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BackgroundMaintaining men on active surveillance for prostate cancer can be challenging. Although most men who eventually undergo treatment have experienced clinical progression, a smaller subset elects treatment in the absence of disease reclassification. This study sought to understand factors associated with treatment in a large, contemporary, prospective cohort.MethodsThis study identified 1789 men in the Canary Prostate Cancer Active Surveillance Study cohort enrolled as of 2020 with a median follow-up of 5.6 years. Clinical and demographic data as well as information on patient-reported quality of life and urinary symptoms were used in multivariable Cox proportional hazards regression models to identify factors associated with the time to treatment RESULTS: Within 4 years of their diagnosis, 33% of men (95% confidence interval [CI], 30%-35%) underwent treatment, and 10% (95% CI, 9%-12%) were treated in the absence of reclassification. The most significant factor associated with any treatment was an increasing Gleason grade group (adjusted hazard ratio [aHR], 14.5; 95% CI, 11.7-17.9). Urinary quality-of-life scores were associated with treatment without reclassification (aHR comparing "mostly dissatisfied/terrible" with "pleased/mixed," 2.65; 95% CI, 1.54-4.59). In a subset analysis (n = 692), married men, compared with single men, were more likely to undergo treatment in the absence of reclassification (aHR, 2.63; 95% CI, 1.04-6.66).ConclusionsA substantial number of men with prostate cancer undergo treatment in the absence of clinical changes in their cancers, and quality-of-life changes and marital status may be important factors in these decisions.Lay summaryThis analysis of men on active surveillance for prostate cancer shows that approximately 1 in 10 men will decide to be treated within 4 years of their diagnosis even if their cancer is stable. These choices may be related in part to quality-or-life or spousal concerns.

Background: Selective serotonin reuptake inhibitors (SSRIs) are used for the treatment of several conditions including anxiety disorders, but the basic neurobiology of serotonin function remains unclear. The amygdala and prefrontal cortex are strongly innervated by serotonergic projections and have been suggested to play an important role in anxiety expression. However, serotonergic function in behaviour and SSRI-mediated neurobiological changes remain incompletely understood. Aims: To investigate the neural correlates of subchronic antidepressant administration. Methods: We investigated whether the 2- to 3-week administration of a highly selective SSRI (escitalopram) would alter brain activation on a task robustly shown to recruit the bilateral amygdala and frontal cortices in a large healthy volunteer sample. Participants performed the task during a functional magnetic resonance imaging acquisition before (n = 96) and after subchronic escitalopram (n = 46, days of administration mean (SD) = 15.7 (2.70)) or placebo (n = 40 days of administration mean (SD) = 16.2 (2.90)) self-administration. Results: Compared to placebo, we found an elevation in right amygdala activation to the task after escitalopram administration without significant changes in mood. This effect was not seen in the left amygdala, the dorsomedial region of interest, the subgenual anterior cingulate cortex or the right fusiform area. There were no significant changes in connectivity between the dorsomedial cortex and amygdala or the subgenual anterior cingulate cortex after escitalopram administration. Conclusions: To date, this most highly powered study of subchronic SSRI administration indicates that, contrary to effects often seen in patients with anxiety disorders, subchronic SSRI treatment may increase amygdala activation in healthy controls. This finding highlights important gaps in our understanding of the functional role of serotonin. [ABSTRACT FROM AUTHOR]

Anxiety alters how we perceive the world and can alter aspects of cognitive performance. Prominent theories of anxiety suggest that the effect of anxiety on cognition is due to anxious thoughts "overloading" limited cognitive resources, competing with other processes. If this is so, then a cognitive load manipulation should impact performance of a task in the same way as induced anxiety. Thus, we examined the impact of a load manipulation on a time perception task that we have previously shown to be reliably impacted by anxiety. In contrast with our prediction, across 3 studies we found that time perception was insensitive to our load manipulation. Our results do not therefore support the idea that anxiety impacts temporal cognition by overloading limited cognitive resources, at least as induced by a commonly used load manipulation. Thus, anxiety might affect temporal cognition in a unique way, via an evolutionary-preserved defense survival system, as suggested by animal-inspired theories of anxiety, rather than competing for limited attentional resources.

