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Although amyloid imaging with PiB-PET ([C-11]Pittsburgh Compound-B positron emission tomography), and now with F-18-labeled tracers, has produced remarkably consistent qualitative findings across a large number of centers, there has been considerable variability in the exact numbers reported as quantitative outcome measures of tracer retention. In some cases this is as trivial as the choice of units, in some cases it is scanner dependent, and of course, different tracers yield different numbers. Our working group was formed to standardize quantitative amyloid imaging measures by scaling the outcome of each particular analysis method or tracer to a 0 to 100 scale, anchored by young controls (≤45 years) and typical Alzheimer's disease patients. The units of this scale have been named "Centiloids." Basically, we describe a "standard" method of analyzing PiB PET data and then a method for scaling any "nonstandard" method of PiB PET analysis (or any other tracer) to the Centiloid scale.

Objective The progressive rise in demand on NHS emergency care resources is partly attributable to increases in attendances of children and older people. A quality gap exists in the care provision for the old and the young. The Five Year Forward View suggested new models of care but that the "answer is not one-size-fits-all". This article discusses the urgent need for person-centred outcome measures to bridge the gap that exists between demand and provision. Design This review is based on evidence gathered from literature searching across several platforms using a variety of search terms to account for the obvious heterogeneity, drawing on key 'think-tank' evidence. Settings Qualitative and quantitative studies examining approaches to caring for individuals at the extremes of age. Participants Individuals at the extremes of age (infants and older people). Main Outcome Measures Understanding similarities and disparities in the care of individuals at the extremes of age in an emergency and non-emergency context. Results There exists several similarities and disparities in the care of individuals at the extremes of age. The increasing burden of health disease on the economy must acknowledge the challenges that exist in managing patients in emergency settings at the extremes of age and build systems to acknowledge the traits these individuals exhibit. Conclusion Commissioners of services must optimise the models of care delivery by appreciating the similarities and differences between care requirements in these two large groups seeking emergency care. [ABSTRACT FROM AUTHOR]

The development of innovative non-invasive neuroimaging methods and biomarkers is critical for studying brain disease. Imaging of cerebrospinal fluid (CSF) pulsatility may inform the brain fluid dynamics involved in clearance of cerebral metabolic waste. In this work, we developed a methodology to characterize the frequency and spatial localization of whole brain CSF pulsations in humans. Using 7 Tesla (T) human magnetic resonance imaging (MRI) and ultrafast echo-planar imaging (EPI), in-vivo images were obtained to capture pulsations of the CSF signal. Physiological data were simultaneously collected and compared with the 7 T MR data. The primary components of signal pulsations were identified using spectral analysis, with the most evident frequency bands identified around 0.3, 1.2, and 2.4 Hz. These pulsations were mapped spatially and temporally onto the MR image domain and temporally onto the physiological measures of electrocardiogram and respiration. We identified peaks in CSF pulsations that were distinct from peaks in grey matter and white matter regions. This methodology may provide novel in vivo biomarkers of disrupted brain fluid dynamics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Martins, de Almeida, Wu, Wilckens, Minhas, Ibinson, Aizenstein, Santini and Ibrahim.)

Pain in rheumatic diseases transcends the traditional nociceptive paradigm, incorporating complex interactions between nociceptive, neuropathic, and nociplastic mechanisms, as well as significant psychosocial factors. Advances in understanding chronic pain highlight the role of peripheral and central sensitization, and the emergence of nociplastic pain-a result of altered central nervous system processing. This modern perspective acknowledges the influence of mood disorders, environmental stressors, and cognitive patterns like catastrophizing, revealing the intricate interplay between biological, psychological, and social determinants of pain. Research emphasizes the brain's pivotal role in pain perception, underscoring the importance of comprehensive approaches that integrate medical, psychological, and social interventions to address the multifaceted nature of chronic pain in rheumatic diseases effectively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

