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This study aimed to improve the predictive accuracy of the Braden assessment for pressure injury risk in skilled nursing facilities (SNFs) by incorporating real‐world data and training a survival model. A comprehensive analysis of 126 384 SNF stays and 62 253 in‐house pressure injuries was conducted using a large calibrated wound database. This study employed a time‐varying Cox Proportional Hazards model, focusing on variations in Braden scores, demographic data and the history of pressure injuries. Feature selection was executed through a forward‐backward process to identify significant predictive factors. The study found that sensory and moisture Braden subscores were minimally contributive and were consequently discarded. The most significant predictors of increased pressure injury risk were identified as a recent (within 21 days) decrease in Braden score, low subscores in nutrition, friction and activity, and a history of pressure injuries. The model demonstrated a 10.4% increase in predictive accuracy compared with traditional Braden scores, indicating a significant improvement. The study suggests that disaggregating Braden scores and incorporating detailed wound histories and demographic data can substantially enhance the accuracy of pressure injury risk assessments in SNFs. This approach aligns with the evolving trend towards more personalized and detailed patient care. These findings propose a new direction in pressure injury risk assessment, potentially leading to more effective and individualized care strategies in SNFs. The study highlights the value of large‐scale data in wound care, suggesting its potential to enhance quantitative approaches for pressure injury risk assessment and supporting more accurate, data‐driven clinical decision‐making. [ABSTRACT FROM AUTHOR]

Modern approaches in metallodrug research focus on compounds that bind protein targets rather than DNA. However, the identification of protein targets and binding sites is challenging. Using intact mass spectrometry and proteomics, we investigated the binding of the antimetastatic agent RAPTA‐C to the model proteins ubiquitin, cytochrome c, lysozyme, and myoglobin. Binding to cytochrome c and lysozyme was negligible. However, ubiquitin bound up to three Ru moieties, two of which were localized at Met1 and His68 as [Ru(cym)], and [Ru(cym)] or [Ru(cym)(PTA)] adducts, respectively. Myoglobin bound up to four [Ru(cym)(PTA)] moieties and five sites were identified at His24, His36, His64, His81/82 and His113. Collision‐induced unfolding (CIU) studies via ion‐mobility mass spectrometry allowed measuring protein folding as a function of collisional activation. CIU of protein–RAPTA‐C adducts showed binding of [Ru(cym)] to Met1 caused a significant compaction of ubiquitin, likely from N‐terminal S−Ru−N chelation, while binding of [Ru(cym)(PTA)] to His residues of ubiquitin or myoglobin induced a smaller effect. Interestingly, the folded state of ubiquitin formed by His functionalization was more stable than Met1 metalation. The data suggests that selective metalation of amino acids at different positions on the protein impacts the conformation and potentially the biological activity of anticancer compounds. [ABSTRACT FROM AUTHOR]

The International Anal Neoplasia Society (IANS) developed consensus guidelines to inform anal cancer screening use among various high‐risk groups. Anal cancer incidence estimates by age among risk groups provided the basis to identify risk thresholds to recommend screening. Guided by risk thresholds, screening initiation at age 35 years was recommended for men who have sex with men (MSM) and transgender women (TW) with HIV. For other people with HIV and MSM and TW not with HIV, screening initiation at age 45 years was recommended. For solid organ transplant recipients, screening initiation beginning from 10 years post‐transplant was recommended. For persons with a history of vulvar precancer or cancer, screening initiation was recommended starting within 1 year of diagnosis of vulvar precancer or cancer. Persons aged ≥45 years with a history of cervical/vaginal HSIL or cancer, perianal warts, persistent (>1 year) cervical HPV16, or autoimmune conditions could be considered for screening with shared decision‐making, provided there is adequate capacity to perform diagnostic procedures (high‐resolution anoscopy [HRA]). Anal cytology, high‐risk (hr) human papillomavirus (HPV) testing (including genotyping for HPV16), and hrHPV‐cytology co‐testing are different strategies currently used for anal cancer screening that show acceptable performance. Thresholds for referral for HRA or follow‐up screening tests are delineated. These recommendations from IANS provide the basis to inform management of abnormal screening results, considering currently available screening tools. These guidelines provide a pivotal foundation to help generate consensus among providers and inform the introduction and implementation of risk‐targeted screening for anal cancer prevention. [ABSTRACT FROM AUTHOR]

Perceptual learning is commonly understood as conferring some benefit to the learner, such as allowing for the extraction of more information from the environment. However, perceptual learning can be biased in several different ways, some of which do not appear to provide such a benefit. Here we outline a systematic framework for thinking about bias in perceptual learning and discuss how several cases fit into this framework. We argue these biases are compatible with an understanding in which perceptual learning is beneficial, but that its benefits are tied to both a person's narrow interests and the training environment or domain, and so if there are changes to either of these, then benefits can turn into liabilities, though these are often temporary.This article is categorized under: Psychology > Learning Philosophy > Value Linguistics > Language Acquisition [ABSTRACT FROM AUTHOR]

Humans routinely form groups to achieve goals that no individual can accomplish alone. Group coordination often brings to mind synchrony and alignment, where all individuals do the same thing (e.g., driving on the right side of the road, marching in lockstep, or playing musical instruments on a regular beat). Yet, effective coordination also typically involves differentiation, where specialized roles emerge for different members (e.g., prep stations in a kitchen or positions on an athletic team). Role specialization poses a challenge for computational models of group coordination, which have largely focused on achieving synchrony. Here, we present the CARMI framework, which characterizes role specialization processes in terms of five core features that we hope will help guide future model development: Communication, Adaptation to feedback, Repulsion, Multi‐level planning, and Intention modeling. Although there are many paths to role formation, we suggest that roles emerge when each agent in a group dynamically allocates their behavior toward a shared goal to complement what they expect others to do. In other words, coordination concerns beliefs (who will do what) rather than simple actions. We describe three related experimental paradigms—"Group Binary Search," "Battles of the Exes," and "Find the Unicorn"—that we have used to study differentiation processes in the lab, each emphasizing different aspects of the CARMI framework. Group coordination often brings to mind group members synchronizing their behaviors, as with soldiers marching in lockstep or audience members spontaneously clapping in unison. However, effective coordination often crucially involves a division of labor in which different members come to adopt different roles. The emergence of specialized roles in the three collective behavior paradigms we review can be understood in terms of five interactive processes: communication, adaptation to feedback, repulsion among member strategies, multi‐level planning, and intention modeling. [ABSTRACT FROM AUTHOR]

