A Novel Approach to Monitoring Cognitive Adverse Events for Interventional Studies Involving Advanced Dementia Patients: Insights From the Electroconvulsive Therapy for Agitation in Dementia Study.

OBJECTIVE: To develop an individualized method for detecting cognitive adverse events (CAEs) in the context of an ongoing trial of electroconvulsive therapy for refractory agitation and aggression for advanced dementia (ECT-AD study). METHODS: Literature search aimed at identifying (a) cognitive measures appropriate for patients with advanced dementia, (b) functional scales to use as a proxy for cognitive status in patients with floor effects on baseline cognitive testing, and (c) statistical approaches for defining a CAE, to develop CAEs monitoring plan specifically for the ECT-AD study. RESULTS: Using the Severe Impairment Battery-8 (SIB-8), baseline floor effects are defined as a score of ≤5/16. For patients without floor effects, a decline of ≥6 points is considered a CAE. For patients with floor effects, a decline of ≥30 points from baseline on the Barthel Index is considered a CAE. These values were derived using the standard deviation index (SDI) approach to measuring reliable change. CONCLUSIONS: The proposed plan accounts for practical and statistical challenges in detecting CAEs in patients with advanced dementia. While this protocol was developed in the context of the ECT-AD study, the general approach can potentially be applied to other interventional neuropsychiatric studies that carry the risk of CAEs in patients with advanced dementia.

Effects of religion on the course of suicidality among geriatric patients with mood disorders.

BACKGROUND: A growing volume of research suggests that religion protects against late-life suicide, but it remains unclear whether effects are relevant to clinical samples, which facets of religion are most relevant, and variations over the course of mood disorders (e.g. during periods of euthymia, depression, and/or heightened suicidality). METHOD: Eighty adults aged 55-85 years with mood disorders completed assessments of religion (affiliation, service attendance, importance of religion, belief and faith in God), depression, and suicidality over time (M = 7.31 measurements over M = 727 days). We computed metrics to identify mean and maximum levels of depression and suicidality, and the number of episodes of significant depression and suicidality experienced by each participant. RESULTS: Religious affiliation and importance of religion, but not service attendance, belief, or faith in God, were associated with lower mean and maximum depression. Conversely, all facets of religion predicted significantly lower mean and maximum levels of suicidality (rs ranging from -0.24 to -0.39), and substantially less likelihood of experiencing significant suicidality during the study (ORs ranging from 0.19 to 0.33). Service attendance, belief, and faith in God predicted less suicidality even among individuals who did not affiliate with a religious group. CONCLUSIONS: Religious factors, particularly faith in God, are associated with substantially less suicidality over time among older adults with mood disorders, irrespective of religious affiliation.

Sudden anisocoria in a healing pediatric multitrauma patient.

ABSTRACT: This article describes a teenager who developed anisocoria with no obvious neurologic deficits or decline after a motor vehicle accident. The condition resolved over several hours before reappearing in the opposite eye 2 days later. Again no clinical neurologic deficits were noted and the condition resolved after several hours. The patient's asymptomatic anisocoria was finally determined to be secondary to aerosolized ipratropium treatments and an ill-fitting mask.

The Effects of Baseline Impaired Global Cognitive Function on the Efficacy and Cognitive Effects of Electroconvulsive Therapy in Geriatric Patients: A Retrospective Cohort Study.

OBJECTIVES: This study explores the association between baseline impaired global cognitive function and changes in global cognitive function and depression among geriatric patients undergoing acute course electroconvulsive therapy (ECT). DESIGN: Retrospective cohort study. SETTING: Single freestanding psychiatric hospital. PARTICIPANTS: Patients aged 50 and older receiving ECT. INTERVENTIONS: 10 ECT treatments. MEASUREMENTS: Cognitive assessments with the Montreal Cognitive Assessment (MoCA). Depression assessment with the Quick Inventory of Depressive Symptomatology Self Report 16 item scale (QIDS). RESULTS: Baseline and follow-up data were available for 684 patients. On average, patients with baseline normal cognition (MoCA ≥26; N = 371) had a decrease in MoCA of -1.44±0.26 points over the course of treatment, while those with baseline impaired global cognitive function (MoCA <26; N = 313) had an increase in MoCA of 1.72±0.25 points. Baseline cognitive status was not associated with a differential response on the QIDS. CONCLUSIONS: Patients with baseline impaired global cognitive function did not demonstrate a worsening in cognition following ECT, and baseline global cognitive function was not associated with a differential change in depression with ECT. These results suggest that impaired global cognitive function should not be viewed as a contraindication to ECT in geriatric patients.

