bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk of malignancy in thyroid nodules selected for fine needle aspiration biopsy based on ultrasound risk stratification
Authors: de Jong Mechteld C , McNamara John , McGlashan Nicholas , Winter Lucinda , Mihai Radu
Published: March 2022

Aim

Risk stratification of thyroid nodules based on ultrasound scan (USS) features using the TIRADS- or U-scale has been widely adopted. However, management decisions for patients whose work-up provide conflicting information, remains challenging. The aim of this study was to assess the rate of malignancy among those with suspicious cytology after USS-evaluation.

Methods

Retrospective review of clinical, radiological and pathological data regarding patients presenting with a thyroid nodule.

Results

Between January 2018 and December 2020, a total of 214 patients underwent surgery after presenting with thyroid nodule(s) and a fine-needle aspiration (FNA) cytology report either suspicious (Thy3–4) or diagnostic (Thy5) for thyroid malignancy. The appearance on USS was stratified using the TIRADS-scale, either to select nodules needing FNA-assessment or to characterise palpable nodules.

For Thy3a-cytology, the risk of malignancy remained low, irrespective of USS-appearance (2/15 in TIRADS2-3 versus 2/9 in TIRADS 4-5). For a Thy3f-cytology, the risk of malignancy was higher if the USS-appearance was also suspicious (11/75 in TIRADS2-3 versus 17/69 in TIRADS 4-5, p=0.03).

High-risk USS-appearance (TIRADS 4-5) in the presence of suspicious/diagnostic cytology (Thy4-5) had a 95% positive predictive value (40/42) of malignancy. Future data collection should assess the risk of malignancy when USS-appearance is malignant (TIRADS 5) yet cytology is benign (Thy2).

Conclusion

The performance of USS and FNA in this cohort corroborates published data. Until genetic panels will complement the assessment of nodules with a Thy3-cytology, diagnostic thyroid lobectomy remains necessary, as the USS has limited ability to increase the yield of malignant nodules.
Reactivation of Graves’ ophthalmopathy post-thyroidectomy for Graves’ disease
Authors: Chiu Stephanie J , Putri Christine , Allahabadia Amit , Balasubramanian Saba P , Salvi Sachin M
Published: March 2022

Introduction

The impact of thyroidectomy for Graves’ disease (GD) on Graves’ ophthalmopathy (GO) is not well understood. It is generally accepted that thyroidectomy does not exacerbate or precipitate GO in the majority. The aim of this study was to evaluate whether prophylactic glucocorticoid use following total thyroidectomy for GD disease prevents early post-operative reactivation of GO.

Methods

A retrospective cohort study covering 5 years, studying patients undergoing total thyroidectomy for GD. Patients were divided into 3 groups. Group A (Clinical Activity Score (CAS) unknown): Patients with symptoms such as dry eyes or signs of inactive GO, as assessed by the Endocrine Surgical team; or patients seen by their local ophthalmologist, but with signs of GO not severe enough to warrant referral to the orbital team (tertiary centre). Group B (CAS=0): Patients with burnt out or no GO, as assessed by the orbital team. Group C (CAS >0): Patients with active GO, as assessed by the Orbital team. All were given prophylactic glucocorticoid cover.

Results

At least one patient in group A (n=14), none in group B (n=10) and five in group C (n=10) had early post-operative reactivation of Graves’ ophthalmopathy. Post-operative worsening of Graves’ ophthalmopathy was associated with CAS >0 (p=0.0325) and thyroid stimulating hormone <0.02 mIU/L (p=0.0136).

Conclusion

In those receiving prophylactic steroid, six (17.6%) demonstrated worsening GO. This was associated with a CAS >0 and TSH <0.02 mIU/L, suggesting either optimisation of both factors prior to thyroidectomy or considering a more potent steroid regimen.
Acute Presentation of an unblocked Phaeochromocytoma with Small Bowel Ischaemia managed by Emergency Laparotomy and Adrenalectomy
Authors: Houghton Neil , Davies Brooke , Hansel Jan , Davies Douglas , Smith Paul , Brown Andrew , Perkins Karen , Krishnaprasad Karnad , Ryska Ondrej , Walls Gerard , Tomlinson Mark
Published: March 2022

Introduction

A 50-year-old male presented as an emergency with acute abdominal pain, reduced consciousness and blood pressure of 230/136mmHg, having felt unwell for a year. CT scans showed a 9cm right adrenal mass, a 27mm left ventricular thrombus and emboli to the distal superior mesenteric artery. Echocardiography demonstrated a reduced ejection fraction of 25%.

Methods

Our regional multidisciplinary team (Endocrinologists, Anaesthetists, Intensivists, Biochemists and Surgeons) utilised their experience to manage this challenging emergency, with supra-regional expert consultation.

Results

In ICU, intravenous phentolamine and unfractionated heparin infusions were given, attempting to avoid surgery until alpha blockade was established. The following day sepsis and peritonitis developed: surgery could no longer be deferred and had to be undertaken without blockade. After anaesthetic induction a 12 minute asystolic arrest ensued, but circulation was restored with CPR and bolus noradrenaline. Intraoperative photographs demonstrate 150cm of infarcted small bowel being resected, and sequential adrenalectomy being undertaken to avoid further catecholamine crisis and anaesthetic, as discussed with supra-regional colleagues. Post-arrest targeted temperature management was instigated alongside empirical steroid replacement. Serum metadrenaline fell from 58,495pmol/L (<510pmol/L) to 174pmol/L and normetadrenaline from 78,731pmol/L (<1180pmol/L) to 330pmol/L post-resection. Histological assessment confirmed phaeochromocytoma with malignant features (PASS=6 and GAPP=5). The patient made a full recovery and ejection fraction improved to 55%.

