The role of the radiologist in the prostate cancer multidisciplinary conference.

The broad range of disease aggressiveness together with imperfect screening, diagnostic, and treatment options in prostate cancer (PCa) makes medical decision-making complex. The primary goal of a multidisciplinary conference is to improve patient outcomes by combining evidence-based data and expert opinion to discuss optimal management, including for those patients with challenging presentations. The primary purpose of the genitourinary imaging specialist in the prostate cancer multidisciplinary conference is to use imaging findings to reduce uncertainty by answering clinical questions. In this review, we discuss the role and the opportunities for an imaging specialist to add value in the care of men with prostate cancer discussed at multidisciplinary conferences.

Thrombospondin-1 Drives Cardiac Remodeling in Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) face a high risk of cardiovascular disease. Previous studies reported that endogenous thrombospondin 1 (TSP1) involves right ventricular remodeling and dysfunction. Here we show that a murine model of CKD increased myocardial TSP1 expression and produced left ventricular hypertrophy, fibrosis, and dysfunction. TSP1 knockout mice were protected from these features. In vitro, indoxyl sulfate is driving deleterious changes in cardiomyocyte through the TSP1. In patients with CKD, TSP1 and aryl hydrocarbon receptor were both differentially expressed in the myocardium. Our findings summon large clinical studies to confirm the translational role of TSP1 in patients with CKD.

Bystander intervention is associated with reduced early mortality among injury victims in Cameroon.

Despite high injury mortality rates, Cameroon currently lacks a formal prehospital care system. In other sub-Saharan African low and middle-income countries, Lay First Responder (LFR) programs have trained non-medical professionals with high work-related exposure to injury in principles of basic trauma care. To develop a context-appropriate LFR program in Cameroon, we used trauma registry data to understand current layperson bystander involvement in prehospital care and explore associations between current non-formally trained bystander-provided prehospital care and clinical outcomes. The Cameroon Trauma Registry (CTR) is a longitudinal, prospective, multisite trauma registry cohort capturing data on injured patients presenting to four hospitals in Cameroon. We assessed prevalence and patterns of prehospital scene care among all patients enrolled the CTR in 2020. Associations between scene care, clinical status at presentation, and outcomes were tested using univariate and multivariate logistic regression. Injury severity was measured using the abbreviated injury score. Data were analyzed using Stata17. Of 2212 injured patients, 455 (21%) received prehospital care (PC) and 1699 (77%) did not receive care (NPC). Over 90% (424) of prehospital care was provided by persons without formal medical training. PC patients were more severely injured (p<0.001), had markers of increased socioeconomic status (p = 0.01), and longer transport distances (p<0.001) compared to NPC patients. Despite increased severity of injury, patients who received PC were more likely to present with a palpable pulse (OR = 6.2, p = 0.02). Multivariate logistic regression adjusted for injury severity, socioeconomic status and travel distance found PC to be associated with reduced emergency department mortality (OR = 0.14, p<0.0001). Although prehospital injury care in Cameroon is rarely performed and is provided almost entirely by persons without formal medical training, prehospital intervention is associated with increased early survival after injury. Implementation of LFR training to strengthen the frequency and quality of prehospital care has considerable potential to improve trauma survival.

Exploiting relationship directionality to enhance statistical modeling of peer-influence across social networks.

