CTAD Task Force Paper: Neuropsychiatric Symptoms in AD: Clinical Trials Targeting Mild Behavioral Impairment: A Report from the International CTAD Task Force.

The International CTAD Task Force (TF) addressed challenges related to designing clinical trials for agitation in dementia, presenting accomplishments from the two previous TFs on neuropsychiatric symptoms (NPS). In addition, this TF proposed a paradigm shift in NPS assessment and management, presenting Mild Behavioral Impairment (MBI) as a clinical syndrome. MBI is marked by later-life emergent and persistent NPS in dementia-free older persons (ranging from cognitively unimpaired to subjective cognitive decline to mild cognitive impairment), which facilitates earlier detection and better prognostication of Alzheimer's disease (AD). The TF has made the following recommendations for incorporation of NPS into AD preventative trials: (1) clinical trials targeting improvement in MBI symptoms should be undertaken; (2) treatment trials for MBI should be disease specific and confirm the diagnosis of participants using biomarkers; trials should include measures sensitive to cognitive changes in preclinical AD, which can serve as outcome measures, in addition to changes in biomarker levels; (3) as a first step, pharmacotherapeutic trials should address the full MBI complex as well as the specific symptoms/domains that constitute MBI; (4) clinical trials using problem-adaptation psychotherapy to target affective MBI should be considered; and (5) MBI should be considered in AD trials of disease modifying therapies. The well-validated and widely-used MBI Checklist (MBI-C) is an appropriate symptom rating scale for these studies, as it was developed specifically to identify and measure MBI in dementia-free persons. Other scales such as the Neuropsychiatric Inventory (NPI) may be used, although administration at two timepoints may be necessary to operationalize the MBI criterion of symptom persistence.

Longitudinal Course of Agitation and Aggression in Patients with Alzheimer's Disease in a Cohort Study: Methods, Baseline and Longitudinal Results of the A3C Study.

BACKGROUND: To present methodology, baseline results and longitudinal course of the Agitation and Aggression in patients with Alzheimer's Disease Cohort (A3C) study. OBJECTIVES: The central objective of A3C was to study the course, over 12 months of clinically significant Agitation and Aggression symptoms based on validated measures, and to assess relationships between symptoms and clinical significance based on global ratings. DESIGN: A3C is a longitudinal, prospective, multicenter observational cohort study performed at eight memory clinics in France, and their associated long-term care facilities. SETTING: Clinical visits were scheduled at baseline, monthly during the first 3 months, at 6 months, at 9 months and at 12 months. The first three months intended to simulate a classic randomized control trial 12-week treatment design. PARTICIPANTS: Alzheimer's Disease patients with clinically significant Agitation and Aggression symptoms lived at home or in long-term care facilities. MEASUREMENTS: Clinically significant Agitation and Aggression symptoms were rated on Neuropsychiatric Inventory (NPI), NPI-Clinician rating (NPI-C) Agitation and Aggression domains, and Cohen Mansfield Agitation Inventory. Global rating of agitation over time was based on the modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. International Psychogeriatric Association "Provisional Diagnostic Criteria for Agitation", socio-demographics, non-pharmacological approaches, psychotropic medication use, resource utilization, quality of life, cognitive and physical status were assessed. RESULTS: A3C enrolled 262 AD patients with a mean age of 82.4 years (SD ±7.2 years), 58.4% women, 69.9% at home. At baseline, mean MMSE score was 10.0 (SD±8.0), Cohen Mansfield Agitation Inventory score was 62.0 (SD±15.8) and NPI-C Agitation and Aggression clinician severity score was 15.8 (SD±10.8). According to the International Psychogeriatric Association agitation definition, more than 70% of participants showed excessive motor activity (n=199, 76.3%) and/or a verbal aggression (n=199, 76.3%) while 115 (44.1%) displayed physical aggression. The change of the CMAI score and the NPI-C Agitation and Aggression at 1-year follow-up period was respectively -11.36 (Standard Error (SE)=1.32; p<0.001) and -6.72 (SE=0.77; p<0.001). CONCLUSION: Little is known about the longitudinal course of clinically significant agitation symptoms in Alzheimer's Disease about the variability in different outcome measures over time, or the definition of a clinically meaningful improvement. A3C may provide useful data to optimize future clinical trials and guide treatment development for Agitation and Aggression in Alzheimer's Disease.