Conclusion

This case adds to the controversial equipoise regarding pre-operative blockade. An experienced multidisciplinary adrenal team was crucial in managing this life threatening combination. Noradrenaline was effective during cardiac arrest whilst the circulation was unresponsive to adrenaline.
Unmeasurable stimulated thyroglobulin before radioactive iodine ablation predicts excellent long term outcome in patients with differentiated thyroid cancer
Authors: Sia Yi , Patel Neil , De Jong Mechteld , Khan Shad , Mihai Radu
Published: March 2022

Aim

To determine the likelihood of reaching unmeasurable stimulated thyroglobulin (sTG) levels after surgery for differentiated thyroid cancer (DTC).

Methods

Data on consecutive patients treated for DTC in a tertiary referral centre between May 2000 and June 2019 were retrospectively collected. Radioactive iodine ablation (RIA) was done after hormone withdrawal (before 2015) or after Thyrogen stimulation (more recent patients). During the study period, the biochemical assay for TG changed from a lower limit of detectability of 5 ng/dl to 0.2 ng/dl.

Results

A total of 403 patients (F=282; M=121) were included. sTG was <0.2 in 41 patients and during a median follow-up of 32 months, none had disease recurrence. sTG was 0.2–4.99 ng/dl in 104 patients and during a median follow-up of 27 months, 5 patients had evidence of either residual disease or local recurrence. sTG was reported as >5 in 258 patients and during a median follow-up of 63 months, 160 patients were disease free at the time of data collection. Patients who presented with locally advanced disease requiring modified radical neck dissection (n=78) had sTG higher than in those with earlier disease (n=325) (median 11.1 vs. 5.0ng/ml). There was a large difference in cervical uptake after RIA in patients with sTG 0.2–4.99 ng/dl (n=24) compared with those with sTG >20 ng/dl (n=32) (0.7% vs 1.54%).

Conclusion

Almost half of all patients with DTC achieved unmeasurable sTG after surgery. This could be due to earlier disease but can also serve as a quality control after thyroidectomy for thyroid cancer.
The use of ARTISS fibrin sealant in thyroid surgery: case series and review of the literature.
Authors: Sekyi-Djan Ntirwa , Chapple Catherine , Myuran Tharsika , Hammond-Kenny Amy , Hilger Andreas
Published: March 2022

Introduction

Many techniques have been described to reduce length of stay and complication rates in thyroid surgery. ARTISS is a fibrin sealant used as an adjunct to sutures or staples, whereby it simultaneously adheres and seals subcutaneous tissues. In the context of thyroid surgery, it can augment the closure of dead space beneath the strap muscles and the platysma flaps.

Methods

A single surgeon adopted this novel technique from February 2017. A retrospective audit of 72 thyroid cases using ARTISS was conducted. Data were collected on patient demographics, ASA grade, procedure, histology, drain insertion and output, length of stay and complications.

Results

71 (99%) patients had a drain inserted. Of the 57 hemithyroidectomies, 13 (23%) patients had their drain removed and were discharged on the same day, 41 (65%) the next day and 3 (6%) remained at 2 days post-operatively. Of the 41 hemithyroidectomies who stayed one night, 21 (51%) patients had been operated on in the afternoon and were discharged the following morning. Of the 15 total thyroidectomies, 9 (60%) patients had their drain removed the following day and 6 (40%) at 2 days post-operatively. There was one post-operative superficial haematoma which did not require re-operation, another which required aspiration only, and one case of suspected wound infection treated with oral antibiotics.

Conclusion

The use of ARTISS fibrin sealant in this case series has been shown to be a safe and successful technique. Most patients are discharged within 24 hours of surgery and no cases required a return to theatre.
Outcomes of Patients with High Risk Thyroid Cancer – T3b to T4
Authors: Chrysostomos Tornari , Tan Jit Kai , Simo Ricard
Published: March 2022

Aims

The aims of this study are to analyse the outcomes of patients with T3b, T4 thyroid cancers (TC) by examining their tumour-node-metastasis (TNM) classification at presentation, the treatments they were offered and any postoperative complications.

Methods

A retrospective analysis of 41 patients who were diagnosed and treated for T3b and T4 thyroid cancer. Comparison of categorical variables was performed using Chi-square (where n ≥ 5) or Fisher’s exact test (where n < 5). Mann Whitney U tests were used to identify statistical significance between data without normal distribution. Outcome measures included perineural invasion (PNI), lymphovascular invasion (LVI), postoperative hypocalcaemia (2 weeks, 3 months and 6 months), postoperative tri-iodothyronine, postoperative thyroxine and postoperative thyroglobulin.

Results

Patients with T4 TC were shown to have an increase in risk of PNI (3.23% vs 30.00%, p = 0.013). LVI was similar in both groups (45.16% vs 50.00%, p = 0.790). T4 patients had higher rates of postoperative hypocalcaemia at 2 weeks (10.00% vs 50.00%, p = 0.006). Postoperative hypocalcaemia was similar at 3 months (9.68% vs 10.00%, p = 0.976) and 6 months (6.67% vs 0.00%, p = 0.426). Low postoperative tri-iodothyronine was more frequent in T3b patients (29.03% vs 10.00%, p = 0.376). High postoperative thyroxine was more common in T3b patients (45.16% vs 20.00%, p = 0.069).