Risky-prescribing is the excessive or inappropriate prescription of drugs that singly or in combination pose significant risks of adverse health outcomes. In the United States, prescribing of opioids and other "risky" drugs is a national public health concern. We use a novel data framework-a directed network connecting physicians who encounter the same patients in a sequence of visits-to investigate if risky-prescribing diffuses across physicians through a process of peer-influence. Using a shared-patient network of 10 661 Ohio-based physicians constructed from Medicare claims data over 2014-2015, we extract information on the order in which patients encountered physicians to derive a directed patient-sharing network. This enables the novel decomposition of peer-effects of a medical practice such as risky-prescribing into directional (outbound and inbound) and bidirectional (mutual) relationship components. Using this framework, we develop models of peer-effects for contagion in risky-prescribing behavior as well as spillover effects. The latter is measured in terms of adverse health events suspected to be related to risky-prescribing in patients of peer-physicians. Estimated peer-effects were strongest when the patient-sharing relationship was mutual as opposed to directional. Using simulations we confirmed that our modeling and estimation strategies allows simultaneous estimation of each type of peer-effect (mutual and directional) with accuracy and precision. We also show that failing to account for these distinct mechanisms (a form of model mis-specification) produces misleading results, demonstrating the importance of retaining directional information in the construction of physician shared-patient networks. These findings suggest network-based interventions for reducing risky-prescribing.

Irritability: associations with real-time affect dynamics, social interactions, and daily substance use in older adolescents.

Irritability is a common and clinically significant symptom associated with a wide range of negative outcomes. Ecological Momentary Assessment (EMA) is a valuable tool for capturing experiences, such as emotions, social interactions, and substance use in real-time, and may be useful in understanding how irritability is related to everyday functioning. We investigated cross-sectional associations between a widely used self-report irritability rating scale and affect dynamics, social interactions, and substance use captured with EMA (5 surveys daily for 14 days) in 349 18-year-olds. We also examined the associations of self- and parent-reported irritability at ages 12 and 15 with the age 18 EMA variables to explore whether these relationships persist over time. Youth-reported irritability at age 18 was linked to greater intensity, variability, and inertia of irritability, sadness, and anxiety, less positive and more negative interpersonal experiences, and greater cigarette and drug use. Most effect sizes were in the medium-small range. Associations of youth- and parent-reported irritability at ages 12 and 15 with the age 18 EMA measures were generally similar, although smaller in magnitude. Findings contribute to understanding how irritability is manifested in real-time affect dynamics and interpersonal functioning, as well as daily substance use. Most effects were evident over the course of up to 6 years - that is, early adolescent irritability, reported by both youth and their parents, was associated with similar real-time affect dynamics and interpersonal experiences at age 18. This study contributes to the literature on the developmental psychopathology of irritability by extending findings to everyday functioning.

Cerebellar output neurons impair non-motor behaviors by altering development of extracerebellar connectivity.

The capacity of the brain to compensate for insults during development depends on the type of cell loss, whereas the consequences of genetic mutations in the same neurons are difficult to predict. We reveal powerful compensation from outside the cerebellum when the excitatory cerebellar output neurons are ablated embryonically and demonstrate that the minimum requirement for these neurons is for motor coordination and not learning and social behaviors. In contrast, loss of the homeobox transcription factors Engrailed1/2 (EN1/2) in the cerebellar excitatory lineage leads to additional deficits in adult learning and spatial working memory, despite half of the excitatory output neurons being intact. Diffusion MRI indicates increased thalamo-cortico-striatal connectivity in En1/2 mutants, showing that the remaining excitatory neurons lacking En1/2 exert adverse effects on extracerebellar circuits regulating motor learning and select non-motor behaviors. Thus, an absence of cerebellar output neurons is less disruptive than having cerebellar genetic mutations.

The Role of Shame in the Sexual-Orientation Disparity in Mental Health: A Prospective Population-Based Study of Multimodal Emotional Reactions to Stigma.

Despite the prominence of shame in stigma theories, its role in explaining population-level mental health disparities between the stigmatized and non-stigmatized has not been investigated. We assessed shame explicitly (via self-report) and implicitly (via a behavioral task) in a prospective, representative cohort of sexual minority and heterosexual young adults in Sweden (baseline n=2,222). Compared to heterosexuals, sexual minorities evidenced higher explicit and implicit shame, which explained sexual orientation disparities in depression, social anxiety, and suicidal thoughts. Among sexual minorities, there was an indirect effect of shame in the association between interpersonal stigma (i.e., past-year family rejection and childhood bullying) and later experiences of adverse mental health; an indirect effect did not exist for the related construct, internalized stigma. Results suggest extending existing stigma theories to consider emotions like shame as characteristic reactions to stigma and guide the search for treatment targets focused on reducing the mental health sequelae of stigma.

