Citations

Background: Psychotic symptoms are common in Alzheimer’s disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice. Objective: To establish research criteria for the diagnosis of psychosis in AD. Methods: The International Society to Advance Alzheimer’s Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria. Results: Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers. Conclusion: We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders.

Abstract Background Extensive work in basic and clinical science suggests that biological mechanisms of aging are causally related to the development of disease and disability in late life. Modulation of the biological mechanisms of aging can extend both life span and health span in animal models, but translation to humans has been slow. Methods Summary of workshop proceedings from the 2018–2019 Epidemiology of Aging Workshop hosted by the Intramural Research Program at the National Institute on Aging. Results Epidemiologic studies play a vital role to progress in this field, particularly in evaluating new risk factors and measures of biologic aging that may influence health span, as well as developing relevant outcome measures that are robust and relevant for older individuals. Conclusions Appropriately designed epidemiological studies are needed to identify targets for intervention and to inform study design and sample size estimates for future clinical trials designed to promote health span.

Abstract Background A cluster of severe lung disease occurred at a manufacturing facility making industrial machines. We aimed to describe disease features and workplace exposures. Methods Clinical, functional, radiologic, and histopathologic features were characterized. Airborne concentrations of thoracic aerosol, metalworking fluid, endotoxin, metals, and volatile organic compounds were measured. Facility airflow was assessed using tracer gas. Process fluids were examined using culture, polymerase chain reaction, and 16S ribosomal RNA sequencing. Results Five previously healthy male never‐smokers, ages 27 to 50, developed chest symptoms from 1995 to 2012 while working in the facility's production areas. Patients had an insidious onset of cough, wheeze, and exertional dyspnea; airflow obstruction (mean FEV 1 = 44% predicted) and reduced diffusing capacity (mean = 53% predicted); and radiologic centrilobular emphysema. Lung tissue demonstrated a unique pattern of bronchiolitis and alveolar ductitis with B‐cell follicles lacking germinal centers, and significant emphysema for never‐smokers. All had chronic dyspnea, three had a progressive functional decline, and one underwent lung transplantation. Patients reported no unusual nonoccupational exposures. No cases were identified among nonproduction workers or in the community. Endotoxin concentrations were elevated in two air samples; otherwise, exposures were below occupational limits. Air flowed from areas where machining occurred to other production areas. Metalworking fluid primarily grew Pseudomonas pseudoalcaligenes and lacked mycobacterial DNA, but 16S analysis revealed more complex bacterial communities. Conclusion This cluster indicates a previously unrecognized occupational lung disease of yet uncertain etiology that should be considered in manufacturing workers (particularly never‐smokers) with airflow obstruction and centrilobular emphysema. Investigation of additional cases in other settings could clarify the cause and guide prevention.

Purpose: We aim to systematically review and analyze the available literature on “exceptional responders” in oncology. We hypothesize that survival or patients with an exceptional response may be predicted based on clinical factors. Materials and Methods: A PICOS/PRISMA/MOOSE selection protocol was used to find studies that reported oncology patients with an exceptional response. A total of 333 initial articles were screened, and 76 articles were included, accounting for 85 patients. The primary outcome was survival after exceptional response therapy (ERT). The secondary outcome was survival since diagnosis. Univariate and multivariate analyses were conducted for both outcomes with 17 covariates. Results: The median age was 52 years (interquartile range, 35-66 y), 51.8% were male individuals, 18 (21.2%) had lung cancer, and 1 patient (1%) met all National Cancer Institute criteria for exceptional response. The most common treatment resulting in exceptional response was a form of chemotherapy (49.2%) followed by targeted therapy (26.8%) and radiation therapy (7.7%). The median time from diagnosis to initiation of ERT was 7.92 months (interquartile range, 0-24.72 mo). On multivariate analysis of survival after initiation of ERT, there were no predictors of exceptional response. On multivariate analysis of survival since diagnosis, predictors of prolonged survival included time between diagnosis and ERT initiation (hazard ratio, 0.52; 95% confidence interval, 0.32-0.87; P=0.0124) and single prior surgery versus none (0.08; 95% confidence interval, 0.01-0.98; P=0.04853). Conclusions: There were no clinically apparent patient or treatment factors that predicted favorable survival following ERT; instead, reporting of exceptional response appears to be biased.

