Optical Approaches for Investigating Neuromodulation and G Protein-Coupled Receptor Signaling.

Despite the fact that roughly 40% of all US Food and Drug Administration (FDA)-approved pharmacological therapeutics target G protein-coupled receptors (GPCRs), there remains a gap in our understanding of the physiologic and functional role of these receptors at the systems level. Although heterologous expression systems and in vitro assays have revealed a tremendous amount about GPCR signaling cascades, how these cascades interact across cell types, tissues, and organ systems remains obscure. Classic behavioral pharmacology experiments lack both the temporal and spatial resolution to resolve these long-standing issues. Over the past half century, there has been a concerted effort toward the development of optical tools for understanding GPCR signaling. From initial ligand uncaging approaches to more recent development of optogenetic techniques, these strategies have allowed researchers to probe longstanding questions in GPCR pharmacology both in vivo and in vitro. These tools have been employed across biologic systems and have allowed for interrogation of everything from specific intramolecular events to pharmacology at the systems level in a spatiotemporally specific manner. In this review, we present a historical perspective on the motivation behind and development of a variety of optical toolkits that have been generated to probe GPCR signaling. Here we highlight how these tools have been used in vivo to uncover the functional role of distinct populations of GPCRs and their signaling cascades at a systems level. SIGNIFICANCE STATEMENT: G protein-coupled receptors (GPCRs) remain one of the most targeted classes of proteins for pharmaceutical intervention, yet we still have a limited understanding of how their unique signaling cascades effect physiology and behavior at the systems level. In this review, we discuss a vast array of optical techniques that have been devised to probe GPCR signaling both in vitro and in vivo.

MELLODDY: Cross-pharma Federated Learning at Unprecedented Scale Unlocks Benefits in QSAR without Compromising Proprietary Information.

Federated multipartner machine learning has been touted as an appealing and efficient method to increase the effective training data volume and thereby the predictivity of models, particularly when the generation of training data is resource-intensive. In the landmark MELLODDY project, indeed, each of ten pharmaceutical companies realized aggregated improvements on its own classification or regression models through federated learning. To this end, they leveraged a novel implementation extending multitask learning across partners, on a platform audited for privacy and security. The experiments involved an unprecedented cross-pharma data set of 2.6+ billion confidential experimental activity data points, documenting 21+ million physical small molecules and 40+ thousand assays in on-target and secondary pharmacodynamics and pharmacokinetics. Appropriate complementary metrics were developed to evaluate the predictive performance in the federated setting. In addition to predictive performance increases in labeled space, the results point toward an extended applicability domain in federated learning. Increases in collective training data volume, including by means of auxiliary data resulting from single concentration high-throughput and imaging assays, continued to boost predictive performance, albeit with a saturating return. Markedly higher improvements were observed for the pharmacokinetics and safety panel assay-based task subsets.

Does Researcher Allegiance Bias Outcomes in Psychotherapy Research? A Quasi-Experimental Secondary Analysis.

Researchers who conduct studies comparing the efficacy of two treatments often find that their preferred treatment outperforms the comparison treatment. This finding has been labelled the allegiance association. Although this association is robust, it is unclear whether it reflects an allegiance bias on the part of the researchers or whether it is noncausal, with researchers being allied to the more effective treatments. This study applied a quasi-experimental method proposed by a previous study to 19 pairs of treatment comparison studies. Each member of a pair had used the same two psychotherapies to treat clients with the same disorder, but the researchers in each of the two studies had opposing allegiances. If the authors of one study in the pair concluded that their preferred treatment was superior and the authors of the other study concluded that their preferred treatment was superior or that the two treatments were equivalent, these patterns would suggest allegiance bias. In 10 of the 19 pairs, the patterns were consistent with the operation of an allegiance bias, indicating that although allegiance biases are not inevitable, they are ubiquitous. Practitioners and other psychotherapy research consumers should use caution when interpreting the findings from treatment comparison studies.

