Roper St. Francis Healthcare

OBJECTIVE: A randomized, placebo-controlled, double-blind, multicenter 52-week phase 2 trial of resveratrol in individuals with mild to moderate Alzheimer disease (AD) examined its safety and tolerability and effects on biomarker (plasma Aβ40 and Aβ42, CSF Aβ40, Aβ42, tau, and phospho-tau 181) and volumetric MRI outcomes (primary outcomes) and clinical outcomes (secondary outcomes). METHODS: Participants (n = 119) were randomized to placebo or resveratrol 500 mg orally once daily (with dose escalation by 500-mg increments every 13 weeks, ending with 1,000 mg twice daily). Brain MRI and CSF collection were performed at baseline and after completion of treatment. Detailed pharmacokinetics were performed on a subset (n = 15) at baseline and weeks 13, 26, 39, and 52. RESULTS: Resveratrol and its major metabolites were measurable in plasma and CSF. The most common adverse events were nausea, diarrhea, and weight loss. CSF Aβ40 and plasma Aβ40 levels declined more in the placebo group than the resveratrol-treated group, resulting in a significant difference at week 52. Brain volume loss was increased by resveratrol treatment compared to placebo. CONCLUSIONS: Resveratrol was safe and well-tolerated. Resveratrol and its major metabolites penetrated the blood-brain barrier to have CNS effects. Further studies are required to interpret the biomarker changes associated with resveratrol treatment. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with AD resveratrol is safe, well-tolerated, and alters some AD biomarker trajectories. The study is rated Class II because more than 2 primary outcomes were designated.

IMPORTANCE: Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD. OBJECTIVE: To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers. INTERVENTIONS: Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). MAIN OUTCOMES AND MEASURES: Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures. RESULTS: Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, -0.24 to 4.20; adjusted P = .40) than the placebo group's decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of "infections or infestations," with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants). CONCLUSIONS AND RELEVANCE: Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00235716.

IMPORTANCE: Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory. OBJECTIVE: The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability. DESIGN, SETTING, AND PARTICIPANTS: The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013. INTERVENTIONS: Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability. MAIN OUTCOMES AND MEASURES: Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events. RESULTS: Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was -0.93 (95% CI, -1.80 to -0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (-1.05 points; 95% CI, -1.97 to -0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group. CONCLUSIONS AND RELEVANCE: Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00898807.

PURPOSE: An estimated 10% of breast and ovarian cancers result from hereditary causes. Current testing guidelines for germ line susceptibility genes in patients with breast carcinoma were developed to identify carriers of BRCA1/ 2 variants and have evolved in the panel-testing era. We evaluated the capability of the National Comprehensive Cancer Network (NCCN) guidelines to identify patients with breast cancer with pathogenic variants in expanded panel testing. METHODS: An institutional review board-approved multicenter prospective registry was initiated with 20 community and academic sites experienced in cancer genetic testing and counseling. Eligibility criteria included patients with a previously or newly diagnosed breast cancer who had not undergone either single- or multigene testing. Consecutive patients 18 to 90 years of age were consented and underwent an 80-gene panel test. Health Insurance Portability and Accountability Act-compliant electronic case report forms collected information on patient demographics, diagnoses, phenotypes, and test results. RESULTS: More than 1,000 patients were enrolled, and data records for 959 patients were analyzed; 49.95% met NCCN criteria, and 50.05% did not. Overall, 8.65% of patients had a pathogenic/likely pathogenic (P/LP) variant. Of patients who met NCCN guidelines with test results, 9.39% had a P/LP variant. Of patients who did not meet guidelines, 7.9% had a P/LP variant. The difference in positive results between these groups was not statistically significant (Fisher's exact test P = .4241). CONCLUSION: Our results indicate that nearly half of patients with breast cancer with a P/LP variant with clinically actionable and/or management guidelines in development are missed by current testing guidelines. We recommend that all patients with a diagnosis of breast cancer undergo expanded panel testing.

