Optogenetic stimulation reveals a latent tipping point in cortical networks during ictogenesis.

Brain-state transitions are readily apparent from changes in brain rhythms,1 but are difficult to predict, suggestive that the underlying cause is latent to passive recording methods. Among the most important transitions, clinically, are the starts of seizures. We here show that an 'active probing' approach may have several important benefits for epileptic management, including by helping predict these transitions. We used mice expressing the optogenetic actuator, channelrhodopsin, in pyramidal cells, allowing this population to be stimulated in isolation. Intermittent stimulation at frequencies as low as 0.033 Hz (period = 30 s) delayed the onset of seizure-like events in an acute brain slice model of ictogenesis, but the effect was lost if stimulation was delivered at even lower frequencies (1/min). Notably, active probing additionally provides advance indication of when seizure-like activity is imminent, revealed by monitoring the postsynaptic response to stimulation. The postsynaptic response, recorded extracellularly, showed an all-or-nothing change in both amplitude and duration, a few hundred seconds before seizure-like activity began-a sufficient length of time to provide a helpful warning of an impending seizure. The change in the postsynaptic response then persisted for the remainder of the recording, indicative of a state change from a pre-epileptic to a pro-epileptic network. This occurred in parallel with a large increase in the stimulation-triggered Ca2+ entry into pyramidal dendrites, and a step increase in the number of evoked postsynaptic action potentials, both consistent with a reduction in the threshold for dendritic action potentials. In 0 Mg2+ bathing media, the reduced threshold was not associated with changes in glutamatergic synaptic function, nor of GABAergic release from either parvalbumin or somatostatin interneurons, but simulations indicate that the step change in the optogenetic response can instead arise from incremental increases in intracellular [Cl-]. The change in the response to stimulation was replicated by artificially raising intracellular [Cl-], using the optogenetic chloride pump, halorhodopsin. By contrast, increases in extracellular [K+] cannot account for the firing patterns in the response to stimulation, although this, and other cellular changes, may contribute to ictal initiation in other circumstances. We describe how these various cellular changes form a synergistic network of positive feedback mechanisms, which may explain the precipitous nature of seizure onset. This model of seizure initiation draws together several major lines of epilepsy research as well as providing an important proof-of-principle regarding the utility of open-loop brain stimulation for clinical management of the condition.

Queensland Trauma Education (QTE): an innovative simulation program that addresses the needs and barriers of interprofessional trauma care education across a complex landscape.

INTRODUCTION: Effective trauma care requires the rapid management of injuries. Rural and remote areas face inequity in trauma care due to time, distance and resource constraints, and experience higher morbidity and mortality rates than urban settings. A training needs analysis (TNA) conducted with stakeholders across Queensland, Australia, revealed a lack of contextual, accessible and interprofessional trauma education for clinicians. The Clinical Skills Development Service and Jamieson Trauma Institute developed the Queensland Trauma Education (QTE) program to address these concerns. QTE comprises a face-to-face training course and open access to online training resources created and reviewed by trauma experts. QTE also supports local training through a statewide simulation network and free access to simulation training equipment. The aim of this article is to review the QTE program and assess the benefits to clinicians in both the delivery of education and the provision of trauma care. METHODS: To evaluate the QTE program, a desktop review was conducted. This included analyses of website data, course and website content, and facilitator, stakeholder, participant and user feedback. The data were evaluated using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework, and the program's alignment with the original TNA outcomes was assessed. RESULTS: The results showed that QTE aligns with the identified training needs. Specifically, QTE provides trauma education that is relevant, sustainable, employs best practice, is locally delivered, provides continuous support, is multidisciplinary, multi-platformed, physically accessible and accredited by the Australasian College for Emergency Medicine. The review also highlights how QTE has effectively been reaching its target population, improves knowledge and skills, has become widely adopted, and been implemented and maintained with relative success. CONCLUSION: The innovative QTE program addresses the previous deficits in trauma education and meets the needs identified in the TNA. The review also reveals further opportunities for continuous improvement and program sustainability.