Abstract Purpose: The evidence on associations of mammographic breast density with breast cancer risk by combination of tumor aggressiveness features is limited. We examined associations of breast density phenotypes with risk of aggressive breast tumor features by menopausal status, and current postmenopausal hormone therapy. Methods: This study included 2,635 invasive breast cancer cases and 4,059 controls from participants of four nested case-control studies within four established cohorts: the Mayo Mammography Health Study, the Nurses Health Study, Nurses Health Study II, and San Francisco Mammography Registry. Percent breast density, absolute dense and non-dense areas were assessed from digitized film-screen mammograms using a computer-assisted threshold technique and standardized across studies. We used polytomous logistic regression to quantify the associations of breast density measures with risk of breast tumor aggressiveness (defined as presence of 2 or more of the following tumor characteristics: size ≥2cm, grade 2 or 3, or positive nodes), stratified by menopausal status and current hormone therapy (i.e., premenopausal, postmenopausal/estrogen therapy, postmenopausal/combined therapy, and postmenopausal/no hormones). We also evaluated differences in the strength of associations across categories. In a secondary analysis, we examined these associations while excluding cases with mammogram date within 2 years of diagnosis. Results: Positive associations of percent density and dense area and inverse associations of non-dense area with breast cancer risk were stronger in aggressive vs. non-aggressive tumors (OR=2.62, 95%CI 2.08-3.31 vs. OR=1.94, 95%CI 1.62-2.33 for percent density≥51% vs. 11-25%, p-heterogeneity=0.001; OR=1.89, 95%CI 1.54-2.31 vs. OR=1.65, 95%CI 1.41-1.93 for dense area 4th vs. 2nd quartile, p-heterogeneity=0.015; OR=0.56, 95%CI 0.44-0.72 vs. OR=0.71, 95%CI 0.59-0.86 for non-dense area 4th vs 2nd quartile, p-heterogeneity=0.007, respectively). These patterns were similar across all menopausal and hormone therapy groups (P-interactions=0.62, 0.76, and 0.23, for percent density, dense area and non-dense area, respectively). Excluding cases diagnosed within 2 years of mammography resulted in similar findings. Conclusion: Mammographic density phenotypes were more strongly associated with aggressive cancer (having two or more of the following: size ≥2cm, grade 2 or 3, or positive nodes) vs. non-aggressive types of breast cancer across categories of menopause and hormone therapy types. Citation Format: Lusine Yaghjyan, Rulla Tamimi, Kimberly Bertrand, Christopher G. Scott, Matthew R. Jensen, Shane Pankratz, Kathleen Brandt, Daniel Visscher, Aaron Norman, Fergus Cough, John Shepherd, Bo Fan, Yunn-Yi Chen, Lin Ma, Andrew H. Beck, Steven R. Cummings, Karla Kerlikowske, Celine Vachon. Interaction of mammographic breast density with menopausal status and postmenopausal hormone use in relation to the risk of aggressive breast cancer subtypes. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B27.

Purpose To compare patellar bone socket and cortical surface fixation techniques for isolated medial patellofemoral ligament (MPFL) reconstruction and determine whether there was a difference in (1) complication rates, including fracture of the patella; (2) redislocation rates; or (3) patient‐reported outcomes. Methods A literature search was conducted following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. We included patients who underwent isolated MPFL reconstruction for recurrent patellar instability. Patients with confirmed concomitant or prior ipsilateral knee procedures, multiligament injury, or less than 3 months of follow‐up were excluded. Risk‐of‐bias assessment was performed using the Methodological Index for Non‐randomized Studies (MINORS) system. Studies were classified by surgical technique (patellar bone socket group [group S] vs cortical fixation group [group F]), and complications, redislocations, and patient‐reported outcomes were collected. Results A total of 29 studies yielded 981 patients with MPFL reconstruction for inclusion. Of the patients, 620 underwent a patellar bone socket technique and 361 underwent a cortical fixation technique. Patients ranged in age from 11 to 68 years. Patellar fracture rates ranged from 0% to 17% in group S and were 0% in all group F studies. Mean Kujala scores ranged from 83.5 to 93.6 in group S and from 84.4 to 94.5 in group F. Mean Lysholm scores ranged from 84.6 to 91.7 in group S and from 83.5 to 95 in group F. Redislocation rates ranged from 0% to 21% in group S and from 0% to 13% in group F. Although heterogeneous in nature, complication rates ranged from 0% to 28% in group S and from 0% to 4% in group F. Conclusions MPFL reconstruction techniques with patellar bone sockets showed a larger range of complication rates than cortical fixation techniques, although overall, complications remained uncommon. Clinically, the bone socket group had comparable postoperative redislocation rates and patient outcomes to the group treated with cortical fixation techniques. Level of Evidence Level IV, systematic review of Level I through IV studies.