BACKGROUND: Agitation is common across neuropsychiatric disorders and contributes to disability, institutionalization, and diminished quality of life for patients and their caregivers. There is no consensus definition of agitation and no widespread agreement on what elements should be included in the syndrome. The International Psychogeriatric Association formed an Agitation Definition Work Group (ADWG) to develop a provisional consensus definition of agitation in patients with cognitive disorders that can be applied in epidemiologic, non-interventional clinical, pharmacologic, non-pharmacologic interventional, and neurobiological studies. A consensus definition will facilitate communication and cross-study comparison and may have regulatory applications in drug development programs. METHODS: The ADWG developed a transparent process using a combination of electronic, face-to-face, and survey-based strategies to develop a consensus based on agreement of a majority of participants. Nine-hundred twenty-eight respondents participated in the different phases of the process. RESULTS: Agitation was defined broadly as: (1) occurring in patients with a cognitive impairment or dementia syndrome; (2) exhibiting behavior consistent with emotional distress; (3) manifesting excessive motor activity, verbal aggression, or physical aggression; and (4) evidencing behaviors that cause excess disability and are not solely attributable to another disorder (psychiatric, medical, or substance-related). A majority of the respondents rated all surveyed elements of the definition as "strongly agree" or "somewhat agree" (68-88% across elements). A majority of the respondents agreed that the definition is appropriate for clinical and research applications. CONCLUSIONS: A provisional consensus definition of agitation has been developed. This definition can be used to advance interventional and non-interventional research of agitation in patients with cognitive impairment.

The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.

OBJECTIVE: To review the mechanism of action, antifungal spectrum of activity, pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of the echinocandins. DATA SOURCES: A MEDLINE search (1982-May 2009) was conducted for articles published in the English language using the key words caspofungin, micafungin, anidulafungin, and echinocandins. STUDY SELECTION AND DATA EXTRACTION: Medicinal chemistry, in vitro, and animal studies, as well as human trials were reviewed for information on the pharmacodynamics, pharmacokinetics, efficacy, and safety of each echinocandin. Clinical trials were reviewed and included to compare and contrast the available echinocandins. DATA SYNTHESIS: Three echinocandin antifungal agents are currently approved for use in the US: caspofungin, micafungin, and anidulafungin. The echinocandins have a unique mechanism of action, inhibiting beta-(1,3)-D-glucan synthase, an enzyme that is necessary for the synthesis of an essential component of the cell wall of several fungi. The echinocandins display fungistatic activity against Aspergillus spp. and fungicidal activity against most Candida spp., including strains that are fluconazole-resistant. The echinocandins have been shown to be efficacious for the treatment of esophageal candidiasis, candidemia, and invasive candidiasis. In addition, caspofungin has demonstrated efficacy as empiric treatment of febrile neutropenia and salvage therapy for the treatment of invasive aspergillosis, and it is the only echinocandin approved for use in pediatric patients. Micafungin is the only echinocandin approved for use as prophylaxis against Candida infections in patients undergoing hematopoietic stem cell transplantation. Overall, resistance to echinocandins is still rare, and all agents are well tolerated, with similar adverse effect profiles and few drug-drug interactions. CONCLUSIONS: Echinocandins, the newest addition to the arsenal of antifungals, offer potential advantages over other classes of agents. Clinicians should assess their distinguishing characteristics, including route of metabolism, drug interaction profile, and approved indications for use, when determining which agent to include on a formulary.

