Circulating pre-treatment T-cell receptor repertoire as a predictive biomarker in advanced or metastatic non-small-cell lung cancer patients treated with pembrolizumab alone or in combination with chemotherapy.

BACKGROUND: The circulating T-cell receptor (TCR) repertoire is a dynamic representation of overall immune responses in an individual. MATERIALS AND METHODS: We prospectively collected baseline blood from patients treated with first-line pembrolizumab monotherapy or in combination with chemotherapy. TCR repertoire metrics were correlated with clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS) and immune-related adverse events (irAEs). We built a logistic regression classifier by fitting all four TCR-ß repertoire metrics to the immune checkpoint inhibitor (ICI) CBR data. In the subsequent receiver operating characteristic (ROC) analysis of the resulting logistic regression model probabilities, the best cut-off value was selected to maximise sensitivity to predict CBR to ICI. RESULTS: We observed an association between reduced number of unique clones and CBR among patients treated with pembrolizumab monotherapy (cohort 1) [risk ratio = 2.86, 95% confidence interval (CI) 1.04-8.73, P = 0.039]. For patients treated with pembrolizumab plus chemotherapy (cohort 2), increased number of unique clones [hazard ratio (HR) = 2.96, 95% CI 1.28-6.88, P = 0.012] and Shannon diversity (HR = 2.73, 95% CI 1.08-6.87, P = 0.033), and reduced evenness (HR = 0.43, 95% CI 0.21-0.90, P = 0.025) and convergence (HR = 0.41, 95% CI 0.19-0.90, P = 0.027) were associated with improved PFS, while only an increased number of unique clones (HR = 4.62, 95% CI 1.52-14.02, P = 0.007) were associated with improved OS. Logistic regression models combining the TCR repertoire metrics improved the prediction of CBR (cohorts 1 and 2) and were strongly associated with PFS (cohort 1, HR = 0.38, 95% CI 0.19-0.78, P = 0.009) and OS (cohort 2, HR = 0.20, 95% CI 0.05-0.76, P < 0.0001). Reduced TCR conversion was associated with increased frequency of irAEs needing systemic steroid treatment. CONCLUSION: Combined pre-treatment circulating TCR metrics might serve as a predictive biomarker for clinical outcomes among patients with advanced non-small-cell lung cancer treated with pembrolizumab alone or in combination with chemotherapy.

Multicentre study of hospitalised patients with sports- and recreational cycling-related traumatic brain injury in Hong Kong.

INTRODUCTION: Cycling is associated with a greater risk of traumatic brain injury (TBI) than other recreational activities. This study aimed to investigate the epidemiology of sports-related TBI in Hong Kong and to examine predictors for recreational cycling-induced intracranial haemorrhage. METHODS: This retrospective multicentre study included patients diagnosed with sports-related TBI in public hospitals in Hong Kong from 2015 to 2019. Computed tomography scans were reviewed by an independent assessor. The primary endpoint was traumatic intracranial haemorrhage. The secondary endpoint was an unfavourable Glasgow Outcome Scale (GOS) score at discharge from hospital. RESULTS: In total, 720 patients were hospitalised with sports-related TBI. The most common sport was cycling (59.2%). The crude incidence of cycling-related TBI was 1.1 per 100 000 population. Cyclists were more likely to exhibit intracranial haemorrhage and an unfavourable GOS score, compared with patients who had TBI because of other sports. Although 47% of cyclists had intracranial haemorrhage, only 15% wore a helmet. In multivariate analysis, significant predictors for intracranial haemorrhage were age ≥60 years, antiplatelet medication, moderate or severe TBI, and skull fracture. Among 426 cyclists, 375 (88%) had mild TBI, and helmet wearing was protective against intracranial haemorrhage, regardless of age, antiplatelet medication intake, and mechanism of injury. Of 426 cyclists, 31 (7.3%) had unfavourable outcomes on discharge from hospital. CONCLUSIONS: The incidence of sports-related TBI is low in Hong Kong. Although cycling-related head injuries carried greater risks of intracranial haemorrhage and unfavourable outcomes compared with other sports, most cyclists experienced good recovery. Helmet wearing among recreational cyclists with mild TBI was protective against intracranial haemorrhage and skull fracture.