Why and how to investigate the role of protein phosphorylation in ZIP and ZnT zinc transporter activity and regulation.

Zinc is required for the regulation of proliferation, metabolism, and cell signaling. It is an intracellular second messenger, and the cellular level of ionic, mobile zinc is strictly controlled by zinc transporters. In mammals, zinc homeostasis is primarily regulated by ZIP and ZnT zinc transporters. The importance of these transporters is underscored by the list of diseases resulting from changes in transporter expression and activity. However, despite numerous structural studies of the transporters revealing both zinc binding sites and motifs important for transporter function, the exact molecular mechanisms regulating ZIP and ZnT activities are still not clear. For example, protein phosphorylation was found to regulate ZIP7 activity resulting in the release of Zn2+ from intracellular stores leading to phosphorylation of tyrosine kinases and activation of signaling pathways. In addition, sequence analyses predict all 24 human zinc transporters to be phosphorylated suggesting that protein phosphorylation is important for regulation of transporter function. This review describes how zinc transporters are implicated in a number of important human diseases. It summarizes the current knowledge regarding ZIP and ZnT transporter structures and points to how protein phosphorylation seems to be important for the regulation of zinc transporter activity. The review addresses the need to investigate the role of protein phosphorylation in zinc transporter function and regulation, and argues for a pressing need to introduce quantitative phosphoproteomics to specifically target zinc transporters and proteins involved in zinc signaling. Finally, different quantitative phosphoproteomic strategies are suggested.

Ventral tegmental area astrocytes orchestrate avoidance and approach behavior.

The ventral tegmental area (VTA) is a heterogeneous midbrain structure, containing neurons and astrocytes, that coordinates behaviors by integrating activity from numerous afferents. Within neuron-astrocyte networks, astrocytes control signals from distinct afferents in a circuit-specific manner, but whether this capacity scales up to drive motivated behavior has been undetermined. Using genetic and optical dissection strategies we report that VTA astrocytes tune glutamatergic signaling selectively on local inhibitory neurons to drive a functional circuit for learned avoidance. In this circuit, astrocytes facilitate excitation of VTA GABA neurons to increase inhibition of dopamine neurons, eliciting real-time and learned avoidance behavior that is sufficient to impede expression of preference for reward. Loss of one glutamate transporter (GLT-1) from VTA astrocytes selectively blocks these avoidance behaviors and spares preference for reward. Thus, VTA astrocytes selectively regulate excitation of local GABA neurons to drive a distinct avoidance circuit that opposes approach behavior.

Survival patterns and cancer determinants in families with myotonic dystrophy type 1.

BACKGROUND AND PURPOSE: Research indicates that patients with myotonic dystrophy type 1 (DM1) are at increased risk of cancer and early death. Family data may provide insights given DM1 phenotypic heterogeneity, the broad range of non-muscular manifestations and the usual delays in the diagnosis of DM1. METHOD: Family history data were collected from 397 genetically and/or clinically confirmed DM1 patients (respondents) enrolled in the US or UK myotonic dystrophy registries. Standardized mortality ratios were calculated for DM1 first-degree relatives (parents, siblings and offspring) by their reported DM1 status (affected, unaffected or unknown). For cancer-related analyses, mixed effects logistic regression models were used to evaluate factors associated with cancer development in DM1 families, including familial clustering. RESULTS: A total of 467 deaths and 337 cancers were reported amongst 1737 first-degree DM1 relatives. Mortality risk amongst relatives reported as DM1-unaffected was comparable to that of the general population [standardized mortality ratio (SMR) 0.82, P = 0.06], whilst significantly higher mortality risks were noted in DM1-affected relatives (SMR = 2.47, P < 0.0001) and in those whose DM1 status was unknown (SMR = 1.60, P < 0.0001). In cancer risk analyses, risk was higher amongst families in which the DM1 respondent had cancer (odds ratio 1.95, P = 0.0001). Unknown DM1 status in the siblings (odds ratio 2.59, P = 0.004) was associated with higher cancer risk. CONCLUSION: There is an increased risk of death, and probably cancer, in relatives with DM1 and in those whose DM1 status is unknown. This suggests a need to perform a careful history and physical examination, supplemented by genetic testing, to identify family members at risk for DM1 and who might benefit from disease-specific clinical care and surveillance.

