Incidence and Durability of SARS-CoV-2 Antibodies in Patients with Cancer and Health Care Workers following the First Wave of the Pandemic.

BACKGROUND: Patients with cancer and health care workers (HCW) are at higher risk for SARS-CoV-2 infection. There are limited data regarding the rate of symptomatic versus asymptomatic infection and subsequent seropositivity in both populations. METHODS: We performed a prospective study of patients and HCW across two institutions during the first wave of the pandemic to analyze the prevalence of SARS-CoV-2 antibodies, the extent of associated symptoms, and durability of serologic response. RESULTS: In 1,953 persons (733 patients and 1,220 HCW), overall seropositivity rates for 3.1% patients (95% CI 2.0-4.7) and 3.7% HCW (95% CI 2.7-4.9, p=0.520), were similar. Each institutions' seropositivity rates were numerically higher in HCW than patients. Non-Hispanic Whites and Asians had lower antibody rates (2.8%, 95% CI 2.0-3.8 and 3.3%, 95% CI 1.2-7.0) compared to Hispanics (6.9%, 95% CI 3.4-12.4) and non-Hispanic Blacks (5.9%, 95% CI 3.3-9.7), p < 0.001. Among persons with a positive SARS-CoV-2 antibody, 87% of patients and 56% of HCW did not recall having had a fever. Among HCW, administrative and technical personnel were most likely to be seropositive. The rate of persistent seropositivity at 3 months was similar between patients and HCW and was not influenced by the reporting of fever, cancer type, or therapy. CONCLUSION: These data suggest that patients are not at higher risk for febrile SARS-CoV-2 infections or more transient immunity than HCWs. Furthermore, racial differences and lack of association with the extent of HCW contact with COVID-19 patients suggest that community rather than hospital virus exposure was a source of many infections.

Addressing fatigue in medical residents with biomathematical fatigue modeling.

Fatigue in resident physicians has been identified as a factor that contributes to burnout and a decline in overall wellbeing. Fatigue risk exists because of poor sleep habits and demanding work schedules that have only increased due to the COVID-19 pandemic. At this time, it is important not to lose sight of how fatigue can impact residents and how fatigue risk can be mitigated. While fatigue mitigation is currently addressed by duty hour restrictions and education about fatigue, Fatigue Risk Management Systems (FRMSs) offer a more comprehensive strategy for addressing these issues. An important component of FRMS in other shiftwork industries, such as aviation and trucking, is the use of biomathematical models to prospectively identify fatigue risk in work schedules. Such an approach incorporates decades of knowledge of sleep and circadian rhythm research into shift schedules, taking into account not just duty hour restrictions but the temporal placement of work schedules. Recent research has shown that biomathematical models of fatigue can be adapted to a resident physician population and can help address fatigue risk. Such models do not require subject matter experts and can be applied in graduate medical education program shift scheduling. It is important for graduate medical education program providers to consider these alternative methods of fatigue mitigation. These tools can help reduce fatigue risk and may improve wellness as they allow for a more precise fatigue management strategy without reducing overall work hours.

Biomathematical Modeling Predicts Fatigue Risk in General Surgery Residents.

OBJECTIVE: To assess resident fatigue risk using objective and predicted sleep data in a biomathematical model of fatigue. DESIGN: 8-weeks of sleep data and shift schedules from 2019 for 24 surgical residents were assessed with a biomathematical model to predict performance ("effectiveness"). SETTING: Greater Washington, DC area hospitals RESULTS: As shift lengths increased, effectiveness scores decreased and the time spent below criterion increased. Additionally, 11.13% of time on shift was below the effectiveness criterion and 42.7% of shifts carried excess sleep debt. Sleep prediction was similar to actual sleep, and both predicted similar performance (p ≤ 0.001). CONCLUSIONS: Surgical resident sleep and shift patterns may create fatigue risk. Biomathematical modeling can aid the prediction of resident sleep patterns and performance. This approach provides an important tool to help educators in creating work-schedules that minimize fatigue risk.

Perspectives of Veterans Affairs mental health providers on working with older adults with dementia and their caregivers.

