is an easily measured clinical variables that is associated with morbidity or mortality of any cause.
Bitter taste receptors
Authors: Wooding Stephen P , Ramirez Vicente A , Behrens Maik
Published: October 2021

Bitter taste perception plays vital roles in animal behavior and fitness. By signaling the presence of toxins in foods, particularly noxious defense compounds found in plants, it enables animals to avoid exposure. In vertebrates, bitter perception is initiated by TAS2Rs, a family of G protein-coupled receptors expressed on the surface of taste buds. There, oriented toward the interior of the mouth, they monitor the contents of foods, drinks and other substances as they are ingested. When bitter compounds are encountered, TAS2Rs respond by triggering neural pathways leading to sensation. The importance of this role placed TAS2Rs under selective pressures in the course of their evolution, leaving signatures in patterns of gene gain and loss, sequence polymorphism, and population structure consistent with vertebrates' diverse feeding ecologies. The protective value of bitter taste is reduced in modern humans because contemporary food supplies are safe and abundant. However, this is not always the case. Some crops, particularly in the developing world, retain surprisingly high toxicity and bitterness remains an important measure of safety. Bitter perception also shapes health through its influence on preference driven behaviors such as diet choice, alcohol intake and tobacco use. Further, allelic variation in TAS2Rs is extensive, leading to individual differences in taste sensitivity that drive these behaviors, shaping susceptibility to disease. Thus, bitter taste perception occupies a critical intersection between ancient evolutionary processes and modern human health.
Simultaneous calibration of instrument scale factor and drift rate in network adjustment for continental-scale gravity survey campaign
Authors: Wang Linhai , Chen Shi , Zhuang Jiancang , Xu Weimin
Published: October 2021

The scale factor of each relative gravimeter must be calibrated both before and after the fieldwork of a terrestrial gravity survey, to reduce uncertainties and ensure high precision. Conventionally, such calibration is a time-consuming process performed following well-established baselines. We propose a new Bayesian method to estimate the scale factor in a hybrid gravity network that includes several absolute gravity observation stations. In this approach, the scale factor is estimated as a hyperparameter using the Akaike Bayesian information criterion and using known absolute gravity stations in the network or/and calibrated instruments as constraints. Testing the sensitivity of the gravity values and the residuals of the gravity difference between two successive stations to the change of the scale factor demonstrates the robustness of this method. We also test the sensitivity of the estimated scale factor in the presence of Gaussian noise and the non-linear instrumental drift rate. Moreover, if the maximum absolute gravity interval is greater than 60 per cent of the range of gravity values in the network, or if the known scale factors of calibrated gravimeters are well calibrated, this approach can provide reasonable estimates of the daily drift rate and the unknown scale factors, where the latter has an error of <3 × 10−5. We apply this approach to real gravity campaign data from Yunnan in China and use a cross-validation method to compare estimated gravity values and corresponding gravity values obtained from absolute gravity observations at the same stations, to validate how the proposed method improves estimation accuracy of the gravity value at each station.
The adeno-associated virus 2 genome and Rep 68/78 proteins interact with cellular sites of DNA damage
Authors: Boftsi Maria , Whittle Fawn B , Wang Juexin , Shepherd Phoenix , Burger Lisa R , Kaifer Kevin A , Lorson Christian L , Joshi Trupti , Pintel David J , Majumder Kinjal
Published: October 2021