Bipolar disorders and narcissism: Diagnostic concerns, conceptual commonalities and potential antecedents.

Narcissistic personality disorder (NPD) and the manic and hypomanic episodes found in the bipolar disorders are characterized by grandiosity. It is possible that this shared grandiosity is a 'homologous structure' or reflects a superficial similarity between two disparate conditions. It is, however, possible that NPD and the bipolar disorders are more closely related than implied by their segregation into the separate superordinate categories of personality disorders and mood disorders. Whereas narcissism is considered to be a life-course, stable trait and the bipolar disorders are characterized by episodes of mania and depression, there is considerable research indicating that narcissism may be linked to mood instability (including depression) and bipolar disorder may have a pervasive personality component (i.e., hypomanic personality). Utilizing dimensional models of psychopathology, the current review examined the evidence linking narcissism and the bipolar disorders and suggests that considerable overlap may exist in the domains associated with reward-seeking, harm avoidance and social functioning.

Arrestin-3 scaffolding of the JNK3 cascade suggests a mechanism for signal amplification.

Scaffold proteins tether and orient components of a signaling cascade to facilitate signaling. Although much is known about how scaffolds colocalize signaling proteins, it is unclear whether scaffolds promote signal amplification. Here, we used arrestin-3, a scaffold of the ASK1-MKK4/7-JNK3 cascade, as a model to understand signal amplification by a scaffold protein. We found that arrestin-3 exhibited >15-fold higher affinity for inactive JNK3 than for active JNK3, and this change involved a shift in the binding site following JNK3 activation. We used systems biochemistry modeling and Bayesian inference to evaluate how the activation of upstream kinases contributed to JNK3 phosphorylation. Our combined experimental and computational approach suggested that the catalytic phosphorylation rate of JNK3 at Thr-221 by MKK7 is two orders of magnitude faster than the corresponding phosphorylation of Tyr-223 by MKK4 with or without arrestin-3. Finally, we showed that the release of activated JNK3 was critical for signal amplification. Collectively, our data suggest a "conveyor belt" mechanism for signal amplification by scaffold proteins. This mechanism informs on a long-standing mystery for how few upstream kinase molecules activate numerous downstream kinases to amplify signaling.

Evidence for the taxonic latent structure for DSM-5 intermittent explosive disorder in adults.

BACKGROUND: Identification of individuals with clinically significant aggressive behavior is critical for the prevention and management of human aggressive behavior. A previous population-based taxometric study reported that the Diagnostic and Statistical Manual of Mental Disorders-4th Edition (DSM-IV) intermittent explosive disorder (IED) belongs to its own discrete class (taxon) rather than existing along a continuum. METHODS: This study sought to extend previous population-based findings in a clinical research sample of adults with DSM-5 IED (n = 346), adults with non-aggressive DSM-5 disorders (n = 293), and adults without any DSM-5 disorder (n = 174), using standardized assessments of DSM-5 diagnoses, aggression, and other related measures not available in past studies. RESULTS: Analyses revealed a taxonic latent structure that overlapped with the DSM-5 diagnosis of IED. Within the sample, taxon group members had higher scores on a variety of measures of psychopathology than did the complement members of the sample. Comorbidity of other diagnoses with IED did not affect these results. CONCLUSION: These findings support the proposition that DSM-5 IED represents a distinct behavioral disorder rather than the severe end of an aggressive behavior continuum.

Neuropsychological Phenotypes of Pediatric Anti-Myelin Oligodendrocyte Glycoprotein Associated Disorders: A Case Series.

