High-Q Magnetic Levitation and Control of Superconducting Microspheres at Millikelvin Temperatures.

We report the levitation of a superconducting lead-tin sphere with 100 µm diameter (corresponding to a mass of 5.6 µg) in a static magnetic trap formed by two coils in an anti-Helmholtz configuration, with adjustable resonance frequencies up to 240 Hz. The center-of-mass motion of the sphere is monitored magnetically using a dc superconducting quantum interference device as well as optically and exhibits quality factors of up to 2.6×10^{7}. We also demonstrate 3D magnetic feedback control of the motion of the sphere. The setup is housed in a dilution refrigerator operating at 15 mK. By implementing a cryogenic vibration isolation system, we can attenuate environmental vibrations at 200 Hz by approximately 7 orders of magnitude. The combination of low temperature, large mass, and high quality factor provides a promising platform for testing quantum physics in previously unexplored regimes with high mass and long coherence times.

Retrospective study to estimate the prevalence and describe the clinicopathological characteristics, treatments received, and outcomes of HER2-low breast cancer.

BACKGROUND: Approximately 80% of all breast cancers (BCs) are currently categorized as human epidermal growth factor receptor 2 (HER2)-negative [immunohistochemistry (IHC) 0, 1+, or 2+/in situ hybridization (ISH) negative]; approximately 60% of BCs traditionally categorized as HER2-negative express low levels of HER2. HER2-low (IHC 1+ or IHC 2+/ISH-) status became clinically actionable with approval of trastuzumab deruxtecan to treat unresectable/metastatic HER2-low BC. Greater understanding of patients with HER2-low disease is urgently needed. PATIENTS AND METHODS: This global, multicenter, retrospective study (NCT04807595) included tissue samples from patients with confirmed HER2-negative unresectable/metastatic BC [any hormone receptor (HR) status] diagnosed from 2014 to 2017. Pathologists rescored HER2 IHC-stained slides as HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2 IHC 0 after training on low-end expression scoring using Ventana 4B5 and other assays at local laboratories (13 sites; 10 countries) blinded to historical scores. HER2-low prevalence and concordance between historical scores and rescores were assessed. Demographics, clinicopathological characteristics, treatments, and outcomes were examined. RESULTS: In rescored samples from 789 patients with HER2-negative unresectable/metastatic BC, the overall HER2-low prevalence was 67.2% (HR positive, 71.1%; HR negative, 52.8%). Concordance was moderate between historical and rescored HER2 statuses (81.3%; κ = 0.583); positive agreement was numerically higher for HER2-low (87.5%) than HER2 IHC 0 (69.9%). More than 30% of historical IHC 0 cases were rescored as HER2-low overall (all assays) and using Ventana 4B5. There were no notable differences between HER2-low and HER2 IHC 0 in patient characteristics, treatments received, or clinical outcomes. CONCLUSIONS: Approximately two-thirds of patients with historically HER2-negative unresectable/metastatic BC may benefit from HER2-low-directed treatments. Our data suggest that HER2 reassessment in patients with historical IHC 0 scores may be considered to help optimize selection of patients for treatment. Further, accurate identification of patients with HER2-low BC may be achieved with standardized pathologist training.

Distal Brachial Artery Perforator flap: a new chimeric option for complex hand and digits defects.

INTRODUCTION: Reconstruction of fingers pose unique challenges, as a thin and flexible flap is needed in order to guarantee a good functional outcome. For the first time, in this report, we present the DBAp (distal brachial artery perforator) flap, based on the distal perforator closer to the medial epicondyle. The DBAp flap was used to reconstruct complex digit defects as free flap, and to cover an elbow defect while raised as a propeller. METHODS: Four patients underwent finger reconstruction (free flaps): two patients presented an unstable finger scar following previous surgery, whereas the other two patients presented a terminalized finger at the level of the middle phalanx. A further patient presented a post-traumatic loss of substance at the elbow and was reconstructed using a perforator propeller DBAP flap. RESULTS: Loss of tissues included skin and subcutaneous tissue in all patients and in one patient it included a bone component. Flap dimensions ranged from 48 to 18 cm2 (average: 32 cm2). Among complications, patient n.2 flap presented a marginal flap necrosis requiring a small skin graft after necrosis debridement. CONCLUSION: The DBAp flap provides a slim, glabrous and pliable skin tissue with a well-hidden donor site scar and thanks to the anatomic location of the distal perforator can be designed to include a vascularized bone graft from the medial epicondyle. Despite the low number of cases, we believe that this flap should be considered as a dependable and effective source for complex reconstructions of both soft tissue and bone in fingers.

