Bipolar disorder: Diagnosis, treatment and future directions.

Bipolar disorder is a relatively common mental illness, characterised by recurrent episodes of mania (or hypomania) and major depression, and associated with a significant burden of morbidity and premature mortality. Physicians across all specialities are likely to encounter individuals with the condition within their clinical practice. This short review provides an up-to-date overview of the clinical features, epidemiology, pathophysiology, evidence-based management, prognosis and future directions for treatment and research in bipolar disorder. Aspects of cross-specialty relevance are highlighted, including the physical health burden associated with the condition, and the side effects and safety considerations of medication regimes used in bipolar disorder.

Crowding in the Emergency Department: Challenges and Recommendations for the Care of Children.

Emergency department (ED) crowding results when available resources cannot meet the demand for emergency services. ED crowding has negative impacts on patients, health care workers, and the community. Primary considerations for reducing ED crowding include improving the quality of care, patient safety, patient experience, and the health of populations, as well as reducing the per capita cost of health care. Evaluating causes, effects, and seeking solutions to ED crowding can be done within a conceptual framework addressing input, throughput, and output factors. ED leaders must coordinate with hospital leadership, health system planners and policy decision makers, and those who provide pediatric care to address ED crowding. Proposed solutions in this policy statement promote the medical home and timely access to emergency care for children.

Crowding in the Emergency Department: Challenges and Best Practices for the Care of Children.

Emergency department (ED) crowding has been and continues to be a national concern. ED crowding is defined as a situation in which the identified need for emergency services outstrips available resources in the ED. Crowding is associated with higher morbidity and mortality, delayed pain control, delayed time to administration of antibiotics, increased medical errors, and less-than-optimal health care. ED crowding impedes a hospital's ability to achieve national quality and patient safety goals, diminishes the effectiveness of the health care safety net, and limits the capacity of hospitals to respond to a disaster and/or sudden surge in disease. Both children and adults seeking care in emergency settings are placed at risk. Crowding negatively influences the experience for patients, families, and providers, and can impact employee turnover and well-being. No single factor is implicated in creating the issue of crowding, but elements that influence crowding can be divided into those that affect input (prehospital and outpatient care), throughput (ED), and output (hospital and outpatient care). The degree of ED crowding is difficult to quantify but has been linked to markers such as hours on ambulance diversion, hours of inpatient boarding in the emergency setting, increasing wait times, and patients who leave without being seen. A number of organizations, including the American College of Emergency Physicians, the Emergency Nurses Association, and the National Quality Forum, have convened to better define emergency metrics and definitions that help provide data for benchmarks for patient throughput performance. The Joint Commission has acknowledged that patient safety is tied to patient throughput and has developed guidance for hospitals to ensure that hospital leadership engages in the process of safe egress of the patient out of the ED and, most recently, to address efficient disposition of patients with mental health emergencies. It is important that the American Academy of Pediatrics acknowledges the potential impact on access to optimal emergency care for children in the face of ED crowding and helps guide health policy decision-makers toward effective solutions that promote the medical home and timely access to emergency care.

Towards personalised predictive psychiatry in clinical practice: an ethical perspective.

Personalised prediction models promise to enhance the speed, accuracy and objectivity of clinical decision-making in psychiatry in the near future. This editorial elucidates key ethical issues at stake in the real-world implementation of prediction models and sets out practical recommendations to begin to address these.

Lessons learned: using adverse incident reports to investigate the characteristics and causes of prescribing errors.

