Standardized prostate cancer incidence and mortality rates following initial non-malignant biopsy result.

OBJECTIVES: To compare the incidence of subsequent prostate cancer diagnosis and death following an initial non-malignant systematic transrectal ultrasonography (TRUS) biopsy with that in an age- and calendar-year matched population over a 20-year period. SUBJECTS AND METHODS: This population-based analysis compared a cohort of all men with initial non-malignant TRUS biopsy in Denmark between 1995 and 2016 (N = 37 231) with the Danish population matched by age and calendar year, obtained from the NORDCAN 9.1 database. Age- and calendar year-corrected standardized prostate cancer incidence (SIR) and prostate cancer-specific mortality ratios (SMRs) were calculated and heterogeneity among age groups was assessed with the Cochran's Q test. RESULTS: The median time to censoring was 11 years, and 4434 men were followed for more than 15 years. The corrected SIR was 5.2 (95% confidence interval [CI] 5.1-5.4) and the corrected SMR was 0.74 (95% CI 0.67-0.81). Estimates differed among age groups (P < 0.001 for both), with a higher SIR and SMR among younger men. CONCLUSION: Men with non-malignant TRUS biopsy have a much higher incidence of prostate cancer but a risk of prostate cancer death below the population average. This underlines that the oncological risk of cancers missed in the initial TRUS biopsy is low. Accordingly, attempts to increase the sensitivity of initial biopsy are unjustified. Moreover, current follow-up after non-malignant biopsy is likely to be overaggressive, particularly in men over the age of 60 years.

Playing With Fear: A Field Study in Recreational Horror.

Haunted attractions are illustrative examples of recreational fear in which people voluntarily seek out frightening experiences in pursuit of enjoyment. We present findings from a field study at a haunted-house attraction where visitors between the ages of 12 and 57 years (N = 110) were equipped with heart rate monitors, video-recorded at peak scare points during the attraction, and asked to report on their experience. Our results show that enjoyment has an inverted-U-shaped relationship with fear across repeated self-reported measures. Moreover, results from physiological data demonstrate that the experience of being frightened is a linear function of large-scale heart rate fluctuations, whereas there is an inverted-U-shaped relationship between participant enjoyment and small-scale heart rate fluctuations. These results suggest that enjoyment is related to forms of arousal dynamics that are "just right." These findings shed light on how fear and enjoyment can coexist in recreational horror.

Play in Cognitive Development: From Rational Constructivism to Predictive Processing.

It is widely believed that play and curiosity are key ingredients as children develop models of the world. There is also an emerging consensus that children are Bayesian learners who combine their structured prior beliefs with estimations of the likelihood of new evidence to infer the most probable model of the world. An influential school of thought within developmental psychology, rational constructivism, combines these two ideas to propose that children learn intuitive theories of how the world works in part by engaging in play activities that allow them to gather new information for testing their theories. There are still, however, at least two pieces missing from rational constructivist theories of development. First, rational constructivism has so far devoted little attention to explaining why children's preferred form of learning, play, feels so fun, enjoyable, and rewarding. Rational constructivism may suggest that children are curious and like to play because reducing uncertainty and learning better theories of the causal workings of the world is enjoyable. What remains unclear, however, is why reducing uncertainty in play is interesting, fun, and joyful, while doing so in other forms of learning can be frustrating or boring. Second, rational constructivism may have overlooked how children, during play, will take control of and manipulate their environment, sometimes in an effort to create ideal niches for surprise-extraction, sometimes for developing strategies for making the world fit with their predictions. These missing elements from rational constructivism can be provided by understanding the contribution of play to development in terms of predictive processing, an influential framework in cognitive neuroscience that models many of the brain's cognitive functions as processes of model-based, probabilistic prediction.

Play in predictive minds: A cognitive theory of play.

In this article, we argue that a predictive processing framework (PP) may provide elements for a proximate model of play in children and adults. We propose that play is a behavior in which the agent, in contexts of freedom from the demands of certain competing cognitive systems, deliberately seeks out or creates surprising situations that gravitate toward sweet-spots of relative complexity with the goal of resolving surprise. We further propose that play is experientially associated with a feel-good quality because the agent is reducing significant levels of prediction error (i.e., surprise) faster than expected. We argue that this framework can unify a range of well-established findings in play and developmental research that highlights the role of play in learning, and that casts children as Bayesian learners. The theory integrates the role of positive valence in play (i.e., explaining why play is fun); and what it is to be in a playful mood. Central to the account is the idea that playful agents may create and establish an environment tailored to the generation and further resolution of surprise and uncertainty. Play emerges here as a variety of niche construction where the organism modulates its physical and social environment in order to maximize the productive potential of surprise. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Mastering uncertainty: A predictive processing account of enjoying uncertain success in video game play.