Identifying Delirium in Persons With Moderate or Severe Dementia: Review of Challenges and an Illustrative Approach.

Delirium and dementia are common causes of cognitive impairment among older adults, which often coexist. Delirium is associated with poor clinical outcomes, and is more frequent and more severe in patients with dementia. Identifying delirium in the presence of dementia, also described as delirium superimposed on dementia (DSD), is particularly challenging, as symptoms of delirium such as inattention, cognitive dysfunction, and altered level of consciousness, are also features of dementia. Because DSD is associated with poorer clinical outcomes than dementia alone, detecting delirium is important for reducing morbidity and mortality in this population. We review a number of delirium screening instruments that have shown promise for use in DSD, including the 4-DSD, combined Six Item Cognitive Impairment Test (6-CIT) and 4 'A's Test (4AT), Confusion Assessment Method (CAM), and the combined UB2 and 3D-CAM (UB-CAM). Each has advantages and disadvantages. We then describe the operationalization of a CAM-based approach in a current ECT in dementia project as an example of modifying an existing instrument for patients with moderate to severe dementia. Ultimately, any instrument modified will need to be validated against a standard clinical reference, in order to fully establish its sensitivity and specificity in the moderate to severe dementia population. Future work is greatly needed to advance the challenging area of accurate identification of delirium in moderate or severe dementia.

Chloride Toxicity to Native Freshwater Species in Natural and Reconstituted Prairie Pothole Waters.

Oil and gas extraction in the Prairie Pothole Region (PPR) of the northern USA has resulted in elevated chloride concentrations in ground and surface water due to widespread contamination with highly saline produced water, or brine. The toxicity of chloride is poorly understood in the high hardness waters characteristic of the region. We evaluated the toxicity of chloride to two endemic species, Daphnia magna (water flea) and Lemna gibba (duckweed), exposed in field-collected waters (hardness ~ 3000 mg/L as CaCO3) and reconstituted waters (hardness 370 mg/L as CaCO3) intended to mimic PPR background waters. We also investigated the role of chloride in the toxicity of water reconstituted to mimic legacy brine-contaminated wetlands, using two populations of native Pseudacris maculata (Boreal Chorus Frog). Chloride toxicity was similar in field-collected and reconstituted waters for both D. magna (LC50s 3070-3788 mg Cl-1/L) and L. gibba (IC50s 2441-2887). Although hardness can ameliorate chloride toxicity at low to high hardness, we did not observe additional protection as hardness increased from 370 to ~ 3000 mg/L. In P. maculata exposures, chloride did not fully explain toxicity. Chloride sensitivity also differed between populations, with mortality at 2000 mg Cl-/L in one population but not the other, and population-specific growth responses. Overall, these results (1) document toxicity to native species at chloride concentrations occurring in the PPR, (2) indicate that very high hardness in the region's waters may not provide additional protection against chloride and (3) highlight challenges of brine investigations, including whether surrogate study populations are representative of local populations.

Using Biological Responses to Monitor Freshwater Post-Spill Conditions over 3 years in Blacktail Creek, North Dakota, USA.

A pipeline carrying unconventional oil and gas (OG) wastewater spilled approximately 11 million liters of wastewater into Blacktail Creek, North Dakota, USA. Flow of the mix of stream water and wastewater down the channel resulted in storage of contaminants in the hyporheic zone and along the banks, providing a long-term source of wastewater constituents to the stream. A multi-level investigation was used to assess the potential effects of oil and brine spills on aquatic life. In this study, we used a combination of experiments using a native fish species, Fathead Minnow (Pimephales promelas), field sampling of the microbial community structure, and measures of estrogenicity. The fish investigation included in situ experiments and experiments with collected site water. Estrogenicity was measured in collected site water samples, and microbial community analyses were conducted on collected sediments. During the initial post-spill investigation, February 2015, performing in situ fish bioassays was impossible because of ice conditions. However, microbial community (e.g., the presence of members of the Halomonadaceae, a family that is indicative of elevated salinity) and estrogenicity differences were compared to reference sites and point to early biological effects of the spill. We noted water column effects on in situ fish survival 6 months post-spill during June 2015. At that time, total dissolved ammonium (sum of ammonium and ammonia, TAN) was 4.41 mg NH4/L with an associated NH3 of 1.09 mg/L, a concentration greater than the water quality criteria established to protect aquatic life. Biological measurements in the sediment defined early and long-lasting effects of the spill on aquatic resources. The microbial community structure was affected during all sampling events. Therefore, sediment may act as a sink for constituents spilled and as such provide an indication of continued and cumulative effects post-spill. However, lack of later water column effects may reflect pulse hyporheic flow of ammonia from shallow ground water. Combining fish toxicological, microbial community structure and estrogenicity information provides a complete ecological investigation that defines potential influences of contaminants at organismal, population, and community levels. In general, in situ bioassays have implications for the individual survival and changes at the population level, microbial community structure defines potential changes at the community level, and estrogenicity measurements define changes at the individual and molecular level. By understanding effects at these various levels of biological organization, natural resource managers can interpret how a course of action, especially for remediation/restoration, might affect a larger group of organisms in the system. The current work also reviews potential effects of additional constituents defined during chemistry investigations on aquatic resources.