IMPORTANCE: Agitation is common among patients with Alzheimer disease; safe, effective treatments are lacking. OBJECTIVE: To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide-quinidine sulfate for Alzheimer disease-related agitation. DESIGN, SETTING, AND PARTICIPANTS: Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012-August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions-Severity agitation score ≥4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed. INTERVENTIONS: In stage 1, 220 patients were randomized in a 3:4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1:1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60). MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]). RESULTS: A total of 194 patients (88.2%) completed the study. With the sequential parallel comparison design, 152 patients received dextromethorphan-quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders) showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan-quinidine vs placebo (ordinary least squares z statistic, -3.95; P < .001). In stage 1, mean NPI Agitation/Aggression scores were reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0 to 5.3 with placebo. Between-group treatment differences were significant in stage 1 (least squares mean, -1.5; 95% CI, -2.3 to -0.7; P<.001). In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatment differences were also significant in stage 2 (least squares mean, -1.6; 95% CI, -2.9 to -0.3; P=.02). Adverse events included falls (8.6% for dextromethorphan-quinidine vs 3.9% for placebo), diarrhea (5.9% vs 3.1% respectively), and urinary tract infection (5.3% vs 3.9% respectively). Serious adverse events occurred in 7.9% with dextromethorphan-quinidine vs 4.7% with placebo. Dextromethorphan-quinidine was not associated with cognitive impairment, sedation, or clinically significant QTc prolongation. CONCLUSIONS AND RELEVANCE: In this preliminary 10-week phase 2 randomized clinical trial of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01584440.

BACKGROUND: Autologous bone marrow-derived stem cells have been ascribed an important therapeutic role in No-Option Critical limb Ischemia (NO-CLI). One primary endpoint for evaluating NO-CLI therapy is major amputation (AMP), which is usually combined with mortality for AMP-free survival (AFS). Only a trial which is double blinded can eliminate physician and patient bias as to the timing and reason for AMP. We examined factors influencing AMP in a prospective double-blinded pilot RCT (2:1 therapy to control) of 48 patients treated with site of service obtained bone marrow cells (BMAC) as well as a systematic review of the literature. METHODS: Cells were injected intramuscularly in the CLI limbs as either BMAC or placebo (peripheral blood). Six month AMP rates were compared between the two arms. Both patient and treating team were blinded of the assignment in follow-up examinations. A search of the literature identified 9 NO-CLI trials, the control arms of which were used to determine 6 month AMP rates and the influence of tissue loss. RESULTS: Fifteen amputations occurred during the 6 month period, 86.7% of these during the first 4 months. One amputation occurred in a Rutherford 4 patient. The difference in amputation rate between patients with rest pain (5.6%) and those with tissue loss (46.7%), irrespective of treatment group, was significant (p = 0.0029). In patients with tissue loss, treatment with BMAC demonstrated a lower amputation rate than placebo (39.1% vs. 71.4%, p = 0.1337). The Kaplan-Meier time to amputation was longer in the BMAC group than in the placebo group (p = 0.067). Projecting these results to a pivotal trial, a bootstrap simulation model showed significant difference in AFS between BMAC and placebo with a power of 95% for a sample size of 210 patients. Meta-analysis of the literature confirmed a difference in amputation rate between patients with tissue loss and rest pain. CONCLUSIONS: BMAC shows promise in improving AMP-free survival if the trends in this pilot study are validated in a larger pivotal trial. The difference in amp rate between Rutherford 4 & 5 patients suggests that these patients should be stratified in future RCTs.

OBJECTIVE: The purpose of this study was to describe the process and cost of delivering a physical therapist-guided synchronous telehealth exercise program appropriate for older adults with functional limitations. Such programs may help alleviate some of the detrimental impacts of social distancing and quarantine on older adults at-risk of decline. METHODS: Data were derived from the feasibility arm of a parent study, which piloted the telehealth program for 36 sessions with 1 participant. The steps involved in each phase (ie, development, delivery) were documented, along with participant and program provider considerations for each step. Time-driven activity-based costing was used to track all costs over the course of the study. Costs were categorized as program development or delivery and estimated per session and per participant. RESULTS: A list of the steps and the participant and provider considerations involved in developing and delivering a synchronous telehealth exercise program for older adults with functional impairments was developed. Resources used, fixed and variable costs, per-session cost estimates, and total cost per person were reported. Two potential measures of the "value proposition" of this type of intervention were also reported. Per-session cost of $158 appeared to be a feasible business case, especially if the physical therapist to trained assistant personnel mix could be improved. CONCLUSIONS: The findings provide insight into the process and costs of developing and delivering telehealth exercise programs for older adults with functional impairments. The information presented may provide a "blue print" for developing and implementing new telehealth programs or for transitioning in-person services to telehealth delivery during periods of social distancing and quarantine. IMPACT: As movement experts, physical therapists are uniquely positioned to play an important role in the current COVID-19 pandemic and to help individuals who are at risk of functional decline during periods of social distancing and quarantine. Lessons learned from this study's experience can provide guidance on the process and cost of developing and delivering a telehealth exercise program for older adults with functional impairments. The findings also can inform new telehealth programs, as well as assist in transitioning in-person care to a telehealth format in response to the COVID-19 pandemic.