Emerging research has demonstrated that anti-myelin oligodendrocyte associated disorders (MOG-AD) are associated with a less severe clinical course than demyelinating conditions associated with the presence of aquaporin-4 antibodies. While a heterogeneity of neuropsychological outcomes in pediatric demyelinating conditions have been described in the literature, no studies to date have investigated the neuropsychological sequelae of pediatric MOG-AD specifically. The objective of the present case series was to describe the clinical and neuropsychological phenotypes of seven pediatric patients (ages 3-15 years) with MOG-AD of different diagnoses (e.g., acute disseminated encephalomyelitis, optic neuritis, multiple sclerosis, and neuromyelitis spectrum disorders). Neuropsychological outcomes were evaluated by retrospective chart review. Results indicated largely intact neuropsychological profiles in five of the seven patients, with mild weaknesses in attention, executive functioning, processing speed, visual-motor/fine-motor skills, and mood concerns being observed. Two patients with a Kurtzke Extended Disability Status Scale of 0 still demonstrated findings on neuropsychological testing. Of the other two patients, one demonstrated higher levels of impairment in the context of a complex medical history and premorbid learning difficulties, while the other demonstrated declines in functioning likely associated with an earlier age of onset. Findings suggest that neuropsychological outcomes may be correspondingly less severe in this population compared with what has previously been described in the pediatric demyelinating disease literature. This differential impact may contribute to the heterogeneity of neuropsychological outcomes found in previous studies, and future research should separate participants with myelin oligodendrocyte antibodies given the difference in clinical course, treatment outcomes, and neuropsychological sequelae.

BRADSHAW: a system for automated molecular design.

This paper introduces BRADSHAW (Biological Response Analysis and Design System using an Heterogenous, Automated Workflow), a system for automated molecular design which integrates methods for chemical structure generation, experimental design, active learning and cheminformatics tools. The simple user interface is designed to facilitate access to large scale automated design whilst minimising software development required to introduce new algorithms, a critical requirement in what is a very fast moving field. The system embodies a philosophy of automation, best practice, experimental design and the use of both traditional cheminformatics and modern machine learning algorithms.

Correction to: BRADSHAW: a system for automated molecular design.

The original version of this article unfortunately contained some mistakes in the references.

Design thinking in medical ethics education.

BACKGROUND: Design thinking (DT) is a tool for generating and exploring ideas from multiple stakeholders. We used DT principles to introduce students to the ethical implications of organ transplantation. Students applied DT principles to propose solutions to maximise social justice in liver transplant allocation. METHODS: A 150 min interactive workshop was integrated into the longitudinal ethics curriculum. Following a group didactic on challenges of organ donation in the USA supplemented by patient stories, teams of students considered alternative solutions to optimise fairness of organ distribution and ethical implications of changing the current model. Facilitators led students through DT steps of empathy, defining the team's point of view, ideating on potential solutions, prototyping a specific idea and testing the idea through oral presentation, with questions and answers by peers and faculty. The curriculum was evaluated with presurveys and postsurveys including quantitative and open-ended items. RESULTS: 100 first year medical students participated. Before the session, 75.3% of students had no practical experience with DT. Following participation, students reported an increased understanding of the current liver transplant allocation system (p<0.01) and an increased appreciation of shortcomings of the current organ allocation system (p<0.01). After the session, 73.8% of students felt that DT could be used to approach complex health system problems. DISCUSSION: Students participating in a DT workshop displayed improved knowledge and attitudes toward organ transplantation and DT. In this pilot study, DT showed promise as a student-led approach emphasising collaboration and creativity in ethics curricula in medical education.

ProSAAS-derived peptides are regulated by cocaine and are required for sensitization to the locomotor effects of cocaine.