Conclusion

Patients with T4 TC had higher rates of PNI and postoperative hypocalcaemia. Postoperative thyroid markers differed slightly but were not statistically significant. Patient demographics and presentations did not have any significant differences.
Influence of Incidental Detection of Thyroid Nodule on Thyroid Cancer Risk and Prognosis – A Systematic Review and Meta-analysis
Authors: Chooi Je Ern , Ravindiran Abiramie , Balasubramanian Saba P
Published: March 2022

Background

Clinically inapparent thyroid nodules discovered serendipitously on imaging for non-thyroid indications are termed as thyroid incidentalomas. It is unclear whether these incidentalomas have a lower prevalence of malignancy or slower tumour progression compared to symptomatic nodules. The aim of this systematic review were to determine the impact of incidental detection of thyroid nodules on both the risk of malignancy and on prognosis in patients with thyroid cancer.

Methods

PubMed and MEDLINE® on Web of Science databases were searched from inception to April 2021 for English language articles reporting on human studies of thyroid cancer risk and/or prognosis in incidental and non-incidental nodules.

Results

Eighteen observational studies published between 1998 and 2020 were eligible for analysis; 4 studies reported on risk, 9 on prognosis and 5 studies reported on both risk and prognosis. When comparing the incidental and non-incidental groups in the risk study, the odds ratios calculated from the case control studies (n=6) ranged from 0.64 to 2.86; the relative risks calculated from the cohort studies (n=3) ranged from 0.13 to 6.27. A meta-analysis of the eligible case control studies (n=3) showed a non-significant summated odds ratio of 1.04 (95% CI=0.63–1.70, p=0.88). In the prognosis study, five direct and thirteen indirect markers of prognosis were compared between the incidental and non-incidental groups. A meta-analysis was not possible but incidentally detected thyroid cancer had better progression-free and overall survival.

Conclusion

Current evidence suggests that investigation and management of thyroid nodules should not be influenced by the mode of detection. However, incidentally detected nodules appear to have a better prognosis.
Parathyroid carcinoma in the Yorkshire and Humber region of the UK – a multi-centre study of presentation, management and outcomes
Authors: Davies Matthew , Balasubramanian Saba , Fraser Sheila , England James , Jackson Richard
Published: March 2022

Purpose

Our objective is to report on the management strategies and outcomes of patients with parathyroid cancer (PC) in the Yorkshire and Humber region of the UK.

Pathology databases were interrogated for patients diagnosed with PC at three major centres in the region. Data was collected by two observers and all pathology reports were reviewed by a single consultant pathologist. The analyses were primarily descriptive and outcomes were compared with recently published literature.

Methods

All cases of PC diagnosed between 2006 and June 2019 were included.

Data on presentation, treatment, histology and outcomes were recorded for each case.

Results

The series includes 27 patients, with a median age of 56 (range 46.5–72.5) years. No gender predisposition (M: F 13:14) was present. Twenty-two had the ipsilateral thyroid lobe (+/- lymph nodes) excised as part of definitive treatment. Nine of these had definitive surgery in two stages. Capsular, vascular and thyroid/soft tissue invasion were seen in 89%, 70% and 70% of patients respectively. One patient received adjuvant radiotherapy treatment. Recurrence was confirmed in one patient, causing mortality 70 months post diagnosis. Three other patients died of other causes during the study period, one of whom was suspected to have recurrent disease.

Conclusions

Rates of recurrence and mortality were low following surgical treatment for PC; however, diagnostic strategies and surgical practices were variable. The development of guidelines on the management of PC may reduce variability in treatment and improve patient outcomes.
Impact of pre-operative Metyrapone therapy on post-operative Steroid dependence in patients undergoing Adrenalectomy for Cushing’s Syndrome
Authors: Clayton Bethan , Doran Helen , Kearney Tara
Published: March 2022

Introduction

Prolonged elevated cortisol in Cushing’s Syndrome can lead to adrenal insufficiency post-adrenalectomy. Metyrapone is licensed to suppress endogenous cortisol production pre-operatively for symptom relief. The aim of this study was to investigate whether pre-treatment of patients with metyrapone led to reduced adrenal insufficiency, hence reduced steroid dependence post-op.

Methods

Cases were identified from UKRETS submissions between 2008–2020, with Electronic Patient Records used for data collection. Patients with adrenocortical carcinoma (ACC) and/or lost to follow-up were excluded. The remaining cases were divided into those treated with metyrapone pre-operatively and those not. Results were analysed via IBM SPSS Statistics software.

Results

Of 59 patients, those lost to follow up (n=6) and those with ACC (n=4) were excluded leaving 49 cases. Metyrapone patients (n=29) had a median of 3 symptoms of cortisol excess (0–9) compared to 2 symptoms (0–5) in non-metyrapone (n=20) (p=0.061). 82.8% (n=24) of metyrapone patients and 65% (n=13) of non-metyrapone patients were successfully weaned off steroids post-op, with the remaining patients still steroid dependent. Cox proportional hazards regression showed metyrapone did not impact steroid dependence (p=0.230). Metyrapone treatment increased the likelihood of adrenal recovery whereas increasing symptom burden reduced the likelihood (hazard ratio 0.271 and -0.143 respectively), however these findings were not significant (p=0.445 and p=0.117 respectively).