Why do we seek out and enjoy uncertain success in playing games? Game designers and researchers suggest that games whose challenges match player skills afford engaging experiences of achievement, competence, or effectance-of doing well. Yet, current models struggle to explain why such balanced challenges best afford these experiences and do not straightforwardly account for the appeal of high- and low-challenge game genres like Idle and Soulslike games. In this article, we show that Predictive Processing (PP) provides a coherent formal cognitive framework which can explain the fun in tackling game challenges with uncertain success as the dynamic process of reducing uncertainty surprisingly efficiently. In gameplay as elsewhere, people enjoy doing better than expected, which can track learning progress. In different forms, balanced, Idle, and Soulslike games alike afford regular accelerations of uncertainty reduction. We argue that this model also aligns with a popular practitioner model, Raph Koster's Theory of Fun for Game Design, and can unify currently differentially modelled gameplay motives around competence and curiosity.

Hunter-Gatherer Children's Object Play and Tool Use: An Ethnohistorical Analysis.

Learning to use, make, and modify tools is key to our species' success. Researchers have hypothesized that play with objects may have a foundational role in the ontogeny of tool use and, over evolutionary timescales, in cumulative technological innovation. Yet, there are few systematic studies investigating children's interactions with objects outside the post-industrialized West. Here, we survey the ethnohistorical record to uncover cross-cultural trends regarding hunter-gatherer children's use of objects during play and instrumental activities. Our dataset, consisting of 434 observations of children's toys and tools from 54 hunter-gatherer societies, reveals several salient trends: Most objects in our dataset are used in play. Children readily manufacture their own toys, such as dolls and shelters. Most of the objects that children interact with are constructed from multiple materials. Most of the objects in our dataset are full-sized or miniature versions of adult tools, reflecting learning for adult roles. Children also engage with objects related to child culture, primarily during play. Taken together, our findings show that hunter-gatherer children grow up playing, making, and learning with objects.

Diagnostic Age, Age at Death and Stage Migration in Men Dying with or from Prostate Cancer in Denmark.

The impact of changes in diagnostic activity and treatment options on prostate cancer epidemiology remains a subject of debate. Newly published long-term survival outcomes may not represent contemporary patients and new perspectives are in demand. All men dying in Denmark with prostate cancer diagnosis during a 10-year period were analyzed to address the stage migration of and time lived with prostate cancer diagnosis. All male deaths in Denmark between 2007 and 2016 (n = 261,657) were obtained and crosslinked with The Danish Prostate Cancer Registry (DaPCaR) and the Danish Cancer Registry. Correlation in diagnostic age and stage (localized, locally advanced, metastatic), age at death and cause of death were investigated by Kruskal-Wallis test and linear regression in 15,692 men diagnosed with prostate cancer. Prostate cancer mortality remained stable during the study period. Among the men who died of prostate cancer, 65% had locally advanced or metastatic disease at diagnosis. Age at diagnosis declined in men diagnosed with localized disease and remained constant in men with locally advanced or metastatic disease. Age at death increased in all men. Despite increased efforts to detect prostate cancer early, two-thirds of men who die from prostate cancer still have advanced prostate cancer at the time of diagnosis. Our data show increased life-expectancy in men diagnosed with prostate cancer, however, this benefit must be weighed against increased time of living with the disease and overdiagnosis. The intensified treatment of elderly men and men with advanced disease may be the key to lower prostate cancer mortality.

Clinical inertia in patients with type 2 diabetes treated with oral antidiabetic drugs: Results from a Japanese cohort study (JDDM53).