This article explores the neuroanatomical subtyping of phobias and its implications for understanding anxiety disorders. It emphasizes the challenges in finding reliable biomarkers for anxiety and the need for larger studies to validate neuroscientific models. The article summarizes a study that examined brain structure differences in animal phobia and blood-injury-injection phobia, finding reductions in subcortical volumes and increases in gray matter thickness and surface area in individuals with phobias. The findings suggest that identifying brain-based measures of pathology in anxiety research is possible. The article also discusses the relationship between brain structure and function, the potential role of developmental trajectories, and the importance of considering functional activation specificity in future studies. [Extracted from the article]

T-cell-engaging bispecifics have great clinical potential for the treatment of cancer and infectious diseases. The binding affinity and kinetics of a bispecific molecule for both target and T-cell CD3 have substantial effects on potency and specificity, but the rules governing these relationships are not fully understood. Using immune mobilizing monoclonal TCRs against cancer (ImmTAC) molecules as a model, we explored the impact of altering affinity for target and CD3 on the potency and specificity of the redirected T-cell response. This class of bispecifics binds specific target peptides presented by human leukocyte antigen on the cell surface via an affinity-enhanced T-cell receptor and can redirect T-cell activation with an anti-CD3 effector moiety. The data reveal that combining a strong affinity TCR with an intermediate affinity anti-CD3 results in optimal T-cell activation, while strong affinity of both targeting and effector domains significantly reduces maximum cytokine release. Moreover, by optimizing the affinity of both parts of the molecule, it is possible to improve the selectivity. These results could be effectively modelled based on kinetic proofreading with limited signalling. This model explained the experimental observation that strong binding at both ends of the molecules leads to reduced activity, through very stable target-bispecific-effector complexes leading to CD3 entering a non-signalling dark state. These findings have important implications for the design of anti-CD3-based bispecifics with optimal biophysical parameters for both activity and specificity. These studies demonstrate how to optimize the fundamental process of T-cell activation, both in terms of affinity and binding kinetics to target cell and T-cell epitopes. Current theories of T-cell biology are used to build a mathematical model that explains most features of the data. How the kinetics of target and cluster of differentiation 3 binding regulate T-cell activation in the context of the clinically validated immune mobilizing monoclonal TCRs against cancer platform, which directly targets peptide-human leukocyte antigen complexes. [ABSTRACT FROM AUTHOR]

Purpose: While the presence of residual disease at the time of radical cystectomy for bladder cancer is an established prognostic indicator, controversy remains regarding the importance of maximal transurethral resection prior to neoadjuvant chemotherapy. We characterized the influence of maximal transurethral resection on pathological and survival outcomes using a large, multi-institutional cohort. Materials and Methods: We identified 785 patients from a multi-institutional cohort undergoing radical cystectomy for muscle-invasive bladder cancer after neoadjuvant chemotherapy. We employed bivariate comparisons and stratified multivariable models to quantify the effect of maximal transurethral resection on pathological findings at cystectomy and survival. Results: Of 785 patients, 579 (74%) underwent maximal transurethral resection. Incomplete transurethral resection was more frequent in patients with more advanced clinical tumor (cT) and nodal (cN) stage (P < .001 and P < .01, respectively), with more advanced ypT stage at cystectomy and higher rates of positive surgical margins (P < .01 and P < .05, respectively). In multivariable models, maximal transurethral resection was associated with downstaging at cystectomy (adjusted odds ratio 1.6, 95% CI 1.1-2.5). In Cox proportional hazards analysis, maximal transurethral resection was not associated with overall survival (adjusted HR 0.8, 95% CI 0.6-1.1). Conclusions: In patients undergoing transurethral resection for muscle-invasive bladder cancer prior to neoadjuvant chemotherapy, maximal resection may improve pathological response at cystectomy. However, the ultimate effects on long-term survival and oncologic outcomes warrant further investigation. [ABSTRACT FROM AUTHOR]