Introduction to the National Cancer Imaging Translational Accelerator (NCITA): a UK-wide infrastructure for multicentre clinical translation of cancer imaging biomarkers.

The National Cancer Imaging Translational Accelerator (NCITA) is creating a UK national coordinated infrastructure for accelerated translation of imaging biomarkers for clinical use. Through the development of standardised protocols, data integration tools and ongoing training programmes, NCITA provides a unique scalable infrastructure for imaging biomarker qualification using multicentre clinical studies.

COVID-19: smoke testing of surgical mask and respirators.

BACKGROUND: Fluid Resistant Surgical Masks have been implemented in UK personal protective equipment (PPE) guidelines for COVID-19 for all care sites that do not include aerosol-generating procedures (AGPs). FFP3 masks are used in AGP areas. Concerns from the ENT and plastic surgery communities out with intensive care units have questioned this policy. Emerging evidence on cough clouds and health care worker deaths has suggested that a review is required. AIMS: To test the efficacy of Fluid Resistant Surgical Mask with and without adaptions for respiratory protection. To test the efficacy of FFP and FFP3 regarding fit testing and usage. METHODS: A smoke chamber test of 5 min to model an 8-h working shift of exposure while wearing UK guideline PPE using an inspiratory breathing mouthpiece under the mask. Photographic data were used for comparison. RESULTS: The Fluid Resistant Surgical Mask gave no protection to inhaled smoke particles. Modifications with tape and three mask layers gave slight benefit but were not considered practical. FFP3 gave complete protection to inhaled smoke but strap tension needs to be 'just right' to prevent facial trauma. Facial barrier creams are an infection risk. CONCLUSIONS: Surgical masks give no protection to respirable particles. Emerging evidence on cough clouds and health care worker deaths suggests the implementation of a precautionary policy of FFP3 for all locations exposed to symptomatic or diagnosed COVID-19 patients. PPE fit testing and usage policy need to improve to include daily buddy checks for FFP3 users.

Anatomically accurate 3D modelling and printing in a case of obstetric brachial plexus injury.

Obstetric brachial plexus injury is reported in 0.42 per 1000 births in UK and Ireland and are associated with a reduction in quality of life for the patient and their carers. In this report we describe the first use of a patient specific, anatomically accurate 3D model as a communication tool in the treatment of a complex case of posterior shoulder subluxation secondary to glenohumeral deformity resulting from obstetric brachial plexus injury. The use of 3D models for surgical planning is associated with decreased operating time and reduction of intra-operative blood loss, whilst their use in patient education increases patient understanding. In this case all surgeons surveyed agreed that it was useful and will use 3D modelling to improve consent processes and to conceptualise novel techniques for complex cases in future. This highly reproducible, low cost technique may be adapted to a variety of upper limb reconstructive surgeries, and as the resolution of image acquisition and additive manufacturing capabilities increase so too do the potential applications of this precise 3D printed surgical adjunct.

Stress and glucocorticoid receptor transcriptional programming in time and space: Implications for the brain-gut axis.