Objective: This study assessed the effect of 1‐year administration of diazoxide choline extended‐release tablet (DCCR) on hyperphagia and other complications of Prader‐Willi syndrome (PWS). Methods: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open‐label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ‐CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. Results: DCCR administration resulted in significant improvements in HQ‐CT (mean [SE] −9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ‐CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment‐emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). Conclusions: DCCR administration to people with PWS was well tolerated and associated with broad‐ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families. [ABSTRACT FROM AUTHOR]

Background: Follow‐up after early medical abortion (EMA) in Australia often entails tracking serum human chorionic gonadotropin levels or performing ultrasonography in‐clinic. In other countries, methods of follow‐up such as using a low‐sensitivity urine pregnancy test (LSUPT), telephone evaluation and a questionnaire have been demonstrated to be safe and acceptable. Aims: To evaluate the safety and efficacy of telephone follow‐up after EMA using an LSUPT and questionnaire. Materials and Methods: A prospective observational cohort study of patients undergoing telephone follow‐up after EMA using an LSUPT and questionnaire was conducted from March 26 to July 31, 2020. Outcomes of patients who returned to clinic because of a positive LSUPT were evaluated and adverse event rates were calculated. Routinely collected adverse event information was used to compare complication rates during the evaluation period with that prior to introduction of the LSUPT. Results: During the study period, 2223 patients underwent the new protocol. One hundred and ninety‐seven patients had a positive LSUPT at their telephone follow‐up. One hundred and thirty‐two had an incomplete abortion, 11 had a continuing pregnancy, 53 had a complete abortion and one left the clinic before full assessment. Conclusions: Introduction of telephone follow‐up with an at‐home LSUPT reduced the number of patients requiring unnecessary clinic appointments, with over 90% of patients completing their follow‐up at home. Complication rates during the study period were found to be at least comparable with previously identified organisational adverse events. [ABSTRACT FROM AUTHOR]

Summary: This systematic review collates studies of dietary or bariatric surgery interventions for obesity using positron emission tomography and single‐photon emission computed tomography. Of 604 publications identified, 22 met inclusion criteria. Twelve studies assessed bariatric surgery (seven gastric bypass, five gastric bypass/sleeve gastrectomy), and ten dietary interventions (six low‐calorie diet, three very low‐calorie diet, one prolonged fasting). Thirteen studies examined neurotransmitter systems (six used tracers for dopamine DRD2/3 receptors: two each for 11C‐raclopride, 18F‐fallypride, 123I‐IBZM; one for dopamine transporter, 123I‐FP‐CIT; one used tracer for serotonin 5‐HT2A receptor, 18F‐altanserin; two used tracers for serotonin transporter, 11C‐DASB or 123I‐FP‐CIT; two used tracer for μ‐opioid receptor, 11C‐carfentanil; one used tracer for noradrenaline transporter, 11C‐MRB); seven studies assessed glucose uptake using 18F‐fluorodeoxyglucose; four studies assessed regional cerebral blood flow using 15O‐H2O (one study also used arterial spin labeling); and two studies measured fatty acid uptake using 18F‐FTHA and one using 11C‐palmitate. The review summarizes findings and correlations with clinical outcomes, eating behavior, and mechanistic mediators. The small number of studies using each tracer and intervention, lack of dietary intervention control groups in any surgical studies, heterogeneity in time since intervention and degree of weight loss, and small sample sizes hindered the drawing of robust conclusions across studies. [ABSTRACT FROM AUTHOR]

Background: The Consortium Linking Academic and Regulatory Insights on Bisphenol A Toxicity (CLARITY‐BPA) was a collaborative research effort to better link academic research with governmental guideline studies. This review explores the secondary goal of CLARITY‐BPA: to identify endpoints or technologies from CLARITY‐BPA and prior/concurrent literature from these laboratories that may enhance the capacity of rodent toxicity studies to detect endocrine disrupting chemicals (EDCs). Methods: A systematic literature search was conducted with search terms for BPA and the CLARITY‐BPA participants. Relevant studies employed a laboratory rodent model and reported results on 1 of the 10 organs/organ systems evaluated in CLARITY‐BPA (brain and behavior, cardiac, immune, mammary gland, ovary, penile function, prostate gland and urethra, testis and epididymis, thyroid hormone and metabolism, and uterus). Study design and findings were summarized, and a risk‐of‐bias assessment was conducted. Results: Several endpoints and methods were identified as potentially helpful to detect effects of EDCs. For example, molecular and quantitative morphological approaches were sensitive in detecting alterations in early postnatal development of the brain, ovary, and mammary glands. Hormone challenge studies mimicking human aging reported increased susceptibility of the prostate to disease following developmental BPA exposure. Statistical analyses for nonmonotonic dose responses, and computational approaches assessing multiple treatment‐related outcomes concurrently in linked hormone‐sensitive organ systems, reported effects at low BPA doses. Conclusions: This review provided an opportunity to evaluate the unique insights provided by nontraditional assessments in CLARITY‐BPA to identify technologies and endpoints to enhance detection of EDCs in future studies. [ABSTRACT FROM AUTHOR]