A well‐documented amygdala‐dorsomedial prefrontal circuit is theorized to promote attention to threat ("threat vigilance"). Prior research has implicated a relationship between individual differences in trait anxiety/vigilance, engagement of this circuitry, and anxiogenic features of the environment (e.g., through threat‐of‐shock and movie‐watching). In the present study, we predicted that—for those scoring high in self‐reported anxiety and a behavioral measure of threat vigilance—this circuitry is chronically engaged, even in the absence of anxiogenic stimuli. Our analyses of resting‐state fMRI data (N = 639) did not, however, provide evidence for such a relationship. Nevertheless, in our planned exploratory analyses, we saw a relationship between threat vigilance behavior (but not self‐reported anxiety) and intrinsic amygdala‐periaqueductal gray connectivity. Here, we suggest this subcortical circuitry may be chronically engaged in hypervigilant individuals, but that amygdala‐prefrontal circuitry may only be engaged in response to anxiogenic stimuli. [ABSTRACT FROM AUTHOR]

Heart rate and heart rate variability have enabled insight into a myriad of psychophysiological phenomena. There is now an influx of research attempting using these metrics within both laboratory settings (typically derived through electrocardiography or pulse oximetry) and ecologically-rich contexts (via wearable photoplethysmography, i.e., smartwatches). However, these signals can be prone to artifacts and a low signal to noise ratio, which traditionally are detected and removed through visual inspection. Here, we developed an open-source Python package, RapidHRV, dedicated to the preprocessing, analysis, and visualization of heart rate and heart rate variability. Each of these modules can be executed with one line of code and includes automated cleaning. In simulated data, RapidHRV demonstrated excellent recovery of heart rate across most levels of noise (>=10 dB) and moderate-to-excellent recovery of heart rate variability even at relatively low signal to noise ratios (>=20 dB) and sampling rates (>=20 Hz). Validation in real datasets shows good-to-excellent recovery of heart rate and heart rate variability in electrocardiography and finger photoplethysmography recordings. Validation in wrist photoplethysmography demonstrated RapidHRV estimations were sensitive to heart rate and its variability under low motion conditions, but estimates were less stable under higher movement settings. [ABSTRACT FROM AUTHOR]

Recent operational experience suggests that supercell thunderstorms occur somewhere in the UK on a handful of days each year, although, as in the US, only some of these storms produce a tornado. These may be compared with suggested threshold minimum values of 18-20ms SP -1 sp (35-40kn) 0-6km AGL bulk wind difference for supercell thunderstorms (e.g. Markowski and Richardson, 2010), and 100-150m SP 2 sp s SP -2 sp storm-relative helicity for supercell tornadoes (e.g. Davies-Jones I et al i ., 1990; Taszarek I et al i ., 2017). The Tornado and Storm Research Organisation (TORRO[1]) was founded in 1974 to investigate recent and historical reports of tornadoes and other phenomena associated with severe local storms, especially in the UK and Ireland (Elsom I et al i ., 2001). On 21 December 2019, a tornado hit several towns and villages in Surrey, UK. [Extracted from the article]

It is well accepted that emotional intensity scales with stimulus strength. Here, we used physiological and neuroimaging techniques to ask whether human body odor—which can convey salient social information—also induces dose-dependent effects on behavior, physiology, and neural responses. To test this, we first collected sweat from 36 males classified as low-, medium-, and high-fear responders. Next, in a double-blind within-subjects functional-MRI design, 31 women were exposed to three doses of fear-associated human chemosignals and neutral sweat while viewing face morphs varying between expressions of fear and disgust. Behaviorally, we found that all doses of fear-sweat volatiles biased participants toward perceiving fear in ambiguous morphs, a dose-invariant effect generally repeated across physiological and neural measures. Bayesian dose-response analysis indicated moderate evidence for the null hypothesis (except for the left amygdala), tentatively suggesting that the human olfactory system engages an all-or-none mechanism for tagging fear above a minimal threshold. [ABSTRACT FROM AUTHOR]

Setting external reminders provides a convenient way to reduce cognitive demand and ensure accurate retrieval of information for prospective tasks. Recent experimental evidence has demonstrated that the decision to offload cognitive information to external resources is guided by metacognitive belief, that is, individuals' confidence in their unaided ability. Other work has also suggested a relationship between metacognitive belief and trait anxiety. In the present study (N = 300), we bridged these two areas by investigating whether trait anxiety correlated with metacognitive belief and—consequently—propensity to offload information in a delayed intentions paradigm. Participants received a financial reward based on their ability to remember targets. However, participants could take a reduced reward per target if they decided to use reminders. We replicated previous findings that participants were biased to use more reminders than would be optimal, and this bias was correlated with metacognitive judgements. However, we show no evidence that trait anxiety held a relationship with metacognitive belief or reminder usage. Indeed, Bayesian analyses strongly favoured the null. Therefore, variation in self-reported trait anxiety does not necessarily influence confidence and strategy when participants remember delayed intentions. [ABSTRACT FROM AUTHOR]