Conclusion

We found metyrapone had no significant impact on rate of adrenal failure. A larger series may more accurately determine whether metyrapone pre-operatively confers a higher likelihood of adrenal recovery and determine whether high symptom burden pre-operatively increases risk of steroid dependence post-operatively.
Microglial large extracellular vesicles propagate early synaptic dysfunction in Alzheimer’s disease
Authors: Gabrielli Martina , Prada Ilaria , Joshi Pooja , Falcicchia Chiara , D’Arrigo Giulia , Rutigliano Grazia , Battocchio Elisabetta , Zenatelli Rossella , Tozzi Francesca , Radeghieri Annalisa , Arancio Ottavio , Origlia Nicola , Verderio Claudia
Published: March 2022

Synaptic dysfunction is an early mechanism in Alzheimer’s disease that involves progressively larger areas of the brain over time. However, how it starts and propagates is unknown.

Here we show that amyloid-β released by microglia in association with large extracellular vesicles (Aβ-EVs) alters dendritic spine morphology in vitro, at the site of neuron interaction, and impairs synaptic plasticity both in vitro and in vivo in the entorhinal cortex–dentate gyrus circuitry. One hour after Aβ-EV injection into the mouse entorhinal cortex, long-term potentiation was impaired in the entorhinal cortex but not in the dentate gyrus, its main target region, while 24 h later it was also impaired in the dentate gyrus, revealing a spreading of long-term potentiation deficit between the two regions. Similar results were obtained upon injection of extracellular vesicles carrying Aβ naturally secreted by CHO7PA2 cells, while neither Aβ42 alone nor inflammatory extracellular vesicles devoid of Aβ were able to propagate long-term potentiation impairment. Using optical tweezers combined to time-lapse imaging to study Aβ-EV–neuron interaction, we show that Aβ-EVs move anterogradely at the axon surface and that their motion can be blocked through annexin-V coating. Importantly, when Aβ-EV motility was inhibited, no propagation of long-term potentiation deficit occurred along the entorhinal–hippocampal circuit, implicating large extracellular vesicle motion at the neuron surface in the spreading of long-term potentiation impairment.

Our data indicate the involvement of large microglial extracellular vesicles in the rise and propagation of early synaptic dysfunction in Alzheimer’s disease and suggest a new mechanism controlling the diffusion of large extracellular vesicles and their pathogenic signals in the brain parenchyma, paving the way for novel therapeutic strategies to delay the disease.
Factors Associated With Systemic Immune Activation Indices in a Global Primary Cardiovascular Disease Prevention Cohort of People With Human Immunodeficiency Virus on Antiretroviral Therapy
Authors: Looby Sara E , Kantor Amy , Burdo Tricia H , Currier Judith S , Fichtenbaum Carl J , Overton Edgar T , Aberg Judith A , Malvestutto Carlos D , Bloomfield Gerald S , Erlandson Kristine M , Cespedes Michelle , Kallas Esper G , Masiá Mar , Thornton Alice C , Smith Mandy D , Flynn Jacqueline M , Kileel Emma M , Fulda Evelynne , Fitch Kathleen V , Lu Michael T , Douglas Pamela S , Grinspoon Steven K , Ribaudo Heather J , Zanni Markella V
Published: March 2022

Background

Among antiretroviral therapy (ART)–treated people with human immunodeficiency virus (PWH), persistent systemic immune activation contributes to atherogenesis atherosclerotic, cardiovascular disease (CVD) events, and mortality. Factors associated with key immune activation indices have not previously been characterized among a global primary CVD prevention cohort of PWH.

Methods

Leveraging baseline Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) data, we evaluated factors associated with soluble CD14 (sCD14) and oxidized low-density lipoprotein (oxLDL).

Results

The primary analysis cohort included 4907 participants from 5 global-burden-of-disease regions (38% female, 48% Black, median age 50 years). In fully adjusted models for sCD14, female sex and White race (among those in high-income regions) were associated with higher sCD14 levels, while higher body mass index (BMI) and current use of nucleoside reverse transcriptase inhibitor + integrase strand transfer inhibitor ART were associated with lower sCD14 levels. In fully adjusted models for oxLDL, male sex, residence in high-income regions, White race (among those in high-income regions), and higher BMI were associated with higher oxLDL levels. In a subanalysis cohort of 1396 women with HIV, increased reproductive age was associated with higher sCD14 levels but not with higher oxLDL levels.

Conclusions

Factors associated with sCD14 and oxLDL, 2 key indices of immune-mediated CVD risk, differ. Future studies will elucidate ways in which medications (eg, statins) and behavioral modifications influence sCD14 and oxLDL and the extent to which dampening of these markers mediates CVD-protective effects.

Clinical Trials Registration

NCT0234429.
Safety and Effectiveness Outcomes From a 14-Country Cohort of Patients With Multi-Drug Resistant Tuberculosis Treated Concomitantly With Bedaquiline, Delamanid, and Other Second-Line Drugs
Authors: Huerga Helena , Khan Uzma , Bastard Mathieu , Mitnick Carole D , Lachenal Nathalie , Khan Palwasha Y , Seung Kwonjune J , Melikyan Nara , Ahmed Saman , Rich Michael L , Varaine Francis , Osso Elna , Rashitov Makhmujan , Salahuddin Naseem , Salia Gocha , Sánchez Epifanio , Serobyan Armine , Rafi Siddiqui Muhammad , Grium Tefera Dri , Vetushko Dmitry , Yeghiazaryan Lusine , Holtzman David , Islam Shirajul , Kumsa Andargachew , Jacques Leblanc Gamarly , Leonovich Olga , Mamsa Shahid , Manzur-ul-Alam Mohammad , Myint Zaw , Padayachee Shrivani , Franke Molly F , Hewison Catherine
Published: March 2022

Background

Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs.