Background: Rejection remains a primary cause of graft loss after heart transplant (HT). Recognizing the immunomodulation of multi‐organ transplant can enhance our understanding of the mechanisms of cardiac rejection. Methods: This retrospective cohort study identified patients from the UNOS database with isolated heart (H, N = 37 433), heart‐kidney (HKi, N = 1516), heart‐liver (HLi, N = 286), and heart‐lung (HLu, N = 408) transplants from 2004 to 2019. Propensity score matching reduced baseline differences between groups. Outcomes included risk of rejection prior to transplant hospital discharge and within 1 year, and mortality within 1 year of transplant. Results: In the propensity score matched data, the relative risk of being treated for rejection prior to transplant hospital discharge was 61% lower for HKi (RR.39, 95% CI.29,.53) and 87% lower for HLi (RR.13, 95% CI.05,.37) compared to H. Similarly, the probability of being treated for rejection in the first year after transplant remained lower in HKi (RR.45, 95% CI.35,.57) and HLi (RR.13, 95% CI.06,.28) compared to H. The 1‐year survival analysis revealed an equivalent risk of death in HKi (HR.84, 95% CI.68, 1.03) and HLi (HR 1.41, 95% CI.83, 2.41) compared to H, while HLu had a higher risk of death in the first year after transplant (HR 1.65, 95% CI 1.17, 2.33). Conclusions: Recipients of HKi and HLi experience a reduced risk of rejection when compared to H, but an equivalent risk of 1 yr mortality. These findings have important implications for the future of HT medicine. [ABSTRACT FROM AUTHOR]

Objective: Rare genetic diseases of obesity typically present with hyperphagia, a pathologic desire to consume food. Cost‐utility models assessing the value of treatments for these rare diseases will require health state utilities representing hyperphagia. This study estimated utilities associated with various hyperphagia severity levels. Methods: Four health state vignettes were developed using published literature and clinician input to represent various severity levels of hyperphagia. Utilities were estimated for these health states in a time trade‐off elicitation study in a UK general population sample. Results: In total, 215 participants completed interviews (39.5% male; mean age 39.1 years). Mean (SD) utilities were 0.98 (0.02) for no hyperphagia, 0.91 (0.10) for mild hyperphagia, 0.70 (0.30) for moderate hyperphagia, and 0.22 (0.59) for severe hyperphagia. Mean (SD) disutilities were −0.08 (0.10) for mild, −0.28 (0.30) for moderate, and −0.77 (0.58) for severe hyperphagia. Conclusions: These data show increasing severity of hyperphagia is associated with decreased utility. Utilities associated with severe hyperphagia are similar to those of other health conditions severely impacting quality of life (QoL). These findings highlight that treatments addressing substantial QoL impacts of severe hyperphagia are needed. Utilities estimated here may be useful in cost‐utility models of treatments for rare genetic diseases of obesity. [ABSTRACT FROM AUTHOR]

Cognitive science has been traditionally organized around the individual as the basic unit of cognition. Despite developments in areas such as communication, human–machine interaction, group behavior, and community organization, the individual‐centric approach heavily dominates both cognitive research and its application. A promising direction for cognitive science is the study of augmented intelligence, or the way social and technological systems interact with and extend individual cognition. The cognitive science of augmented intelligence holds promise in helping society tackle major real‐world challenges that can only be discovered and solved by teams made of individuals and machines with complementary skills who can productively collaborate with each other. [ABSTRACT FROM AUTHOR]

Unhealthy alcohol consumption is a global health problem. Adverse individual, public health, and socioeconomic consequences are attributable to harmful alcohol use. Epidemiological studies have shown that alcohol use disorder (AUD) and alcohol‐associated liver disease (ALD) are the top two pathologies among alcohol‐related diseases. Consistent with the major role that the liver plays in alcohol metabolism, uncontrolled drinking may cause significant damage to the liver. This damage is initiated by excessive fat accumulation in the liver, which can further progress to advanced liver disease. The only effective therapeutic strategies currently available for ALD are alcohol abstinence or liver transplantation. Any molecule with dual‐pronged effects at the central and peripheral organs controlling addictive behaviors and associated metabolic pathways are a potentially important therapeutic target for treating AUD and ALD. Ghrelin, a hormone primarily derived from the stomach, has such properties, and regulates both behavioral and metabolic functions. In this review, we highlight recent advances in understanding the peripheral and central functions of the ghrelin system and its role in AUD and ALD pathogenesis. We first discuss the correlation between blood ghrelin concentrations and alcohol use or abstinence. Next, we discuss the role of ghrelin in alcohol‐seeking behaviors and finally its role in the development of fatty liver by metabolic regulations and organ crosstalk. We propose that a better understanding of the ghrelin system could open an innovative avenue for improved treatments for AUD and associated medical consequences, including ALD. [ABSTRACT FROM AUTHOR]

SUMMARY: Flowering of the reference legume Medicago truncatula is promoted by winter cold (vernalization) followed by long‐day photoperiods (VLD) similar to winter annual Arabidopsis. However, Medicago lacks FLC and CO, key regulators of Arabidopsis VLD flowering. Most plants have two INHIBITOR OF GROWTH (ING) genes (ING1 and ING2), encoding proteins with an ING domain with two anti‐parallel alpha‐helices and a plant homeodomain (PHD) finger, but their genetic role has not been previously described. In Medicago, Mting1 gene‐edited mutants developed and flowered normally, but an Mting2‐1 Tnt1 insertion mutant and gene‐edited Mting2 mutants had developmental abnormalities including delayed flowering particularly in VLD, compact architecture, abnormal leaves with extra leaflets but no trichomes, and smaller seeds and barrels. Mting2 mutants had reduced expression of activators of flowering, including the FT‐like gene MtFTa1, and increased expression of the candidate repressor MtTFL1c, consistent with the delayed flowering of the mutant. MtING2 overexpression complemented Mting2‐1, but did not accelerate flowering in wild type. The MtING2 PHD finger bound H3K4me2/3 peptides weakly in vitro, but analysis of gene‐edited mutants indicated that it was dispensable to MtING2 function in wild‐type plants. RNA sequencing experiments indicated that >7000 genes are mis‐expressed in the Mting2‐1 mutant, consistent with its strong mutant phenotypes. Interestingly, ChIP‐seq analysis identified >5000 novel H3K4me3 locations in the genome of Mting2‐1 mutants compared to wild type R108. Overall, our mutant study has uncovered an important physiological role of a plant ING2 gene in development, flowering, and gene expression, which likely involves an epigenetic mechanism. Significance Statement: The timing of flowering is important for plant adaptation and crop productivity, but knowledge on how this is regulated in legumes is limited. Here, we report the functional characterization of MtING2 and show that it is important in regulating plant architecture and flowering time in the model legume Medicago truncatula, providing evidence of the physiological role of an ING‐like gene in plants. [ABSTRACT FROM AUTHOR]