Thalamocortical Connections and Executive Function in Pediatric Temporal and Frontal Lobe Epilepsy.

BACKGROUND AND PURPOSE: Largely accepted in the literature is the role the interconnections between the thalamus and cortex play in generalized epilepsy. However, thalamocortical involvement is less understood in focal epilepsy in terms of the effect of seizures on thalamocortical circuitry in the developing brain and subsequent cognitive outcome. We investigated thalamocortical pathway microstructure in pediatric frontal lobe epilepsy and temporal lobe epilepsy and examined the associations between pathway microstructure and measures of executive function. MATERIALS AND METHODS: We examined thalamocortical connections in 24 children with frontal lobe epilepsy, 17 patients with temporal lobe epilepsy, and 25 healthy children using DTI. We investigated several executive function measures in patients and controls, which were distilled into latent executive function components to compare among groups, and the associations between measures of thalamocortical microstructure and executive function. RESULTS: We found no differences in thalamocortical pathway microstructure between the groups, but aspects of executive function (mental flexibility/inhibition/shifting) were impaired in the frontal lobe epilepsy group compared with controls. In patients with frontal lobe epilepsy, younger age at seizure onset and a greater number of antiepileptic drugs were associated with DTI indices indicative of damaged/less developed thalamocortical pathways. In patients with temporal lobe epilepsy, poorer performance on all measures of executive function was associated with DTI indices reflective of damaged/less developed pathways. CONCLUSIONS: Our results give insight into vulnerable neural networks in pediatric focal epilepsy and suggest thalamocortical pathway damage as a potential mechanism of executive function impairment in temporal lobe epilepsy but not frontal lobe epilepsy. Identifying structure-function relations can help inform how we measure functional and cognitive/behavioral outcomes in these populations.

Thyroid surgery as a 23-hour stay procedure.

INTRODUCTION: The main barriers to short stay thyroidectomy are haemorrhage, bilateral recurrent laryngeal nerve palsy causing respiratory compromise and hypocalcaemia. This study assessed the safety and effectiveness of thyroidectomy as a 23-hour stay procedure. METHODS: All patients undergoing total or completion thyroidectomy were prescribed calcium and vitamin D3 supplements following surgery. Retrospective analysis identified patients admitted for longer than 23 hours and any readmissions. RESULTS: A total of 164 patients were admitted for 23-hour stay thyroid surgery over a 25-month period between 2008 and 2010. Four patients (2%) required admission for longer than 23 hours. No patients required emergency intervention for postoperative haemorrhage or airway compromise. Biochemical hypocalcaemia (despite calcium supplements) was detected in one patient when measured at the outpatient clinic two weeks following surgery. Twelve patients (7.3%) attended the accident and emergency department following discharge; four required admission for intravenous antibiotics for wound infection and one for biochemical hypocalcaemia. CONCLUSIONS: This single centre UK experience demonstrates that thyroidectomy can be carried out both safely and effectively as a 23-hour stay procedure. Prophylactic prescription of calcium and vitamin D3 reduces hypocalcaemia, and thereby also prolonged admission and readmission due to hypocalcaemia. Supplements are an acceptable, cost effective method of reducing hypocalcaemia and shortening postoperative length of stay.

Brain symmetry plane detection based on fractal analysis.

In neuroimage analysis, the automatic identification of symmetry plane has various applications. Despite the considerable amount of research, this remains an open problem. Most of the existing work based on image intensity is either sensitive to strong noise or not applicable to different imaging modalities. This paper presents a novel approach for identifying symmetry plane in three-dimensional brain magnetic resonance (MR) images based on the concepts of fractal dimension and lacunarity analysis which characterizes the complexity and homogeneity of an object. Experimental results, evaluation, and comparison with two other state-of-the-art techniques show the accuracy and the robustness of our method.

PTF 11kx: a type Ia supernova with a symbiotic nova progenitor.