Engrailed transcription factors direct excitatory cerebellar neuron diversity and survival.

The excitatory neurons of the three cerebellar nuclei (eCN) form the primary output for the cerebellum. The medial eCN (eCNm) were recently divided into molecularly defined subdomains in the adult, however how they are established during development is not known. We define molecular subdomains of the embryonic eCNm using scRNA-seq and spatial expression analysis, showing they evolve during embryogenesis to prefigure the adult. Furthermore, the medial eCN are transcriptionally divergent from the other nuclei by E14.5. We previously showed that loss of the homeobox genes En1 and En2 leads to loss of approximately half of embryonic eCNm. We demonstrate that mutation of En1/2 in embryonic eCNm results in death of specific posterior eCNm molecular subdomains and down regulation of TBR2 (EOMES) in an anterior embryonic subdomain, as well as reduced synaptic gene expression. We further reveal a similar function for EN1/2 in mediating TBR2 expression, neuron differentiation and survival in the other excitatory neurons (granule and unipolar brush cells). Thus, our work defines embryonic eCNm molecular diversity and reveals conserved roles for EN1/2 in the cerebellar excitatory neuron lineage.

CCT and Cullin1 Regulate the TORC1 Pathway to Promote Dendritic Arborization in Health and Disease.

The development of cell-type-specific dendritic arbors is integral to the proper functioning of neurons within their circuit networks. In this study, we examine the regulatory relationship between the cytosolic chaperonin CCT, key insulin pathway genes, and an E3 ubiquitin ligase (Cullin1) in dendritic development. CCT loss of function (LOF) results in dendritic hypotrophy in Drosophila Class IV (CIV) multi-dendritic larval sensory neurons, and CCT has recently been shown to fold components of the TOR (Target of Rapamycin) complex 1 (TORC1) in vitro. Through targeted genetic manipulations, we confirm that an LOF of CCT and the TORC1 pathway reduces dendritic complexity, while overexpression of key TORC1 pathway genes increases the dendritic complexity in CIV neurons. Furthermore, both CCT and TORC1 LOF significantly reduce microtubule (MT) stability. CCT has been previously implicated in regulating proteinopathic aggregation, thus, we examine CIV dendritic development in disease conditions as well. The expression of mutant Huntingtin leads to dendritic hypotrophy in a repeat-length-dependent manner, which can be rescued by Cullin1 LOF. Together, our data suggest that Cullin1 and CCT influence dendritic arborization through the regulation of TORC1 in both health and disease.

Paenilamicins from the honey bee pathogen Paenibacillus larvae are context-specific translocation inhibitors of protein synthesis.

The paenilamicins are a group of hybrid non-ribosomal peptide-polyketide compounds produced by the honey bee pathogen Paenibacillus larvae that display activity against Gram-positive pathogens, such as Staphylococcus aureus. While paenilamicins have been shown to inhibit protein synthesis, their mechanism of action has remained unclear. Here, we have determined structures of the paenilamicin PamB2 stalled ribosomes, revealing a unique binding site on the small 30S subunit located between the A- and P-site tRNAs. In addition to providing a precise description of interactions of PamB2 with the ribosome, the structures also rationalize the resistance mechanisms utilized by P. larvae. We could further demonstrate that PamB2 interferes with the translocation of mRNA and tRNAs through the ribosome during translation elongation, and that this inhibitory activity is influenced by the presence of modifications at position 37 of the A-site tRNA. Collectively, our study defines the paenilamicins as a new class of context-specific translocation inhibitors.

Community perceived barriers to uptake of health services among men at Sedibeng district in South Africa.