Transcription of endogenous retroviral elements are tightly regulated during development by members of the KRAB‐containing zinc finger proteins (KRAB‐ZFPs) and the co‐repressor Trim28 (also known as Kap‐1 or Tif1β). KRAB‐ZFPs form the largest family of transcription regulators in mammals and initiate transcriptional silencing by tethering Trim28 to a target locus. Subsequently, Trim28 recruits chromatin modifying effectors resulting in the formation of heterochromatin. In the present study, we identify surface exposed residues on the central six turns of the Trim28 coiled‐coil region forming the binding interface for the KRAB domain. Using AlphaFold2 (AF2) we provide high confidence models of the interface between Trim28 and the KRAB domain and identified leucine 301 on each chain of the Trim28 monomer to act as a pin extending into a hydrophobic pocket on the KRAB domain surface. Site directed mutations in the Trim28‐KRAB binding interface abolished binding to the KRAB domain. Our work provides a detailed understanding of the specific interactions between the KRAB domain and the Trim28 coiled‐coil and how this interaction may be regulated during silencing events. [ABSTRACT FROM AUTHOR]

Aim: We sought to identify genetic differences between right‐ and left‐sided colon cancers and using these differences explain lower survival in right‐sided cancers. Method: A retrospective review of patients diagnosed with colon cancer was performed using The Cancer Genome Atlas, a cancer genetics registry with patient and tumour data from 20 North American institutions. The primary outcome was 5‐year overall survival. Predictors for survival were identified using directed acyclic graphs and Cox proportional hazards models. Results: A total of 206 right‐ and 214 left‐sided colon cancer patients with 84 recorded deaths were identified. The frequency of mutated alleles differed significantly in 12 of 25 genes between right‐ and left‐sided tumours. Right‐sided tumours had worse survival with a hazard ratio of 1.71 (95% confidence interval 1.10–2.64, P = 0.017). The total effect of the genetic loci on survival showed five genes had a sizeable effect on survival: DNAH5, MUC16, NEB, SMAD4, and USH2A. Lasso‐penalized Cox regression selected 13 variables for the highest‐performing model, which included cancer stage, positive resection margin, and mutated alleles at nine genes: MUC16, USH2A, SMAD4, SYNE1, FLG, NEB, TTN, OBSCN, and DNAH5. Post‐selection inference demonstrated that mutations in MUC16 (P = 0.01) and DNAH5 (P = 0.02) were particularly predictive of 5‐year overall survival. Conclusions: Our study showed that genetic mutations may explain survival differences between tumour sites. Further studies on larger patient populations may identify other genes, which could form the foundation for more precise prognostication and treatment decisions beyond current rudimentary TNM staging. [ABSTRACT FROM AUTHOR]

Although current exemplar models of category learning are flexible and can capture how different features are emphasized for different categories, they still lack the flexibility to adapt to local changes in category learning, such as the effect of different sequences of study. In this paper, we introduce a new model of category learning, the Sequential Attention Theory Model (SAT-M), in which the encoding of each presented item is influenced not only by its category assignment (global context) as in other exemplar models, but also by how its properties relate to the properties of temporally neighboring items (local context). By fitting SAT-M to data from experiments comparing category learning with different sequences of trials (interleaved vs. blocked), we demonstrate that SAT-M captures the effect of local context and predicts when interleaved or blocked training will result in better testing performance across three different studies. Comparatively, ALCOVE, SUSTAIN, and a version of SAT-M without locally adaptive encoding provided poor fits to the results. Moreover, we evaluated the direct prediction of the model that different sequences of training change what learners encode and determined that the best-fit encoding parameter values match learners' looking times during training. [ABSTRACT FROM AUTHOR]

How do people use information from others to solve complex problems? Prior work has addressed this question by placing people in social learning situations where the problems they were asked to solve required varying degrees of exploration. This past work uncovered important interactions between groups' connectivity and the problem's complexity: the advantage of less connected networks over more connected networks increased as exploration was increasingly required for optimally solving the problem at hand. We propose the Social Interpolation Model (SIM), an agent‐based model to explore the cognitive mechanisms that can underlie exploratory behavior in groups. Through results from simulation experiments, we conclude that "exploration" may not be a single cognitive property, but rather the emergent result of three distinct behavioral and cognitive mechanisms, namely, (a) breadth of generalization, (b) quality of prior expectation, and (c) relative valuation of self‐obtained information. We formalize these mechanisms in the SIM, and explore their effects on group dynamics and success at solving different kinds of problems. Our main finding is that broad generalization and high quality of prior expectation facilitate successful search in environments where exploration is important, and hinder successful search in environments where exploitation alone is sufficient. [ABSTRACT FROM AUTHOR]