Continuing education directed at building providers' skills and knowledge in geriatrics represents a practical approach to addressing the geriatric mental health (MH) care workforce shortage. To inform the development of professional training curricula, we surveyed MH providers (N = 65) at a Veterans Affairs medical center on working with older persons with dementia (PwD) and informal caregivers. Providers rated service provision to PwD and caregivers as highly important but endorsed modest self-efficacy. Half of respondents were minimally confident in managing risk of harm to self or others in a PwD. Respondents believed PwD can benefit from MH treatments, yet identified several barriers to providing care, including inadequate time and staffing resources. Interest in geriatric training topics was high. Findings demonstrate that MH providers at this site value care provision to PwD and caregivers, and desire additional training to serve this population. System-level barriers to MH care for PwD should also be identified and addressed.

Fatigue in surgical residents an analysis of duty-hours and the effect of hypothetical naps on predicted performance.

PURPOSE: Sleep loss and fatigue, common in resident physicians, are related to increased medical errors and decreased physician wellbeing. Biomathematical modeling of fatigue can illuminate the relationship between surgical resident fatigue and work scheduling. METHODS: General surgery resident schedules were analyzed using the Sleep, Activity, Fatigue and Task Effectiveness model to predict resident performance during work hours. Hypothetical naps were built into the model to assess their effect on predicted performance and fatigue risk. RESULTS: 12 months of duty-hours logged by 89 residents, ranging from post-graduate year (PGY) 1-5, were analyzed. Residents had moderate levels of fatigue risk over 12 month schedules, with at least an 8-h sleep debt during 24.36% of shifts. Performance scores decreased as shift lengths increased. The addition of hypothetical naps increased predicted performance and reduced shift time with fatigue risk. CONCLUSIONS: Biomathematical modeling of resident schedules and predicts a concerning level of fatigue and decreased effectiveness. Naps may improve performance without decreasing scheduled hours.

Trends in Strategic Napping in Surgical Residents by Gender, Postgraduate Year, Work Schedule, and Clinical Rotation.

OBJECTIVE: To identify surgical resident and clinical rotation attributes which predict on-shift napping through objectively measured sleep patterns and work schedules over a 2-month period. DESIGN: In a cross-sectional study, participants provided schedules, completed the Epworth Sleepiness Scale (ESS), and wore sleep-tracking devices (Zulu watch) continuously for 8 weeks. Multiple linear regression predicted percent days with on-shift napping from resident and rotation characteristics. SETTING: Greater Washington, DC area hospitals. PARTICIPANTS: Twenty-two (n = 22) surgical residents rotating in at least 1 of 5 different clinical rotation categories. RESULTS: Residents slept 6 hours within a 24-hour period (370 ± 129 minutes) with normal sleep efficiency (sleep efficiency (SE): 87.13% ± 7.55%). Resident ESS scores indicated excessive daytime sleepiness (11.64 ± 4.03). Ninety-five percent (n = 21) of residents napped on-shift. Residents napped on-shift approximately 32% of their working days and were most likely to nap when working between 23:00 and 05:00 hours. Earlier shift start times predicted less on-shift napping (B = -0.08, SE = 0.04, ß = -2.40, t = -2.09, p = 0.05) while working more night shifts (B = 1.55, SE = 0.44, ß = 4.12, t = 3.52, p = 0.003) and shifts over 24 hours (B = 1.45, SE = 0.55, ß = 1.96, t = 2.63, p = 0.01) predicted more frequent on-shift napping. CONCLUSIONS: Residents are taking advantage of opportunities to nap on-shift. Working at night seems to drive on-shift napping. However, residents still exhibit insufficient sleep and daytime sleepiness which could reduce competency and represent a safety risk to themselves and/or patients. These findings will help inform intervention strategies which are tailored to surgical residents using a biomathematical model of fatigue.

Reinstating Elective Surgeries in MedStar Health: A Roadmap for Healthcare Organizations.

Introduction: Coronavirus disease 2019 (COVID-19) infections have strained hospital resources worldwide. As a result, many facilities have suspended elective operations and ambulatory procedures. As the incidence of new cases of COVID-19 decreases, hospitals will need policies and algorithms to facilitate safe and orderly return of normal activities. We describe the recommendations of a task force established in a multi-institutional healthcare system for resumption of elective operative and ambulatory procedures applicable to all hospitals and service lines. Methods: MedStar Health created a multidisciplinary task force to develop guidelines for resumption of elective surgeries/procedures. The primary focus areas included the establishment of a governance structure at each healthcare facility, prioritization of elective cases, preoperative severe acute respiratory syndrome coronavirus 2 testing, and an assessment of the needs and availability of staff, personal protective equipment, and other essential resources. Results: Each hospital president was tasked with establishing a local perioperative leadership team answering directly to them and granted the authority to prioritize elective surgery and ambulatory procedures. An elective surgery algorithm was established using a simplified Medically Necessary Time Sensitive score, with multiple steps requiring a "go/no-go" assessment based on local resources. In addition, mandatory preoperative COVID testing policies were developed and operationalized. Conclusions: Even when the COVID pandemic has passed, hospitals and surgical centers will require COVID screening and testing, case prioritization, and supply chain management to provide care essential to the surgical patient while protecting their safety and that of staff. Our guidelines consider these factors and are applicable to both tertiary academic medical centers and smaller community facilities.