BACKGROUND: Chronic psychological stress is associated with enhanced abdominal pain and altered intestinal barrier function that may result from a perturbation in the hypothalamic-pituitary-adrenal (HPA) axis. The glucocorticoid receptor (GR) exploits diverse mechanisms to activate or suppress congeneric gene expression, with regulatory variation associated with stress-related disorders in psychiatry and gastroenterology. PURPOSE: During acute and chronic stress, corticotropin-releasing hormone drives secretion of adrenocorticotropic hormone from the pituitary, ultimately leading to the release of cortisol (human) and corticosterone (rodent) from the adrenal glands. Cortisol binds with the GR in the cytosol, translocates to the nucleus, and activates the NR3C1 (nuclear receptor subfamily 3, group C, member 1 [GR]) gene. This review focuses on the rapidly developing observations that cortisol is responsible for driving circadian and ultradian bursts of transcriptional activity in the CLOCK (clock circadian regulator) and PER (period circadian clock 1) gene families, and this rhythm is disrupted in major depressive disorder, bipolar disorder, and stress-related gastrointestinal and immune disorders. Glucocorticoid receptor regulates different sets of transcripts in a tissue-specific manner, through pulsatile waves of gene expression that includes occupancy of glucocorticoid response elements located within constitutively open spatial domains in chromatin. Emerging evidence supports a potentially pivotal role for epigenetic regulation of how GR interacts with other chromatin regulators to control the expression of its target genes. Dysregulation of the central and peripheral GR regulome has potentially significant consequences for stress-related disorders affecting the brain-gut axis.

Effects of obesity on health-related quality of life in juvenile-onset systemic lupus erythematosus.

OBJECTIVE: This study evaluated the effects of obesity on health-related quality of life (HRQOL) measures in juvenile-onset systemic lupus erythematosus (jSLE). METHODS: Obesity was defined as a body mass index (BMI) ≥ 95 th percentile according to the Sex-specific Center for Disease Control BMI-For-Age Charts and determined in a multicenter cohort of jSLE patients. In this secondary analysis, the domain and summary scores of the Pediatric Quality of Life (PedsQL) Inventory and the Child Health Questionnaire (CHQ) of obese jSLE patients were compared to those of non-obese jSLE patients as well as historical obese and non-obese healthy controls. Mixed-effects modeling was performed to evaluate the relationship between obesity and HRQOL measures. RESULTS: Among the 202 jSLE patients, 25% (n = 51) were obese. Obesity had a significant negative impact on HRQOL in jSLE, even after adjusting for differences in current corticosteroid use, disease activity, disease damage, gender and race between groups. Obese jSLE patients had lower physical functioning compared to non-obese jSLE patients, and to non-obese and obese healthy controls. Compared to their non-obese counterparts, obese jSLE patients also had worse school functioning, more pain, worse social functioning and emotional functioning. Parents of obese jSLE patients worry more. The CHQ scores for obese jSLE patients were also worse compared to non-obese jSLE patients in several other domains. CONCLUSION: Our study demonstrates the detrimental effects of obesity on patient-reported outcomes in jSLE. This supports the importance of weight management for the therapeutic plan of jSLE.

Risk factors for failure of supraglottoplasty.

OBJECTIVES: To assess for identifiable risk factors for failed surgical intervention in children with laryngomalacia. METHODS: Retrospective case note review between September 2007 and March 2012. Case notes were reviewed for demographic data, symptoms, co-morbidities, operative technique, postoperative recovery, complications, length of hospital stay including intensive care unit (ICU) care, and resolution of symptoms. RESULTS: 148 children underwent supraglottoplasty. Case notes were available for 115 (78%) patients. 35% (41/115) of cases were females and 65% (74/115) were male. A bimodal age distribution was observed with peaks at 3 months and 3.5 years. Those over one year of age were more likely to have complications (p = 0.035). There was no significant difference in outcomes for age (p > 0.05). In patients less than one year, reflux symptoms were significantly associated with a higher likelihood of failure of the operation (p = 0.013). Patients under one year with pre-operatively identified comorbid conditions were less likely to have an improvement in breathing (p = 0.002). Cold steel was used in 55% (63/115) of cases, laser only in 17% (20/115) cases and a combination of the two techniques in 28%, (32/115). There was no association between the surgical technique used and complications (p = 0.558). There was no association between improvement in symptoms and surgical technique used (p = 0.560). There was a significant association between delayed post-operative neurological diagnosis and failure of the operation (p < 0.001). 21 (18%) patients required a second procedure. CONCLUSIONS: Pre-operative predictors of failure were patients with reflux symptoms (p = 0.013). Patients that required a second procedure were 37 times more likely to have a delayed diagnosis of an underlying neurological condition. Failure of symptoms to improve after supraglottoplasty should alert the clinician to the possibility of an underlying neurological disorder.