Nuclear DNA viruses simultaneously access cellular factors that aid their life cycle while evading inhibitory factors by localizing to distinct nuclear sites. Adeno-associated viruses (AAVs), which are Dependoviruses in the family Parvovirinae, are non-enveloped icosahedral viruses, which have been developed as recombinant AAV vectors to express transgenes. AAV2 expression and replication occur in nuclear viral replication centers (VRCs), which relies on cellular replication machinery as well as coinfection by helper viruses such as adenoviruses or herpesviruses, or exogenous DNA damage to host cells. AAV2 infection induces a complex cellular DNA damage response (DDR), in response to either viral DNA or viral proteins expressed in the host nucleus during infection, where VRCs co-localized with DDR proteins. We have previously developed a modified iteration of a viral chromosome conformation capture (V3C-seq) assay to show that the autonomous parvovirus minute virus of mice localizes to cellular sites of DNA damage to establish and amplify its replication. Similar V3C-seq assays to map AAV2 show that the AAV2 genome co-localized with cellular sites of DNA damage under both non-replicating and replicating conditions. The AAV2 non-structural protein Rep 68/78, also localized to cellular DDR sites during both non-replicating and replicating infections, and also when ectopically expressed. Ectopically expressed Rep could be efficiently re-localized to DDR sites induced by micro-irradiation. Recombinant AAV2 gene therapy vector genomes derived from AAV2 localized to sites of cellular DNA damage to a lesser degree, suggesting that the inverted terminal repeat origins of replication were insufficient for targeting.
Differential impact of Kv8.2 loss on rod and cone signaling and degeneration
Authors: Inamdar Shivangi M , Lankford Colten K , Poria Deepak , Laird Joseph G , Solessio Eduardo , Kefalov Vladimir J , Baker Sheila A
Published: October 2021

Heteromeric Kv2.1/Kv8.2 channels are voltage-gated potassium channels localized to the photoreceptor inner segment. They carry IKx, which is largely responsible for setting the photoreceptor resting membrane potential. Mutations in Kv8.2 result in childhood-onset cone dystrophy with supernormal rod response (CDSRR). We generated a Kv8.2 knockout (KO) mouse and examined retinal signaling and photoreceptor degeneration to gain deeper insight into the complex phenotypes of this disease. Using electroretinograms, we show that there were delayed or reduced signaling from rods depending on the intensity of the light stimulus, consistent with reduced capacity for light-evoked changes in membrane potential. The delayed response was not seen ex vivo where extracellular potassium levels were controlled by the perfusion buffer, so we propose the in vivo alteration is influenced by genotype-associated ionic imbalance. We observed mild retinal degeneration. Signaling from cones was reduced but there was no loss of cone density. Loss of Kv8.2 altered responses to flickering light with responses attenuated at high frequencies and altered in shape at low frequencies. The Kv8.2 KO line on an all-cone retina background had reduced cone-driven ERG b wave amplitudes and underwent degeneration. Altogether, we provide insight into how a deficit in the dark current affects the health and function of photoreceptors.
Expanded practice for rural community pharmacy: what are we waiting for?
Authors: Taylor Selina M , Cairns Alice , Glass Beverley D
Published: October 2021

Objective

To synthesise stakeholder (consumer, pharmacist and health professional) perspectives of expanded pharmacy practice in rural and remote community pharmacy.

Methods

Comparison of perspectives of stakeholder groups identified by four studies has highlighted the expected outcomes and anticipated barriers to expanded pharmacy practice. Aligning the studies has identified priority areas of health for which pharmacists may be able to provide expanded service delivery.

Key findings

Expanded pharmacy services are supported by consumers, pharmacists and health professionals and are expected to improve health outcomes for rural and remote populations. Barriers will need to be overcome for expanded services to be sustainable in the future.

Conclusion

The pharmacy profession will need to undertake a paradigm shift to professional practice and work towards this should begin to reduce the health inequality for rural populations.
Comorbid insomnia among breast cancer survivors and its prediction using machine learning: a nationwide study in Japan
Authors: Ueno Taro , Ichikawa Daisuke , Shimizu Yoichi , Narisawa Tomomi , Tsuji Katsunori , Ochi Eisuke , Sakurai Naomi , Iwata Hiroji , Matsuoka Yutaka J
Published: October 2021

Objective

Insomnia is an increasingly recognized major symptom of breast cancer which can seriously disrupt the quality of life during and many years after treatment. Sleep problems have also been linked with survival in women with breast cancer. The aims of this study were to estimate the prevalence of insomnia in breast cancers survivors, clarify the clinical characteristics of their sleep difficulties and use machine learning techniques to explore clinical insights.

Methods

Our analysis of data, obtained in a nationwide questionnaire survey of breast cancer survivors in Japan, revealed a prevalence of suspected insomnia of 37.5%. With the clinical data obtained, we then used machine learning algorithms to develop a classifier that predicts comorbid insomnia. The performance of the prediction model was evaluated using 8-fold cross-validation.