Identifying Better Outcome Measures to Improve Treatment of Agitation in Dementia: A Report from the EU/US/CTAD Task Force.

For the second time in the past 3 years, the EU-US CTAD Task Force addressed challenges related to designing clinical trials for agitation in dementia, which is one of the most disruptive aspects of the condition for both patients and caregivers. Six recommendations emerged from the Task Force meeting: 1 - Operationalizing agitation criteria established by the IPA; 2 - Combining clinician- and caregiver-derived outcomes as primary outcome measures; 3 - Using global ratings to define clinically meaningful effects and power studies; 4 - Improving the accuracy of caregiver reports by better training and education of caregivers; 5 - Employing emerging technologies to collect near real-time behavioral data; and 6 - Utilizing innovative trial designs and increasing the use of biomarkers to maximize the productivity of clinical trials for neuropsychiatric symptoms.

EU/US/CTAD Task Force: Lessons Learned from Recent and Current Alzheimer's Prevention Trials.

At a meeting of the EU/US/Clinical Trials in Alzheimer's Disease (CTAD) Task Force in December 2016, an international group of investigators from industry, academia, and regulatory agencies reviewed lessons learned from ongoing and planned prevention trials, which will help guide future clinical trials of AD treatments, particularly in the pre-clinical space. The Task Force discussed challenges that need to be addressed across all aspects of clinical trials, calling for innovation in recruitment and retention, infrastructure development, and the selection of outcome measures. While cognitive change provides a marker of disease progression across the disease continuum, there remains a need to identify the optimal assessment tools that provide clinically meaningful endpoints. Patient- and informant-reported assessments of cognition and function may be useful but present additional challenges. Imaging and other biomarkers are also essential to maximize the efficiency of and the information learned from clinical trials.

Changing Metrics of Organ Procurement Organization Performance in Order to Increase Organ Donation Rates in the United States.

The shortage of deceased-donor organs is compounded by donation metrics that fail to account for the total pool of possible donors, leading to ambiguous donor statistics. We sought to assess potential metrics of organ procurement organizations (OPOs) utilizing data from the Nationwide Inpatient Sample (NIS) from 2009-2012 and State Inpatient Databases (SIDs) from 2008-2014. A possible donor was defined as a ventilated inpatient death ≤75 years of age, without multi-organ system failure, sepsis, or cancer, whose cause of death was consistent with organ donation. These estimates were compared to patient-level data from chart review from two large OPOs. Among 2,907,658 inpatient deaths from 2009-2012, 96,028 (3.3%) were a "possible deceased-organ donor." The two proposed metrics of OPO performance were: (1) donation percentage (percentage of possible deceased-donors who become actual donors; range: 20.0-57.0%); and (2) organs transplanted per possible donor (range: 0.52-1.74). These metrics allow for comparisons of OPO performance and geographic-level donation rates, and identify areas in greatest need of interventions to improve donation rates. We demonstrate that administrative data can be used to identify possible deceased donors in the US and could be a data source for CMS to implement new OPO performance metrics in a standardized fashion.

The role of STIM1 and SOCE in smooth muscle contractility.