Background: This qualitative study aimed to investigate the barriers that hinder men's utilisation of healthcare services in the Sedibeng district of South Africa. Methods: The study was conducted using flyers with questions posted on the Best Health Solutions' Facebook page for two weeks. A convenience sampling method was used and a total of 104 comments were collected from 64 respondents. The authors analysed the participants' self-reported data thematically on demographics, geographic area, and reasons for men not using healthcare services. Results: The findings revealed that sociocultural norms played a significant role in men's reluctance to seek medical help, as it was perceived as a sign of weakness. The scarcity of male healthcare professionals hinders open discussions. Stigma and discrimination were identified as substantial barriers. Convenience, trust, and confidentiality concerns, along with the influence of intimate partners, also influence men's decision-making. Conclusion: This study highlights the complex interplay between various barriers that impact men's utilisation of healthcare services in the district. By addressing these factors, healthcare providers and policymakers can enhance healthcare access and promote better health outcomes for men in Sedibeng district. Contribution: The manuscript's primary contribution lies in uncovering multifaceted barriers to men's healthcare utilisation in Sedibeng district. It explores socio-cultural norms, healthcare worker demographics, stigma, discrimination, convenience factors, trust, confidentiality concerns, and the influence of intimate partners on men's healthcare choices. These insights illuminate the complex factors affecting men's healthcare access, providing valuable knowledge for healthcare providers and policymakers.

Relative contributions of the face and body to social judgements: emotion, threat and status.

Do the nonverbal signals used to make social judgements differ depending on the type of judgement being made and what other nonverbal signals are visible? Experiment 1 investigated how nonverbal signals across three channels (face: angry/fearful, posture: expanded/contracted, lean: forward/backward), when viewed together, were used for judgements of emotion, threat, and status. Experiment 2 replicated Experiment 1 and explored how use of the body channels differed in making social judgements when the face channel was obscured. Both experiments found facial anger linked to high anger, threat, and status ratings; facial fear was linked to low ratings. Expanded body posture increased threat and status judgements, while backward lean decreased anger and threat. With the face channel blocked (Experiment 2B), the influence of body posture increased across emotion, threat, and status judgements, while body lean was more consistent. Findings demonstrate that despite the face's importance across types of social judgements, the body channels differentially contribute to judgements of emotion, threat and status. Further, they are differentially affected by the absence of facial information. How much face and body-related channels are used in social judgements is moderated by the type of judgement being made and the availability of other (particularly facial) channel information.

Thalamocortical architectures for flexible cognition and efficient learning.

The brain exhibits a remarkable ability to learn and execute context-appropriate behaviors. How it achieves such flexibility, without sacrificing learning efficiency, is an important open question. Neuroscience, psychology, and engineering suggest that reusing and repurposing computations are part of the answer. Here, we review evidence that thalamocortical architectures may have evolved to facilitate these objectives of flexibility and efficiency by coordinating distributed computations. Recent work suggests that distributed prefrontal cortical networks compute with flexible codes, and that the mediodorsal thalamus provides regularization to promote efficient reuse. Thalamocortical interactions resemble hierarchical Bayesian computations, and their network implementation can be related to existing gating, synchronization, and hub theories of thalamic function. By reviewing recent findings and providing a novel synthesis, we highlight key research horizons integrating computation, cognition, and systems neuroscience.

Effect of manual OCTA segmentation correction to improve image quality and visibility of choroidal neovascularization in AMD.

In this retrospective case series on neovascular age-related macular degeneration (nAMD), we aimed to improve Choroidal Neovascularization (CNV) visualization in Optical Coherence Tomography Angiography (OCTA) scans by addressing segmentation errors. Out of 198 eyes, 73 OCTA scans required manual segmentation correction. We compared uncorrected scans to those with minimal (2 corrections), moderate (10 corrections), and detailed (50 corrections) efforts targeting falsely segmented Bruch's Membrane (BM). Results showed that 55% of corrected OCTAs exhibited improved quality after manual correction. Notably, minimal correction (2 scans) already led to significant improvements, with additional corrections (10 or 50) not further enhancing expert grading. Reduced background noise and improved CNV identification were observed, with the most substantial improvement after two corrections compared to baseline uncorrected images. In conclusion, our approach of correcting segmentation errors effectively enhances image quality in OCTA scans of nAMD. This study demonstrates the efficacy of the method, with 55% of resegmented OCTA images exhibiting enhanced quality, leading to a notable increase in the proportion of high-quality images from 63 to 83%.