Results

When using optimal hyperparameters, the L2 penalized logistic regression model and the XGBoost model provided predictive accuracy of 71.5 and 70.6% for the presence of suspected insomnia, with areas under the curve of 0.76 and 0.75, respectively. Population segments with high risk of insomnia were also extracted using the RuleFit algorithm. We found that cancer-related fatigue is a predictor of insomnia in breast cancer survivors.

Conclusions

The high prevalence of sleep problems and its link with mortality warrants routine screening. Our novel predictive model using a machine learning approach offers clinically important insights for the early detection of comorbid insomnia and intervention in breast cancer survivors.
From Traction to Treaty-Bound: Jus Cogens, Erga Omnes and Corporate Subjectivity in International Investment Arbitration
Authors: Crow Kevin , Lorenzoni-Escobar Lina
Published: October 2021

This article suggests that the arbitral use of jus cogens and erga omnes is slowly producing a ‘presumption of applicability’ in investor–state arbitration tribunals tasked with determining whether international law applies to investors. Looking backward from two recent counterclaims at tribunals established under investor–state dispute settlement (ISDS) clauses in international investment agreements that support our claim, the article first analyses the evolution and use of jus cogens in attaching rights-claims to non-State subjects of international law. Secondly, it explores the origins and uses of obligations erga omnes in attaching obligations-claims to non-State subjects of international law. It attempts to define the contours of jus cogens and erga omnes as they are deployed in recent ISDS case law and highlights the limits of each concept. The article concludes that there is a potential for a presumption of applicability in international investment arbitration for investor obligations and that this presumption can be sourced from general international law.
Endoscopic transorbital management of frontal sinus mucocele: a case report and review of the literature
Authors: Alaraifi Abdulaziz K , Alrusayyis Danah F , Alzuwayed Abdullah , Alobaid Fahad , AlRajeh Mohammed , Alhedaithy Riyadh
Published: October 2021

The frontal sinus is the most common site for paranasal mucoceles, resulting in potentially threatening intraorbital or intracranial complications. Surgical drainage of mucoceles is the mainstay of treatment, which can be achieved usually through open or endoscopic transnasal approaches. Transorbital endoscopic surgery is a relatively novel approach to selective skull base lesions with limited data in the literature. It could be utilized as a safe and effective alternative approach in managing frontal sinus lesions when the endoscopic transnasal access alone is insufficient or inadequate. Here, we present a case of an isolated lateral left frontal mucocele that was managed successfully using an endoscopic transorbital approach alone with complete resolution of symptoms during a 10-month follow-up period.
Accretion of tidally disrupted asteroids on to white dwarfs: direct accretion versus disc processing
Authors: Li Daohai , Mustill Alexander J , Davies Melvyn B
Published: October 2021

Atmospheric heavy elements have been observed in more than a quarter of white dwarfs (WDs) at different cooling ages, indicating ongoing accretion of asteroidal material, whilst only a few per cent of the WDs possess a dust disc, and all these WDs are accreting metals. Here, assuming that a rubble-pile asteroid is scattered inside a WD’s Roche lobe by a planet, we study its tidal disruption and the long-term evolution of the resulting fragments. We find that after a few pericentric passages, the asteroid is shredded into its constituent particles, forming a flat, thin ring. On a time-scale of Myr, tens of per cent of the particles are scattered on to the WD, and are therefore directly accreted without first passing through a circularized close-in disc. Fragment mutual collisions are most effective for coplanar fragments, and are thus only important in 103−104 yr before the orbital coplanarity is broken by the planet. We show that for a rubble pile asteroid with a size frequency distribution of the component particles following that of the near earth objects, it has to be roughly at least 10 km in radius such that enough fragments are generated and $\ge 10{{\ \rm per\ cent}}$ of its mass is lost to mutual collisions. At relative velocities of tens of km s−1, such collisions grind down the tidal fragments into smaller and smaller dust grains. The WD radiation forces may shrink those grains’ orbits, forming a dust disc. Tidal disruption of a monolithic asteroid creates large km-size fragments, and only parent bodies ≥100 km are able to generate enough fragments for mutual collisions to be significant. Hence, those large asteroids experience a disc phase before being accreted.
Enhancer architecture-dependent multilayered transcriptional regulation orchestrates RA signaling-induced early lineage differentiation of ESCs
Authors: Su Guangsong , Wang Wenbin , Zhao Xueyuan , Chen Jun , Zheng Jian , Liu Man , Bi Jinfang , Guo Dianhao , Chen Bohan , Zhao Zhongfang , Shi Jiandang , Zhang Lei , Lu Wange
Published: October 2021