Factors Associated With Short-Term Recovery Following Single-Event Multilevel Surgery for Children With Cerebral Palsy.

PURPOSE: To examine the role of multiple factors, including therapy dose, on recovery of mobility function during post-single-event multilevel surgery (SEMLS) rehabilitation in youth with cerebral palsy. METHODS: Several factors expected to influence postoperative change in Gross Motor Function Measure (GMFM) were examined: age, Gross Motor Function Classification System (GMFCS) level, cognition, number of osteotomies, surgical complications, medical comorbidities, number of therapy sessions, and preoperative measures of gait, balance, and gross motor function. RESULTS: Sixty-nine youth with cerebral palsy, GMFSC levels I-IV, who had undergone SEMLS and rehabilitation had on average 2.6 osteotomies and 89 postoperative therapy sessions. Fewer osteotomies, higher therapy dose, higher preoperative GMFM, and lower GMFM at postoperative admission were significant in determining GMFM change. CONCLUSIONS: The most relevant factors on post-SEMLS recovery were therapy dose, surgical burden, and level of gross motor function immediately before and after surgery.

Impact of preoperative pelvic floor muscle training (pretraining) on urinary storage and emptying symptoms in women undergoing sling surgery.

INTRODUCTION AND HYPOTHESIS: Although pelvic floor muscle training (PFMT) is an option for female mixed incontinence (MUI), the role of PFMT prior to midurethral sling (MUS) surgery is not well defined. We hypothesize that preoperative PFMT (pretraining) positively impacts urinary storage and voiding symptoms prior to retropubic MUS. METHODS: We carried out an institutional review board-approved, retrospective chart review of women with stress-predominant MUI undergoing a retropubic MUS. Seventy-two women elected for initial PFMT before MUS (group 1). These were age-matched with 72 women who underwent MUS only (group 2). The primary outcome was the change in urinary voiding and storage symptoms (Emptying [E] and Inhibition [I; UUI] subsets of the SEAPI classification). Additional outcomes were stress urinary incontinence (SUI) resolution and change in quality of life (QoL) indices. RESULTS: Mean age and follow-up were 49 ± 12 years and 33 ± 12 months respectively. After MUS, SUI resolved in 79.2% and 69.4% in groups 1 and 2 respectively (p > 0.05). In group 1, 18% and 20.8% had improvement/resolution in the E and I subsets prior to MUS. Postoperatively, similar rates of improvement/resolution in the E (25% for both) and I (68% vs 63.9%) subsets were observed in groups 1 and 2 respectively. Postoperative QoL indices were statistically improved in both groups, with no significant difference between groups. CONCLUSIONS: Pretraining with PFMT before MUS was associated with preoperative improvement in emptying symptoms and UUI. Although not statistically significant, pretraining was associated with a higher chance of SUI resolution in the long term. If pretraining is beneficial before MUS, the effect appears to be small.

Lazarus Syndrome - Challenges Created by Pediatric Autoresuscitation.

ABSTRACT: Pediatric autoresuscitation is extremely rare, with only 4 documented cases in the literature. The longest recorded time between stopping cardio pulmonary resuscitation (CPR) and return of spontaneous circulation is 2 minutes. We report a previously well 18-month-old who attended the emergency department after an unexplained cardiac arrest. After 10 cycles of CPR, resuscitation was stopped; 6 minutes later, the patient had a return of spontaneous circulation and was transferred to the pediatric intensive care unit. The patient remains alive but with significant neurological impairment. There are a variety of theories regarding the pathology of pediatric autoresuscitation. The most commonly accepted model is that there is a degree of autopositive end-expiratory pressure impending venous return as a consequence of vigorous ventilation during CPR. This case challenges clinicians to reassess our current definition of death and reaffirms the need for clearer guidelines surrounding the certification of death.

Fulminant Myocarditis with Combination Immune Checkpoint Blockade.

Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly with combination immunotherapy. We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab. In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates. Selective clonal T-cell populations infiltrating the myocardium were identical to those present in tumors and skeletal muscle. Pharmacovigilance studies show that myocarditis occurred in 0.27% of patients treated with a combination of ipilimumab and nivolumab, which suggests that our patients were having a rare, potentially fatal, T-cell-driven drug reaction. (Funded by Vanderbilt-Ingram Cancer Center Ambassadors and others.).

Indwelling ports for prophylactic RBC exchanges in sickle cell patients: Comparison of bard and vortex ports.

INTRODUCTION: Red blood cell exchange (RCE) procedures are commonly used for stroke prevention in sickle cell disease (SCD) patients. We compared two different dual lumen ports used for RCE because differences between the port and catheter design may lead to functional variance. METHODS: We reviewed the RCE parameters of SCD patients following implantable port placement encountered at a single institution. Five Vortex and four Bard ports were used and compared. Patients were followed for 1-24 exchange procedures over 3-26 months performed between 2013 and 2015. RESULTS: Nine patients underwent 124 RCE procedures with no failures. A total of 74 exchanges used Vortex ports with a mean flow rate of 45.2 mL/min while 50 exchanges used Bard ports with a mean flow rate of 42.1 mL/min which was a significant difference (P = .002). A total of 85 exchanges with tPA administration preprocedure had a mean flow rate of 43.8 mL/min while 39 exchanges without had a mean flow rate of 45.4 mL/min which was not a significant difference (P = .19). CONCLUSION: Both the Bard and Vortex ports functioned well during our study period with no treatment failures, no significant complications requiring removal or replacement, and adequate mean flow rates. While the difference in mean flow rates was statistically significant between Vortex and Bard ports, there may not be a practical difference in performance. There also does not appear to be a significant benefit in flow rates with preprocedure tPA. We conclude that both ports may be a satisfactory choice for vascular access in SCD patients expected to undergo regularly scheduled RCE.

Relationship between medication synchronization and antiretroviral adherence.

OBJECTIVES: To compare antiretroviral adherence (measured as the proportion of days covered [PDC]) and change in viral load in insured, HIV-infected, adult outpatients enrolled and not enrolled in a medication synchronization program. METHODS: This was a multicenter, retrospective, pilot cohort study. Fifty-eight insured, HIV-infected, outpatients at least 18 years of age receiving antiretroviral therapy (ART) for at least 3 months as of August 2015 were included. PDC, viral load, PDC dichotomized into adherent or nonadherent, and viral load dichotomized into detectable or undetectable were collected for each patient. Study data were compared in those with (enrolled) and without (not enrolled or control) medication synchronization. The study end points were analyzed between the 2 groups retrospectively after 3 months. RESULTS: PDC in patients undergoing medication synchronization was significantly higher than in control patients: mean ± SD 96 ± 9% versus 71 ± 27%, respectively (P < 0.0001). The medication synchronization group was also more likely to be adherent to ART than the control group (odds ratio 10.67, 95% confidence interval 2.63-43.31). In the medication synchronization group, 75.9% of patients had an undetectable baseline viral load, and 83.3% had an undetectable viral load at study completion. In the control group, 62.1% and 64.7% had an undetectable viral load at baseline and completion, respectively. No statistically significant change in viral load was observed between groups (P = 0.34). CONCLUSION: In insured, HIV-infected, adult outpatients, implementation of a medication synchronization program was associated with improved ART adherence. Future studies are needed to better assess the impact of medication synchronization on clinical outcomes.

A Collision Tumor in the Breast Consisting of Invasive Ductal Carcinoma and Malignant Melanoma.

Collision tumors are rare neoplasms that consist of at least two different cell lineages at the same site. Given the many possible combinations that can occur, collision tumors, while rare, have been reported in multiple locations such as the stomach, bladder, and thyroid. Collision tumors are rarely found in breast tissue, with only a few cases reported in the literature. We herein report a unique case of a 79-year-old woman with a history of melanoma who presented with a left breast mass that was subsequently found to have invasive ductal carcinoma (IDC) and metastatic melanoma in the breast tissue. This is one of the first reported combinations of these two malignancies.