The U.S. is grappling with an opioid epidemic, with millions of adults on long-term opioid therapy (LTOT). Although patients often report pain relief and improved daily function with opioids, research shows no significant differences in short-term outcomes between opioid and non-opioid users, as well as no long-term opioid benefits. This scoping review aims to identify lesser-known side effects of long-term opioid use and increase awareness of them, allowing healthcare providers and patients to better assess the risks and benefits of opioid use. Our data search from PubMed and Google Scholar used keywords related to opioids, chronic pain, hypogonadism, endocrinopathies, cancer progression, cardiovascular events, renovascular events, sleep disturbances, mood disorders and others, narrowing down to English-language full articles published from January 2018 to April 2023. This review emphasizes the probable serious adverse consequences of long-term opioid use on various body systems in patients with chronic pain. Given the lack of long-term benefits and significant adverse effects, our review underscores the critical need for healthcare providers to include these risks in discussions with patients when considering the long-term use of opioid therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Effective management of chronic pain necessitates multidisciplinary approaches including medical treatment, physical therapy, lifestyle interventions, and behavioral or mental health therapy. Medical providers regularly report high levels of stress and challenge when treating patients with chronic pain, which recur in part due to improper education on contributors to pain and misalignment in patient and provider goals and expectations for treatment. The current paper reviews common challenges and misconceptions in the setting of chronic pain management as well as strategies for effective patient education and goal setting related to these issues. The paper also outlines key aspects of provider burnout, its relevance for medical providers in chronic pain management, and recommendations for burnout prevention in navigating issues of patient education and treatment planning., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: Declaration of competing interest No conflict of interest or funding.

Introduction: Down syndrome (DS) is a genetic cause of early-onset Alzheimer's disease (AD). The National Institute on Aging-Alzheimer's Association AT(N) Research Framework is a staging model for AD biomarkers but has not been assessed in DS., Method: Data are from the Alzheimer's Biomarker Consortium-Down Syndrome. Positron emission tomography (PET) amyloid beta (Aβ; 15 mCi of [ 11 C]Pittsburgh compound B) and tau (10 mCi of [ 18 F]AV-1451) were used to classify amyloid (A) -/+ and tau (T) +/-. Hippocampal volume classified neurodegeneration (N) -/+. The modified Cued Recall Test assessed episodic memory., Results: Analyses included 162 adults with DS (aged M = 38.84 years, standard deviation = 8.41). Overall, 69.8% of participants were classified as A-/T-/(N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. Participants deemed cognitively stable were most likely to be A-T-(N)- and A+T-(N)-. Tau PET (T+) most closely aligning with memory impairment and AD clinical status., Discussion: Findings add to understanding of AT(N) biomarker profiles in DS., Highlights: Overall, 69.8% of adults with Down syndrome (DS) aged 25 to 61 years were classified as amyloid (A)-/tau (T)-/neurodegeneration (N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. The AT(N) profiles were associated with clinical Alzheimer's disease (AD) status and with memory performance, with the presence of T+ aligned with AD clinical symptomology. Findings inform models for predicting the transition to the prodromal stage of AD in DS., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Tau accumulation in Alzheimer's disease is associated with short term clinical progression and faster rates of cognitive decline in individuals with high amyloid-β deposition. Defining an optimal threshold of tau accumulation predictive of cognitive decline remains a challenge., Objective: We tested the ability of regional tau PET sensitivity and specificity thresholds to predict longitudinal cognitive decline. We also tested the predictive performance of thresholds in the proposed new NIA-AA biological staging for Alzheimer's disease where multiple levels of tau positivity are used to stage participants., Methods: 18F-flortaucipir scans from 301 non-demented participants were processed and sampled. Four cognitive measures were assessed longitudinally. Regional standardized uptake value ratios were split into infra- and suprathreshold groups at baseline using previously derived thresholds. Survival analysis, log rank testing, and Generalized Estimation Equations assessed the relationship between the application of regional sensitivity/specificity thresholds and change in cognitive measures as well as tau threshold performance in predicting cognitive decline within the new NIA-AA biological staging., Results: The meta temporal region was best for predicting risk of short-term cognitive decline in suprathreshold, as compared to infrathreshold participants. When applying multiple levels of tau positivity, each subsequent level of tau identified cognitive decline at earlier timepoints., Conclusions: When using 18F-flortaucipir, meta temporal suprathreshold classification was associated with increased risk of cognitive decline, suggesting that abnormal tau deposition in the cortex predicts decline. Likewise, the application of multiple levels of tau clearly predicts the distinctive cognitive trajectories in the new NIA-AA biological staging framework.