Aim: In colorectal cancer (CRC), surgery of the primary site is commonly curative. Our aim was to determine estimates of 'no surgery' for primary CRC while identifying common reasons for no surgery. Method: We identified all patients with a diagnosis of colorectal adenocarcinoma from the National Cancer Database between January 2004 and December 2016. Then, we identified patients who did not undergo surgery on the primary tumour and their demographic, tumour and institutional characteristics. Kaplan–Meier and logistic regression analyses were used to evaluate specific factors associated with overall survival as related to no surgery and recommendations against operative management. Results: A total of 1,208,878 patients with CRC were identified, 14.5% of whom had no surgery of the primary cancer. No surgery was more common in rectal cancer than in colon cancer. Despite a steady incidence of CRC diagnoses, the likelihood of no surgery grew by 170% over the study period. Metastatic disease was noted in 53.7% of the no surgery cohort. Nine per cent of the no surgery patient cohort received a recommendation against surgery despite the absence of metastatic disease, 7.5% refused surgery and only 2% underwent palliative surgery. On multivariable analysis, patients who were not recommended to have surgery were more likely to be older, uninsured, comorbid and receive care at a single hospital. The no surgery patients had significantly lower overall survival. Conclusion: A substantial proportion of patients with CRC do not have surgery. Interventions aimed at expanding access and promoting second opinions at other cancer hospitals might reduce the growing rate of no surgery in CRC. [ABSTRACT FROM AUTHOR]

Metal complexes can be considered a "paradigm of promiscuity" when it comes to their interactions with proteins. They often form adducts with a variety of donor atoms in an unselective manner. We have characterized the adducts formed between a series of isostructural N‐heterocyclic carbene (NHC) complexes with Ru, Os, Rh, and Ir centers and the model protein hen egg white lysozyme by X‐ray crystallography and mass spectrometry. Distinctive behavior for the metal compounds was observed with the more labile Ru and Rh complexes targeting mainly a surface l‐histidine moiety through cleavage of p‐cymene or NHC co‐ligands, respectively. In contrast, the more inert Os and Ir derivatives were detected abundantly in an electronegative binding pocket after undergoing ligand exchange of a chlorido ligand for an amino acid side chain. Computational studies supported the binding profiles and hinted at the role of the protein microenvironment for metal complexes eliciting selectivity for specific binding sites on the protein. [ABSTRACT FROM AUTHOR]

We explore different ways in which the human visual system can adapt for perceiving and categorizing the environment. There are various accounts of supervised (categorical) and unsupervised perceptual learning, and different perspectives on the functional relationship between perception and categorization. We suggest that common experimental designs are insufficient to differentiate between hypothesized perceptual learning mechanisms and reveal their possible interplay. We propose a relatively underutilized way of studying potential categorical effects on perception, and we test the predictions of different perceptual learning models using a two‐dimensional, interleaved categorization‐plus‐reconstruction task. We find evidence that the human visual system adapts its encodings to the feature structure of the environment, uses categorical expectations for robust reconstruction, allocates encoding resources with respect to categorization utility, and adapts to prevent miscategorizations. [ABSTRACT FROM AUTHOR]

Summary: Across three experiments featuring naturalistic concepts (psychology concepts) and naïve learners, we extend previous research showing an effect of the sequence of study on learning outcomes, by demonstrating that the sequence of examples during study changes the representation the learner creates of the study materials. We compared participants' performance in test tasks requiring different representations and evaluated which sequence yields better learning in which type of tests. We found that interleaved study, in which examples from different concepts are mixed, leads to the creation of relatively interrelated concepts that are represented by contrast to each other and based on discriminating properties. Conversely, blocked study, in which several examples of the same concept are presented together, leads to the creation of relatively isolated concepts that are represented in terms of their central and characteristic properties. These results argue for the integrated investigation of the benefits of different sequences of study as depending on the characteristics of the study and testing situation. [ABSTRACT FROM AUTHOR]

Summary: The UK has made a well‐recognised contribution to the international effort to understand and treat acute lymphoblastic leukaemia (ALL) in adults. Work done in the UK by numerous personnel over many years has been instrumental in developing novel risk stratifications, evaluating treatment strategies for adult patients with de novo and relapsed disease and in making novel scientific contributions. The UK has championed and achieved very high levels of recruitment to clinical trials and, in particular, is known for success in large, investigator‐initiated randomised controlled trials. This historical review charts the progress of clinical research in adult ALL from its inception to the present day. [ABSTRACT FROM AUTHOR]

Objective: Differences in the content and distribution of body fat and ectopic lipids may be responsible for ethnic variations in metabolic disease susceptibility. The aim of this study was to examine the ethnic distribution of body fat in two separate UK‐based populations. Methods: Anthropometry and body composition were assessed in two separate UK cohorts: the Hammersmith cohort and the UK Biobank, both comprising individuals of South Asian descent (SA), individuals of Afro‐Caribbean descent (AC), and individuals of European descent (EUR). Regional adipose tissue stores and liver fat were measured by magnetic resonance techniques. Results: The Hammersmith cohort (n = 747) had a mean (SD) age of 41.1 (14.5) years (EUR: 374 men, 240 women; SA: 68 men, 22 women; AC: 14 men, 29 women), and the UK Biobank (n = 9,533) had a mean (SD) age of 55.5 (7.5) years (EUR: 4,483 men, 4,873 women; SA: 80 men, 43 women, AC: 31 men, 25 women). Following adjustment for age and BMI, no significant differences in visceral adipose tissue or liver fat were observed between SA and EUR individuals in the either cohort. Conclusions: Our data, consistent across two independent UK‐based cohorts, present a limited number of ethnic differences in the distribution of body fat depots associated with metabolic disease. These results suggest that the ethnic variation in susceptibility to features of the metabolic syndrome may not arise from differences in body fat. [ABSTRACT FROM AUTHOR]

Members of the TRIM protein family have been shown to inhibit a range of viral infections. Recently, TRIM69 was identified as a potent inhibitor of Vesicular stomatitis Indiana virus infection, with its inhibition being dependent upon multimerization. Using SEC‐MALLS analysis, it is demonstrated that the assembly of TRIM69 is mediated through the RING domain and not the Bbox domain as has been shown for other TRIM proteins. Using X‐ray crystallography, the structure of the TRIM69 RING domain has been determined to a resolution of 2.1 Å, the oligomerization interface has been identified and regions outside the four‐helix bundle have been observed to form interactions that are likely to support assembly. [ABSTRACT FROM AUTHOR]