PURPOSE: The objectives of this study were to (1) measure the prevalence of incontinence-associated dermatitis (IAD) and pressure ulcers (PUs) on admission to a long-term acute care (LTAC) facility; (2) identify factors associated with IAD and PU on admission to an LTAC facility; and (3) measure the incidence of incontinence and PUs in LTAC patients. DESIGN: This was a longitudinal, repeated-measures study; data were collected over a 12-week period. SUBJECTS AND SETTING: One hundred seventy-one patients, with a median age of 55 years. Fifty-four women and 117 men were evaluated. The sample comprises all patients admitted to the 4 LTAC units at the Drake Center in Cincinnati, Ohio. METHODS: Patients were examined using the "Hospital Survey on Incontinence and Perineal Skin Injury" instrument within 24 hours of admission and they were reevaluated weekly using the same tool until discharge. All data were collected by the Drake Center Advanced Wound Team. Prevalence was defined as the frequency of PUs or IAD identified at admission. Incidence was calculated using the formula: the number of new IAD cases/the number of patients without IAD on admission. Pressure ulcer incidence was measured using 2 formulas: (1) the number of patients with new PUs/the number of all patients who did not have PU on admission and (2) the number of patients with new PUs or a PU in a new location/the number of all patients. RESULTS: Thirty-nine out of 171 patients had IAD on admission, yielding a prevalence of 22.8%. Sixty of 171 patients had a PU on admission, yielding a prevalence of 35.1%. Ten of 132 patients who did not have IAD at admission developed IAD during follow-ups, yielding a 7.6% incidence. Two PU incidence rates were measured; those patients without PUs on admission 3.6% (4/111) and all patients 8.2% (14/171). CONCLUSION: The LTAC admission PU prevalence rate in this study was greater than that reported previously in acute or long-term care settings. The LTAC PU incidence rate was less than those reported for both acute and long-term care settings. The LTAC IAD admission prevalence rate closely reflected the acute care rate but was substantially higher than the long-term care rate.

Indirect calorimetry (IC) is the gold standard for measuring resting energy expenditure (REE) in the critically ill patient. The use of predictive equations to develop nutrition regimens can be problematic in the critical care setting, because the effects that disease, injury, and stress have on REE are often varied and unpredictable. IC testing ensures that the specific conditions of the critically ill patient are taken into account, thereby preventing potential complications from over- and underfeeding. The clinical indications for and appropriate applications of IC testing are discussed. In addition, 3 case studies are presented that highlight the application of IC. The clinician can face numerous obstacles in implementing IC testing, including lack of equipment, staff shortages, and lack of knowledge regarding application and interpretation of the IC study. Recommendations for addressing these challenges are discussed. In addition, guidelines on ordering and interpreting the IC study are provided. Best practices for predictive equations in critically and acutely ill patients are also presented, since IC testing is not feasible in certain situations. Given the importance of predicting REE in the critically ill patient, it is paramount that more healthcare professionals incorporate IC testing into practice. A multidisciplinary approach is helpful in developing a well-established clinical practice. Nutrition support clinicians can promote optimal nutrition management by being well-informed and able to provide evidence-based recommendations for the use of IC.