There is a consensus that type Ia supernovae (SNe Ia) arise from the thermonuclear explosion of white dwarf stars that accrete matter from a binary companion. However, direct observation of SN Ia progenitors is lacking, and the precise nature of the binary companion remains uncertain. A temporal series of high-resolution optical spectra of the SN Ia PTF 11kx reveals a complex circumstellar environment that provides an unprecedentedly detailed view of the progenitor system. Multiple shells of circumstellar material are detected, and the SN ejecta are seen to interact with circumstellar material starting 59 days after the explosion. These features are best described by a symbiotic nova progenitor, similar to RS Ophiuchi.

Case report. A novel approach to the management of a ruptured Type II endoleak following endovascular repair of an internal iliac artery aneurysm.

Endovascular repair of isolated iliac artery aneurysms is an established safe and effective management option. Type II endoleak is a potential complication, but rarely results in significant morbidity or mortality. We report a case of a patient who presented with a ruptured internal iliac artery aneurysm secondary to a Type II endoleak. To our knowledge this and the following method of managing this have not been previously reported. Established methods of managing endoleaks, such as intravascular transfemoral embolisation and open or laparoscopic ligation, were not possible. Therefore, we resorted to a novel approach to this type of aneurysm and successfully performed a transcutaneous direct puncture and embolisation of the superior gluteal artery.

Hydrogen-poor superluminous stellar explosions.

Supernovae are stellar explosions driven by gravitational or thermonuclear energy that is observed as electromagnetic radiation emitted over weeks or more. In all known supernovae, this radiation comes from internal energy deposited in the outflowing ejecta by one or more of the following processes: radioactive decay of freshly synthesized elements (typically (56)Ni), the explosion shock in the envelope of a supergiant star, and interaction between the debris and slowly moving, hydrogen-rich circumstellar material. Here we report observations of a class of luminous supernovae whose properties cannot be explained by any of these processes. The class includes four new supernovae that we have discovered and two previously unexplained events (SN 2005ap and SCP 06F6) that we can now identify as members of the same class. These supernovae are all about ten times brighter than most type Ia supernova, do not show any trace of hydrogen, emit significant ultraviolet flux for extended periods of time and have late-time decay rates that are inconsistent with radioactivity. Our data require that the observed radiation be emitted by hydrogen-free material distributed over a large radius (∼10(15) centimetres) and expanding at high speeds (>10(4) kilometres per second). These long-lived, ultraviolet-luminous events can be observed out to redshifts z > 4.

An extremely luminous panchromatic outburst from the nucleus of a distant galaxy.

Variable x-ray and γ-ray emission is characteristic of the most extreme physical processes in the universe. We present multiwavelength observations of a unique γ-ray-selected transient detected by the Swift satellite, accompanied by bright emission across the electromagnetic spectrum, and whose properties are unlike any previously observed source. We pinpoint the event to the center of a small, star-forming galaxy at redshift z = 0.3534. Its high-energy emission has lasted much longer than any γ-ray burst, whereas its peak luminosity was ∼100 times higher than bright active galactic nuclei. The association of the outburst with the center of its host galaxy suggests that this phenomenon has its origin in a rare mechanism involving the massive black hole in the nucleus of that galaxy.

BiVisu: software tool for bicluster detection and visualization.

UNLABELLED: BiVisu is an open-source software tool for detecting and visualizing biclusters embedded in a gene expression matrix. Through the use of appropriate coherence relations, BiVisu can detect constant, constant-row, constant-column, additive-related as well as multiplicative-related biclusters. The biclustering results are then visualized under a 2D setting for easy inspection. In particular, parallel coordinate (PC) plots for each bicluster are displayed, from which objective and subjective cluster quality evaluation can be performed. AVAILABILITY: BiVisu has been developed in Matlab and is available at http://www.eie.polyu.edu.hk/~nflaw/Biclustering/.

Pediatricians' views of postpartum depression: a self-administered survey.