INTRODUCTION: Prescribing errors are a principal cause of preventable harm in healthcare. This study aims to establish a systematic approach to analysing prescribing-related adverse incident reports, in order to elucidate the characteristics and contributing factors of common prescribing errors and target multifaceted quality improvement initiatives. METHODS: All prescribing-related adverse incident reports submitted across one NHS board over 12 months were selected. Incidents involving commonly implicated drugs (involved in ≥10 incidents) underwent analysis to establish likely underlying causes using Reason's Model of Accident Causation. RESULTS: 330 prescribing-related adverse incident reports were identified. Commonly implicated drugs were insulin (10% of incidents), gentamicin (7%), co-amoxiclav (5%) and amoxicillin (5%). The most prevalent error types were prescribing amoxicillin when contraindicated due to allergy (5%); prescribing co-amoxiclav when contraindicated due to allergy (5%); prescribing the incorrect type of insulin (3%); and omitting to prescribe insulin (3%). Error-producing factors were identified in 86% of incidents involving commonly implicated drugs. 53% of incidents involved error-producing factors related to the working environment; 38% involved factors related to the healthcare team; and 37% involved factors related to the prescriber. DISCUSSION: This study establishes that systematic analysis of adverse incident reports can efficiently identify the characteristics and contributing factors of common prescribing errors, in a manner useful for targeting quality improvement. Furthermore, this study produced a number of salient findings. First, a narrow range of drugs were implicated in the majority of incidents. Second, a small number of error types were highly recurrent. Lastly, a range of contributing factors were evident, with those related to the working environment contributing to the majority of prescribing errors analysed.

More than just filler: an empirically informed ethical analysis of non-surgical cosmetic procedures in body dysmorphic disorder.

OBJECTIVES: To identify and analyse ethical considerations raised when individuals with body dysmorphic disorder (BDD) consult for non-surgical cosmetic procedures. METHODS: Ethical analysis was conducted addressing the issues of best interests and capacity to consent for non-surgical cosmetic procedures in individuals with BDD. Analysis was informed by the findings of semistructured interviews with non-surgical cosmetic practitioners and mental health professionals. FINDINGS: Non-surgical cosmetic interventions were viewed not to be in the best interests of individuals with BDD, as they fail to address core psychological issues, result in dissatisfaction post-procedure, and risk harm. Referral to mental health services was advocated, however numerous obstacles to this were perceived. The issue of capacity to consent to non-surgical cosmetic procedures raised questions regarding whether standard capacity assessment is sensitive to the manner in which BDD may influence decision-making processes. In addition, concerns were voiced that decisions made by individuals with BDD in this context may be judged foolish, and thus wrongly equated with lack of capacity. DISCUSSION/CONCLUSIONS: Ethical analysis, informed by the available evidence base, suggests that it is generally not in the best interests of individuals with BDD to undergo non-surgical cosmetic intervention, and referral to mental health services is indicated. Analysis of capacity draws parallels between BDD and anorexia nervosa, as decision-making capacity in both conditions can be impaired by pathological values derived from the disorder. Means of differentiating clinical assessment of pathological values from inappropriate value judgements are advocated, in order to safeguard against the latter encroaching into capacity assessment.

The benefit of foresight? An ethical evaluation of predictive testing for psychosis in clinical practice.

Risk prediction for psychosis has advanced to the stage at which it could feasibly become a clinical reality. Neuroimaging biomarkers play a central role in many risk prediction models. Using such models to predict the likelihood of transition to psychosis in individuals known to be at high risk has the potential to meaningfully improve outcomes, principally through facilitating early intervention. However, this compelling benefit must be evaluated in light of the broader ethical ramifications of this prospective development in clinical practice. This paper advances ethical discussion in the field in two ways: firstly, through in-depth consideration of the distinctive implications of the clinical application of predictive tools; and, secondly, by evaluating the manner in which newer predictive models incorporating neuroimaging alter the ethical landscape. We outline the current state of the science of predictive testing for psychosis, with a particular focus on emerging neuroimaging biomarkers. We then proceed to ethical analysis employing the four principles of biomedical ethics as a conceptual framework. We conclude with a call for scientific advancement to proceed in tandem with ethical consideration, informed by empirical study of the views of high risk individuals and their families. This collaborative approach will help ensure that predictive testing progresses in an ethically acceptable manner that minimizes potential adverse effects and maximizes meaningful benefits for those at high risk of psychosis.

Purpura fulminans associated with acute West Nile virus encephalitis.

Purpura fulminans is a progressive thrombotic disorder that presents with widespread purpura due to deficiency or dysfunction of protein C or protein S. Lesions present as well-demarcated erythematous macules that progress to irregular areas of hemorrhagic necrosis.West Nile virus is a member of the Flaviviridae family transmitted to humans through the bite of various mosquito species. It manifests as West Nile fever in 25% of those infected and less commonly as neuroinvasive disease. An African American man in his fortiespresented with altered mental status and was noted to have evidence of disseminated intravascular coagulation according to his lab data. He then developed dusky skin discoloration and systemic flaccid bullae with desquamation. Biopsy was consistent with purpura fulminans and the patient eventually developed symmetric peripheral gangrene, requiring amputations of all four extremities. Infectious work up revealed positive testing for IgM and IgG antibodies in serum and cerebrospinal fluid leading to the diagnosis of acute West Nile Virus encephalitis. We present this case to describe the rarely reported association of purpura fulminans with West Nile Virus infection.