Contraction is a central feature for skeletal, cardiac and smooth muscle; this unique feature is largely dependent on calcium (Ca2+) signaling and therefore maintenance of internal Ca2+ stores. Stromal interaction molecule 1 (STIM1) is a single-pass transmembrane protein that functions as a Ca2+ sensor for the activation store-operated calcium channels (SOCCs) on the plasma membrane in response to depleted internal sarco(endo)plasmic (S/ER) reticulum Ca2+ stores. STIM1 was initially characterized in non-excitable cells; however, evidence from both animal models and human mutations suggests a role for STIM1 in modulating Ca2+ homeostasis in excitable tissues as well. STIM1-dependent SOCE is particularly important in tissues undergoing sustained contraction, leading us to believe STIM1 may play a role in smooth muscle contraction. To date, the role of STIM1 in smooth muscle is unknown. In this review, we provide a brief overview of the role of STIM1-dependent SOCE in striated muscle and build off that knowledge to investigate whether STIM1 contributes to smooth muscle contractility. We conclude by discussing the translational implications of targeting STIM1 in the treatment of smooth muscle disorders.

Risk factors for lymph node metastases in women with endometrial cancer: A population-based, nation-wide register study-On behalf of the Swedish Gynecological Cancer Group.

The role of lymphadenectomy in the management of early endometrial cancer remains controversial. In the recent ESMO-ESGO-ESTRO guidelines, lymphadenectomy is recommended for patients with endometrioid adenocarcinoma Grade 3 with deep myometrial invasion, but complete agreement was not achieved. In Sweden, DNA aneuploidy has been included as a high-risk factor. The aim of our study was to evaluate the impact of tumor histology, FIGO grade, DNA ploidy and myometrial invasion (MI) on occurrence of lymph node metastasis (LNM) in patients with endometrial cancer. The study design is a retrospective cohort study based on prospectively recorded register data. Endometrial cancer patients registered in the Swedish Quality Registry for Gynecologic Cancer 2010-2015 with FIGO Stages I-III and verified nodal status were included. Data on DNA ploidy, histology, FIGO grade and MI were included in multivariable log-binomial regression analyses with LNM as dependent variable. 1,165 cases fulfilled the inclusion criteria. The multivariable analyses revealed increased risk of LNM in patients with tumors with MI ≥ 50% (risk ratio [RR] = 4.1; 95% confidence interval [CI] 3.0-5.6), nonendometrioid compared to endometrioid histology (RR 1.8; CI 1.4-2.4) and FIGO Grade 3 compared to Grade 1-2 tumors (RR 1.5; CI 1.1-2.0). No statistically significant association between DNA ploidy status and LNM was detected. This population-based, nation-wide study in women with endometrial cancer confirms a strong association between MI ≥ 50%, nonendometrioid histology and FIGO Grade 3, respectively, and LNM. DNA ploidy should not be included in the preoperative decision making of removing nodes or not.

The effects of intravenous lipid emulsion on hemodynamic recovery and myocardial cell mitochondrial function after bupivacaine toxicity in anesthetized pigs.

Local anesthetic toxicity is thought to be mediated partly by inhibition of cardiac mitochondrial function. Intravenous (i.v.) lipid emulsion may overcome this energy depletion, but doses larger than currently recommended may be needed for rescue effect. In this randomized study with anesthetized pigs, we compared the effect of a large dose, 4 mL/kg, of i.v. 20% Intralipid® ( n = 7) with Ringer's acetate ( n = 6) on cardiovascular recovery after a cardiotoxic dose of bupivacaine. We also examined mitochondrial respiratory function in myocardial cell homogenates analyzed promptly after needle biopsies from the animals. Bupivacaine plasma concentrations were quantified from plasma samples. Arterial blood pressure recovered faster and systemic vascular resistance rose more rapidly after Intralipid than Ringer's acetate administration ( p < 0.0001), but Intralipid did not increase cardiac index or left ventricular ejection fraction. The lipid-based mitochondrial respiration was stimulated by approximately 30% after Intralipid ( p < 0.05) but unaffected by Ringer's acetate. The mean (standard deviation) area under the concentration-time curve (AUC) of total bupivacaine was greater after Intralipid (105.2 (13.6) mg·min/L) than after Ringer's acetate (88.1 (7.1) mg·min/L) ( p = 0.019). After Intralipid, the AUC of the lipid-un-entrapped bupivacaine portion (97.0 (14.5) mg·min/L) was 8% lower than that of total bupivacaine ( p < 0.0001). To conclude, 4 mL/kg of Intralipid expedited cardiovascular recovery from bupivacaine cardiotoxicity mainly by increasing systemic vascular resistance. The increased myocardial mitochondrial respiration and bupivacaine entrapment after Intralipid did not improve cardiac function.