PURPOSE: Diagnosis of lung cancer at advanced stages can result in missed treatment opportunities, worse outcomes, and higher health care costs. This study evaluated the wait time to diagnose non-small-cell lung cancer (NSCLC) and the cost of diagnosis and treatment based on the stage at diagnosis. PATIENTS AND METHODS: Adult patients diagnosed with NSCLC between January 2007 and September 2011 were identified from a proprietary oncology registry and linked to health insurance claims from a large US health insurance company. Continuous enrollment in the health plan was required for at least 12 months prediagnosis (baseline) and at least 3 months postdiagnosis (follow-up). Use of diagnostic tests and time to diagnosis were examined. The rates of health care utilization and per-patient per-month (PPPM) health care costs were calculated. RESULTS: A total of 1,210 patients with NSCLC were included in the analysis. Most patients (93.6%) had evidence of diagnostic tests beginning 5 to 6 months prior to diagnosis, and most were diagnosed at an advanced stage (23% Stage IIIb and 46% Stage IV). The PPPM total health care costs in USD pre- and postdiagnosis were $2,407±$3,364 (mean±standard deviation) and $16,577±$33,550, respectively. PPPM total health care costs and utilization after lung cancer diagnosis were significantly higher among patients diagnosed at Stage IV disease and lowest among patients diagnosed at Stage I disease ($7,239 Stage I, $9,484 Stage II, $11,193 Stage IIIa, $17,415 Stage IIIb, and $21,441 Stage IV). CONCLUSION: This study showed that most patients experienced long periods of delay between their first diagnostic test for lung cancer and a definitive diagnosis, and the majority were diagnosed at advanced stages of disease. Costs associated with the management of lung cancer increased substantially with higher stages at diagnosis. Procedures that diagnose lung cancer at earlier stages may allow for less resource use and costs among patients with lung cancer.

BACKGROUND: Obstructive sleep apnea (OSA) patients are at increased risk for pulmonary and cardiovascular complications; perioperative mortality risk is unclear. This report analyzes cases submitted to the OSA Death and Near Miss Registry, focusing on factors associated with poor outcomes after an OSA-related event. We hypothesized that more severe outcomes would be associated with OSA severity, less intense monitoring, and higher cumulative opioid doses. METHODS: Inclusion criteria were age ≥18 years, OSA diagnosed or suspected, event related to OSA, and event occurrence 1992 or later and <30 days postoperatively. Factors associated with death or brain damage versus other critical events were analyzed by tests of association and odds ratios (OR; 95% confidence intervals [CIs]). RESULTS: Sixty-six cases met inclusion criteria with known OSA diagnosed in 55 (83%). Patients were middle aged (mean = 53, standard deviation [SD] = 15 years), American Society of Anesthesiologists (ASA) III (59%, n = 38), and obese (mean body mass index [BMI] = 38, SD = 9 kg/m); most had inpatient (80%, n = 51) and elective (90%, n = 56) procedures with general anesthesia (88%, n = 58). Most events occurred on the ward (56%, n = 37), and 14 (21%) occurred at home. Most events (76%, n = 50) occurred within 24 hours of anesthesia end. Ninety-seven percent (n = 64) received opioids within the 24 hours before the event, and two-thirds (41 of 62) also received sedatives. Positive airway pressure devices and/or supplemental oxygen were in use at the time of critical events in 7.5% and 52% of cases, respectively. Sixty-five percent (n = 43) of patients died or had brain damage; 35% (n = 23) experienced other critical events. Continuous central respiratory monitoring was in use for 3 of 43 (7%) of cases where death or brain damage resulted. Death or brain damage was (1) less common when the event was witnessed than unwitnessed (OR = 0.036; 95% CI, 0.007-0.181; P < .001); (2) less common with supplemental oxygen in place (OR = 0.227; 95% CI, 0.070-0.740; P = .011); (3) less common with respiratory monitoring versus no monitoring (OR = 0.109; 95% CI, 0.031-0.384; P < .001); and (4) more common in patients who received both opioids and sedatives than opioids alone (OR = 4.133; 95% CI, 1.348-12.672; P = .011). No evidence for an association was observed between outcomes and OSA severity or cumulative opioid dose. CONCLUSIONS: Death and brain damage were more likely to occur with unwitnessed events, no supplemental oxygen, lack of respiratory monitoring, and coadministration of opioids and sedatives. It is important that efforts be directed at providing more effective monitoring for OSA patients following surgery, and clinicians consider the potentially dangerous effects of opioids and sedatives-especially when combined-when managing OSA patients postoperatively.