The development and delivery of a female chronic pelvic pain management programme: a specialised interdisciplinary approach.

CONTEXT/BACKGROUND: Chronic pelvic pain (CPP) is a physically and psychologically debilitating condition. European Association of Urology (EAU) Guidelines (2013) and Royal College of Obstetricians and Gynaecologists (RCOG) guidelines (2012) place strong emphasis upon multi-speciality assessment and liaison, as well as interdisciplinary assessment and intervention in reference to the management of CPP. OBJECTIVES: The aim was to introduce and describe the development and delivery of an interdisciplinary pain management programme (PMP), at a Specialised Pain Management Centre in Liverpool, United Kingdom, for women diagnosed with CPP. METHOD: The format and content of the CPP PMP at The Walton Centre, Liverpool, is described and the preliminary results from the CPP PMP are presented. RESULTS: Preliminary data suggest that outcomes on the specialised CPP PMP indicate that patients are able to make clinically important change across a range of outcome measures. Moreover, these results compare favourably to the established PMP for generalised chronic pain when comparing clinically significant outcomes with the Walton Centre's (a tertiary-level pain management centre) 2013 PMP Audit document. Patients attending the CPP PMP positively appraised the PMP and felt it was useful and supportive to be in a group dedicated to CPP. CONCLUSIONS: This article presents some preliminary results that suggest there is value in delivering a specialised multidisciplinary PMP for this group. There is a clear need for further clinical research into the effectiveness of similar interventions for CPP, including the early identification of those CPP patients who may benefit from both multi-specialty and interdisciplinary management.

Disseminated nocardiosis in a patient on infliximab and methylprednisolone for treatment-resistant Sweet's syndrome.

A 62-year-old white man with a 10-year history of treatment-refractory Sweet's syndrome was admitted to the hospital with the onset of purpuric lesions. Methylprednisolone and infliximab were administered. Our patient developed disseminated Nocardia infection and eventually succumbed. Opportunistic infections such as Nocardia have been associated with infliximab and other tumour necrosis factor (TNF)-α inhibitors. The astute clinician should be aware of the risk of rare opportunistic infections, particularly in patients on TNF-α inhibitors and systemic corticosteroids.

IgG/IgA pemphigus.

IgG/IgA pemphigus has recently been described in the literature as an overlap of pemphigus vulgaris or pemphigus foliaceus with IgA pemphigus. There has also been some postulation that this IgG/IgA pemphigus may be associated with internal malignancy as well. Our case demonstrates the unique clinical, histopathological, and direct immunofluorescence findings of IgG/IgA pemphigus and further highlights the possibility of association of this disease with internal malignancy.

Decidual-secreted factors alter invasive trophoblast membrane and secreted proteins implying a role for decidual cell regulation of placentation.

Inadequate or inappropriate implantation and placentation during the establishment of human pregnancy is thought to lead to first trimester miscarriage, placental insufficiency and other obstetric complications. To create the placental blood supply, specialized cells, the 'extravillous trophoblast' (EVT) invade through the differentiated uterine endometrium (the decidua) to engraft and remodel uterine spiral arteries. We hypothesized that decidual factors would regulate EVT function by altering the production of EVT membrane and secreted factors. We used a proteomics approach to identify EVT membrane and secreted proteins regulated by decidual cell factors. Human endometrial stromal cells were decidualized in vitro by treatment with estradiol (10(-8) M), medroxyprogesterone acetate (10(-7) M) and cAMP (0.5 mM) for 14 days. Conditioned media (CM) was collected on day 2 (non-decidualized CM) and 14 (decidualized CM) of treatment. Isolated primary EVT cultured on Matrigel™ were treated with media control, non-decidualized or decidualized CM for 16 h. EVT CM was fractionated for proteins <30 kDa using size-exclusion affinity nanoparticles (SEAN) before trypsin digestion and HPLC-MS/MS. 43 proteins produced by EVT were identified; 14 not previously known to be expressed in the placenta and 12 which had previously been associated with diseases of pregnancy including preeclampsia. Profilin 1, lysosome associated membrane glycoprotein 1 (LAMP1), dipeptidyl peptidase 1 (DPP1/cathepsin C) and annexin A2 expression by interstitial EVT in vivo was validated by immunhistochemistry. Decidual CM regulation in vitro was validated by western blotting: decidualized CM upregulated profilin 1 in EVT CM and non-decidualized CM upregulated annexin A2 in EVT CM and pro-DPP1 in EVT cell lysate. Here, non-decidualized factors induced protease expression by EVT suggesting that non-decidualized factors may induce a pro-inflammatory cascade. Preeclampsia is a pro-inflammatory condition. Overall, we have demonstrated the potential of a proteomics approach to identify novel proteins expressed by EVT and to uncover the mechanisms leading to disease states.