Purpose: To assess for ectopic ocular calcification in a series of patients with hypophosphatasia (HPP) treated with asfotase alfa, a recombinant tissue-nonspecific alkaline phosphatase. Methods: This is a retrospective analysis of subjects enrolled at Duke University Medical Center in ENB-009-10 (ClinicalTrials.gov: NCT01163149), a randomized controlled trial of asfotase alfa in adolescents and adults with HPP. Seven patients between the ages of 45 and 66 years diagnosed with HPP based on clinical features and low serum alkaline phosphatase levels were enrolled at our site. Subjects were randomized to receive either daily subcutaneous injections of asfotase alfa or no treatment. After 24 weeks, during the open-label extension phase, all subjects received treatment for at least 4 years. All subjects underwent comprehensive eye examinations at baseline and at 24-week intervals throughout the study to assess for development of ocular calcifications. Results: By week 120, all 7 subjects developed asymptomatic white refractile deposits in the interpalpebral perilimbal conjunctiva. Biopsy of the conjunctival lesions in 2 subjects revealed elastosis with subepithelial calcification. The lesions were nonprogressive and in 5 subjects exhibited some degree of regression. Conclusions: Asfotase alfa was invariably associated with development of mild focal conjunctival calcification, likely through disinhibition of hydroxyapatite crystal propagation. The calcifications were not symptomatic or vision-threatening and should not preclude enzyme replacement therapy for patients with this rare and often debilitating disease.