Mitochondrial dysfunction and mitophagy: the beginning and end to diabetic nephropathy?

Diabetic nephropathy (DN) is a progressive microvascular complication arising from diabetes. Within the kidney, the glomeruli, tubules, vessels and interstitium are disrupted, ultimately impairing renal function and leading to end-stage renal disease (ESRD). Current pharmacological therapies used in individuals with DN do not prevent the inevitable progression to ESRD; therefore, new targets of therapy are urgently required. Studies from animal models indicate that disturbances in mitochondrial homeostasis are central to the pathogenesis of DN. Since renal proximal tubule cells rely on oxidative phosphorylation to provide adequate ATP for tubular reabsorption, an impairment of mitochondrial bioenergetics can result in renal functional decline. Defects at the level of the electron transport chain have long been established in DN, promoting electron leakage and formation of superoxide radicals, mediating microinflammation and contributing to the renal lesion. More recent studies suggest that mitochondrial-associated proteins may be directly involved in the pathogenesis of tubulointerstitial fibrosis and glomerulosclerosis. An accumulation of fragmented mitochondria are found in the renal cortex in both humans and animals with DN, suggesting that in tandem with a shift in dynamics, mitochondrial clearance mechanisms may be impaired. The process of mitophagy is the selective targeting of damaged or dysfunctional mitochondria to autophagosomes for degradation through the autophagy pathway. The current review explores the concept that an impairment in the mitophagy system leads to the accelerated progression of renal pathology. A better understanding of the cellular and molecular events that govern mitophagy and dynamics in DN may lead to improved therapeutic strategies.

BK virus encoded microRNAs are present in blood of renal transplant recipients with BK viral nephropathy.

BK viral infection is an important cause of renal transplant dysfunction and failure. Current strategies utilize surveillance for infection with DNA polymerase chain reaction assays and modulation of immunosuppression. Many viruses including polyomaviruses encode microRNAs (miRNAs). We have detected BK virus (BKV) encoded miRNAs in the blood of infected renal transplant recipients, and see a strong correlation between BKV encoded miRNA and BKV DNA in blood and a relationship between levels of bkv-miR-B1-5p and the presence of biopsy-proven BK viral nephropathy. Further research is needed to determine whether the detection of this and other virally encoded miRNAs may be useful in the diagnosis of active viral replication.

A back translation of pregabalin and carbamazepine against evoked and non-evoked endpoints in the rat spared nerve injury model of neuropathic pain.

The purpose of the present study was twofold. First to characterize endpoints distinct to the reflexive responses to sensory stimuli typically used in neuropathic pain models. A second aim was to evaluate two clinically approved drugs carbamazepine (Tegretol) and pregabalin (Lyrica) against these endpoints with the purpose to backtranslate from the clinical to preclinical setting. The selected neuropathic pain model was the spared nerve injury (SNI) model and the endpoints were burrowing and measures of paw posture in Sprague Dawley rats. As previously described, SNI surgery produced a robust heightened sensitivity to tactile and thermal (cold) stimuli. SNI surgery also produced robust decreases in burrowing and affected multiple measures of paw position. There was no correlation between magnitude of change in burrowing and sensory allodynia within SNI operated rats. Pregabalin (10-30 mg/kg IP) produced a reliable reversal of both tactile and cold allodynia and also the burrowing deficit, with minimal effect on neurological function evaluated using rotorod, beam walking and open field activity. Pregabalin did not affect any measure of paw position. Pharmacokinetic studies conducted in satellite animals identified plasma levels of pregabalin at the 10 mg/kg IP dose to be equivalent to clinically efficacious levels recorded in neuropathic patients (3-6 µg/ml). In contrast carbamazepine (10-60 mg/kg IP) had only a very modest effect against a reflexive (tactile) measure, and no effect against the burrowing deficit. Carbamazepine also affected various measures of neurological function, complicating interpretation of the reflexive measure. Measurement of burrowing appears to detect a behavioural deficit associated with the SNI model, that may be attenuated by pregabalin but not carbamazepine. Overall the present findings support an advantage of pregabalin over carbamazepine in terms of both efficacy and tolerability which is consistent with clinical experience. The inclusion of additional endpoints beyond traditional reflexive behaviours further supports the value of rodent neuropathic pain models, such as the SNI, as behavioural assays to detect new chemical entities to treat this pain condition.