Objective: To examine predictors of early readmissions after radical cystectomy (RC). Factors associated with preventable readmissions may be most evident in readmissions that occur within 3 days of discharge, commonly termed 'bounce‐back' readmissions, and identifying such factors may inform efforts to reduce surgical readmissions. Patients and Methods: We utilised the Healthcare Cost and Utilization Project's State Inpatient Databases to examine 1867 patients undergoing RC in 2009 and 2010, and identified all patients readmitted within 30 days of discharge. We assessed differences between patients experiencing bounce‐back readmission compared to those readmitted 8–30 days after discharge using logistic regression models and also calculated abbreviated LACE scores to assess the utility of common readmissions risk stratification algorithms. Results: The 30‐day and bounce‐back readmission rates were 28.4% and 5.6%, respectively. Although no patient or index hospitalisation characteristics were significantly associated with bounce‐back readmissions in adjusted analyses, bounce‐back patients did have higher rates of gastrointestinal (14.3% vs 6.7%, P = 0.02) and wound (9.5% vs 3.0%, P < 0.01) diagnoses, as well as increased index and readmission length of stay (5 vs 4 days, P = 0.01). Overall, the median abbreviated LACE score was 7, which fell into the moderate readmission risk category, and no difference was observed between readmitted and non‐readmitted patients. Conclusion: One in five readmissions after RC occurs within 3 days of initial discharge, probably due to factors present at discharge. However, sociodemographic and clinical factors, as well as traditional readmission risk tools were not predictive of this bounce‐back. Effective strategies to reduce bounce‐back readmission must identify actionable clinical factors prior to discharge. [ABSTRACT FROM AUTHOR]

Objectives: To characterise bone scan use, and potential overuse, after radical prostatectomy (RP) using data from a large, national integrated delivery system. Overuse of imaging is well documented in the setting of newly diagnosed prostate cancer, but whether overuse persists after RP remains unknown. Patients and methods: We identified 12 269 patients with prostate cancer treated with RP between 2005 and 2008 using the Veterans Administration Central Cancer Registry. We used administrative and laboratory data to examine rates of bone scan use, including preceding prostate‐specific antigen (PSA) levels, and receipt of adjuvant or salvage therapy. We then performed multivariable logistic regression to identify factors associated with post‐RP bone scan use. Results: At a median follow‐up of 6.8 years, one in five men (22%) underwent a post‐RP bone scan at a median PSA level of 0.2 ng/mL. Half of bone scans (48%) were obtained in men who did not receive further treatment with androgen‐deprivation or radiation therapy. After adjustment, post‐RP bone scan was associated with a prior bone scan (adjusted odds ratio [aOR] 1.55, 95% confidence interval [CI] 1.32–1.84), positive surgical margin (aOR 1.68, 95% CI 1.40–2.01), preoperative PSA level (aOR 1.02, 95% CI 1.01–1.03), as well as Hispanic ethnicity, Black race, and increasing D'Amico risk category, but not with age or comorbidity. Conclusion: We found a substantial rate of bone scan utilisation after RP. The majority were performed for PSA levels of <1 ng/mL where the likelihood of a positive test is low. More judicious use of imaging appears warranted in the post‐RP setting. [ABSTRACT FROM AUTHOR]

The data submitted by our VCN users include some high-profile weather events, such as the highest UK maximum temperature on record of 38.7°C at Cambridge, Botanic Garden on 25 July 2019 (as shown in Figure 2). Nowcasting WOW is also being used to combine crowdsourced data with observations from the Met Office's official network of automatic surface stations, the Meteorological Monitoring System (MMS). WOW is therefore able to provide a more detailed picture of the current weather situation than is possible when using data from the MMS network alone. [Extracted from the article]