To identify neuropeptides that are regulated by cocaine, we used a quantitative peptidomic technique to examine the relative levels of neuropeptides in several regions of mouse brain following daily intraperitoneal administration of 10 mg/kg cocaine or saline for 7 days. A total of 102 distinct peptides were identified in one or more of the following brain regions: nucleus accumbens, caudate putamen, frontal cortex, and ventral tegmental area. None of the peptides detected in the caudate putamen or frontal cortex were altered by cocaine administration. Three peptides in the nucleus accumbens and seven peptides in the ventral tegmental area were significantly decreased in cocaine-treated mice. Five of these ten peptides are derived from proSAAS, a secretory pathway protein and neuropeptide precursor. To investigate whether proSAAS peptides contribute to the physiological effects of psychostimulants, we examined acute responses to cocaine and amphetamine in the open field with wild-type (WT) and proSAAS knockout (KO) mice. Locomotion was stimulated more robustly in the WT compared to mutant mice for both psychostimulants. Behavioral sensitization to amphetamine was not maintained in proSAAS KO mice and these mutants failed to sensitize to cocaine. To determine whether the rewarding effects of cocaine were altered, mice were tested in conditioned place preference (CPP). Both WT and proSAAS KO mice showed dose-dependent CPP to cocaine that was not distinguished by genotype. Taken together, these results suggest that proSAAS-derived peptides contribute differentially to the behavioral sensitization to psychostimulants, while the rewarding effects of cocaine appear intact in mice lacking proSAAS.

Mutation of putative GRK phosphorylation sites in the cannabinoid receptor 1 (CB1R) confers resistance to cannabinoid tolerance and hypersensitivity to cannabinoids in mice.

For many G-protein-coupled receptors (GPCRs), including cannabinoid receptor 1 (CB1R), desensitization has been proposed as a principal mechanism driving initial tolerance to agonists. GPCR desensitization typically requires phosphorylation by a G-protein-coupled receptor kinase (GRK) and interaction of the phosphorylated receptor with an arrestin. In simple model systems, CB1R is desensitized by GRK phosphorylation at two serine residues (S426 and S430). However, the role of these serine residues in tolerance and dependence for cannabinoids in vivo was unclear. Therefore, we generated mice where S426 and S430 were mutated to nonphosphorylatable alanines (S426A/S430A). S426A/S430A mutant mice were more sensitive to acutely administered delta-9-tetrahydrocannabinol (Δ(9)-THC), have delayed tolerance to Δ(9)-THC, and showed increased dependence for Δ(9)-THC. S426A/S430A mutants also showed increased responses to elevated levels of endogenous cannabinoids. CB1R desensitization in the periaqueductal gray and spinal cord following 7 d of treatment with Δ(9)-THC was absent in S426A/S430A mutants. Δ(9)-THC-induced downregulation of CB1R in the spinal cord was also absent in S426A/S430A mutants. Cultured autaptic hippocampal neurons from S426A/S430A mice showed enhanced endocannabinoid-mediated depolarization-induced suppression of excitation (DSE) and reduced agonist-mediated desensitization of DSE. These results indicate that S426 and S430 play major roles in the acute response to, tolerance to, and dependence on cannabinoids. Additionally, S426A/S430A mice are a novel model for studying pathophysiological processes thought to involve excessive endocannabinoid signaling such as drug addiction and metabolic disease. These mice also validate the approach of mutating GRK phosphorylation sites involved in desensitization as a general means to confer exaggerated signaling to GPCRs in vivo.

Tolerance to the antinociceptive effects of chronic morphine requires c-Jun N-terminal kinase.