This article is largely based on the recommendations of the AARP's Global Council on Brain Health (GCBH) and aims to provide an overview of evidence from current literature and expert opinion on key elements known to be relevant in preserving brain health as people age. Although we realize that there may be other lifestyle choices of importance to brain health, the GCBH has decided to initially focus on the issues below based on the preferences and concerns of its members. The areas to be discussed are: mental well-being, exercise, cognitively stimulating activities, sleep, nutrition, and social connectedness. Our review concluded that each of these areas offer opportunities for aging individuals to make lifestyle adjustments to positively impact brain health.

Continuous electronic monitoring of patient respiratory status frequently includes PetCO2 (end tidal CO2), RR (respiration rate), SpO2 (arterial oxygen saturation), and PR (pulse rate). Interpreting and integrating these vital signs as numbers or waveforms is routinely done by anesthesiologists and intensivists but is challenging for clinicians in low acuity areas such as medical wards, where continuous electronic respiratory monitoring is becoming more common place. We describe a heuristic algorithm that simplifies the interpretation of these four parameters in assessing a patient’s respiratory status, the Integrated Pulmonary Index (IPI). The IPI algorithm is a mathematical model combining SpO2, RR, PR, and PetCO2 into a single value between 1 and 10 that summarizes the adequacy of ventilation and oxygenation at that point in time. The algorithm was designed using a fuzzy logic inference model to incorporate expert clinical opinions. The algorithm was verified by comparison to experts’ scoring of clinical scenarios. The validity of the index was tested in a retrospective analysis of continuous SpO2, RR, PR, and PetCO2 readings obtained from 523 patients in a variety of clinical settings. IPI correlated well with expert interpretation of the continuous respiratory data (R = 0.83, p <<< 0.001), with agreement of −0.5 ± 1.4. Receiver operating curves analysis resulted in high levels of sensitivity (ranging from 0.83 to 1.00), and corresponding specificity (ranging from 0.96 to 0.74), based on IPI thresholds 3−6. The IPI reliably interpreted the respiratory status of patients in multiple areas of care using off-line continuous respiratory data. Further prospective studies are required to evaluate IPI in real time in clinical settings.

Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer's diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could serve as a marker for Alzheimer's pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET were included from ADNI. Cross-sectional relationships of plasma p-tau181 with PET biomarkers were tested. Longitudinally, we further investigated whether different p-tau181 levels at baseline predicted different progression of Alzheimer's pathological changes in the brain. We found plasma p-tau181 significantly correlated with brain amyloid (Spearman ρ = 0.45, P < 0.0001), tau (0.25, P = 0.0003), and FDG PET uptakes (-0.37, P < 0.0001), and increased along the Alzheimer's continuum. Individually, plasma p-tau181 could detect abnormal amyloid, tau pathologies and hypometabolism in the brain, similar with or even better than clinical indicators. The diagnostic accuracy of plasma p-tau181 elevated significantly when combined with clinical information (AUC = 0.814 for amyloid PET, 0.773 for tau PET, and 0.708 for FDG PET). Relationships of plasma p-tau181 with brain pathologies were partly or entirely mediated by the corresponding CSF biomarkers. Besides, individuals with abnormal plasma p-tau181 level (>18.85 pg/ml) at baseline had a higher risk of pathological progression in brain amyloid (HR: 2.32, 95%CI 1.32-4.08) and FDG PET (3.21, 95%CI 2.06-5.01) status. Plasma p-tau181 may be a sensitive screening test for detecting brain pathologies, and serve as a predictive biomarker for Alzheimer's pathophysiology.

Abstract A biological research framework to define Alzheimer’ disease with dichotomized biomarker measurement was proposed by National Institute on Aging–Alzheimer’s Association (NIA–AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic 18 F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline 18 F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal β-amyloid in neocortical regions but prompt cognitive decline by interacting with β-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer’s disease could be illustrated with biomarker measurement under NIA–AA framework. Clinical–neuroimaging–neuropathological studies in other cohorts are needed to validate these findings.