Intravenous lipid emulsion for levobupivacaine intoxication in acidotic and hypoxaemic pigs.

Intravenous lipid emulsion is, in some countries, the recommended treatment for local anaesthetic toxicity. Systemic local anaesthetic toxicity results in hypoxaemia and acidosis, and whether this influences the effects of lipid therapy on drug concentrations and cardiovascular recovery is currently unknown. Twenty anaesthetised pigs were given a 3-mg/kg bolus of levobupivacaine followed by a five minute phase of hypoventilation and 1 mmol/kg of lactic acid in one minute. After lactic acid infusion, pigs were treated, in randomised order, with either 20% lipid emulsion or Ringer's acetate for 30 min: a 1.5-ml/kg bolus followed by a 0.25-ml/kg/minute infusion. Haemodynamic parameters were recorded and blood samples were collected for pharmacokinetic analysis. There was no difference between the groups in the area under the plasma levobupivacaine concentration-time curve (AUC) or between that and AUC of unentrapped levobupivacaine in the Lipid group, or in the plasma half-lives. The cardiovascular outcome and normalisation of the electrocardiogram were similar in both groups. Five pigs developed marked hypotension: one in both groups died, while two in the Lipid group and one in the Ringer group needed adrenaline. Administration of lipid emulsion did not improve cardiovascular recovery from levobupivacaine toxicity exacerbated by acidosis and hypoxaemia. Lipid emulsion did not entrap levobupivacaine or affect levobupivacaine pharmacokinetics.

Incidence of severe local anaesthetic toxicity and adoption of lipid rescue in Finnish anaesthesia departments in 2011-2013.

BACKGROUND: Although the incidence of severe local anaesthetic systemic toxicity (LAST) has been declining, the risk of LAST still remains. There are no national treatment guidelines for LAST in Finland. We performed a national survey of the occurrence of LAST and its treatment in 2011-2013. METHODS: A structured electronic questionnaire was sent to the anaesthesia department chiefs of all Finnish public hospitals (n = 45) in spring 2014. We collected information about the occurrence and outcome of LASTs and existence of treatment protocols. RESULTS: The questionnaire response rate was 100% covering approximately 95% of all regional anaesthesias managed by anaesthesiologists in Finnish hospitals. The total number of regional anaesthesias, excluding spinal anaesthesia, performed by anaesthesiologists was approximately 211,700 during the survey period. Fifteen cases of LAST were reported (0.7 : 10,000); all patients recovered without negative sequelae. Fourteen patients, in five of whom ultrasound guidance had been applied, developed central nervous system toxicity symptoms and only one cardiac symptoms. Lipid emulsion was given to this latter patient, and to four of the other 14. The relative risk (95% confidence intervals) for occurrence of LAST in non-academic hospital vs. university hospitals was 3.3 (1.0-10.3; P = 0.04). Treatment protocols for LAST included lipid emulsion in 47% of the departments. CONCLUSIONS: The incidence of LAST in Finland is very low. Several departments have adopted lipid emulsion treatment for LAST despite lack of national recommendations and knowledge of the possible mechanism of action.

Familial testicular germ cell tumors (FTGCT) - overview of a multidisciplinary etiologic study.