Background Adductor canal block (ACB) is an alternative method to femoral nerve block (FNB) for post-operative analgesia for anterior cruciate ligament reconstruction (ACLR) in pediatric and adolescent patients. Prior studies have suggested that FNB is associated with persistent strength deficits at 6 months after ACLR in this population. Proponents of the ACB consider that this method may result in a decreased incidence of quadriceps strength deficits during post-operative rehabilitation. The purpose of this study was to compare knee strength and function at 6 and 9 months after ACLR in pediatric and adolescent patients who received FNB versus ACB peri-operatively. Methods Patients 18 years or younger who underwent primary ACLR between 2002 and 2017 at a single institution were identified. ACLR was performed with either a patellar tendon autograft or hamstring autograft. A transphyseal ACLR was performed in patients with open physes. All patients participated in a comprehensive rehabilitation program which included isokinetic strength testing and functional testing at 6 and/or 9 months postoperatively. Patients were excluded if they underwent multiligamentous knee reconstruction, concomitant cartilage restoration procedures, did not receive perioperative FNB or ACB, or if they did not complete isokinetic strength and functional testing at 6 or 9 months. The included cohort was separated into FNB group and ACB group for comparison. Isokinetic extension and flexion strength deficits and functional deficits in vertical jump, single hop, and triple hop between the two groups were compared at both time points. A strength deficit of 15% or less and a functional deficit of 10% or less compared to the contralateral side were considered satisfactory. Univariate analysis was performed to assess for differences in patient demographics and surgical variables. A 1:1 matched subgroup analysis between the two groups was performed to account for possible differences in outcomes associated to graft types, concomitant meniscus repair, and BMI. Results Of the 240 patients identified, 85 patients (64 FNB, 21 ACB) with a mean age of 15.9 years (Range: 11-18) met inclusion criteria for comparison at 6 months and 76 patients (40 FNB, 36 ACB) with a mean age of 15.5 years (Range: 12-17) met inclusion criteria for comparison at 9 months. Univariate analysis showed significantly greater deficits at 6 months in the FNB with respect to fast isokinetic flexion strength (7.7% vs. -4.9%; p = .03). There were no differences in slow isokinetic flexion (10.5% vs. 6.8%; p = .79) and fast isokinetic extension (11.9% vs. 13.9%; p = .68) strength deficits between the groups. There were clinically relevant greater deficits in the FNB group with respect to slow isokinetic extension (19.3% vs. 12.0%; p = .24), but this did not reach statistical significance. This clinical difference in satisfactory scores between the groups with respect to slow isokinetic extension was accentuated with the 1:1 matched outcome trial (23.9% vs. 12.1%; p = .20). With respect to function, there were no differences in deficits for vertical jump (8.4% vs. 4.3%; p = .55), single hop (7.4% vs. 9.3%; p = .65), or triple hop (6.0% vs. 7.1%; p = .77) between the two groups. Univariate analysis showed significant greater deficits at 9 months in the FNB with respect to slow isokinetic flexion strength (9.6% vs. 0.4%; p = .01). There were no differences in fast isokinetic flexion (-0.2% vs. 0.7%; p = .87) and fast isokinetic extension (6.0% vs. 2.7%; p = .51) strength deficits between the groups. There were clinically relevant greater deficits in the FNB group with respect to slow isokinetic extension (17.3% vs -14.0%, p = .19), but this did not reach statistical significance. With respect to function, there were no differences in deficits for vertical jump (5.2% vs. 6.5%, p = .85), single hop (7.7% vs. 6.2%; p = .79), or triple hop (1.9% vs. 3.9%; p = .35) between the two groups. Conclusion Because previous studies have shown a significant delay in return of strength with FNB, ACB began to be employed at our center for post-operative pain control following ACLR in pediatric and adolescent patients. This study showed that pediatric and adolescent patients treated with FNB as a method of post-operative analgesia after ACLR had significantly greater deficits in fast isokinetic flexion at 6 months and slow isokinetic flexion at 9 months compared to those who received ACB. These differences may or may not have clear clinical relevance. However, patients treated with FNB showed clinically relevant greater deficits in slow isokinetic extension strength at 6 and 9 months postoperatively compared to those who received ACB if 85% strength return is used as criteria to return to sport. Pediatric and adolescent patients could benefit from undergoing perioperative analgesia with ACB instead of FNB, but comparison between these two methods of regional anesthesia may require a prospective trial. Level of Evidence Retrospective cohort study, Level IV [Table: see text][Table: see text]

Abstract Airway smooth muscle (ASM) regulation of airway structure and contractility is critical in fetal/neonatal physiology in health and disease. Fetal lungs experience higher Ca 2+ environment that may impact extracellular Ca 2+ ([Ca 2+ ] o ) sensing receptor (CaSR). Well‐known in the parathyroid gland, CaSR is also expressed in late embryonic lung mesenchyme. Using cells from 18‐22 week human fetal lungs, we tested the hypothesis that CaSR regulates intracellular Ca 2+ ([Ca 2+ ] i ) in fetal ASM (fASM). Compared with adult ASM, CaSR expression was higher in fASM, while fluorescence Ca 2+ imaging showed that [Ca 2+ ] i was more sensitive to altered [Ca 2+ ] o . The fASM [Ca 2+ ] i responses to histamine were also more sensitive to [Ca 2+ ] o (0–2 mM) compared with an adult, enhanced by calcimimetic R568 but blunted by calcilytic NPS2143. [Ca 2+ ] i was enhanced by endogenous CaSR agonist spermine (again higher sensitivity compared with adult). Inhibition of phospholipase C (U73122; siRNA) or inositol 1,4,5‐triphosphate receptor (Xestospongin C) blunted [Ca 2+ ] o sensitivity and R568 effects. NPS2143 potentiated U73122 effects. Store‐operated Ca 2+ entry was potentiated by R568. Traction force microscopy showed responsiveness of fASM cellular contractility to [Ca 2+ ] o and NPS2143. Separately, fASM proliferation showed sensitivity to [Ca 2+ ] o and NPS2143. These results demonstrate functional CaSR in developing ASM that modulates airway contractility and proliferation.