Behavioral Health Needs of Older Adults in the Emergency Department.

Behavioral health disorders are common among older adults and, owing to limited access to resources for mental health care in the community, emergency department providers are often on the front lines of mental health crises. This article reviews the available literature regarding the care of behavioral health emergencies in older adults and provides a framework for navigating the evaluation and management of older adults presenting to the emergency department with behavioral health concerns.

Ectopic parathyroid adenoma in the pyriform sinus.

BACKGROUND: Ectopic parathyroid glands may complicate the surgical approach to primary hyperparathyroidism. We describe a rare ectopic parathyroid location, the pyriform sinus. METHODS: Three patients, 2 after prior unsuccessful parathyroid exploration, were found to have ectopic parathyroid adenomas in the pyriform sinus. Two cases were identified by 4D-CT of the neck. The other was localized by a technetium 99m sestamibi single photon emission CT (SPECT). In each case, office endoscopy confirmed the lesions. The patients were treated by either transoral laser or robotic resection of the parathyroid adenoma. RESULTS: After surgery, the patients had resolution of their hyperparathyroidism. CONCLUSION: Ectopic parathyroid adenomas in the pyriform sinus are rare, but should be considered in those patients who have had a failed neck exploration and in those who undergo 4D-CT scanning or SPECT scanning.

Glucose-deprivation increases thyroid cancer cells sensitivity to metformin.

Metformin inhibits thyroid cancer cell growth. We sought to determine if variable glucose concentrations in medium alter the anti-cancer efficacy of metformin. Thyroid cancer cells (FTC133 and BCPAP) were cultured in high-glucose (20 mM) and low-glucose (5 mM) medium before treatment with metformin. Cell viability and apoptosis assays were performed. Expression of glycolytic genes was examined by real-time PCR, western blot, and immunostaining. Metformin inhibited cellular proliferation in high-glucose medium and induced cell death in low-glucose medium. In low-, but not in high-glucose medium, metformin induced endoplasmic reticulum stress, autophagy, and oncosis. At micromolar concentrations, metformin induced phosphorylation of AMP-activated protein kinase and blocked p-pS6 in low-glucose medium. Metformin increased the rate of glucose consumption from the medium and prompted medium acidification. Medium supplementation with glucose reversed metformin-inducible morphological changes. Treatment with an inhibitor of glycolysis (2-deoxy-d-glucose (2-DG)) increased thyroid cancer cell sensitivity to metformin. The combination of 2-DG with metformin led to cell death. Thyroid cancer cell lines were characterized by over-expression of glycolytic genes, and metformin decreased the protein level of pyruvate kinase muscle 2 (PKM2). PKM2 expression was detected in recurrent thyroid cancer tissue samples. In conclusion, we have demonstrated that the glucose concentration in the cellular milieu is a factor modulating metformin's anti-cancer activity. These data suggest that the combination of metformin with inhibitors of glycolysis could represent a new strategy for the treatment of thyroid cancer.

Spinal metastases due to thyroid carcinoma: an analysis of 202 patients.