The effects of lossy compression on diagnostically relevant seizure information in EEG signals.

This paper examines the effects of compression on EEG signals, in the context of automated detection of epileptic seizures. Specifically, it examines the use of lossy compression on EEG signals in order to reduce the amount of data which has to be transmitted or stored, while having as little impact as possible on the information in the signal relevant to diagnosing epileptic seizures. Two popular compression methods, JPEG2000 and SPIHT, were used. A range of compression levels was selected for both algorithms in order to compress the signals with varying degrees of loss. This compression was applied to the database of epileptiform data provided by the University of Freiburg, Germany. The real-time EEG analysis for event detection automated seizure detection system was used in place of a trained clinician for scoring the reconstructed data. Results demonstrate that compression by a factor of up to 120:1 can be achieved, with minimal loss in seizure detection performance as measured by the area under the receiver operating characteristic curve of the seizure detection system.

P. aeruginosa LPS stimulates calcium signaling and chloride secretion via CFTR in human bronchial epithelial cells.

BACKGROUND: Pseudomonas aeruginosa airway infection is associated with a high mortality rate in cystic fibrosis. Lipopolysaccharide (LPS), a main constituent of the outer membrane of P. aeruginosa, is responsible for activation of innate immune response but its role on airway epithelium ion transport, is not well known. The aim of this study was to determine the role for P. aeruginosa LPS in modulating chloride secretion and intracellular calcium in the human bronchial epithelial cell line, 16HBE14o-. METHODS: We used intracellular calcium imaging and short-circuit current measurement upon exposure of cells to P. aeruginosa LPS. RESULTS: Apical LPS stimulated intracellular calcium release and calcium entry and enhanced chloride secretion. This latter effect was significantly inhibited by CFTR(inh)-172 and BAPTA-AM (intracellular Ca(2+) chelator). CONCLUSIONS: Our data provides evidence for a new role of P. aeruginosa LPS in stimulating calcium entry and release and a subsequent chloride secretion via CFTR in human bronchial epithelium.

Evaluation of chemically diverse 5-HT2c receptor agonists on behaviours motivated by food and nicotine and on side effect profiles.

RATIONALE: Selective 5-HT2C receptor agonists, such as lorcaserin, are being developed for the treatment of obesity. Studies suggest that they may also have therapeutic potential for addictive behaviours including nicotine dependence, although few drugs of this class have been evaluated. OBJECTIVES: The primary aim was to evaluate the highly selective 5-HT2C agonist, CP-809101, against food-motivated (operant FR5 and progressive ratio schedules, palatability-induced feeding) and nicotine-motivated (intravenous self-administration, drug discrimination) behaviours in rats and to compare with equivalent findings for the structurally distinct 5-HT2C receptor agonists lorcaserin and Ro 60-0175. The secondary aims were to evaluate the side effect profiles of lorcaserin and CP-809101 and to determine the plasma levels of lorcaserin at a dose (1 mg/kg) that reduces both food and nicotine reinforcement for comparison to plasma concentrations reported in human trials. RESULTS: CP-809101 (0.3-3 mg/kg SC) reduced responding for both nicotine and food and blocked the discriminative stimulus properties of nicotine in a similar manner to lorcaserin and Ro 60-0175. Behaviours such as hypolocomotion, chewing and ptosis became evident following both CP-809101 and lorcaserin administration at higher doses. Plasma levels of lorcaserin were of similar range to those reported in obesity trials. CONCLUSIONS: These studies support the utility of 5-HT2C agonists as a therapeutic approach to treat nicotine dependence. Plasma exposure levels after acute lorcaserin treatment suggest that equivalent dosages could be used to evaluate these drugs in obesity and smoking cessation trials. Finally, there may be differences in the side effect profiles between lorcaserin and CP-809101, raising the possibility for tolerability differences amongst 5-HT2C agonists.