Signaling pathway-driven target gene transcription is critical for fate determination of embryonic stem cells (ESCs), but enhancer-dependent transcriptional regulation in these processes remains poorly understood. Here, we report enhancer architecture-dependent multilayered transcriptional regulation at the Halr1–Hoxa1 locus that orchestrates retinoic acid (RA) signaling-induced early lineage differentiation of ESCs. We show that both homeobox A1 (Hoxa1) and Hoxa adjacent long non-coding RNA 1 (Halr1) are identified as direct downstream targets of RA signaling and regulated by RARA/RXRA via RA response elements (RAREs). Chromosome conformation capture-based screens indicate that RA signaling promotes enhancer interactions essential for Hoxa1 and Halr1 expression and mesendoderm differentiation of ESCs. Furthermore, the results also show that HOXA1 promotes expression of Halr1 through binding to enhancer; conversely, loss of Halr1 enhances interaction between Hoxa1 chromatin and four distal enhancers but weakens interaction with chromatin inside the HoxA cluster, leading to RA signaling-induced Hoxa1 overactivation and enhanced endoderm differentiation. These findings reveal complex transcriptional regulation involving synergistic regulation by enhancers, transcription factors and lncRNA. This work provides new insight into intrinsic molecular mechanisms underlying ESC fate determination during RA signaling-induced early differentiation.
FAN1’s protection against CGG repeat expansion requires its nuclease activity and is FANCD2-independent
Authors: Zhao Xiaonan , Lu Huiyan , Usdin Karen
Published: October 2021

The Repeat Expansion Diseases, a large group of human diseases that includes the fragile X-related disorders (FXDs) and Huntington's disease (HD), all result from expansion of a disease-specific microsatellite via a mechanism that is not fully understood. We have previously shown that mismatch repair (MMR) proteins are required for expansion in a mouse model of the FXDs, but that the FANCD2 and FANCI associated nuclease 1 (FAN1), a component of the Fanconi anemia (FA) DNA repair pathway, is protective. FAN1’s nuclease activity has been reported to be dispensable for protection against expansion in an HD cell model. However, we show here that in a FXD mouse model a point mutation in the nuclease domain of FAN1 has the same effect on expansion as a null mutation. Furthermore, we show that FAN1 and another nuclease, EXO1, have an additive effect in protecting against MSH3-dependent expansions. Lastly, we show that the loss of FANCD2, a vital component of the Fanconi anemia DNA repair pathway, has no effect on expansions. Thus, FAN1 protects against MSH3-dependent expansions without diverting the expansion intermediates into the canonical FA pathway and this protection depends on FAN1 having an intact nuclease domain.
Unprecedented heat mortality of Magellanic Penguins
Authors: Holt Katie A , Boersma P Dee
Published: October 2021

Extreme weather events are becoming more frequent and severe, leading to an increase in direct, adverse thermoregulatory impacts on wildlife. Here, we document an unprecedented, single-day, heat-related mortality event of Magellanic Penguins (Spheniscus magellanicus) at Punta Tombo, Chubut Province, Argentina, one of the largest breeding colonies for this species. We found 264 dead adults and 90 dead chicks in the breeding colony and along the beaches after recording the highest temperature in the shade (44°C on January 19, 2019) since the study started in December 1982. We found dead adults and chicks in postures used to release heat (i.e. lying prone with flippers and feet extended away from the body and/or bills open). We found no evidence for other causes of mortality other than heat (e.g., disease, toxic algae, starvation). Adults potentially died of dehydration, because dead adults were in significantly worse body condition than adults that survived. Dead adults had either empty stomachs or <50 g of food, and 27% of the dead adults died traveling between the nesting area and the water. More males died than females (83% male and 17% female; n = 94). In one section of the colony, ~5% of 1,153 adults died in the heat. Mortality rates of adults were unevenly distributed across the colony, suggesting that the presence of microclimates or easier beach access was an important factor to penguin survival. The body condition indices of dead and live chicks were similar and chicks that died from heat had food in their stomachs (mean = 405 ± 128 g; n = 14), suggesting that food likely inhibited their ability to thermoregulate. Documenting the effects of extreme weather events on populations is crucial to predicting how they will respond to climate change because these events, although rare, are expected to become more frequent and could have severe impacts on populations.
Mutual upregulation of HY5 and TZP in mediating phytochrome A signaling
Authors: Li Cong , Qi Lijuan , Zhang Shaoman , Dong Xiaojing , Jing Yanjun , Cheng Jinkui , Feng Ziyi , Peng Jing , Li Hong , Zhou Yangyang , Wang Xiaoji , Han Run , Duan Jie , Terzaghi William , Lin Rongcheng , Li Jigang
Published: October 2021