Prolyl isomerase Pin1 regulates transcription factor LSF (TFCP2) by facilitating dephosphorylation at two serine-proline motifs.

Transcription factor LSF is essential for cell cycle progression, being required for activating expression of the thymidylate synthase (Tyms) gene at the G1/S transition. We previously established that phosphorylation of LSF in early G1 at Ser-291 and Ser-309 inhibits its transcriptional activity and that dephosphorylation later in G1 is required for its reactivation. Here we reveal the role of prolyl cis-trans isomerase Pin1 in activating LSF, by facilitating dephosphorylation at both Ser-291 and Ser-309. We demonstrate that Pin1 binds LSF both in vitro and in vivo. Using coimmunoprecipitation assays, we identify three SP/TP motifs in LSF (at residues Ser-291, Ser-309, and Thr-329) that are required and sufficient for association with Pin1. Co-expression of Pin1 enhances LSF transactivation potential in reporter assays. The Pin1-dependent enhancement of LSF activity requires residue Thr-329 in LSF, requires both the WW and PPiase domains of Pin1, and correlates with hypophosphorylation of LSF at Ser-291 and Ser-309. These findings support a model in which the binding of Pin1 at the Thr-329-Pro-330 motif in LSF permits isomerization by Pin1 of the peptide bonds at the nearby phosphorylated SP motifs (Ser-291 and Ser-309) to the trans configuration, thereby facilitating their dephosphorylation.

Activation domain-dependent degradation of somatic Wee1 kinase.

Cell cycle progression is dependent upon coordinate regulation of kinase and proteolytic pathways. Inhibitors of cell cycle transitions are degraded to allow progression into the subsequent cell cycle phase. For example, the tyrosine kinase and Cdk1 inhibitor Wee1 is degraded during G(2) and mitosis to allow mitotic progression. Previous studies suggested that the N terminus of Wee1 directs Wee1 destruction. Using a chemical mutagenesis strategy, we report that multiple regions of Wee1 control its destruction. Most notably, we find that the activation domain of the Wee1 kinase is also required for its degradation. Mutations in this domain inhibit Wee1 degradation in somatic cell extracts and in cells without affecting the overall Wee1 structure or kinase activity. More broadly, these findings suggest that kinase activation domains may be previously unappreciated sites of recognition by the ubiquitin proteasome pathway.

Oral features and dental health in Hurler Syndrome following hematopoietic stem cell transplantation.

BACKGROUND: Hurler Syndrome is associated with a deficiency of a specific lysosomal enzyme involved in the degradation of glycosaminoglycans. Hematopoietic stem cell transplantation (HSCT) in early infancy is undertaken to help prevent the accumulation of glycosaminoglycans and improve organ function. AIM: To investigate the oral features and dental health of patients with Hurler Syndrome who have undergone successful HSCT. MATERIALS AND METHODS: Twenty-five patients (median age 8.6 years) post-HSCT (mean age 9.4 months) underwent oral assessment (mean of 7.5 years post-HSCT). RESULTS: Dental development was delayed. Numerous occlusal anomalies were noted including: open-bite, class III skeletal base, dental spacing, primary molar infra-occlusion and ectopic tooth eruption. Dental anomalies included hypodontia, microdontia, enamel defects, thin tapering canine crowns, pointed molar cusps, bulbous molar crowns and molar taurodontism. Tooth roots were usually short/blunted/spindle-like in permanent molars. The prevalence of dental caries was low in the permanent dentition (mean DMFT 0.7) but high in the primary dentition (mean dmft 2.4). Oral hygiene instruction with plaque and or calculus removal was indicated in 71% of those that were dentate. CONCLUSION: Patients with Hurler Syndrome post-HSCT are likely to have delayed dental development, a malocclusion, and dental anomalies, particularly hypodontia and microdontia.

Mortality and morbidity rounds (MMR) in pathology: relative contribution of cognitive bias vs. systems failures to diagnostic error.