Summary: Late relapse [>3 years from complete remission (CR)] in acute lymphoblastic leukaemia (ALL), is unusual. Data from the MRC UKALLXII/ECOG E2993 trial are presented to evaluate the incidence and characteristics of late relapse in adult ALL. Of 1,909 patients, 1,752 (92%) achieved CR and among these 757 (43·2%) relapsed; 691 (91·3%) within three years and 66 (8·7%) beyond. Among these 66 patients, median time to relapse was 47 (37–144) months. Relapse beyond three years occurred in 3·8% of all who achieved CR. The cumulative risk of relapse was 40%, 43% and 45% at three, five and ten years respectively. Out of the 1 752 patients who achieved CR, 11·7% underwent autologous and 40·6% allogeneic transplant, while in CR1. Of the autologous patients, 43·2% relapsed early and 3·4% relapsed late. However, among the allogeneic patients, 13·2% relapsed early and only 1·3% late. The five‐year overall survival from relapse was 5·8% and 20% in the early and late relapse patients respectively. In conclusion, late relapse in adults with ALL is not uncommon, and is associated with better outcome after relapse compared to early relapse. [ABSTRACT FROM AUTHOR]

How, and how well, do people switch between exploration and exploitation to search for and accumulate resources? We study the decision processes underlying such exploration/exploitation trade‐offs using a novel card selection task that captures the common situation of searching among multiple resources (e.g., jobs) that can be exploited without depleting. With experience, participants learn to switch appropriately between exploration and exploitation and approach optimal performance. We model participants' behavior on this task with random, threshold, and sampling strategies, and find that a linear decreasing threshold rule best fits participants' results. Further evidence that participants use decreasing threshold‐based strategies comes from reaction time differences between exploration and exploitation; however, participants themselves report non‐decreasing thresholds. Decreasing threshold strategies that "front‐load" exploration and switch quickly to exploitation are particularly effective in resource accumulation tasks, in contrast to optimal stopping problems like the Secretary Problem requiring longer exploration. [ABSTRACT FROM AUTHOR]

Summary: Background: Onychomycosis is a fungal infection of the nails and is one of the most common dermatological infections worldwide. Infection occurs predominantly in the nails of the feet and if left untreated patients, particularly in at‐risk populations, can develop more serious complications, including pain, fissuring and secondary infections. Fungal infections are also contagious and may spread to other nails or to family members. Topical treatments can be effective for mild cases of the disease and typically have fewer contraindications. However, generation of robust efficacy data for topical therapies is often hindered by the difficulties associated with monitoring progression of mild onychomycosis using the conventional methods of mycological culture to obtain confirmation of podiatrist assessments. Objectives: The aim of this study was to demonstrate image analysis as an effective method to monitor progression of fungal nail infections. Methods: A novel digital image analysis technique was used to evaluate improvement in the visual signs of onychomycosis, when using a topical treatment kit for mild fungal nail infections in 60 participants over a 280‐day period. Results: Image analysis demonstrated a significant (P <.0001) reduction from baseline of the affected nail area throughout the study period, results which were also perceived by the subjects themselves. Use of the treatment kit also limited the deterioration of the infection and prevented transmission to other nails. Conclusions: Image analysis was established as a viable method to monitor the progression of fungal nail infections over long periods and demonstrate a clinical benefit following treatment. [ABSTRACT FROM AUTHOR]

Aim: Clinical staging in psychiatry aims to classify patients according to the severity of their symptoms, from stage 0 (increased risk, asymptomatic) to stage 4 (severe illness), enabling adapted treatment at each stage of the illness. The staging model would gain specificity if one or more quantifiable biological markers could be identified. Several biomarkers reflecting possible causal mechanisms and/or consequences of the pathophysiology are candidates for integration into the clinical staging model of psychiatric illnesses. Methods: This review covers the evolution (from stage 0 to stage 4) of the most important brain functioning impairments as measured with electroencephalography (EEG), in psychosis spectrum and in severe mood disorders. Results: The present review of the literature demonstrates that it is currently not possible to draw any conclusion with regard to the state or trait character of any of the EEG impairments in both major depressive disorder and bipolar disorder. As for schizophrenia, the most promising markers of the stage of the illness are the pitch mismatch negativity as well as the p300 event‐related potentials, as these components seem to deteriorate with increasing severity of the illness. Conclusions: Given the complexity of major psychiatric disorders, and that not a single impairment can be observed in all patients, future research should most likely consider combinations of markers in the quest for a better identification of the stages of the psychiatric illnesses. [ABSTRACT FROM AUTHOR]

Cognitive science continues to make a compelling case for having a coherent, unique, and fundamental subject of inquiry: What is the nature of minds, where do they come from, and how do they work? Central to this inquiry is the notion of agents that have goals, one of which is their own persistence, who use dynamically constructed knowledge to act in the world to achieve those goals. An agentive perspective explains why a special class of systems have a cluster of co‐occurring capacities that enable them to exhibit adaptive behavior in a complex environment: perception, attention, memory, representation, planning, and communication. As an intellectual endeavor, cognitive science may not have achieved a hard core of uncontested assumptions that Lakatos (1978) identifies as emblematic of a successful research program, but there are alternative conceptions according to which cognitive science has been successful. First, challenges of the early, core tenet of "Mind as Computation" have helped put cognitive science on a stronger foundation—one that incorporates relations between minds and their environments. Second, even if a full cross‐disciplinary theoretic consensus is elusive, cognitive science can inspire distant, deep, and transformative connections between pairs of fields. To be intellectually vital, cognitive science need not resemble a traditional discipline with its associated insularity and unchallenged assumptions. Instead, there is strength and resilience in the diverse perspectives and methods that cognitive science assembles together. This interdisciplinary enterprise is fragile and perhaps inherently unstable, as the looming absorption of cognitive science into psychology shows. Still, for many researchers, the excitement and benefits of triangulating on the nature of minds by integrating diverse cases cannot be secured by a stable discipline with an uncontested core of assumptions. [ABSTRACT FROM AUTHOR]