Simulated Electroconvulsive Therapy: A Novel Approach to a Control Group in Clinical Trials.

OBJECTIVES: Agitation is the most common behavioral symptom of Alzheimer disease (AD) affecting approximately 40% to 60% of the AD population, yet there are no Food and Drug Administration-approved therapies for the myriad of behavioral or psychological symptoms of dementia. There is growing evidence from naturalistic studies that electroconvulsive therapy (ECT) is a safe and effective treatment for agitation in AD patients who are refractory to pharmacotherapy and behavioral interventions. Despite the existing evidence, ECT remains underused because of stigma, lack of education, and concerns regarding adverse cognitive effects. Randomized controlled clinical trials of ECT are an opportunity to provide high-quality evidence of ECT as a safe and efficacious treatment for agitation in the AD population. We describe the methods for the Electroconvulsive Therapy in Alzheimer's Dementia study, which uses a novel, simulated ECT (S-ECT) control group to conduct a single-blind efficacy study of ECT for the treatment of agitation and aggression in individuals with moderate to severe AD. METHODS: We discuss the rationale, study design, methodology, ethical and practical challenges, and management strategies in using an S-ECT group as the comparator arm in this randomized controlled trial of ECT in AD-related treatment refractory agitation and aggression. CONCLUSIONS: Validation of the safety and efficacy of ECT in patients with advanced AD with refractory agitation and aggression is necessary. This can be accomplished through creative formulation of S-ECT groups that effectively maintain the blind while providing scientific integrity.

Cannabinoids for Agitation in Alzheimer's Disease.

Agitation is a common neuropsychiatric symptom of Alzheimer's disease (AD) that greatly impacts quality of life and amplifies caregiver burden. Agitation in AD may be associated with volume loss in the anterior cingulate cortex, posterior cingulate cortex, insula, amygdala, and frontal cortex, as well as with degeneration of monoaminergic neurotransmission, disrupted circadian rhythms, and frailty. Current pharmacologic options have troubling safety concerns and only modest efficacy. There is increasing interest in cannabinoids as promising agents due to preclinical and early clinical research that suggest cannabinoids can elicit anxiolytic, antidepressant, and/or anti-inflammatory effects. Cannabinoids may relieve agitation by regulating neurotransmitters, improving comorbidities and circadian rhythms, and increasing cerebral circulation. Here we discuss the possible contributory mechanisms for agitation in AD and the therapeutic relevance of cannabinoids, including CBD and THC.

Dependent Personality in Depressed Older Adults: A Case Report and Systematic Review.

Personality pathology in older adults is largely understudied. Here, we present a case report of an older adult who presented to an inpatient geriatric psychiatry unit with dependent personality traits in the context of chronic major depressive disorder, followed by a systematic review of the literature to identify research regarding the diagnosis and prevalence of dependent personality in depressed older adults. We identified 11 studies relevant to this topic. Synthesis of these data revealed that dependent personality is generally more common in depressed older adults compared to other personality disorders. However, studies were limited by small sample sizes and the use of assessments not validated for use in older adults. Therefore, it is difficult to draw conclusions from the available data. Potential implications for patient outcomes and health care services utilization are discussed. Our review highlights the need for larger scale research and personality assessments which are sensitive to age-related factors in order to draw evidence-based conclusions.

Study rationale and baseline data for pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer's dementia (THC-AD).

Agitation is a common complication of Alzheimer's dementia (Agit-AD) associated with substantial morbidity, high healthcare service utilization, and adverse emotional and physical impact on care partners. There are currently no FDA-approved pharmacological treatments for Agit-AD. We present the study design and baseline data for an ongoing multisite, three-week, double-blind, placebo-controlled, randomized clinical trial of dronabinol (synthetic tetrahydrocannabinol [THC]), titrated to a dose of 10 mg daily, in 80 participants to examine the safety and efficacy of dronabinol as an adjunctive treatment for Agit-AD. Preliminary findings for 44 participants enrolled thus far show a predominately female, white sample with advanced cognitive impairment (Mini Mental Status Examination mean 7.8) and agitation (Neuropsychiatric Inventory-Clinician Agitation subscale mean 14.1). Adjustments to study design in light of the COVID-19 pandemic are described. Findings from this study will provide guidance for the clinical utility of dronabinol for Agit-AD. ClinicalTrials.gov Identifier: NCT02792257.