Leukemia inhibitory factor enhances endometrial stromal cell decidualization in humans and mice.

Adequate differentiation or decidualization of endometrial stromal cells (ESC) is critical for successful pregnancy in humans and rodents. Here, we investigated the role of leukemia inhibitory factor (LIF) in human and murine decidualization. Ex vivo human (H) ESC decidualization was induced by estrogen (E, 10(-8) M) plus medroxyprogesterone acetate (MPA, 10(-7) M). Exogenous LIF (≥50 ng/ml) induced STAT3 phosphorylation in non-decidualized and decidualized HESC and enhanced E+MPA-induced decidualization (measured by PRL secretion, P<0.05). LIF mRNA in HESC was down-regulated by decidualization treatment (E+MPA) whereas LIF receptor (R) mRNA was up-regulated, suggesting that the decidualization stimulus 'primed' HESC for LIF action, but that factors not present in our in vitro model were required to induce LIF expression. Ex vivo first trimester decidual biopsies secreted >100 pg/mg G-CSF, IL6, IL8, and MCP1. Decidualized HESC secreted IL6, IL8, IL15 and MCP1. LIF (50 ng/ml) up-regulated IL6 and IL15 (P<0.05) secretion in decidualized HESC compared to 0.5 ng/ml LIF. In murine endometrium, LIF and LIFR immunolocalized to decidualized stromal cells on day 5 of gestation (day 0 = day of plug detection). Western blotting confirmed that LIF and the LIFR were up-regulated in intra-implantation sites compared to inter-implantation sites on Day 5 of gestation. To determine the role of LIF during in vivo murine decidualization, intra-peritoneal injections of a long-acting LIF antagonist (PEGLA; 900 or 1200 µg) were given just post-attachment, during the initiation of decidualization on day 4. PEGLA treatment reduced implantation site decidual area (P<0.05) and desmin staining immuno-intensity (P<0.05) compared to control on day 6 of gestation. This study demonstrated that LIF was an important regulator of decidualization in humans and mice and data provides insight into the processes underlying decidualization, which are important for understanding implantation and placentation.

JAAD grand rounds quiz*: Dusky intertriginous plaques and acral erythema after bone marrow transplant.

LEARNING OBJECTIVES: At the conclusion of this learning activity, physician participants should be able to assess their own diagnostic and patient management skills and use the results of this exercise to help determine personal learning needs that can be addressed through subsequent CME involvement. Instructions for claiming CME credit appear in the front advertising section. See last page of Contents for page number. INSTRUCTIONS: In answering each question, refer to the specific directions provided. Because it is often necessary to provide information occurring later in a series that give away answers to earlier questions, please answer the questions in each series in sequence.

Bradykinin stimulates endothelial cell fatty acid oxidation by CaMKK-dependent activation of AMPK.