BACKGROUND: Spinal metastases (SMs) due to thyroid cancer (TC) are associated with significantly reduced quality of life. The goal of this study is to analyze the clinical manifestations, presentation, and treatments of TC SMs, and to describe specific features of SMs associated with different TC types. PATIENTS AND METHODS: A retrospective analysis of 202 TC SM patients treated at Medstar Washington Hospital Center (37) and collected from the literature (165) was performed. RESULTS: The mean age of patients with SMs was 56.9±14.7 years, and the female-to-male ratio was 2.1:1. Of all patients, 29% (28% of follicular thyroid cancer [FTC] and 37% of papillary thyroid cancer [PTC]) had SMs only. Twenty-nine percent of all patients and 54% of patients with single-site SMs had neither bone non-SMs nor solid organ metastases at the time of presentation. Thirty-five percent of patients had SMs as an initial presentation of TC. TC patients presenting with SMs had a lower rate of other bone and visceral involvement compared with patients whose SMs were diagnosed at the time of thyroid surgery or during follow-up (p<0.05). SMs were more often the initial manifestation of FTC (41% vs. 24%), while PTC SMs were more commonly diagnosed after TC diagnosis (76% vs. 59%; p<0.05). PTC SMs were more frequently diagnosed as synchronous (63% vs. 36% in FTC) versus FTC SMs that developed as metachronous metastases (64% vs. 37% in PTC; p<0.01). All FTC SMs developed within 82 (0-372) months and all PTC SMs within 35 (0-144) months (p<0.01). In FTC SMs as TC manifestation, solid organ metastases involvement was less common than in FTC SMs that were found after TC diagnosis (34% vs. 67%; p<0.01); multisite FTC SMs compared to solitary FTC SMs were associated with the development of other bone nonspinal metastases (82% vs. 30%; p<0.01) and solitary organ metastases (65% vs. 41%; p<0.01). These correlations were not observed in PTC SMs. FTC patients often had neural structure compression (myelopathy/radiculopathy; 72% vs. 36% in PTC), while PTC patients frequently were asymptomatic (38% vs. 5% in FTC; p<0.01). FTC SMs more commonly were (131)I-avid (p<0.01). FTC patients required surgery more frequently (72% vs. 55% in PTC; p<0.05). CONCLUSIONS: Our study reveals that a significant part of TC SMs patients have solitary spinal involvement at the time of presentation and may be considered for aggressive treatment with the intention to improve quality of life and survival. FTC SMs and PTC SMs appear to have distinct presentations, behavior, and treatment modalities, and should be categorized separately for treatment and follow-up planning.

Current treatment modalities for spinal metastases secondary to thyroid carcinoma.

BACKGROUND: The spine is the most common site of bone metastases due to thyroid cancer, which develop in more than 3% of patients with well-differentiated thyroid cancer. Nearly half of patients with bone metastases from thyroid cancer develop vertebral metastases. Spinal metastases are associated with significantly reduced quality of life due to pain, neurological deficit, and increased mortality. SUMMARY: Treatment options for patients with thyroid spinal metastases include radioiodine therapy, pharmacologic therapy, and surgical treatments, with recent advances in radiosurgery and minimally invasive spinal surgery as well. Therapeutic interventions require a multidisciplinary approach and aim to control pain, preserve or improve neurologic function, optimize local tumor control, and improve quality of life. We have proposed a three-tiered approach to the management and practical algorithms for patients with spinal metastases from thyroid carcinoma. CONCLUSIONS: The introduction of novel and improved techniques for the treatment of spinal metastases has created the opportunity to significantly improve control of metastatic tumor growth and the quality of life for the patients with spinal metastases from thyroid cancer. In order for these options to be effectively used, a multidisciplinary approach must be applied in the management of the patients with thyroid spinal metastases.

The HIV protease inhibitor nelfinavir down-regulates RET signaling and induces apoptosis in medullary thyroid cancer cells.

CONTEXT: Mutations of RET tyrosine kinase are associated with the development of medullary thyroid cancer (MTC). The heat shock protein (HSP) 90 chaperone is required for folding and stability of RET mutants. HSP90 is a molecular target for the HIV protease inhibitor nelfinavir (NFV). OBJECTIVE: We hypothesized that treatment with NFV may lead to the inhibition of RET signaling and induction of apoptosis in MTC cells. DESIGN: Two human MTC cell lines, TT and MZ-CRC-1, which harbor endogenous C634W or M918T RET mutations, respectively, were exposed to clinically achievable concentrations of NFV. JC-1 staining and caspase-3 cleavage assays were performed to measure mitochondrial membrane potential and apoptosis. Activation of RET signaling was examined by Western blot. Autophagy was monitored by the detection of the light-chain 3BII. Expression of HSP90 and LC3B were examined in 36 human MTCs. RESULTS: At a therapeutic serum concentration (10 µM), NFV inhibited the viability of TT and MZ-CRC-1 cells by 55% and 10%, respectively. In a dose-dependent manner, NFV inhibited cyclin D1 and caused caspase-3 cleavage. NFV decreased the level of RET protein and blocked the activation of RET downstream targets (phosphorylated ERK, phosphorylated AKT, and p70S6K/pS6). NFV induced metabolic stress, activated AMP-activated protein kinase and increased autophagic flux. Pharmacological inhibition of autophagy (chloroquine) augmented NFV-inducible cytotoxicity, suggesting that autophagy was protective in NFV-treated cells. NFV led to mitochondrial membrane depolarization and induced both oxidative stress and DNA damage. An antioxidant (n-acetylcysteine) attenuated DNA damage and prevented NFV-inducible apoptosis. HSP90 overexpression was found in 17 of 36 human MTCs and correlated with metastases and RET mutations. LC3B was detected in 20 of 36 human MTCs. CONCLUSIONS: NFV has a wide spectrum of activity against MTC cells, and its cytotoxicity can be augmented by inhibiting autophagy. Expression of NFV molecular targets in metastatic MTC suggests that NFV has a potential to become a thyroid cancer therapeutic agent.