Associations between polygenic risk scores for cardiometabolic phenotypes and adolescent depression and body dissatisfaction.

BACKGROUND: Adolescents with elevated body mass index (BMI) are at an increased risk for depression and body dissatisfaction. Type 2 diabetes (T2D) is an established risk factor for depression. However, shared genetic risk between cardiometabolic conditions and mental health outcomes remains understudied in youth. METHODS: The current study examined associations between polygenic risk scores (PRS) for BMI and T2D, and symptoms of depression and body dissatisfaction, in a sample of 827 community adolescents (Mage = 13.63, SDage = 1.01; 76% girls). BMI, depressive symptoms, and body dissatisfaction were assessed using validated self-report questionnaires. RESULTS: BMI-PRS was associated with phenotypic BMI (ß = 0.24, p < 0.001) and body dissatisfaction (ß = 0.17, p < 0.001), but not with depressive symptoms. The association between BMI-PRS and body dissatisfaction was significantly mediated by BMI (indirect effect = 0.10, CI [0.07-0.13]). T2D-PRS was not associated with depression or body dissatisfaction. CONCLUSIONS: The results suggest phenotypic BMI may largely explain the association between genetic risk for elevated BMI and body dissatisfaction in adolescents. Further research on age-specific genetic effects is needed, as summary statistics from adult discovery samples may have limited utility in youth. IMPACT: The association between genetic risk for elevated BMI and body dissatisfaction in adolescents may be largely explained by phenotypic BMI, indicating a potential pathway through which genetic predisposition influences body image perception. Furthermore, age-specific genetic research is needed to understand the unique influences on health outcomes during adolescence. By identifying BMI as a potential mediator in the association between genetic risk for elevated BMI and body dissatisfaction, the current findings offer insights that could inform interventions targeting body image concerns and mental health in this population.

The ABCF ATPase New1 resolves translation termination defects associated with specific tRNAArg and tRNALys isoacceptors in the P site.

The efficiency of translation termination is determined by the nature of the stop codon as well as its context. In eukaryotes, recognition of the A-site stop codon and release of the polypeptide are mediated by release factors eRF1 and eRF3, respectively. Translation termination is modulated by other factors which either directly interact with release factors or bind to the E-site and modulate the activity of the peptidyl transferase center. Previous studies suggested that the Saccharomyces cerevisiae ABCF ATPase New1 is involved in translation termination and/or ribosome recycling, however, the exact function remained unclear. Here, we have applied 5PSeq, single-particle cryo-EM and readthrough reporter assays to provide insight into the biological function of New1. We show that the lack of New1 results in ribosomal stalling at stop codons preceded by a lysine or arginine codon and that the stalling is not defined by the nature of the C-terminal amino acid but rather by the identity of the tRNA isoacceptor in the P-site. Collectively, our results suggest that translation termination is inefficient when ribosomes have specific tRNA isoacceptors in the P-site and that the recruitment of New1 rescues ribosomes at these problematic termination contexts.

Advanced age worsens respiratory function and pulmonary inflammation after burn injury and this correlates with changes in the fecal microbiome in mice.