Phytochrome A (phyA) is the far-red (FR) light photoreceptor in plants that is essential for seedling de-etiolation under FR-rich environments, such as canopy shade. TANDEM ZINC-FINGER/PLUS3 (TZP) was recently identified as a key component of phyA signal transduction in Arabidopsis thaliana; however, how TZP is integrated into the phyA signaling networks remains largely obscure. Here, we demonstrate that ELONGATED HYPOCOTYL5 (HY5), a well-characterized transcription factor promoting photomorphogenesis, mediates FR light induction of TZP expression by directly binding to a G-box motif in the TZP promoter. Furthermore, TZP physically interacts with CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1), an E3 ubiquitin ligase targeting HY5 for 26S proteasome-mediated degradation, and this interaction inhibits COP1 interaction with HY5. Consistent with those results, TZP post-translationally promotes HY5 protein stability in FR light, and in turn, TZP protein itself is destabilized by COP1 in both dark and FR light conditions. Moreover, tzp hy5 double mutants display an additive phenotype relative to their respective single mutants under high FR light intensities, indicating that TZP and HY5 also function in largely independent pathways. Together, our data demonstrate that HY5 and TZP mutually upregulate each other in transmitting the FR light signal, thus providing insights into the complicated but delicate control of phyA signaling networks.
SCREENING MAMMOGRAPHY: DIAGNOSTIC EFFICACY—ISSUES AND CONSIDERATIONS FOR THE 2020S
Authors: Hooshmand Sahand , Reed Warren M , Suleiman Mo'ayyad E , Brennan Patrick C
Published: October 2021

Diagnostic efficacy in medical imaging is ultimately a reflection of radiologist performance. This can be influenced by numerous factors, some of which are patient related, such as the physical size and density of the breast, and machine related, where some lesions are difficult to visualise on traditional imaging techniques. Other factors are human reader errors that occur during the diagnostic process, which relate to reader experience and their perceptual and cognitive oversights. Given the large-scale nature of breast cancer screening, even small increases in diagnostic performance equate to large numbers of women saved. It is important to identify the causes of diagnostic errors and how detection efficacy can be improved. This narrative review will therefore explore the various factors that influence mammographic performance and the potential solutions used in an attempt to ameliorate the errors made.
The launch of EMU and German export interests
Authors: Tober Tobias
Published: October 2021

In this paper, I examine the support of German businesses—especially exporters—for the Economic and Monetary Union before 1999. I argue that the support of the German export sector for the EMU depends crucially on its implications for export competitiveness. If exporters conclude that the EMU will improve their competitive position, they will likely support monetary integration. In contrast, other business actors should be more skeptical about the prospects of a European currency union. I therefore expect that the major export enterprises will use their dominant position in the business community to assert their interests. The empirical analysis is based on enterprise surveys and a detailed qualitative study of the role of export interests in Germany’s peak industrial association. I close by discussing how my results provide important insights for various scholarly debates, including the debate on Germany’s role in the Eurozone.
Susceptibility of the Banana Inflorescence to Blood Disease
Authors: Ray Jane D. , Subandiyah Siti , Rincón-Flórez Vivian A. , Prakoso Ady B. , Carvalhais Lilia C. , Drenth André
Published: October 2021