A methodology for determining tau PET thresholds is needed to confidently detect early tau deposition. We compared multiple threshold-determining methods in participants who underwent either 18 F-flortaucipir or 18 F-MK-6240 PET scans. Methods: 18 F-flortaucipir ( n = 798) and 18 F-MK-6240 ( n = 216) scans were processed and sampled to obtain regional SUV ratios. Subsamples of the cohorts were based on participant diagnosis, age, amyloid-β status (positive or negative), and neurodegeneration status (positive or negative), creating older-adult (age ≥ 55 y) cognitively unimpaired (amyloid-β-negative, neurodegeneration-negative) and cognitively impaired (mild cognitive impairment/Alzheimer disease, amyloid-β-positive, neurodegeneration-positive) groups, and then were further subsampled via matching to reduce significant differences in diagnostic prevalence, age, and Mini-Mental State Examination score. We used the biostatistical estimation of tau threshold hallmarks (BETTH) algorithm to determine sensitivity and specificity in 6 composite regions. Results: Parametric double receiver operating characteristic analysis yielded the greatest joint sensitivity in 5 of the 6 regions, whereas hierarchic clustering, gaussian mixture modeling, and k-means clustering all yielded perfect joint specificity (2.00) in all regions. Conclusion: When 18 F-flortaucipir and 18 F-MK-6240 are used, Alzheimer disease-related tau status is best assessed using 2 thresholds, a sensitivity one based on parametric double receiver operating characteristic analysis and a specificity one based on gaussian mixture modeling, delimiting an uncertainty zone indicating participants who may require further evaluation., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Chronic pain is a burdensome and prevalent symptom in individuals with rheumatic disease. The International Association for the Study of Pain classifies pain into 3 descriptive categories: nociceptive, neuropathic, and nociplastic. These categories are intended to provide information about the mechanisms underlying the pain, which can then serve as targets for drug or non-drug treatments. This review describes the 3 types of pain as they relate to patients seen by rheumatology health care providers. The focus is on identifying individuals with nociplastic pain, which can either occur in isolation as in fibromyalgia, or as a comorbidity in individuals with primary autoimmune conditions, such as rheumatoid arthritis and systemic lupus erythematosus. Practical information about how rheumatology health care providers can approach and manage chronic pain is also provided., (© 2023 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: Medication access and adherence play key roles in determining patient outcomes. We investigated whether cost-related non-adherence (CRNA) to prescription medications was associated with worse patient-reported outcomes in a population-based systemic lupus erythematosus (SLE) cohort., Methods: Sociodemographic and prescription data were collected by structured interviews in 2014-2015 from patients meeting SLE criteria in the established Michigan Lupus Epidemiology & Surveillance (MILES) Cohort. We examined the associations between CRNA and potential confounders such as sociodemographics and health insurance coverage, and outcome measures of SLE activity and damage using multivariable linear regression., Results: 462 SLE participants completed the study visit: 430 (93.1%) female, 208 (45%) Black, and mean age 53.3 years. 100 (21.6%) participants with SLE reported CRNA in the preceding 12 months. After adjusting for covariates, CRNA was associated with both higher levels of current SLE disease activity [SLAQ: β coeff 2.7 (95% CI 1.3, 4.1), p < 0.001] and damage [LDIQ β coeff 1.4 (95% CI 0.5, 2.4), p = 0.003]. Race, health insurance status, and fulfilling Fibromyalgia (FM) Survey Criteria were independently associated with both higher (worse) SLAQ and LDIQ scores; female sex was further associated with higher SLAQ scores., Conclusion: Patients with SLE who reported CRNA in the previous 12 months had significantly worse self-reported current disease activity and damage scores compared to those not reporting CRNA. Raising awareness and addressing barriers or concerns related to financial implications and accessibility issues in care plans may help to improve these outcomes.