Importance: Systemic therapy for metastatic melanoma has evolved rapidly during the last decade, and patient treatment has become more complex. Objective: To evaluate the survival benefit achieved through surgical resection of melanoma metastatic to the abdominal viscera in patients treated in the modern treatment environment. Design, Setting, and Participants: This retrospective review of the institutional melanoma database from the John Wayne Cancer Institute at Providence St Johns Health Center, a tertiary-level melanoma referral center, included 1623 patients with melanoma diagnosed as having potentially resectable abdominal metastases before (1969-2003) and after (2004-2014) advances in systemic therapy. Main Outcomes and Measures: Overall survival (OS). Results: Of the 1623 patients identified in the database with abdominal melanoma metastases, 1097 were men (67.6%), and the mean (SD) age was 54.6 (14.6) years. Of the patients with metastatic melanoma, 1623 (320 [19.7%] in the 2004-2014 period) had abdominal metastases, including 336 (20.7%) with metastases in the gastrointestinal tract, 697 (42.9%) in the liver, 138 (8.5%) in the adrenal glands, 38 (2.3%) in the pancreas, 109 (6.7%) in the spleen, and 305 (18.8%) with multiple sites. Median OS was superior in surgical (n = 392; 18.0 months) vs nonsurgical (n = 1231; 7.0 months) patients (P < .001). The most favorable 1-year and 2-year OS was seen after surgery for gastrointestinal tract (52% and 41%) and liver (51% and 38%) metastases, respectively. Multivariable analysis found increasing age (hazard ratio [HR], 1.01; 95% CI, 1.00-1.01; P = .02) and the presence of ulceration (HR, 1.21; 95% CI, 1.01-1.45; P = .04) were associated with a worse OS. Alternatively, treatment with metastasectomy (HR, 0.59; 95% CI, 0.46-0.74; P < .001) and metastases involving the gastrointestinal tract (HR, 0.65; 95% CI, 0.48-0.87; P = .004) were associated with a better OS. The systemic treatment era did not significantly affect outcomes (HR, 0.82; 95% CI, 0.67-1.02; P = .15). Overall, patients with gastrointestinal tract metastases undergoing complete, curative resection derived the greatest benefit, with a median OS of 64 months. Conclusions and Relevance: To our knowledge, this series is the largest single-institution experience with abdominal melanoma metastases, demonstrating that surgical resection remains an important treatment consideration even in the systemic treatment era.

OBJECTIVE: To examine the cost associated with targeted surveillance for methicillin-resistant Staphylococcus aureus (MRSA) and the effect of such surveillance on the rate of nosocomial MRSA infection in a community hospital system. DESIGN: A before-and-after study comparing the rate of MRSA infection before (BES) and after (AES) the initiation of expanded surveillance. Cost-effectiveness was calculated as the difference between the cost savings associated with preventing nosocomial MRSA bacteremias and surgical site infections AES and the cost of MRSA cultures and contact isolation for patients colonized with MRSA. SETTING AND PARTICIPANTS: Patients in a 400-bed tertiary-care facility (Roper Hospital) and a 180-bed suburban hospital (St. Francis Hospital), both in Charleston, South Carolina.Interventions. Beginning in September 2001, patients were screened for MRSA colonization upon admission to the intensive care unit and weekly thereafter. In July 2002, surveillance was expanded to include targeted screening of patients admitted to general wards who were at risk of MRSA colonization. Colonized patients were placed in contact isolation. RESULTS: The mean rate of nosocomial MRSA infection decreased at Roper (0.76 cases per 1,000 patient-days BES and 0.45 per 1000 patient-days AES; P = .05) and at St. Francis (0.73 cases per 1,000 patient-days BES and 0.57 cases per 1000 patient-days AES; P=.35). Surveillance was cost-effective, preventing 13 nosocomial MRSA bacteremias and 9 surgical site infections, for a savings of 1,545,762 US dollars. CONCLUSIONS: Targeted surveillance for MRSA colonization was cost-effective and provided substantial benefits by reducing the rate of nosocomial MRSA infections in a community hospital system.