Dementia care in rural China.

Dementia is a major cause of disability and has immense cost implications for the individual suffering from the condition, family caregivers and society. Given the high prevalence of dementia in China with its enormous and rapidly expanding population of elderly adults, it is necessary to develop and test approaches to the care for patients with this disorder. The need is especially great in rural China where access to mental healthcare is limited, with the task made more complex by social and economic reforms over the last 30 years that have transformed the Chinese family support system, family values and health delivery systems. Evidence-based collaborative care models for dementia, depression and other chronic diseases that have been developed in some Western countries serve as a basis for discussion of innovative approaches in the management of dementia in rural China, with particular focus on its implementation in the primary care system.

How do the PHQ-2, the PHQ-9 perform in aging services clients with cognitive impairment?

OBJECTIVE: To examine the performance of the Patient Health Questionnaire-2 (PHQ-2) and the PHQ-9 in detecting current major depressive episode (MDE) in aging services care management clients who screen positive for cognitive impairment (CI). METHODS: Cross-sectional observational study of 236 care management clients ages ≥60 years recruited from an Upstate NY aging services agency. The test characteristics of the PHQ-2 and PHQ-9 to screen for depression were calculated using the Structured Clinical Interview for DSM-IV (SCID) to identify MDE (gold standard). CI was identified with the Six-Item Screen (SIS). RESULTS: Participants had a mean age of 77 years, 68% female, 16% non-white, and 26% had less than a high school education. 16% of participants had CI identified by ≥2 errors on SIS. Of these, 41% had positive PHQ-2 (scores ≥3), 43% had positive PHQ-9 (scores ≥10), while 24% met criteria for MDE. In the sample with CI, the PHQ-2, using a cutoff of 3, had sensitivity = 0.78, specificity = 0.71, and receiver operating characteristic (ROC) area under the curve (AUC) = 0.81, compared with 0.79, 0.82, and 0.88, respectively, for those without CI. In the sample with CI, the PHQ-9, using a cutoff of 10, had sensitivity = 0.89, specificity = 0.71, and AUC = 0.85, compared with 0.85, 0.89, and 0.91, respectively, for those without CI. CONCLUSIONS: Cognitive status should be considered when using the PHQ as a depression screener due to poorer specificity in seniors with CI.

Mental distress and service utilization among help-seeking, community-dwelling older adults.

BACKGROUND: This study aimed to characterize healthcare and human services utilization among mentally distressed and non-distressed clients receiving in-home care management assessment by aging services provider network (ASPN) agencies in the U.S.A. METHODS: A two-hour research interview was administered to 378 English-speaking ASPN clients aged 60+ years in Monroe County, NY. A modified Cornell Services Index measured service utilization for the 90 days prior to the ASPN assessment. Clients with clinically significant anxiety or depressive symptoms were considered distressed. RESULTS: ASPN clients utilized a mean of 2.93 healthcare and 1.54 human services. The 42% of subjects who were distressed accessed more healthcare services (e.g. mental health, intensive medical services) and had more outpatient visits and days hospitalized than the non-distressed group. Contrary to expectations, distressed clients did not receive more human services. Among those who were distressed, over half had discussed their mental health with a medical professional in the past year, and half were currently taking a medication for their emotional state. A far smaller proportion had seen a mental health professional. CONCLUSIONS: In the U.S.A., aging services providers serve a population with high medical illness burden and medical service utilization. Many clients also suffer from anxiety and depression, which they often have discussed with a medical professional and for which they are receiving medications. Few, however, have seen a mental health specialist preceding intake by the ASPN agency. Optimal care for this vulnerable, service intensive group would integrate primary medical and mental healthcare with delivery of community-based social services for older adults.