The bacterium Ralstonia syzygii subsp. celebesensis causes Blood disease of banana, a vascular wilt of economic significance in Indonesia and Malaysia. Blood disease has expanded its geographic range in the last 20 years and is an emerging threat to Southeast Asian banana production. Many aspects of the disease cycle and biology are not well understood, including the ability of different parts of the female and male inflorescence of banana to act as infection courts. This study confirms that the banana varieties of Cavendish, and Kepok ‘Kuning’ are susceptible to Blood disease and that an inoculum concentration of 102 CFU/ml of R. syzygii subsp. celebesensis is adequate to initiate disease after pseudostem inoculation. Data show that infection occurs through both the male and female parts of a banana inflorescence and the rachis when snapped to remove the male bell. The infection courts are the female flowers, the male bell bract scar, the male bell flower cushion, the snapped rachis, and deflowered fingers. The location of these infection courts concurs with the dye studies demonstrating that dye externally applied to these plants parts enters the plant vascular system. Thus, the hypothesis is supported that infection of R. syzygii subsp. celebesensis occurs through open xylem vessels of the male and female parts of the banana inflorescence.
The Entomopathogenic Fungi Metarhizium brunneum and Beauveria bassiana Promote Systemic Immunity and Confer Resistance to a Broad Range of Pests and Pathogens in Tomato
Authors: Gupta Rupali , Keppanan Ravindran , Leibman-Markus Meirav , Rav-David Dalia , Elad Yigal , Ment Dana , Bar Maya
Published: October 2021

Biocontrol agents can control pathogens by reenforcing systemic plant resistance through systemic acquired resistance (SAR) or induced systemic resistance (ISR). Trichoderma spp. can activate the plant immune system through ISR, priming molecular mechanisms of defense against pathogens. Entomopathogenic fungi (EPF) can infect a wide range of arthropod pests and play an important role in reducing pests’ population. Here, we investigated the mechanisms by which EPF control plant diseases. We tested two well studied EPF, Metarhizium brunneum isolate Mb7 and Beauveria bassiana as the commercial product Velifer, for their ability to induce systemic immunity and disease resistance against several fungal and bacterial phytopathogens, and their ability to promote plant growth. We compared the activity of these EPF to an established biocontrol agent, Trichoderma harzianum T39, a known inducer of systemic plant immunity and broad disease resistance. The three fungal agents were effective against several fungal and bacterial plant pathogens and arthropod pests. Our results indicate that EPF induce systemic plant immunity and disease resistance by activating the plant host defense machinery, as evidenced by increases in reactive oxygen species production and defense gene expression, and that EPF promote plant growth. EPF should be considered as control means for Tuta absoluta. We demonstrate that, with some exceptions, biocontrol in tomato can be equally potent by the tested EPF and T. harzianum T39, against both insect pests and plant pathogens. Taken together, our findings suggest that EPF may find use in broad-spectrum pest and disease management and as plant growth promoting agents.
BRAF mutations in thyroid cancer
Authors: Scheffel Rafael Selbach , Dora Jose Miguel , Maia Ana Luiza
Published: October 2021

Purpose of review

Activating mutations in the mitogen-activated protein kinase (MAPK) pathway play an important role in papillary (PTC) and anaplastic (ATC) thyroid cancer. The aim of this review is to discuss the impact of BRAF mutations on clinical features and treatment of patients with thyroid cancer.

Recent findings

Despite the unfavorable course associated with PTCs harboring BRAF V600E mutation, its prognostic role remains debated. BRAF V600E-driven tumors exhibit high Extracellular signal-regulated kinase phosphorylation, leading to unregulated cell proliferation and inhibition of the required genes for radioiodine responsiveness in thyroid cancer. The mechanism associated with the variable BRAF-mutant tumor aggressiveness remains unclear and other pathways are likely to co-operate to promote cancer progression. Overexpression of the Notch signaling and loss of individual switch/ sucrose non-fermentable chromatin-remodeling complexes subunits might be involved. The combination of the BRAF inhibitor dabrafenib and the mitogen-activated protein kinase kinase inhibitor trametinib has shown remarkable results in clinical trials of patients with BRAF-mutated ATCs.

The impact of BRAF mutations on the clinical outcomes of PTC remains debatable. In ATCs, in turn, BRAF mutations identify patients eligible for targeted therapy, which is now considered in two settings: as neoadjuvant for unresectable tumors and as a treatment for metastatic or unresectable disease.