Methods

We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented.

Results

Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 patients (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died, and 7.2% experienced treatment failure.

Conclusions

Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.
Cereblon, a novel target in heart failure: but is calcium really everything?
Authors: Sequeira Vasco , Maack Christoph
Published: March 2022

This editorial refers to ‘Cereblon contributes to cardiac dysfunction by degrading Cav1.2α’, by N. Park et al., https://doi.org/10.1093/eurheartj/ehac072.
The mysterious role of fibrillin in plastid metabolism: current advances in understanding
Authors: Kim Inyoung , Kim Hyun Uk
Published: March 2022

Fibrillins (FBNs) are a family of genes in cyanobacteria, algae, and plants. The proteins they encode possess a lipid-binding motif, exist in various types of plastids, and are associated with lipid bodies called plastoglobules, implicating them in lipid metabolism. FBNs present in the thylakoid and stroma are involved in the storage, transport, and synthesis of lipid molecules for photoprotective functions against high-light stress. In this review, the diversity of subplastid locations in the evolution of FBNs, regulation of FBNs expression by various stresses, and the role of FBNs in plastid lipid metabolism are comprehensively summarized and directions for future research are discussed.
Investigating the nature of the ultraluminous X-ray sources in the galaxy NGC 925
Authors: Salvaggio Chiara , Wolter A , Pintore F , Pinto C , Ambrosi E , Israel G L , Marino A , Salvaterra R , Zampieri L , Belfiore A
Published: March 2022

Variability is a powerful tool to investigate properties of X-ray binaries (XRB), in particular for Ultraluminous X-ray sources (ULXs) that are mainly detected in the X-ray band. For most ULXs the nature of the accretor is unknown, although a few ULXs have been confirmed to be accreting at super-Eddington rates on to a neutron star (NS). Monitoring these sources is particularly useful both to detect transients and to derive periodicities, linked to orbital and super-orbital modulations. Here, we present the results of our monitoring campaign of the galaxy NGC 925, performed with the Neil Gehrels Swift Observatory. We also include archival and literature data obtained with Chandra, XMM–Newton, and NuSTAR. We have studied spectra, light curves, and variability properties on days to months time-scales. All the three ULXs detected in this galaxy show flux variability. ULX-1 is one of the most luminous ULXs known, since only 10 per cent of the ULXs exceed a luminosity of ∼5 × 1040 erg s−1, but despite its high flux variability we found only weak spectral variability. We classify it as in a hard ultraluminous regime of super-Eddington accretion. ULX-2 and ULX-3 are less luminous but also variable in flux and possibly also in spectral shape. We classify them as in between the hard and the soft ultraluminous regimes. ULX-3 is a transient source: by applying a Lomb–Scargle algorithm, we derive a periodicity of ∼126 d, which could be associated with an orbital or superorbital origin.
Angular systematics-free cosmological analysis of galaxy clustering in configuration space
Authors: Paviot Romain , de la Torre Sylvain , de Mattia Arnaud , Zhao Cheng , Bautista Julian , Burtin Etienne , Dawson Kyle , Escoffier Stéphanie , Jullo Eric , Raichoor Anand , Ross Ashley J , Rossi Graziano
Published: March 2022

Galaxy redshift surveys are subject to incompleteness and inhomogeneous sampling due to the various constraints inherent to spectroscopic observations. This can introduce systematic errors on the summary statistics of interest, which need to be mitigated in cosmological analysis to achieve high accuracy. Standard practices involve applying weighting schemes based on completeness estimates across the survey footprint, possibly supplemented with additional weighting schemes accounting for density-dependent effects. In this work, we concentrate on pure angular systematics and describe an alternative approach consisting in analysing the galaxy two-point correlation function where angular modes are nulled. By construction, this procedure removes all possible known and unknown sources of angular observational systematics, but also part of the cosmological signal. We use a modified Landy–Szalay estimator for the two-point correlation function that relies on an additional random catalogue where angular positions are randomly drawn from the galaxy catalogue, and provide an analytical model to describe this modified statistic. We test the model by performing an analysis of the full anisotropic clustering in mock catalogues of luminous red and emission-line galaxies at 0.43 < z < 1.1. We find that the model fully accounts for the modified correlation function in redshift space, without introducing new nuisance parameters. The derived cosmological parameters from the analysis of baryon acoustic oscillations and redshift-space distortions display slightly larger statistical uncertainties, mostly for the growth rate of structure parameter fσ8 that exhibits a $50{{\ \rm per\ cent}}$ statistical error increase, but free from angular systematic error.
Characteristics of chromospheric oscillation periods in magnetic bright points
Authors: Sadeghi Rayhane , Tavabi Ehsan
Published: March 2022