Aims: The use of cystoscopy and hydrodistention in the management of interstitial cystitis/bladder pain syndrome (IC/BPS) varies widely between providers. Current evidence regarding the risks and benefits of hydrodistention, as well as the long term effects of repeated hydrodistention are not well established. We sought to characterize the effects of hydrodistention on IC/BPS symptoms as well as bladder capacity. Methods: We retrospectively queried our institutional records for patients with non‐ulcerative IC/BPS who underwent hydrodistention over an 11‐year period to obtain demographic and clinical factors at the time of diagnosis and treatment. Symptom relief and bladder capacity changes were assessed, and multivariable models were used to predict response to treatment. Results: There were 328 patients who underwent hydrodistention during the study period, of whom 36% received the procedure multiple times, and overall median follow‐up was 38.6 months. Patients with repeated hydrodistentions were more likely to be female, have more comorbid pain disorders, and have trialed anticholinergic medications and intravesical instillations. No decrease in mean bladder capacity was observed over time (P = 0.40). Significant decreases in symptom scores were observed following the procedure on multiple questionnaires. Conclusions: Hydrodistention does not decrease bladder capacity even with multiple procedures, and measurably improves symptoms in some patients with IC/BPS. Continuing efforts to better identify those patients most likely to benefit from this procedure are justified. [ABSTRACT FROM AUTHOR]

ABSTRACT: On 1 July 2015, severe hailstorms developed over northern England. One storm tracked across an area with a dense network of privately owned (i.e. ‘home’) automatic weather stations (AWSs), permitting analysis of surface wind, pressure and temperature fields on the storm scale. The home AWS data were filtered and corrected by comparison with data from the nearest United Kingdom Met Office AWS, where measurements are made with calibrated sensors having known error characteristics. A time‐compositing technique was applied to the corrected home AWS data, before interpolation onto a 1 km grid using Delaunay triangulation. The resulting analyses were compared with radar data to assess their quality and provide insights into storm evolution and structure. Surface analyses resolved a pressure anomaly couplet on the right, rear flank of the storm, gust fronts, and regions of inflow and outflow. The pressure couplet was closely collocated with the radar‐observed mid‐level updraught position, with the mesolow (mesohigh) situated underneath the downshear (upshear) flank. The mesolow was also collocated with the strongest inflow winds. Structural features in the surface analyses (e.g. forward‐ and rear‐flank gust fronts and a prominent inflow notch) compared well with radar‐observed structures, and conformed closely to established conceptual models of supercell storm morphology. Further insight into storm structure was gained by synthesis of the surface analyses, Doppler radar data, crowd‐sourced hail reports and eyewitness photographs. Collectively, the results demonstrate that the gridded home AWS data may be of sufficient quality for use in post‐event studies of severe thunderstorms and, potentially, in the operational forecasting environment. [ABSTRACT FROM AUTHOR]

Objectives To assess bone‐density testing (BDT) use amongst prostate cancer survivors receiving androgen‐deprivation therapy (ADT), and downstream implications for osteoporosis and fracture diagnoses, as well as pharmacological osteoporosis treatment in a national integrated delivery system. Patients and methods We identified 17 017 men with prostate cancer who received any ADT between 2005 and 2014 using the Veterans Health Administration cancer registry and administrative data. We identified claims for BDT within a 3‐year period of ADT initiation. We then used multivariable regression to examine the association between BDT use and incident osteoporosis, fracture, and use of pharmacological treatment. Results We found that a minority of patients received BDT (n = 2 502, 15%); however, the rate of testing increased to >20% by the end of the study period. Men receiving BDT were older at diagnosis and had higher‐risk prostate cancer (both P < 0.001). Osteoporosis and fracture diagnoses, use of vitamin D ± calcium, and bisphosphonates were all more common in men who received BDT. After adjustment, BDT, and to a lesser degree ≥2 years of ADT, were both independently associated with incident osteoporosis, fracture, and osteoporosis treatment. Conclusions BDT is rare amongst patients with prostate cancer treated with ADT in this integrated delivery system. However, BDT was associated with substantially increased treatment of osteoporosis indicating an underappreciated burden of osteoporosis amongst prostate cancer survivors initiating ADT. Optimising BDT use and osteoporosis management in this at‐risk population appears warranted. [ABSTRACT FROM AUTHOR]