Shultziner and Goldberg are is correct to say we need to treat the various stages of social movement origins, protests, and outcomes separately, with detailed analysis of each stage. However, a triparte stage theory may be insufficient, as each stage can have diverse potential trajectories driven by distinct causal mechanisms. Social movement analysis should help us recognize the many points at which complex movement trajectories can be advanced or reversed, and how actions at each stage create reverberations in the wider society. [ABSTRACT FROM AUTHOR]

Many viral genomes encode kinase and phosphatase enzymes to manipulate pathways that are controlled by phosphorylation events. The majority of viral phosphatase genes occur in the Baculoviridae and Poxviridae families of large DNA viruses. The corresponding protein sequences belong to four major homology groups, and structures are currently available for only two of these. Here, the first structure from the third group, the protein tyrosine phosphatase‐2 (PTP‐2) class of viral phosphatases, is described. It is shown that Cydia pomonella granulovirus PTP‐2 has the same general fold and active‐site architecture as described previously for other phosphatases, in the absence of significant sequence homology. Additionally, it has a novel C‐terminal extension in an area corresponding to the interface of dimeric poxvirus phosphatases belonging to the Tyr–Ser protein phosphatase homology group. The crystal structure of the protein phosphatase PTP‐2 from Cydia pomonella granulovirus, a betabaculovirus, has been determined at 1.65 Å resolution. The structure shows that the molecule has a typical protein phosphatase fold with a unique β‐sheet extension at the C‐terminus. [ABSTRACT FROM AUTHOR]

Although the incidence of many cancers is decreasing in the United States, the incidence of anal squamous cell cancer is increasing, and mortality appears to be outpacing the increased incidence in the number of new cases. Furthermore, patients are presenting with more advanced disease. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Despite the thalamus’ dense connectivity with both cortical and subcortical structures, few studies have specifically investigated how thalamic connectivity changes with age and how such changes are associated with behavior. This study investigated the effect of age on thalamo‐cortical and thalamo‐hippocampal functional connectivity (FC) and the association between thalamic FC and visual–spatial memory and reaction time (RT) performance in older adults. Methods: Resting‐state functional magnetic resonance images were obtained from younger (n = 20) and older (n = 20) adults. A seed‐based approach was used to assess the FC between the thalamus and (1) sensory resting‐state networks; (2) the hippocampus. Participants also completed visual–spatial memory and RT tasks, from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Results: Older adults exhibited a loss of specificity in the FC between sensory thalamic subregions and corresponding sensory cortex. Greater thalamo‐motor FC in older adults was associated with faster RTs. Furthermore, older adults exhibited greater thalamo‐hippocampal FC compared to younger adults, which was greatest for those with the poorest visual–spatial memory performance. Conclusion: Although older adults exhibited poorer visual–spatial memory and slower reaction times compared to younger adults, “good” and “poorer” older performers exhibited different patterns of thalamo‐cortical and thalamo‐hippocampal FC. These results highlight the potential role of thalamic connectivity in supporting reaction times and memory in aging. Furthermore, these results highlight the importance of including the thalamus in studies of aging to fully understand how brain changes with age may be associated with behavior. [ABSTRACT FROM AUTHOR]

A new optimized size exclusion chromatography small‐angle X‐ray scattering (SEC‐SAXS) system for biomolecular SAXS at the Australian Synchrotron SAXS/WAXS beamline has been developed. The compact configuration reduces sample dilution to maximize sensitivity. Coflow sample presentation allows an 11‐fold increase in flux on sample without capillary fouling, improving throughput and data quality, which are now primarily limited by the full flux available on the beamline. Multi‐wavelength fibre optic UV analysis in close proximity to the X‐ray beam allows for accurate concentration determination for samples with known UV extinction coefficients and thus estimation of the molecular weight of the scattering particle from the forward X‐ray scattering intensity. Fast‐flow low‐volume SEC columns provide sample throughput competitive with batch concentration series measurements, albeit with a concomitant reduction of potential resolution relative to lower flow rates and larger SEC columns. The performance of the system is demonstrated using a set of model proteins, and its utility to solve various challenges is illustrated with a diverse suite of protein samples. These developments increase the quality and rigor of SEC‐SAXS analysis and open new avenues for biomolecular solution SEC‐SAXS studies that have been challenged by low sample yields, temporal instability, radiation sensitivity and complex mixtures. [ABSTRACT FROM AUTHOR]

Background: Human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) are at disproportionately high risk for anal cancer. There is no definitive approach to the management of high-grade squamous intraepithelial lesions (HSIL), which are precursors of anal cancer, and evidence suggests that posttreatment adjuvant quadrivalent human papillomavirus (qHPV) vaccination improves HSIL treatment effectiveness. The objectives of this study were to evaluate the optimal HSIL management strategy with respect to clinical effectiveness and cost-effectiveness and to identify the optimal age for initiating HSIL management.Methods: A decision analytic model of the natural history of anal carcinoma and HSIL management strategies was constructed for HIV-positive MSM who were 27 years old or older. The model was informed by the Surveillance, Epidemiology, and End Results-Medicare database and published studies. Outcomes included the lifetime cost, life expectancy, quality-adjusted life expectancy, cumulative risk of cancer and cancer-related deaths, and cost-effectiveness from a societal perspective.Results: Active monitoring was the most effective approach in patients 29 years or younger; thereafter, HSIL treatment plus adjuvant qHPV vaccination became most effective. When cost-effectiveness was considered (ie, an incremental cost-effectiveness ratio [ICER] < $100,000/quality-adjusted life-year), do nothing was cost-effective until the age of 38 years, and HSIL treatment plus adjuvant qHPV vaccination was cost-effective beyond the age of 38 years (95% confidence interval, 34-43 years). The ICER decreased as the age at HSIL management increased. Outcomes were sensitive to the rate of HSIL regression or progression and the cost of high-resolution anoscopy and biopsy.Conclusions: The management of HSIL in HIV-positive MSM who are 38 years old or older with treatment plus adjuvant qHPV vaccination is likely to be cost-effective. The conservative approach of no treatment is likely to be cost-effective in younger patients. Cancer 2017;123:4709-4719. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