BACKGROUND: Morphine and fentanyl are opioid analgesics in wide clinical use that act through the µ-opioid receptor (MOR). However, one limitation of their long-term effectiveness is the development of tolerance. Receptor desensitization has been proposed as a putative mechanism driving tolerance to G protein-coupled receptor (GPCR) agonists. Recent studies have found that tolerance to morphine is mediated by the c-Jun N-terminal Kinase (JNK) signaling pathway. The goal of the present study was to test the hypotheses that: 1) JNK inhibition will be antinociceptive on its own; 2) JNK inhibition will augment morphine antinociception and; 3) JNK mediates chronic tolerance for the antinociceptive effects of morphine using acute (hotplate and tail-flick), inflammatory (10 µl of formalin 2.5%) and chemotherapy (cisplatin 5 mg/kg ip once weekly)-induced neuropathic pain assays. RESULTS: We found that JNK inhibition by SP600125 (3 mg/kg) produces a greater antinociceptive effect than morphine (6 mg/kg) alone in the formalin test. Moreover, co-administration of morphine (6 mg/kg) with SP600125 (3 mg/kg) produced a sub-additive antinociceptive effect in the formalin test. We also show that pre-treatment with SP600125 (3 or 10 mg/kg), attenuates tolerance to the antinociceptive effects of morphine (10 mg/kg), but not fentanyl (0.3 mg/kg), in the tail-flick and hotplate tests. Pre-treatment with SP600125 also attenuates tolerance to the hypothermic effects of both morphine and fentanyl. We also examined the role of JNK in morphine tolerance in a cisplatin-induced model of neuropathic pain. Interestingly, treatment with SP600125 (3 mg/kg) alone attenuated mechanical and cold allodynia in a chemotherapy-induced pain model using cisplatin. Strikingly, SP600125 (3 mg/kg) pre-treatment prolonged the anti-allodynic effect of morphine by several days (5 and 7 days for mechanical and cold, respectively). CONCLUSIONS: These results demonstrate that JNK signaling plays a crucial role in mediating antinociception as well as chronic tolerance to the antinociceptive effects of morphine in acute, inflammatory, and neuropathic pain states. Thus, inhibition of JNK signaling pathway, via SP600125, represents an efficacious pharmacological approach to delay tolerance to the antinociceptive effects of chronic morphine in diverse pain models.

Homosexuality as a Discrete Class.

Previous research on the latent structure of sexual orientation has returned conflicting results, with some studies finding a dimensional structure (i.e., ranging quantitatively along a spectrum) and others a taxonic structure (i.e., categories of individuals with distinct orientations). The current study used a sample (N = 33,525) from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). A series of taxometric analyses were conducted using three indicators of sexual orientation: identity, behavior, and attraction. These analyses, performed separately for women and men, revealed low-base-rate same-sex-oriented taxa for men (base rate = 3.0%) and women (base rate = 2.7%). Generally, taxon membership conferred an increased risk for psychiatric and substance-use disorders. Although taxa were present for men and women, women demonstrated greater sexual fluidity, such that any level of same-sex sexuality conferred taxon membership for men but not for women.

How diverse are diversity assessment methods? A comparative analysis and benchmarking of molecular descriptor space.

Chemical diversity is a widely applied approach to select structurally diverse subsets of molecules, often with the objective of maximizing the number of hits in biological screening. While many methods exist in the area, few systematic comparisons using current descriptors in particular with the objective of assessing diversity in bioactivity space have been published, and this shortage is what the current study is aiming to address. In this work, 13 widely used molecular descriptors were compared, including fingerprint-based descriptors (ECFP4, FCFP4, MACCS keys), pharmacophore-based descriptors (TAT, TAD, TGT, TGD, GpiDAPH3), shape-based descriptors (rapid overlay of chemical structures (ROCS) and principal moments of inertia (PMI)), a connectivity-matrix-based descriptor (BCUT), physicochemical-property-based descriptors (prop2D), and a more recently introduced molecular descriptor type (namely, "Bayes Affinity Fingerprints"). We assessed both the similar behavior of the descriptors in assessing the diversity of chemical libraries, and their ability to select compounds from libraries that are diverse in bioactivity space, which is a property of much practical relevance in screening library design. This is particularly evident, given that many future targets to be screened are not known in advance, but that the library should still maximize the likelihood of containing bioactive matter also for future screening campaigns. Overall, our results showed that descriptors based on atom topology (i.e., fingerprint-based descriptors and pharmacophore-based descriptors) correlate well in rank-ordering compounds, both within and between descriptor types. On the other hand, shape-based descriptors such as ROCS and PMI showed weak correlation with the other descriptors utilized in this study, demonstrating significantly different behavior. We then applied eight of the molecular descriptors compared in this study to sample a diverse subset of sample compounds (4%) from an initial population of 2587 compounds, covering the 25 largest human activity classes from ChEMBL and measured the coverage of activity classes by the subsets. Here, it was found that "Bayes Affinity Fingerprints" achieved an average coverage of 92% of activity classes. Using the descriptors ECFP4, GpiDAPH3, TGT, and random sampling, 91%, 84%, 84%, and 84% of the activity classes were represented in the selected compounds respectively, followed by BCUT, prop2D, MACCS, and PMI (in order of decreasing performance). In addition, we were able to show that there is no visible correlation between compound diversity in PMI space and in bioactivity space, despite frequent utilization of PMI plots to this end. To summarize, in this work, we assessed which descriptors select compounds with high coverage of bioactivity space, and can hence be used for diverse compound selection for biological screening. In cases where multiple descriptors are to be used for diversity selection, this work describes which descriptors behave complementarily, and can hence be used jointly to focus on different aspects of diversity in chemical space.