In this investigation, oscillation periods in Mg ii k-line intensity, brightness temperature, and Doppler velocity obtained above magnetic bright points (MBPs) are investigated. For this purpose, data from the Interface Region Imaging Spectrometer (IRIS) observing the higher chromosphere and transition region (TR) were analysed, together with imaging and magnetogram data obtained by the Solar Dynamics Observatory(SDO). The MBPs were identified by combining Si iv 1403-Å slit-jaw images with magnetogram information from the Heliospheric and Magnetic Imager (HMI). A time-slice analysis followed by a wavelet inspection were carried out on the Mg ii k (2796-Å and 10 000 K) resonance lines for the detection of the oscillation period. Finally, a power spectrum analysis was performed to characterize the oscillations. It was found that the network points feature a typical intensity, temperature, and velocity oscillation period of about 300 s. The internetwork points have a mean intensity oscillation period of about 180 s, a mean temperature oscillation period of about 202 s, and a mean velocity oscillation period of about 202 s. In addition, one BP that was analysed in detail demonstrates intensity oscillation periods with a value of 500 s, which are obviously not related to the common 3- or 5-min oscillations typically found elsewhere in chromospheric/photospheric structures.
The MYC oncoprotein directly interacts with its chromatin cofactor PNUTS to recruit PP1 phosphatase
Authors: Wei Yong , Redel Cornelia , Ahlner Alexandra , Lemak Alexander , Johansson-Åkhe Isak , Houliston Scott , Kenney Tristan M G , Tamachi Aaliya , Morad Vivian , Duan Shili , Andrews David W , Wallner Björn , Sunnerhagen Maria , Arrowsmith Cheryl H , Penn Linda Z
Published: March 2022

Despite MYC dysregulation in most human cancers, strategies to target this potent oncogenic driver remain an urgent unmet need. Recent evidence shows the PP1 phosphatase and its regulatory subunit PNUTS control MYC phosphorylation, chromatin occupancy, and stability, however the molecular basis remains unclear. Here we demonstrate that MYC interacts directly with PNUTS through the MYC homology Box 0 (MB0), a highly conserved region recently shown to be important for MYC oncogenic activity. By NMR we identified a distinct peptide motif within MB0 that interacts with PNUTS residues 1–148, a functional unit, here termed PNUTS amino-terminal domain (PAD). Using NMR spectroscopy we determined the solution structure of PAD, and characterised its MYC-binding patch. Point mutations of residues at the MYC-PNUTS interface significantly weaken their interaction both in vitro and in vivo, leading to elevated MYC phosphorylation. These data demonstrate that the MB0 region of MYC directly interacts with the PAD of PNUTS, which provides new insight into the control mechanisms of MYC as a regulator of gene transcription and a pervasive cancer driver.
Correlation Between Temperature Rise After Sympathetic Block and Pain Relief in Patients with Complex Regional Pain Syndrome
Authors: Samen Christelle D K , Sutton Olivia M , Rice Ambrose E , Zaidi Munfarid A , Siddarthan Ingharan J , Crimmel Stephanie D , Cohen Steven P
Published: March 2022

Objective

Determine the correlation between post–sympathetic block temperature change and immediate- and intermediate-term pain relief.

Design

Retrospective analysis.

Setting

Academic setting.

Subjects

Seventy-nine patients with complex regional pain syndrome who underwent sympathetic block.

Methods

Pre- and post-block temperatures in the affected extremity and pain scores immediately (based on 6-hour pain diary) after the block and at the intermediate-term 4- to 8-week follow-up were recorded. Post-block pain reductions of 30–49% and ≥50% were designated as partially sympathetically maintained pain and sympathetically maintained pain, respectively. A decrease in pain score ≥2 points lasting ≥4 weeks was considered a positive intermediate-term outcome for sympathetic block.

Results

A weak correlation was found between immediate-term pain relief and the extent of temperature rise for the cohort (R = 0.192, P = 0.043). Greater immediate-term pain reduction was reported among patients who experienced a temperature increase ≥7.5°C (mean 4.1; 95% confidence interval [CI]: 3.33 to 4.76) than among those who experienced a temperature increase <2°C (2.3; 95% CI: 1.36 to 3.31) or ≥2°C to <7.5°C (2.9; 95% CI: 1.8 to 3.9; P = 0.036). The correlations between temperature increase and intermediate-term pain score reduction at 4–8 weeks (R = 0.052, P = 0.329) and between immediate- and intermediate-term pain relief (R = 0.139, P = 0.119) were not statistically significant.

Conclusions

A weak correlation was found for those who experienced greater temperature increases after the block to also experience greater immediate pain relief. Higher temperature increase cutoffs than are typically used might be necessary to determine whether a patient with complex regional pain syndrome has sympathetically maintained pain.
Origin and Diversification of the Saguaro Cactus (Carnegiea gigantea): A Within-Species Phylogenomic Analysis
Authors: Sanderson Michael J , Búrquez Alberto , Copetti Dario , McMahon Michelle M , Zeng Yichao , Wojciechowski Martin F
Published: March 2022