Trait neuroticism, depression, and cognitive function in older primary care patients.

OBJECTIVE: Prior studies on the association of trait neuroticism and cognitive function in older adults have yielded mixed findings. The authors tested hypotheses that neuroticism is associated with measures of cognition and that depression moderates these relationships. DESIGN: Cross-sectional observational study. SETTING: Primary care offices. PARTICIPANTS: Primary care patients aged > or =65 years. MEASUREMENTS: Trait neuroticism was assessed by the NEO-Five Factor Inventory. Major and minor depressions were determined by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and depressive symptom severity by the Hamilton Depression Rating Scale (Ham-D). Cognitive measures included the Mini-Mental State Examination (MMSE), Initiation-Perseveration subscale of the Mattis Dementia Rating Scale, and Trail-Making tests A and B. RESULTS: In multiple regression analyses, neuroticism was associated with MMSE score independent of depression diagnosis (beta = -0.04, chi2 = 14.2, df = 1, p = 0.0002, 95% confidence interval [CI] = -0.07 to -0.02) and Ham-D score (beta = -0.04, chi2 = 8.97, df = 1, p = 0.003, 95% CI = -0.06 to -0.01). Interactions between neuroticism and depression diagnosis (chi2 = 7.21, df = 2, p = 0.03) and Ham-D scores (chi2 = 0.55, df = 1, p = 0.46) failed to lend strong support to the moderation hypothesis. CONCLUSION: Neuroticism is associated with lower MMSE scores. Findings do not confirm a moderating role for depression but suggest that depression diagnosis may confer additional risk for poorer global cognitive function in patients with high neuroticism. Further study is necessary.

Depression predicts cognitive disorders in older primary care patients.

OBJECTIVE: To investigate whether depression is independently associated with increased risk of incident dementia or cognitive disorder not otherwise specified (NOS) in an older primary care population. METHOD: This was a prospective 3-year cohort study of 470 patients aged >or= 65 years without baseline cognitive disorders who were recruited from primary care offices. Annual assessments completed from March 2003 through December 2005 included the use of the Structured Clinical Interview for DSM-IV to diagnose major depressive disorder (MDD) and minor depression (MinD) and the Hamilton Depression Rating Scale (HDRS) for depressive symptom severity. The Mini-Mental State Exam, Mattis Dementia Rating Scale-initiation/perseveration subscale, and the Trail Making Tests A and B informed diagnoses of dementia and cognitive disorder NOS. RESULTS: 36 subjects, representing a cumulative incidence of 13%, developed dementia or cognitive disorder NOS over 3 years. Using Cox proportional hazard survival models to calculate the risk ratio of depression for development of cognitive disorders, MDD and MinD (HR = 3.68; 95% CI, 2.1-6.42 and HR = 1.84; 95% CI, 1.05-3.21, respectively) and HDRS scores (HR = 1.07; 95% CI, 1.02-1.12) predicted new onset dementia or cognitive disorder NOS, when covarying age, gender, and education. CONCLUSIONS: Depressive disorders pose increased risk of incident dementia or cognitive disorder NOS in older primary care patients. Clinicians treating depressed older adults should monitor for development of cognitive disorders.

Memantine in the treatment of mild-to-moderate Alzheimer's disease.

Memantine is the first and only medication that has been approved by European, US and Canadian regulatory agencies for the treatment of moderate-to-severe Alzheimer's disease (AD). It is an NMDA receptor antagonist that works to prevent excitotoxicity and cell death, which are mediated by the excessive influx of calcium during a sustained release of glutamate. Preclinical studies of memantine reveal that it has the potential to improve memory and learning processes after impairment has occurred, as well as to prevent further neuronal damage. Although memantine has been considered for the treatment of earlier AD, it has not yet been approved for this. Randomized controlled trials of memantine in the treatment of mild-to-moderate AD have demonstrated small treatment effects in measures of cognition, global assessment and behavior favoring the use of memantine. However, the differences between treatment groups were not consistently significant. Two ongoing long-term trials are further investigating the efficacy of memantine in the treatment of mild-to-moderate AD.