Background Heuristics and cognitive biases are thought to play an important role in diagnostic medical error. How to systematically determine and capture these kinds of errors remains unclear. Morbidity and mortality rounds (MMRs) are generally focused on reducing medical error by identifying and correcting systems failures. However, they may also provide an educational platform for recognizing and raising awareness on cognitive errors. Methods A total of 49 MMR cases spanning the period 2008-2015 in our pathology department were examined for the presence of cognitive errors and/or systems failures by eight study participant raters who were trained on a subset of 16 of these MMR cases (excluded from the main study analysis) to identify such errors. The Delphi method was used to obtain group consensus on error classification on the remaining 33 study cases. Cases with <75% inter-rater agreement were subjected to subsequent rounds of Delphi analysis. Inter-rater agreement at each round was determined by Fleiss' kappa values. Results Thirty-six percent of the cases presented at our pathology MMRs over an 8-year period were found to contain errors likely due to cognitive bias. Conclusions These data suggest that the errors identified in our pathology MMRs represent not only systems failures but may also be composed of a significant proportion of cognitive errors. Teaching trainees and health professionals to correctly identify different types of cognitive errors may present an opportunity for quality improvement interventions in the interests of patient safety.

Survey of state vocational rehabilitation counselor roles and competencies in assistive technology.

The delivery of assistive technology (AT) within the state and federal vocational rehabilitation systems in the United States has been developing and refining itself over the last twenty years. Many challenges have been confronted in an attempt to use this relatively new service to increase the employment options and success for individuals with disabilities. In this process, the rehabilitation counselor serves as a critical player in the planning and delivery of AT as it articulates with other rehabilitation services. This study investigated counselor views regarding their role and competence in providing AT services and devices to individuals with disabilities throughout the state of Wisconsin. The results of the survey indicated, in general, that counselors find AT to be a cost-effective service that can increase employment related outcomes. As with other service areas, the counselors' role in AT service delivery involves coordinating, purchasing and following up on services. Interestingly, while counselors expressed confidence in performing these overall functions, they reported a lack of confidence in identifying the need for AT services. Without a comfort level to make this determination, benefits from the implementation of AT may be quite limited. Results suggest that intervention is needed to improve counselors' abilities to make decisions regarding AT services.

Understanding quality patient care and the role of the practicing nurse.

Nurses play a vital role in improving the safety and quality of patient care. The authors provide the front-line nurse providers with an overview of critical concepts related to quality management of patient care. A historical approach provides the reader with an overview of the trajectory or the quality in health care movement. Furthermore, the article provides the nurse with a basic understanding of national and international organizations that focus on quality patient care. A brief introduction of measures of quality care is presented as well as implications for nursing practice.

Comparative analysis of Rb1, P16 and ER as diagnostic, prognostic and potential targets for therapeutic agents in ovarian epithelial tumors: an immunohistochemical study of 130 ovarian carcinomas.

BACKGROUND: Deregulation of CDK4/6, cyclin D/P16 and retinoblastoma (Rb) are known aberrations in certain malignancies. There has been a recent interest in exploring the combination of letrozole and CDK4/6 inhibitors in recurrent ER+ ovarian cancers. METHODS: This study aimed to determine the frequency of expression of Rb1, P16 and ER in ovarian epithelial tumors by immunohistochemistry. RESULTS: Co-expression of all 3 markers studied was seen in 10% of high grade serous carcinoma (HGSC) and low grade serous carcinoma (LGSC). Coordinate expression of Rb1+ and ER+ in HGSC and LGSC was seen in 67% of grade 1/2 vs. 44 % of grade three tumors (p < 0.05). The reverse was true with positive P16 staining in 73% of grade three vs. 32% of grade 1/2 tumors (p < 0.001). CONCLUSIONS: Coordinate pattern of Rb1+ and ER+ in HGSC and LGSC is 19 and 50%, respectively. Rb1 and P16 show inverse expression pattern according to tumor grade with more frequent Rb1 in low grade vs. more frequent P16 in grade 3 tumors. These data provide a rational basis for clinical trials that aim to target these proteins.