AIMS/INTRODUCTION: Treatment intensification is commonly delayed in people with type 2 diabetes, resulting in poor glycemic control for an unacceptable length of time and increased risk of complications. MATERIALS AND METHODS: This retrospective study investigated clinical inertia in 33,320 Japanese adults with type 2 diabetes treated with oral antidiabetic drugs (OADs) between 2009 and 2018, using data from the Computerized Diabetes Care (CoDiC® ) database. RESULTS: The median time from first reported glycated hemoglobin (HbA1c) ≥7.0% (≥53 mmol/mol) to treatment intensification was considerably longer and HbA1c levels were higher the more OADs the patient was exposed to. For patients receiving three OADs, the median times from HbA1c ≥7.0% (53 mmol/mol) to intensification with OAD, glucagon-like peptide-1 receptor agonist or insulin were 8.1, 9.1 and 6.7 months, with a mean HbA1c level at the time of intensification of 8.4%, 8.9% and 9.3%, respectively. The cumulative incidence for time since the first reported HbA1c ≥7.0% (≥53 mmol/mol) to intensification confirmed the existence of clinical inertia, identifying patients whose treatment was not intensified despite poor glycemic control. HbA1c levels ≥7.0% (≥53 mmol/mol) after ≥6 months on one, two or three OADs were observed in 42%, 51% and 58% of patients, respectively, showing that approximately 50% of patients are above HbA1c target regardless of how many OADs they take. CONCLUSIONS: Real-world data here show clinical inertia in Japanese adults with type 2 diabetes from early diabetes stages when they are receiving OADs, and illustrate a need for earlier, more effective OADs or injectable treatment intensification and better communication around the existence of clinical inertia.

Clinical inertia in basal insulin-treated patients with type 2 diabetes - Results from a retrospective database study in Japan (JDDM 43).

AIMS: This retrospective cohort study investigated whether clinical inertia, the failure to intensify treatment when required, exists in Japanese clinical practice, using the CoDiC® database. How and when patients with type 2 diabetes treated with basal insulin received treatment intensification was also described. MATERIALS AND METHODS: Patients with type 2 diabetes who initiated basal insulin between 2004 and 2011 were eligible for inclusion. Patients with an HbA1c ≥7.0% (≥53.0 mmol/mol) after 180 days of basal insulin titration were eligible for intensification, and their treatment was followed for up to 1.5 years. Endpoints were time to intensification, changes in HbA1c, and insulin dose. RESULTS: Overall, 2351 patients initiated basal insulin treatment (mean HbA1c 9.4% [79.2 mmol/mol]), and 1279 patients were eligible for treatment intensification (HbA1c ≥7.0% [≥53.0 mmol/mol]) after the 180-day titration period. During the 1.5-year follow-up period (beyond the 180-day titration period), 270 (21%) of these patients received treatment intensification. In patients receiving treatment intensification, mean HbA1c decreased from 8.6 to 8.2% (70.5 to 66.1 mmol/mol) at end of follow-up. Treatment was intensified using bolus insulin in 126 (47%) patients and with premixed insulin in 144 (53%) patients. The estimated probability of intensifying treatment during the 12 months after recording HbA1c ≥7.0% (≥53.0 mmol/mol) was 22.8%, and 27.5% after 17 months. Mean end-of-follow-up daily insulin dose was 35.11 units for basal-bolus compared with 20.70 units for premix therapy. CONCLUSIONS: This study suggests clinical inertia exists in basal insulin-treated patients with type 2 diabetes in Japan. Strategies are needed to increase the number of patients undergoing therapy intensification and to reduce the delay in intensification in Japan.

Long-Term Retrospective Analysis of Gene Therapy with Alipogene Tiparvovec and Its Effect on Lipoprotein Lipase Deficiency-Induced Pancreatitis.

Alipogene tiparvovec (Glybera) is a gene therapy product approved in Europe under the "exceptional circumstances" pathway as a treatment for lipoprotein lipase deficiency (LPLD), a rare genetic disease resulting in chylomicronemia and a concomitantly increased risk of acute and recurrent pancreatitis, with potentially lethal outcome. This retrospective study analyzed the frequency and severity of pancreatitis in 19 patients with LPLD up to 6 years after a single treatment with alipogene tiparvovec. An independent adjudication board of three pancreas experts, blinded to patient identification and to pre- or post-gene therapy period, performed a retrospective review of data extracted from the patients' medical records and categorized LPLD-related acute abdominal pain events requiring hospital visits and/or hospitalizations based on the adapted 2012 Atlanta diagnostic criteria for pancreatitis. Both entire disease time period data and data from an equal time period before and after gene therapy were analyzed. Events with available medical record information meeting the Atlanta diagnostic criteria were categorized as definite pancreatitis; events treated as pancreatitis but with variable levels of laboratory and imaging data were categorized as probable pancreatitis or acute abdominal pain events. A reduction of approximately 50% was observed in all three categories of the adjudicated post-gene therapy events. Notably, no severe pancreatitis and only one intensive care unit admission was observed in the post-alipogene tiparvovec period. However, important inter- and intraindividual variations in the pre- and post-gene therapy incidence of events were observed. There was no relationship between the posttreatment incidence of events and the number of LPL gene copies injected, the administration of immunosuppressive regimen or the percent triglyceride decrease achieved at 12 weeks (primary end point in the prospective clinical studies). Although a causal relationship cannot be established and despite the limited number of individuals evaluated, results from this long-term analysis suggest that alipogene tiparvovec was associated with a lower frequency and severity of pancreatitis events, and a consequent overall reduction in health care resource use up to 6 years posttreatment.