Reconstructing accurate historical relationships within a species poses numerous challenges, not least in many plant groups in which gene flow is high enough to extend well beyond species boundaries. Nonetheless, the extent of tree-like history within a species is an empirical question on which it is now possible to bring large amounts of genome sequence to bear. We assess phylogenetic structure across the geographic range of the saguaro cactus, an emblematic member of Cactaceae, a clade known for extensive hybridization and porous species boundaries. Using 200 Gb of whole genome resequencing data from 20 individuals sampled from 10 localities, we assembled two data sets comprising 150,000 biallelic single nucleotide polymorphisms (SNPs) from protein coding sequences. From these, we inferred within-species trees and evaluated their significance and robustness using five qualitatively different inference methods. Despite the low sequence diversity, large census population sizes, and presence of wide-ranging pollen and seed dispersal agents, phylogenetic trees were well resolved and highly consistent across both data sets and all methods. We inferred that the most likely root, based on marginal likelihood comparisons, is to the east and south of the region of highest genetic diversity, which lies along the coast of the Gulf of California in Sonora, Mexico. Together with striking decreases in marginal likelihood found to the north, this supports hypotheses that saguaro’s current range reflects postglacial expansion from the refugia in the south of its range. We conclude with observations about practical and theoretical issues raised by phylogenomic data sets within species, in which SNP-based methods must be used rather than gene tree methods that are widely used when sequence divergence is higher. These include computational scalability, inference of gene flow, and proper assessment of statistical support in the presence of linkage effects. [Phylogenomics; phylogeography; rooting; Sonoran Desert.]
COVID-19 testing: disparity between national and institution-based case detection
Authors: Aitman Timothy J , Bauld Linda , Carruthers Kathryn F , Gilbert Nick , Turok Neil
Published: March 2022

Reports of COVID-19 prevalence through national statistics, community surveys and targeted testing at places of work or study have guided national and institutional responses to the pandemic. The University of Edinburgh established a mass testing programme, TestEd, for detection of COVID-19 in asymptomatic staff and students who are studying or working on campus. The study has tested more than 100,000 samples with more than 170 confirmed positive results. Since the introduction of a change in policy in England and the UK devolved nations in early January 2022, to limit eligibility for PCR testing in the community to those with symptoms, we have noticed a divergence between the reports in Scottish and UK-wide prevalence, and the magnitude and frequency of positive results in the University datasets. While the national UK-wide and Scottish case figures show declining or stable prevalence, University case reports have risen more than five-fold since early December 2021 and continue to rise. These observations could be important in the face of future variants of concern and emphasise the need for continued access to high sensitivity PCR testing and other forms of surveillance.
Plasma metabolomics of primary open-angle glaucoma in three prospective US cohorts and the UK Biobank
Authors: Zeleznik Oana , Kang Jae H. , Lasky-Su Jessica , Eliassen A. Heather , Frueh Lisa , Clish Clary , Rosner Bernard A. , Elze Tobias , Hysi Pirro , Khawaja Anthony , Wiggs Janey L. , Pasquale Louis R.
Published: March 2022

Purpose

To better understand the etiologic pathways in glaucoma, we aimed to identify pre-diagnostic plasma metabolites associated with glaucoma risk.

Methods

In a case-control study from the Nurses’ Health Study (NHS), NHSII and Health Professionals Follow-Up Study (HPFS), 599 incident primary open-angle glaucoma (POAG) cases (mean time between blood draw and diagnosis was 10.3 years) were 1:1 matched to 599 controls. Plasma metabolites were measured with LC-MS/MS at the Broad Institute (Cambridge, MA, USA); 367 metabolites from 17 metabolite classes passed quality control analyses. For comparison, in a cross-sectional study in the UK Biobank, 168 NMR metabolites (Nightingale, Finland; version 2020) were measured in serum samples from 2,238 prevalent glaucoma cases and 44,723 controls. Metabolites were probit-score transformed for normality; multiple logistic regression was used to identify metabolites associated with POAG in NHS/NHSII/HPFS and glaucoma in UK Biobank. In NHS/NHSII/HPFS, we also used Metabolite Set Enrichment Analysis to identify metabolite classes associated with POAG. All analyses adjusted for established glaucoma risk factors. False discovery rate (FDR) and number of effective tests (NEF) were used to adjust for multiple comparisons.

Results

Nine metabolite classes were associated (FDR<0.05) with POAG in NHS/NHSII/HPFS: triglycerides, diglycerides, two lysophospholipids classes [lysophosphatidylcholines and lysophosphatidylethanolamines], and two phospholipid class [phosphatidylethanolamines and phosphatidylcholines] were positively associated, while cholesteryl esters, carnitines, and organic acids and derivatives were inversely associated with POAG risk; further adjustment for covariates minimally altered the results. These associations were particularly stronger for POAG with paracentral visual field loss. In the UK Biobank, notably, triglycerides and phospholipids (from which lysophospholipids are derived through hydrolysis), were confirmed to be associated (p<0.05) with higher glaucoma risk. Also, in the UK Biobank, the metabolites of tyrosine, glucose, and glutamine were positively associated (NEF<0.2) while 3-hydroxybutyrate, acetate, citrate, pyruvate, and lactate (the latter 4 being anionic organic acids) were inversely associated with glaucoma (NEF<0.05).

Conclusions

Higher levels of glycerides (diglycerides and triglycerides) and phospholipids were adversely associated with glaucoma in both the NHS/NHSII/HPFS and the UK Biobank, suggesting that they play an important role in glaucoma pathogenesis.