Multiatlas segmentation of thoracic and abdominal anatomy with level set-based local search.

Segmentation of organs at risk (OARs) remains one of the most time-consuming tasks in radiotherapy treatment planning. Atlas-based segmentation methods using single templates have emerged as a practical approach to automate the process for brain or head and neck anatomy, but pose significant challenges in regions where large interpatient variations are present. We show that significant changes are needed to autosegment thoracic and abdominal datasets by combining multi-atlas deformable registration with a level set-based local search. Segmentation is hierarchical, with a first stage detecting bulk organ location, and a second step adapting the segmentation to fine details present in the patient scan. The first stage is based on warping multiple presegmented templates to the new patient anatomy using a multimodality deformable registration algorithm able to cope with changes in scanning conditions and artifacts. These segmentations are compacted in a probabilistic map of organ shape using the STAPLE algorithm. Final segmentation is obtained by adjusting the probability map for each organ type, using customized combinations of delineation filters exploiting prior knowledge of organ characteristics. Validation is performed by comparing automated and manual segmentation using the Dice coefficient, measured at an average of 0.971 for the aorta, 0.869 for the trachea, 0.958 for the lungs, 0.788 for the heart, 0.912 for the liver, 0.884 for the kidneys, 0.888 for the vertebrae, 0.863 for the spleen, and 0.740 for the spinal cord. Accurate atlas segmentation for abdominal and thoracic regions can be achieved with the usage of a multi-atlas and perstructure refinement strategy. To improve clinical workflow and efficiency, the algorithm was embedded in a software service, applying the algorithm automatically on acquired scans without any user interaction.

Endogenous opioids facilitate stress-induced binge eating via an insular cortex-claustrum pathway.

Stress has been shown to promote the development and persistence of binge eating behaviors. However, the neural circuit mechanisms for stress-induced binge-eating behaviors are largely unreported. The endogenous dynorphin (dyn)/kappa opioid receptor (KOR) opioid neuropeptide system has been well-established to be a crucial mediator of the anhedonic component of stress. Here, we aimed to dissect the basis of dynorphinergic control of stress-induced binge-like eating behavior. We first established a mouse behavioral model for stress-induced binge-like eating behaviors. We found that mice exposed to stress increased their food intake of familiar palatable food (high fat, high sugar, HPD) compared to non-stressed mice. Following a brain-wide analysis, we isolated robust cFos-positive cells in the Claustrum (CLA), a subcortical structure with highly abundant KOR expression, following stress-induced binge-eating behavior. We report that KOR signaling in CLA is necessary for this elevated stress-induced binge eating behavior using local pharmacology and local deletion of KOR. In vivo calcium recordings using fiber photometry revealed a disinhibition circuit structure in the CLA during the initiation of HPD feeding bouts. We further established the dynamics of endogenous dynorphinergic control of this behavior using a genetically encoded dynorphin biosensor, Klight. Combined with 1-photon single-cell calcium imaging, we report significant heterogeneity with the CLA population during stress-induced binge eating and such behavior attenuates local dynorphin tone. Furthermore, we isolate the anterior Insular cortex (aIC) as the potential source of endogenous dynorphin afferents in the CLA. By characterizing neural circuits and peptidergic mechanisms within the CLA, we uncover a pathway that implicates endogenous opioid regulation stress-induced binge eating.