This Review summarizes the cumulative results of the National Cancer Institute Clinical Genetics Branch Multidisciplinary Etiologic Study of Familial Testicular Germ Cell Tumors (FTGCT). Initiated 12 years ago, this protocol enrolled 724 subjects from 147 unrelated families with either ≥2 affected men (n = 90) with TGCT or a proband with bilateral TGCT and a negative family history for this cancer (n = 57). Data were collected directly from 162 subjects evaluated at the NIH Clinical Center, and 562 subjects provided information from their home communities (Field Cohort). The primary study aims included (i) ascertaining, enrolling eligible FTGCT kindred, (ii) characterizing the clinical phenotype of multiple-case families, (iii) identifying the underlying genetic mechanism for TGCT susceptibility in families, (iv) evaluating counseling, psychosocial, and behavioral issues resulting from membership in an FTGCT family, and (v) creating an annotated biospecimen repository to permit subsequent translational research studies. Noteworthy findings include (i) documenting the epidemiologic similarities between familial and sporadic TGCT, (ii) demonstrating significantly younger age-at-diagnosis for familial vs. sporadic TGCT, (iii) absence of a dysmorphic phenotype in affected family members, (iv) shifting the focus of gene discovery from a search for rare, highly penetrant susceptibility variants to the hypothesis that multiple, more common, lower penetrance genes underlie TGCT genetic risk, (v) implicating testicular microlithiasis in FTGCT risk, and (vi) observing that aberrant methylation may contribute to FTGCT risk. A clinically based, biospecimen-intensive, multidisciplinary research strategy has provided novel, valuable insights into the etiology of FTGCT, and created a research resource which will support FTGCT clinical and laboratory studies for years to come.

The challenge of understanding cerebral white matter injury in the premature infant.

White matter injury in the premature infant leads to motor and more commonly behavioral and cognitive problems that are a tremendous burden to society. While there has been much progress in understanding unique vulnerabilities of developing oligodendrocytes over the past 30years, there remain no proven therapies for the premature infant beyond supportive care. The lack of translational progress may be partially explained by the challenge of developing relevant animal models when the etiology remains unclear, as is the case in this disorder. There has been an emphasis on hypoxia-ischemia and infection/inflammation as upstream etiologies, but less consideration of other contributory factors. This review highlights the evolution of white matter pathology in the premature infant, discusses the prevailing proposed etiologies, critically analyzes a sampling of common animal models and provides detailed support for our hypothesis that nutritional and hormonal deprivation may be additional factors playing critical and overlooked roles in white matter pathology in the premature infant.

National critical incident reporting systems relevant to anaesthesia: a European survey.

BACKGROUND: Critical incident reporting is a key tool in the promotion of patient safety in anaesthesia. METHODS: We surveyed representatives of national incident reporting systems in six European countries, inviting information on scope and organization, and intelligence on factors determining success and failure. RESULTS: Some systems are government-run and nationally conceived; others started out as small, specialty-focused initiatives, which have since acquired a national reach. However, both national co-ordination and specialty enthusiasts seem to be necessary for an optimally functioning system. The role of reporting culture, definitional issues, and dissemination is discussed. CONCLUSIONS: We make recommendations for others intending to start new systems and speculate on the prospects for sharing patient safety lessons relevant to anaesthesia at European level.

Robotic-assisted transperitoneal aortic lymphadenectomy as part of staging procedure for gynaecological malignancies: single institution experience.

Introduction. This study was designed to confirm the feasibility and safety of robotic-assisted transperitoneal aortic lymphadenectomy as part of staging procedure for gynecologic malignancies. Methods. Chart review of 51 patients who had undergone robotic staging with aortic lymphadenectomy for different gynaecologic malignancies was performed. Results. The primary diagnosis was as follows: 6 cases of endometrial cancer, 31 epithelial ovarian cancer, 9 nonepithelial ovarian cancer, 4 tubal cancer, and 1 cervical cancer. Median BMI was 23 kg/m(2). Except for a single case of aortic lymphadenectomy only, both aortic and pelvic lymphadenectomies were performed at the time of the staging procedure. All the para-aortic lymphadenectomies were carried out to the level of the renal veinl but 6 cases were carried out to the level of the inferior mesenteric artery. Hysterectomy was performed in 24 patiens (47%). There was no conversion to LPT. The median console time was 285 (range 195-402) with a significant difference between patients who underwent hysterectomy and those who did not. The median estimated blood loss was 50 mL (range 20-200). The mean number of removed nodes was 29 ± 9.6. The mean number of pelvic nodes was 15 ± 7.6, whereas the mean number of para-aortic nodes was 14 ± 6.6. Conclusions. Robotic transperitoneal infrarenal aortic lymphadenectomy as part of staging procedure is feasible and can be safely performed. Additional trocars are needed when pelvic surgery is also performed.