PRÉCIS

Higher glyceride and phospholipid levels in pre-diagnostic plasma was associated with glaucoma risk in three cohorts and were associated with prevalent glaucoma in the UK Biobank. Altered lipid metabolism may be etiologically important in glaucoma.
The role of liver fat in cardiometabolic diseases is highlighted by genome-wide association study of MRI-derived measures of body composition
Authors: van der Meer Dennis , Gurholt Tiril P. , Sønderby Ida E. , Shadrin Alexey A. , Hindley Guy , Rahman Zillur , de Lange Ann-Marie G. , Frei Oleksandr , Leinhard Olof D. , Linge Jennifer , Simon Rozalyn , Westlye Lars T. , Halvorsen Sigrun , Dale Anders M. , Karlsen Tom H. , Kaufmann Tobias , Andreassen Ole A.
Published: March 2022

Background & Aims

Obesity and associated morbidities, metabolic associated liver disease (MAFLD) included, constitute some of the largest public health threats worldwide. Body composition and related risk factors are known to be heritable and identification of their genetic determinants may aid in the development of better prevention and treatment strategies. Recently, large-scale whole-body MRI data has become available, providing more specific measures of body composition than anthropometrics such as body mass index. Here, we aimed to elucidate the genetic architecture of body composition, by conducting the first genome-wide association study (GWAS) of these MRI-derived measures.

Methods

We ran both univariate and multivariate GWAS on fourteen MRI-derived measurements of adipose and muscle tissue distribution, derived from scans from 34,036 White European UK Biobank participants (mean age of 64.5 years, 51.5% female).

Results

Through multivariate analysis, we discovered 108 loci with distributed effects across the body composition measures and 256 significant genes primarily involved in immune system functioning. Liver fat stood out, with a highly discoverable and oligogenic architecture and the strongest genetic associations. Comparison with 21 common cardiometabolic traits revealed both shared and specific genetic influences, with higher mean heritability for the MRI measures (h2=.25 vs. .16, p=1.4×10−6). We found substantial genetic correlations between the body composition measures and a range of cardiometabolic diseases, with the strongest correlation between liver fat and type 2 diabetes (rg=.48, p=1.6×10−22).

Conclusions

These findings show that MRI-derived body composition measures complement conventional body anthropometrics and other biomarkers of cardiometabolic health, highlighting the central role of liver fat, and improving our knowledge of the genetic architecture of body composition and related diseases.
Impact of a sanitation intervention on quality of life and mental wellbeing in low-income urban neighbourhoods of Maputo, Mozambique
Authors: Ross Ian , Greco Giulia , Adriano Zaida , Nala Rassul , Brown Joe , Opondo Charles , Cumming Oliver
Published: March 2022

Objectives

Toilet users often report valuing privacy and safety more highly than reduced disease, but effects of urban sanitation interventions on such outcomes have never been assessed quantitatively. In this study, we evaluate the impact of a shared sanitation intervention on quality of life (QoL) and mental wellbeing.

Design

We interviewed individuals living in intervention and control clusters of a recent non-randomised controlled trial, and used generalised linear mixed regression models to make an observational comparison of outcomes.

Setting

low-income unsewered areas of Maputo City, Mozambique

Participants

We interviewed 424 participants, 222 from the prior trial’s intervention group, and 202 from the control group.

Interventions

The control group used low-quality pit latrines. The intervention group received high-quality shared toilets, contributing 10-15% of capital cost.

Outcomes

Our primary outcome was the sanitation-related quality of life (SanQoL) index, which applies respondent-derived weights to combine toilet users’ perceptions of sanitation-related disgust, privacy, safety, health, and shame. Secondary outcomes were the WHO-5 mental wellbeing index and a sanitation visual analogue scale.

Results

The intervention group experienced a 1.6 standard deviation gain in SanQoL compared to the control group. This adjusted SanQoL gain was 0.34 (95% CI: 0.29-0.38) on a 0-1 scale with control mean 0.49. Effect sizes were largest for safety and privacy attributes. Intervention respondents also experienced a 0.2 standard deviation gain in mental wellbeing. The adjusted gain was 6.2 (95% CI: 0.3-12.2) on a 0-100 scale with control mean 54.4.

Conclusions

Quality of life outcomes highly valued by toilet users and can be improved by sanitation interventions. Such outcomes should be measured in future sanitation trials, to help identify interventions which most improve people’s lives. Since SanQoL weights are derived from respondent valuation, the measure can also be used in economic evaluation.
The ITPRIPL1- CD3ε axis: a novel immune checkpoint controlling T cells activation
Authors: Deng Shouyan , Wang Yiting , Brosseau Jean-Philippe , Wang Yungang , Xu Jie
Published: March 2022

The immune system is critical to fighting infections and disease. The molecular recognition of harmful entities takes place when antigen-presenting cells (APC) harboring major histocompatibility complex (MHC) molecules bound to peptides derived from harmful antigens (ligand) dock on specific T cell receptor (TCR)-CD3 complex (receptor) at the surface of CD8+ T cells. The discovery of a general immune checkpoint mechanism to avoid the harmful impact of T cell hyperactivation provoked a paradigm shift. The clinical relevance of this mechanism is highlighted by the fact that PD-1 and PD-L1 inhibitors are very effective at boosting immune reactions. Still, immune evasion frequently happens. The observation that some PD-1/PD-L1 negative tumors have a poor immune response opens the door to identifying a novel immune checkpoint mechanism. Here, we discovered that ITPRIPL1, a gene with unknown function, impairs T cell activation. Surprisingly, we found that CD3ε is the direct receptor of ITPRIPL1. This novel immune checkpoint was validated as a drug target using ITPRIPL1 KO mice and monoclonal antibodies. Thus, targeting the ITPRIPL1-CD3e axis, especially in PD-1 - PDL-1 negative patients, is a promising therapeutic strategy to reduce immune evasion.