The role of local heating in the formation process of UV written optical waveguides.

A behavior is reported where the index change process used for UV writing of integrated optical waveguides in deuterium loaded Ge:SiO2 glass can become unstable and suddenly switch off or on. It is shown that such discontinuities are associated with abrupt changes in the amount of absorbed UV power. We suggest that these events are controlled by a coupling between UV absorption, local heating and the D2-GeO2 reaction rate. From our findings we predict, and confirm experimentally, that strong waveguides can not be fabricated under normal UV writing conditions in thin core layers with a low initial UV absorption. Our findings show that an improved understanding of the waveguide formation process and future process development requires that thermal effects are taken into account.

Substrate specificity and novel selective inhibitors of TNF-alpha converting enzyme (TACE) from two-dimensional substrate mapping.

We report a systematic analysis of the P1' and P2' substrate specificity of TNF-alpha converting enzyme (TACE) using a peptide library and a novel analytical method, and we use the substrate specificity information to design novel reverse hydroxamate inhibitors. Initial truncation studies, using the amino acid sequence around the cleavage site in precursor-TNF-alpha, showed that good turnover was obtained with the peptide DNP-LAQAVRSS-NH2. Based on this result, 1000 different peptide substrates of the form Biotin-LAQA-P1'-P2'-SSK(DNP)-NH2 were prepared, with 50 different natural and unnatural amino acids at P1' in combination with 20 different amino acids at P2'. The peptides were pooled, treated with purified microsomal TACE, and the reaction mixtures were passed over a streptavidin affinity column to remove unreacted substrate and the N-terminal biotinylated product. C-terminal cleavage products not binding to streptavidin were subjected to liquid chromatography/mass spectrometry analysis where individual products were identified and semiquantitated. 25 of the substrates were resynthesized as discrete peptides and assayed with recombinant TACE. The experiments show that recombinant TACE prefers lipophilic amino acids at the P1' position, such as phenylglycine, homophenylalanine, leucine and valine. At the P2' position, TACE can accommodate basic amino acids, such as arginine and lysine, as well as certain non-basic amino acids such as citrulline, methionine sulfoxide and threonine. These substrate preferences were used in the design of novel reverse hydroxamate TACE inhibitors with phenethyl and 5-methyl-thiophene-methyl side-chains at P1', and threonine and nitro-arginine at P2'.

Increased Risk of Severe Hypoglycemic Events with Increasing Frequency of Non-severe Hypoglycemic Events in Patients with Type 1 and Type 2 Diabetes.

INTRODUCTION: Severe hypoglycemic events (SHEs) are associated with significant morbidity, mortality and costs. However, the more common non-severe hypoglycemic events (NSHEs) are less well explored. We investigated the association between reported frequency of NSHEs and SHEs among patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in the PREDICTIVE study. METHODS: PREDICTIVE was a global, prospective, observational study. Patients with T1DM (n = 7,420) or T2DM (n = 12,981), starting treatment with insulin detemir, reported the number of NSHEs and SHEs experienced during the 4 weeks prior to baseline and follow-up visits (mean 14.4 weeks). Logistic regression was used to determine the odds ratio (OR) of experiencing ≥1 SHE, in patients having 1-4 or ≥5 NSHEs, versus those having 0 NSHEs, while controlling for baseline covariates. RESULTS: Hypoglycemia rates were lower at follow-up than baseline. At baseline 59.2% (T1DM) and 18.8% (T2DM) reported any hypoglycemia and at follow-up 39.5% (T1DM) and 8.6% (T2DM). There was a significant (P < 0.0001) increase in the odds of ≥1 SHEs with increasing frequency of NSHEs in T1DM and T2DM, for both crude and adjusted estimates. At baseline, in T1DM, ORs for ≥1 SHE were 1.92 and 2.13 for 1-4 and ≥5 NSHEs, respectively; the corresponding ORs in T2DM were 10.83 and 15.36, respectively. At follow-up, the ORs for ≥1 SHE were 2.01 and 3.20 (T1DM) and 18.99 and 24.29 (T2DM) for 1-4 and ≥5 NSHEs, respectively. CONCLUSION: A statistically significant association between NSHE and SHE frequency was found in T1DM and T2DM. These data provide a clear rationale for the reduction of hypoglycemic events, regardless of severity, while striving for optimal glycemic control.