OBJECTIVE: To assess pediatricians' knowledge and views about postpartum depression (PPD). METHOD: Self-administered survey of a nationwide random sample of general pediatricians. RESULTS: Of 1200 eligible pediatricians sampled, 389 responded (32%). Half of pediatricians (49%) reported little or no education about PPD. Many respondents (51%) underestimated the overall incidence of PPD. Most pediatricians (80%) estimated the incidence in their practice as less than the published incidence. Few pediatricians felt confident they would recognize PPD (31%). Pediatricians were rarely familiar with available screening tools (7%). Many pediatricians (51%) felt screening was feasible in their practices. In logistic regression analysis, intent to begin screening was independently associated with <6 years in practice, positive view of feasibility and greater awareness of PPD. CONCLUSIONS: Pediatricians sampled have limited awareness of PPD and are unfamiliar with screening tools. Efforts to involve pediatricians in screening should address these knowledge barriers.

A case of cutaneous leukocytoclastic vasculitis associated with gabapentin.

Gabapentin was approved for use in the USA in 1994 as an add-on drug in adults who have partial seizures either alone or with secondary generalised seizures. Its use has been expanded to include treatment for other conditions such as neuropathic pain and paraesthesiae. Gabapentin was prescribed for our patient who had persistent left-sided hemi-paraesthesiae consequential of a previous thalamic infarct. One week after commencement of gabapentin, she developed an adverse reaction in the form of a purpuric rash over bilateral lower limbs. Skin biopsy revealed histological features of cutaneous leukocytoclastic vasculitis. This rash completely resolved with withdrawal of gabapentin and steroidal treatment. This cutaneous adverse reaction to gabapentin has not been reported in the medical literature.

Etiology of leg ulcers, healing and recurrence rates in octo- and nonagenarians.

BACKGROUND: A high proportion of leg ulcers refractory to ambulatory compression therapy have a mixed etiology. This study evaluates this mixed etiology and the healing and recurrence rate in octo- and nonagenarians. METHODS: The study group comprised 101 patients with 119 legs affected by ulcers. Concomitant diseases, ulcer size, healing time and time for the ulcer to recur were documented. RESULTS: Sixty-four ulcers were of venous origin [healing rate (HR): 45.3%, recurrence rate [(RR): 10.3%], 23 ulcers were complicated by 1 additional disease process (HR: 47.8%, RR: 45.5%), 13 ulcers were complicated by 2 or more concomitant diseases (HR: 46.2%, RR: 16.6%) and 19 ulcers (HR: 26.3%, RR: 20%) were of non-venous origin. CONCLUSIONS: This study showed that venous reflux in combination with local or systemic disease in our elderly patient group increases the chance of recurrence. Non-venous ulcers appear to have a reduced healing rate possibly due to the underlying pathology.

Cholinergic stimulation enhances colonic motor activity, transit, and sensation in humans.

The cholinesterase inhibitor neostigmine indirectly stimulates muscarinic M(1)/M(2)/M(3) receptors, thereby reducing colonic distension in acute colonic pseudo-obstruction. We investigated the dose-response profile for the colonic sensorimotor effects of neostigmine and bethanechol, a direct muscarinic M(2)/M(3) agonist in humans. A barostat-manometric assembly recorded phasic pressures, tone, and pressure-volume relationships (compliance) in the descending colon and rectum of 30 healthy subjects who received intravenous neostigmine (0.25, 0.75, or 1.5 mg; n = 15) or subcutaneous bethanechol (2.5, 5, or 10 mg; n = 15). Sensation to luminal distension was also assessed. Thereafter, the effects of neostigmine and bethanechol on colonic transit (geometric center) were compared with those of saline by scintigraphy in 21 subjects. Both drugs increased colonic phasic pressure activity, reduced rectal compliance, and enhanced urgency during rectal distension. Neostigmine also reduced colonic and rectal balloon volumes, reflecting increased tone by an average of 12% and 25% for the highest dose, respectively. Only neostigmine reduced colonic compliance, accelerated colonic transit [mean geometric center at 90 min 2.5 vs. 1.0 (placebo)], and increased pain perception during colonic distension. We conclude that neostigmine has more prominent colonic motor and sensory effects than bethanechol. Moreover, neostigmine induces coordinated colonic propulsion, perhaps by stimulating muscarinic M(1) receptors in the myenteric plexus.