Monetary and non-monetary rewards reduce attentional capture by emotional distractors.

Irrelevant emotional stimuli often capture attention, disrupting ongoing cognitive processes. In two experiments, we examined whether availability of rewards (monetary and non-monetary) can prevent this attentional capture. Participants completed a central letter identification task while attempting to ignore negative, positive, and neutral distractor images that appeared above or below the targets on 25% of trials. Distraction was indexed by slowing on distractor-present trials. Half the participants completed the task with no performance-contingent reward, while the other half earned points for fast and accurate performance. In Experiment 1, points translated into monetary reward, but in Experiment 2, points had no monetary value. In both experiments, reward reduced capture by emotional distractors, showing that even non-monetary reward can aid attentional control. These findings suggest that motivation encourages use of effective cognitive control mechanisms that effectively prevent attentional capture, even when distractors are emotional.

The role of dopamine D1 receptors in MDMA-induced memory impairments.

(±) 3,4-Methylenedioxymethamphetamine (MDMA) is a recreationally abused psychostimulant that impairs memory performance. This effect is often attributed to a working memory impairment resulting from compromised serotonin systems. However, recent evidence from non-human animal experimental studies suggests that acute MDMA may indirectly impair memory performance through overstimulation of dopamine (DA) D1 receptors, which increases perseverative responding during memory tasks. This hypothesis was explored using DA D1 mutant (DAD1-/-) rats which possess a selective down-regulation in functional D1 receptors. Adult male Wistar DAD1-/- rats and wild type controls were trained over 25 sessions on a spatial working memory T-maze delayed non-matching to position (DNMTP) task. Once trained, the rats were administered MDMA (1.5, 2.25 and 3 mg/kg) or saline fifteen minutes prior to testing on DNMTP with all subjects experiencing all drug doses and saline three times. We predicted that controls would demonstrate decreased task accuracy following MDMA, driven by an increase in perseverative errors. In contrast, we predicted that DAD1-/- rats would be protected from MDMA-induced perseverative errors due to their reduced D1 receptor function. As predicted, during the third block of MDMA administration, control rats demonstrated decreased task accuracy following 2.25 and 3 mg/kg doses, driven by an increase in perseverative errors. In addition, DAD1-/- rats were protected from MDMA-induced task deficits. These findings challenge the assumption that MDMA's acute effects on memory performance are predominantly due to serotonergic mechanisms and provide support for the hypothesis that acute MDMA impairs memory performance in rats via overstimulation of D1 receptors by increasing perseverative behaviour.

Clinical Trials and Tribulations in the COVID-19 Era.

Advances in treating and preventing Alzheimer disease and other neurocognitive disorders of aging arise from rigorous preclinical and clinical research, with randomized controlled treatment trials as the last and definitive test. The COVID-19 pandemic has greatly disrupted ongoing interventional studies and researchers are scrambling to find ways to safely continue this critical work amidst rapidly shifting guidelines from sponsors, institutions, and state and federal guidelines. Here the authors describe novel approaches and work-flow adaptations to study visits, drug delivery and interim and endpoint safety and outcomes assessments to avoid sacrificing years of preparation and substantial financial investments, to work in the best interest of participants and their caregivers, and to continue on the path toward discovering disease-modifying treatments for the millions of individuals impacted by major neurocognitive disorders.

A suspension-feeding anomalocarid from the Early Cambrian.

Large, actively swimming suspension feeders evolved several times in Earth's history, arising independently from groups as diverse as sharks, rays and stem teleost fishes, and in mysticete whales. However, animals occupying this niche have not been identified from the early Palaeozoic era. Anomalocarids, a group of stem arthropods that were the largest nektonic animals of the Cambrian and Ordovician periods, are generally thought to have been apex predators. Here we describe new material from Tamisiocaris borealis, an anomalocarid from the Early Cambrian (Series 2) Sirius Passet Fauna of North Greenland, and propose that its frontal appendage is specialized for suspension feeding. The appendage bears long, slender and equally spaced ventral spines furnished with dense rows of long and fine auxiliary spines. This suggests that T. borealis was a microphagous suspension feeder, using its appendages for sweep-net capture of food items down to 0.5 mm, within the size range of mesozooplankton such as copepods. Our observations demonstrate that large, nektonic suspension feeders first evolved during the Cambrian explosion, as part of an adaptive radiation of anomalocarids. The presence of nektonic suspension feeders in the Early Cambrian, together with evidence for a diverse pelagic community containing phytoplankton and mesozooplankton, indicate the existence of a complex pelagic ecosystem supported by high primary productivity and nutrient flux. Cambrian pelagic ecosystems seem to have been more modern than previously believed.