Endothelial cell lipotoxicity mediated by accumulation of free fatty acids is an early event in the pathogenesis of atherosclerosis. The energy-sensor AMP-activated protein kinase (AMPK) is a key regulator of endothelial cell lipid metabolism. To test the hypothesis that bradykinin (BK) regulates AMPK and fatty acid oxidation in endothelium, stimulations of bovine aortic endothelial cells (BAECs) with bradykinin were performed. BK stimulation caused a 2.3-fold increase in AMPK activity (p<0.05). Activation of AMPK by BK in BAECs was inhibited by STO-609, an inhibitor of calmodulin-dependent kinase kinase (CaMKK), which is a known kinase upstream of AMPK. BK stimulation of BAECs also increased phosphorylation of acetyl-CoA carboxylase and this was inhibited by both STO-609 and over expression of an adenovirus encoded AMPK dominant negative (Ad-AMPK-DN). Furthermore, BK caused a 1.7-fold increase in palmitate oxidation in BAECs (p<0.05) and this increase was completely inhibited by the Ad-AMPK-DN (p<0.005). Inhibition of AMPK activation in response to BK by STO-609 had no effect on activating phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser(1177), consistent with CaMKK and AMPK not being required for phosphorylation of eNOS in response to BK. In conclusion, BK stimulates endothelial cell fatty acid oxidation by CaMKK-dependent activation of AMPK. The effect of BK on endothelial lipid metabolism represents a novel pathway for targeting fatty acid mediated endothelial cell dysfunction.

Phosphorylation of neuronal and endothelial nitric oxide synthase in the kidney with high and low salt diets.

BACKGROUND: Renal nitric oxide (NO) synthesis increases with increasing salt intake, however, the mechanisms underlying this are poorly understood. We hypothesized that activating or inhibitory phosphorylation of neuronal and endothelial nitric oxide synthase (nNOS, eNOS) regulates renal NO production in response to altered dietary salt. METHODS: Sprague-Dawley rats were fed low, normal or high salt diets for 12 h or 2 weeks, and kidney NOS phosphorylation was analyzed by Western blot using phosphopeptide antibodies against the sites nNOS-Ser(1412), nNOS-Ser(847), eNOS-Ser(1176) and eNOS-Thr(494). RESULTS: At 12 h, total nNOS increased 1.4-fold (p < 0.01) in the high salt group and decreased by 26% (p < 0.05) in the low salt group. Changes in expression of phospho-nNOS at 12 h were accounted for by the changes in total nNOS. No change in total or phospho-eNOS was seen at 12 h. At 2 weeks, in the low salt group expression of total nNOS increased 1.8-fold (p < 0.05) whereas expression of nNOS phosphorylated at the inhibitory site Ser(847) increased 4.3-fold (p < 0.01). Total eNOS was increased 3-fold in the low salt group (p < 0.01), with parallel increases in eNOS phosphorylated at both activating and inhibitory sites (p < 0.05). In the 2-week high salt group no changes in NOS expression or phosphorylation were seen, despite the observed increased excretion of urinary NO metabolites. CONCLUSION: In summary, changes in phospho-nNOS and phospho-eNOS expression occurred in parallel with changes in total expression, thus, the overall activating and inhibitory effects of nNOS and eNOS phosphorylation at the sites studied were not changed by altered dietary salt.

Enhanced replicative capacity and pathogenicity of HIV-1 isolated from individuals infected with drug-resistant virus and declining CD4+ T-cell counts.

Virologic failure on continuous antiretroviral therapy (ART) is associated with variable changes in CD4 T-cell counts: peripheral CD4 T-cell counts decrease in conjunction with a resurgence of plasma virus (nonresponders) or remain stable or continue to increase despite ongoing virus replication (discordant responders). This study found that HIV-1 isolated from nonresponders had significantly greater replicative capacity in activated peripheral blood mononuclear cells (PBMCs) as well as an enhanced ability to induce apoptosis in both HIV-1-infected and HIV-1-uninfected CD4 T cells compared with virus isolated from discordant responders. Enhanced replicative capacity in PBMCs of virus isolated from nonresponders was inhibited by AMD3100, a CXCR4 antagonist. Virus quasispecies isolated from PBMCs from nonresponders used both CC chemokine receptor 5 (CCR5) and CX chemokine receptor 4 (CXCR4) for entry, in contrast to virus isolated from PBMCs from discordant responders, which predominantly used CCR5. In contrast, virus isolated from plasma from both groups predominantly used CCR5. In summary, although drug resistance may lead to impaired viral fitness, the capacity of virus quasispecies from PBMCs to use CXCR4 may have significant consequences on viral replicative capacity and potentially on clinical outcome.