Clinical inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people.

OBJECTIVE: To determine time to treatment intensification in people with type 2 diabetes treated with one, two, or three oral antidiabetes drugs (OADs) and associated levels of glycemic control. RESEARCH DESIGN AND METHODS: This was a retrospective cohort study based on 81,573 people with type 2 diabetes in the U.K. Clinical Practice Research Datalink between January 2004 and December 2006, with follow-up until April 2011. RESULTS: In people with HbA1c ≥7.0, ≥7.5, or ≥8.0% (≥53, ≥58, or ≥64 mmol/mol), median time from above HbA1c cutoff to intensification with an additional OAD was 2.9, 1.9, or 1.6 years, respectively, for those taking one OAD and >7.2, >7.2, and >6.9 years for those taking two OADs. Median time to intensification with insulin was >7.1, >6.1, or 6.0 years for those taking one, two, or three OADs. Mean HbA1c at intensification with an OAD or insulin for people taking one, two, or three OADs was 8.7, 9.1, and 9.7%. In patients taking one, two, or three OADs, median time from treatment initiation to intensification with an OAD or insulin exceeded the maximum follow-up time of 7.2 years. The probability of patients with poor glycemic control taking one, two, or three OADs, intensifying at end of follow-up with an OAD, was 21.1-43.6% and with insulin 5.1-12.0%. CONCLUSIONS: There are delays in treatment intensification in people with type 2 diabetes despite suboptimal glycemic control. A substantial proportion of people remain in poor glycemic control for several years before intensification with OADs and insulin.

Collective-goal ascription increases cooperation in humans.

BACKGROUND: Cooperation is necessary in many types of human joint activity and relations. Evidence suggests that cooperation has direct and indirect benefits for the cooperators. Given how beneficial cooperation is overall, it seems relevant to investigate the various ways of enhancing individuals' willingness to invest in cooperative endeavors. We studied whether ascription of a transparent collective goal in a joint action promotes cooperation in a group. METHODS: A total of 48 participants were assigned in teams of 4 individuals to either a "transparent goal-ascription" or an "opaque goal-ascription" condition. After the manipulation, the participants played an anonymous public goods game with another member of their team. We measured the willingness of participants to cooperate and their expectations about the other player's contribution. RESULTS: Between subjects analyses showed that transparent goal ascription impacts participants' likelihood to cooperate with each other in the future, thereby greatly increasing the benefits from social interactions. Further analysis showed that this could be explained with a change in expectations about the partner's behavior and by an emotional alignment of the participants. CONCLUSION: The study found that a transparent goal ascription is associated with an increase of cooperation. We propose several high-level mechanisms that could explain the observed effect: general affect modulation, trust, expectation and perception of collective efficacy.

Efficacy of citalopram in the prevention of recurrent depression in elderly patients: placebo-controlled study of maintenance therapy.

BACKGROUND: The highly recurrent nature of major depression in the young and the elderly warrants long-term antidepressant treatment. AIMS: To compare the prophylactic efficacy of citalopram and placebo in elderly patients; to evaluate long-term tolerability of citalopram. METHOD: Out-patients, > or =65 years, with unipolar major depression (DSM-IV: 296.2 x or 296.3 x) and Montgomery-Asberg Depression Rating Scale score > or =22 were treated with citalopram 20-40 mg for 8 weeks. Responders continued on their final fixed dose of citalopram for 16 weeks before randomisation to double-blind treatment with citalopram or placebo for at least 48 weeks. RESULTS: Nineteen of the 60 patients using citalopram v. 41 of the 61 patients using placebo had recurrence. Time to recurrence was significantly different between citalopram- and placebo-patients, in favour of citalopram (log-rank test, P<0.0001). Long-term treatment was well tolerated. CONCLUSIONS: Long-term treatment with citalopram is effective in preventing recurrence of depression in the elderly and is well tolerated.