Effect of prophylactic cranial irradiation on survival in elderly patients with limited-stage small cell lung cancer.

BACKGROUND: Prophylactic cranial irradiation (PCI) improves survival in patients with limited-stage small cell lung cancer (SCLC) who have a complete response to chemotherapy and radiotherapy, yet to the best of the authors' knowledge, data specific to the elderly population are lacking. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, the authors identified 1926 patients aged ≥ 70 years who were diagnosed with limited-stage SCLC between 1988 and 1997. Overall survival (OS) for patients who received PCI versus those who did not were estimated using the Kaplan-Meier method and compared with the log-rank test. A Cox proportional hazards model was further fitted to estimate the effect of PCI on OS after adjusting for age, race, sex, tumor size, lymph node status, stage of disease, and receipt of thoracic radiotherapy and surgery. RESULTS: The median age of the patients was 75 years (range, 70 years-94 years) and 138 patients (7.2 %) received PCI. The 2-year and 5-year OS rates were 33.3% (95% confidence interval [95% CI], 25.6%-41.2%) and 11.6% (95% CI, 6.9%-17.6%), respectively, among patients who received PCI versus 23.1% (95% CI, 21.2%-25.1%) and 8.6% (95% CI, 7.3%-9.9%), respectively, among patients who did not receive PCI (P = .028). On multivariable analysis, PCI was found to be an independent predictor of OS (hazards ratio, 0.72; 95% CI, 0.54-0.97 [P = .032]). On subgroup analysis, PCI remained an independent predictor of OS among patients aged ≥ 75 years, but not among patients aged ≥ 80 years. CONCLUSIONS: The receipt of PCI is associated with improved OS in patients aged ≥ 70 years with SCLC, suggesting that the benefit of PCI is maintained in the elderly population.

Therapeutic options for a rising PSA after radical prostatectomy.

INTRODUCTION: Radical prostatectomy is an effective primary treatment for clinically localized prostate cancer. While many patients are cured of their disease after surgery, there are still a significant proportion of men who will develop a biochemical recurrence (BCR). In this review, we detail existing treatment algorithms for this group of patients as well as future therapies that show great promise. MATERIALS AND METHODS: A review of the literature was performed, and relevant, high-impact articles were identified and reviewed focusing on the treatment of men with BCR after surgery for prostate cancer. Wherever possible, we used data from randomized, controlled trials. When lacking, multi-institutional retrospective studies were utilized. RESULTS: In a man with BCR, it is important to differentiate between local and distant failure to help guide treatment decision-making. In many of these men, adjuvant or salvage radiotherapy can improve local control, and in the case of salvage radiotherapy, it can improve overall survival (OS). Moreover, there are several systemic therapies available to men with gross metastases and/or castration resistant prostate cancer (CRPC) that have demonstrated a significant survival advantage as well as symptom control. CONCLUSIONS: In the setting of BCR, many treatment options exist. Each modality has an effective role in the management of men with locally recurrent or metastatic prostate cancer. Furthermore, there are currently a number of effective therapies for men who progress to metastatic CRPC. In this review, we present current data detailing the role/efficacy of each therapy for a rising prostate-specific antigen (PSA) after definitive surgical therapy.

When, If Ever, Is It Appropriate to Regard a Patient as "Too Medically Complex" for One Inpatient Service, But Not Another?

Patients with chronic health conditions often find their admission for orthopedic surgery from the emergency department held up due to disagreement between orthopedists and internal medicine physicians, such as hospitalists. One reason for this delay is that orthopedists must decide which patients they will admit. Although this decision is based on clinical criteria, variation in orthopedists' practices and views of a patient's condition's medical complexity is a common source of physician disagreement. This commentary on a case describes constraints on hospitalists and orthopedists, as well as other factors in patient disposition, and suggests quality improvements to admissions processes that might help mitigate the distress that patients can experience as a result of health professional disagreement.