Lamotrigine Therapy and Biomarkers of Cerebral Energy Metabolism in Older Age Bipolar Depression.

OBJECTIVE: This study compared brain energy metabolism, as measured by cerebral concentrations of glutamate (Glu), glutamine (Gln), and N-acetyl aspartate (NAA), in older age bipolar depression (OABD) to that of psychiatrically healthy comparison subjects using proton (1H) magnetic resonance spectroscopy imaging at 4-Tesla. Metabolite levels were assessed in OABD subjects before and after 8 weeks of lamotrigine therapy with the goal of determining relationships between cerebral energy metabolism, depression symptom severity, and changes in depression symptom response. METHODS: Individuals (n = 21, mean age: 62.0 ± 5.9 years) with bipolar disorder, current episode depressed, and a healthy comparison group (n = 14, mean age: 67.5 ± 8.8 years) were selected. Participants with bipolar disorder, current episode depressed, were treated in open label fashion with lamotrigine monotherapy for 8 weeks. All subjects were scanned with 1H magnetic resonance spectroscopy at 4T at baseline and again after 8 weeks to assess levels of cerebral metabolites in the anterior cingulate cortex and parieto-occipital cortex. Metabolite levels were examined as ratios relative to creatine (Cr). Response to 8 weeks of lamotrigine treatment in the bipolar disorder, current episode depressed group, was assessed as a continuous measure on the Montgomery-Asberg Depression Rating Scale. RESULTS: NAA/Cr ratio in OABD was significantly lower by 14% (95% confidence interval: [1%, 26%]) than in comparison subjects at baseline. However, there were no associations between NAA/Cr, Glu/Cr, or Gln/Cr and either depression severity or lamotrigine treatment. CONCLUSION: Group differences in NAA suggest evidence for a deficit in cerebral energy metabolism in OABD.

Spiritual Psychotherapy for Inpatient, Residential, and Intensive Treatment.

In this article, a clinical protocol for delivering a flexible, spiritually integrated cognitive-behavioral therapy, called spiritual psychotherapy for inpatient, residential, and intensive treatment (SPIRIT), is presented, and its implementation is described.

Sustainable Hydrogels Based on Lignin-Methacrylate Copolymers with Enhanced Water Retention and Tunable Material Properties.

Synthesizing lignin-based copolymers would valorize a major coproduct stream from pulp and paper mills and biorefineries as well as reduce the dependence on petrochemical-based consumer goods. In this study, we used organosolv lignin isolated from hybrid poplar ( Populus trichocarpa × P. deltoides) to generate lignin-containing methacrylate hydrogels. The copolymer hydrogels were synthesized by first grafting 2-hydroxyethyl methacrylate (HEMA) onto lignin (OSLH) via esterification and then by free radical polymerization of OSLH with excess HEMA. The copolymer hydrogels were prepared with different stoichiometric ratios of OSLH (e.g., 0, 10, 20, and 40 wt %) with respect to HEMA. Copolymerization with OSLH led to an increase in cross-linking density, which in turn enhanced the hydrogel's material properties; we report up to 39% improvement in water retention, 20% increase in thermostability, and up to a 3 order increase in magnitude of the storage modulus ( G'). The copolymer's properties, such as water retention and glass transition temperature, could be tuned by altering the percent functionalization of lignin OH groups and the ratio of OSLH to HEMA.

A Case of Congenital Dyserythropoeitic Anemia Type IV Caused by E325K Mutation in Erythroid Transcription Factor KLF1.

Congenital dyserythropoetic anemias (CDA) represent a heterogeneous group of inherited red cell disorders resulting in ineffective erythropoiesis. Several CDA variants have been identified. KLF1 is a transcription factor required for cell division in erythroid differentiation and maturation, and the switch from fetal to adult hemoglobin. Mutations in KLF1 gene can result in a wide range of phenotypes. This case illustrates the E325K mutation in KLF1 presenting with severe anemia in infancy, persistently elevated fetal hemoglobin, and progressive improvement with age. This case of CDA because of KLF1 mutation highlights the common features and expected disease course of CDA type IV.