Cutaneous burn injury in the elderly is associated with poor clinical outcomes and increased pulmonary-related complications. We and others have shown that burn injury triggers a cascade of inflammatory mediators which increase gut permeability and dysbiosis of the fecal microbiota and this is more dramatic in the aged. Since cross-talk between intestinal microbes and the lung, termed the "gut-lung axis," impacts immunity and homeostasis in the airway, we hypothesized that the increased intestinal dysbiosis in age and burn injury may contribute to excessive pulmonary inflammation and poor prognosis after injury. To explore this hypothesis, we used a clinically relevant murine model of burn injury in which young and aged mice are subjected to a 12% total body surface area dorsal scald burn or sham injury. 24 hours after injury, lung function was assessed and lungs and feces were collected for analysis of inflammatory mediators and fecal microbial species. The results show that, when compared to younger mice, burn injury in aged mice triggers a decline in respiratory function and exacerbates pulmonary inflammation. In addition to heightened levels of the neutrophil recruiting chemokine CXCL1, aged mice displayed a profound increase in the pro-inflammatory protein, calprotectin, in the lung after burn injury. Comparison of the fecal microbiome and inflammatory markers in the lung revealed unique, age-dependent, correlation patterns between individual taxa and pulmonary inflammation. Taken together, these findings suggest that the post-burn dysbiosis of the gut flora in aged mice may contribute to the changes in pulmonary inflammatory profiles.

Molecular mechanism of the ischemia-induced regulatory switch in mammalian complex I.

Respiratory complex I is an efficient driver for oxidative phosphorylation in mammalian mitochondria, but its uncontrolled catalysis under challenging conditions leads to oxidative stress and cellular damage. Ischemic conditions switch complex I from rapid, reversible catalysis into a dormant state that protects upon reoxygenation, but the molecular basis for the switch is unknown. We combined precise biochemical definition of complex I catalysis with high-resolution cryo-electron microscopy structures in the phospholipid bilayer of coupled vesicles to reveal the mechanism of the transition into the dormant state, modulated by membrane interactions. By implementing a versatile membrane system to unite structure and function, attributing catalytic and regulatory properties to specific structural states, we define how a conformational switch in complex I controls its physiological roles.

Lung sparing in MR-guided non-adaptive SBRT treatment of peripheral lung tumors.

Objective.We aim to: (1) quantify the benefits of lung sparing using non-adaptive magnetic resonance guided stereotactic body radiotherapy (MRgSBRT) with advanced motion management for peripheral lung cancers compared to conventional x-ray guided SBRT (ConvSBRT); (2) establish a practical decision-making guidance metric to assist a clinician in selecting the appropriate treatment modality.Approach.Eleven patients with peripheral lung cancer who underwent breath-hold, gated MRgSBRT on an MR-guided linear accelerator (MR linac) were studied. Four-dimensional computed tomography (4DCT)-based retrospective planning using an internal target volume (ITV) was performed to simulate ConvSBRT, which were evaluated against the original MRgSBRT plans. Metrics analyzed included planning target volume (PTV) coverage, various lung metrics and the generalized equivalent unform dose (gEUD). A dosimetric predictor for achievable lung metrics was derived to assist future patient triage across modalities.Main results.PTV coverage was high (median V100% > 98%) and comparable for both modalities. MRgSBRT had significantly lower lung doses as measured by V20 (median 3.2% versus 4.2%), mean lung dose (median 3.3 Gy versus 3.8 Gy) and gEUD. Breath-hold, gated MRgSBRT resulted in an average reduction of 47% in PTV volume and an average increase of 19% in lung volume. Strong correlation existed between lung metrics and the ratio of PTV to lung volumes (RPTV/Lungs) for both modalities, indicating that RPTV/Lungsmay serve as a good predictor for achievable lung metrics without the need for pre-planning. A threshold value of RPTV/Lungs< 0.035 is suggested to achieve V20 < 10% using ConvSBRT. MRgSBRT should otherwise be considered if the threshold cannot be met.Significance.The benefits of lung sparing using MRgSBRT were quantified for peripheral lung tumors; RPTV/Lungswas found to be an effective predictor for achievable lung metrics across modalities. RPTV/Lungscan assist a clinician in selecting the appropriate modality without the need for labor-intensive pre-planning, which has significant practical benefit for a busy clinic.