Comparison of coagulation and blood loss during anaesthesia with inhaled isoflurane or intravenous propofol.

Propofol has been reported to affect blood coagulation. This prospective, randomized study compared coagulation and blood loss during anaesthetic maintenance with target-controlled intravenous propofol infusion vs. inhaled isoflurane. Thirty-eight ASA I-III patients undergoing head and neck surgery were allocated randomly to receive either inhaled isoflurane at end-tidal concentration 1-1.5% (group I, n=20) or target-controlled infusion (TCI) of propofol at target concentration 2-5 microg ml(-1) (group P, n=18). Thrombelastography on recalcified whole blood was performed pre-induction, and at 15, 30, 60, 90, 120 min post-induction and 30 min after anaesthesia in both groups. Blood loss was estimated from weighing swabs and the volume in suction bottles. Induced hypotension was not used, and perioperative body temperature was similar between groups. There were no significant differences in thrombelastographic coagulation (R-time, K-time, maximum amplitude and angle) or fibrinolytic variables (lysis index at 30 and 60 min) at all times between groups. Total blood loss was also not significantly different (median group I: 350 ml, range 20-1200 ml; group P: 200 ml, range 50-800 ml). Shortening of R-time and widening of angle developed over time in both groups (P<0.05 groups I and P, repeated measures ANOVA). We conclude that maintenance of anaesthesia with propofol TCI at 2-5 microg ml(-1) does not cause detectable coagulation changes on thrombelastography nor increase surgical blood loss when compared to inhaled isoflurane.

Developing a multimedia model of chemical dynamics in an urban area.

A multimedia model has been developed to account for the movement of semi-volatile organic compounds (SOCs) in an urban environment. The model, based on a Level III fugacity model of D. Mackay (Multimedia Environmental Models: The Fugacity Approach, Lewis Publishers, Boca Raton, FL, 1991), consists of six compartments: air, surface water, sediment, soil, vegetation, and an organic film that coats impervious surfaces. The latter is a newly identified compartment into which gas-phase SOCs partition and particle-phase SOCs are believed to be efficiently captured (M.L. Diamond, S.E. Gingrich, K. Fertuck, B.E. McCarry, G.A. Stern, B. Billeck, B. Grift, D. Brooker, T.D. Yager, Environ. Sci. Technol., 34 (2000a), 2900-2908). The model, parameterized for downtown Toronto, Ontario, Canada, and run with an illustrative emission rate for selected polycyclic aromatic hydrocarbons and homologues of polychlorinated dibenzodioxins, indicates that the film achieves the highest concentrations among media but that soils are the greatest sink for all but the least hydrophobic chemicals. The film "reflects" the more volatile chemicals into air, facilitates removal to surface waters by wash-off, and provides a surface on which photolytic degradation can occur. As such, the film is a transient sink that increases chemical mobility in urban areas by increasing air concentrations and the cycling of these compounds between air and urban surfaces and increasing water concentrations. Vegetation also accumulates SOCs, a portion of which is transferred to soil that reduces chemical mobility.

Vibrational spectroscopy of the oxygen-evolving complex and of manganese model compounds.

A number of molecularly specific models for the oxygen-evolving complex in photosystem II (PSII) and of manganese-substrate water intermediates that may occur in this process have been proposed recently. We summarize this work briefly. Fourier transform infrared techniques have emerged as fruitful tools to study the molecular structures of Y(Z) and the manganese complex. We discuss recent work in which mid-IR (1000-2000 cm(-1)) methods have been used in this effort. The low-frequency IR region (<1000 cm(-1)) has been more difficult to access for technical reasons, but good progress has been made in overcoming these obstacles. We update recent low-frequency work on PSII and then present a detailed summary of relevant manganese model compounds that will be of importance in understanding the emerging biological data.