ABSTRACT In the last decade, numerous growth factors and biomaterials have been explored for the treatment of myocardial infarction (MI). While pre-clinical studies have demonstrated promising results, clinical trials have been disappointing and inconsistent, likely due to poor translatability. In the present study, we investigate a potential myocardial regenerative therapy consisting of a protein-engineered dimeric fragment of hepatocyte growth factor (HGFdf) encapsulated in a shear-thinning, self-healing, bioengineered hydrogel (SHIELD). We hypothesized that SHIELD would facilitate targeted, sustained intramyocardial delivery of HGFdf thereby attenuating myocardial injury and post-infarction remodeling. Adult male Wistar rats ( n = 45) underwent sham surgery or induction of MI followed by injection of phosphate buffered saline (PBS), 10 μg HGFdf alone, SHIELD alone, or SHIELD encapsulating 10 μg HGFdf. Ventricular function, infarct size, and angiogenic response were assessed 4 weeks post-infarction. Treatment with SHIELD + HGFdf significantly reduced infarct size and increased both ejection fraction and borderzone arteriole density compared to the controls. Thus, sustained delivery of HGFdf via SHIELD limits post-infarction adverse ventricular remodeling by increasing angiogenesis and reducing fibrosis. Encapsulation of HGFdf in SHIELD improves clinical translatability by enabling minimally-invasive delivery and subsequent retention and sustained administration of this novel, potent angiogenic protein analog. Biotechnol. Bioeng. 2017;114: 2379-2389. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objective: Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum insulin-like growth factor-I (IGF-I) may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF-I concentrations on WM tract and neuropsychological recovery after TBI.Methods: Thirty-nine adults after TBI (84.6% male, median age = 30.5 years, 87.2% moderate-severe, median time since TBI = 16.3 months, n = 4 with GHD) were scanned twice, 13.3 months (range = 12.1-14.9) apart, and 35 healthy controls were scanned once. Symptom and quality of life questionnaires and cognitive assessments were completed at both visits (n = 33). Our main outcome measure was fractional anisotropy (FA), a measure of WM tract integrity, in a priori regions of interest: splenium of corpus callosum (SPCC) and posterior limb of internal capsule (PLIC).Results: At baseline, FA was reduced in many WM tracts including SPCC and PLIC following TBI compared to controls, indicating axonal injury, with longitudinal increases indicating axonal recovery. There was a significantly greater increase in SPCC FA over time in patients with serum IGF-I above versus below the median for age. Only the higher IGF-I group had significant improvements in immediate verbal memory recall over time.Interpretation: WM recovery and memory improvements after TBI were greater in patients with higher serum IGF-I at baseline. These findings suggest that the growth hormone/IGF-I system may be a potential therapeutic target following TBI. Ann Neurol 2017;82:30-43. [ABSTRACT FROM AUTHOR]

Background In 2014, a composite pack containing mifepristone-buccal misoprostol, indicated for use to 63 days gestation replaced the existing regimen for early medical abortion ( EMA) in Australia. Aims To provide updated efficacy and safety information for the use of mifepristone-buccal misoprostol for EMA in Australia, and assess the effect of patient age and gestational age on efficacy. Materials and methods Observational cohort study of 15 008 women attending one of 16 Marie Stopes International clinics in Australia for an EMA (gestational age ≤ 63 days) between 1 March 2013 and 30 September 2015. Administration of 200 mg oral mifepristone in-clinic was followed 24-48 h later by 800 μg buccal misoprostol self-administered at home. Method success was defined as complete abortion not requiring surgical intervention. Results Follow-up information was available for 87.14% (13 078/15 008) of women. Likelihood of follow-up was significantly lower for women from rural or remote locations (adjusted odds ratio, 0.47; P < 0.001). Medical abortion was successful in 95.16% (12 445/13 078) of women with follow-up. Higher patient and gestational ages were associated ( P < 0.001) with a slight increase in method failure. There were 674 serious adverse events (5.15%), mainly due to method failure. Infection (15; 0.11%) and haemorrhage (17; 0.13%) were rare. One death was recorded (<0.01%); however, an association between EMA and cause of death, necrotising pneumonia, was not established. Conclusion Mifepristone-buccal misoprostol is an effective and safe alternative to surgical termination of pregnancy up to 63 days gestation. [ABSTRACT FROM AUTHOR]

Background Australia's abortion rates are among the highest in the developed world. Efficacy of the most commonly used form of contraception (oral contraceptives and condoms) relies on regular user compliance. Long-acting reversible contraception (LARC) virtually eradicates contraceptive failure as it is not user-dependent; however, its uptake has been low. Aim To provide an overview of barriers to LARC use in Australia and potential strategies to overcome these barriers. Method A roundtable of Australian experts was convened to share clinical perspectives and to explore the barriers and potential strategies to increase LARC use. Results Three broad barriers to LARC uptake were identified. (i) A paucity of Australian research exists that impedes closure of evidence gaps regarding contraceptive prescription and use. Systematic data collection is required. (ii) Within primary care, lack of familiarity with LARC and misperceptions about its use, lack of access to general practitioners (GPs) trained in LARC insertion/removal and affordability impede LARC uptake. Potential strategies to encourage LARC use include, GP education to promote informed choice by women, training in LARC insertions/removals, effective funding models for nurses to perform LARC insertions/removals, and rapid referral pathways. (iii) At the health system level, primary care incentives to provide LARC to women and health economic analyses to inform government policy changes are required. Conclusions Although LARC decreases unintended pregnancies by eliminating user compliance issues, its uptake is low in Australia. Strategies that promote LARC uptake by targeting specific barriers may effectively reduce Australia's high unintended pregnancy rate. [ABSTRACT FROM AUTHOR]