Introduction: Recently, an increasing number of tau tracers have become available. There is a need to standardize quantitative tau measures across tracers, supporting a universal scale. We developed several cortical tau masks and applied them to generate a tau imaging universal scale., Method: One thousand forty-five participants underwent tau scans with either 18 F-flortaucipir, 18 F-MK6240, 18 F-PI2620, 18 F-PM-PBB3, 18 F-GTP1, or 18 F-RO948. The universal mask was generated from cognitively unimpaired amyloid beta (Aβ)- subjects and Alzheimer's disease (AD) patients with Aβ+. Four additional regional cortical masks were defined within the constraints of the universal mask. A universal scale, the CenTauR z , was constructed., Results: None of the regions known to display off-target signal were included in the masks. The CenTauR z allows robust discrimination between low and high levels of tau deposits., Discussion: We constructed several tau-specific cortical masks for the AD continuum and a universal standard scale designed to capture the location and degree of abnormality that can be applied across tracers and across centers. The masks are freely available at https://www.gaain.org/centaur-project., Competing Interests: Victor Villemagne has received research grants from NHMRC (GNT2001320), the Aging Mind Foundation (DAF2255207) and NIH (2P01AG025204‐16) and is and has been a consultant or paid speaker at sponsored conference sessions for Eli Lilly, Life Molecular Imaging, ACE Barcelona, and IXICO. Sandra Sanabria Bohorquez and Robby Weimer are a full‐time employees and stock owners of Roche. Santiago Bullich and Andrew Stephen are full‐time employees of Life Molecular Imaging GmbH. Hitoshi Shimada and Makoto Higuchi hold patents on compounds related to the present report (JP 5422782/EP 12 884 742.3/CA2894994/HK1208672). Christopher C. Rowe has received research grants from NHMRC, Enigma Australia, Biogen, Eisai, and Abbvie. He is on the scientific advisory board for Cerveau Technologies and consulted for Prothena, Eisai, Roche, and Biogen Australia. Oskar Hansson has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Genentech, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens. The other authors did not report any conflict of interest., (© 2023 CSIRO and The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose of Review: Individuals with rheumatoid arthritis (RA) have traditionally been characterized as having nociceptive pain, leading to the assumption that effective immunosuppression should be enough to provide effective pain management. However, despite therapeutic advancements providing excellent control of inflammation, patients continue to have significant pain and fatigue. The presence of concurrent fibromyalgia, driven by augmented central nervous system processing and largely unresponsive to peripheral therapies, may contribute to this pain persistence. This review provides updates on fibromyalgia and RA as relevant for the clinician., Recent Findings: Patients with RA have high levels of concomitant fibromyalgia and nociplastic pain. The presence of fibromyalgia can lead to higher scores on disease measures, erroneously indicating that worse disease is presently leading to the increased use of immunosuppressives and opioids. Disease scores that provide a comparison between patient-reported and provider-reported and clinical factors may be helpful to indicate centralized pain. IL-6 and Janus kinase inhibitors, in addition to targeting peripheral inflammation, may provide pain relief by acting on peripheral and central pain pathways., Summary: Central pain mechanisms that may be contributing to pain in RA are common and should be distinguished from pain directly arising from peripheral inflammation., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most prescribed pharmacologic therapies worldwide due to their therapeutic analgesic efficacy and relative tolerability. In the past several decades, various cardiovascular (CV) adverse events have emerged regarding both traditional NSAIDs (tNSAIDs) and cyclo-oxygenase 2 (COX-2) selective (coxibs). This review will provide an updated report on the CV risk profile of NSAIDs, focusing on several of the larger clinical trials, meta-analyses, and registry studies. We aim to provide rheumatologists with a framework for NSAID use in the context of rheumatologic chronic pain management. Recent findings: In patients with and without CV diseases, the use of NSAIDs, both tNSAIDs and coxibs, is associated with an increased risk of adverse CV events, myocardial infarction, heart failure, and cerebrovascular events. These CV risks have increased within weeks of coxib use and higher doses of tNSAIDs. The risk of adverse CV events is heterogenous across NSAIDs; naproxen and low-dose ibuprofen appear to have lower increased CV risk among NSAIDs. A variation in CV risk is associated with multiple factors, including NSAID class, COX-2 selectivity, treatment dose and duration, and baseline patient risk. Summary: Many important questions remain regarding the safety of NSAIDs and whether the culmination of research performed could inform us whether specific patient subtypes or NSAID class may have a more favorable profile. tNSAIDs such as naproxen and low-dose ibuprofen may have a lower CV risk profile, while coxibs have a more favorable GI risk profile. In general, any NSAID can be optimized if used at the lowest effective dose for the shortest amount of time, especially among individuals with increased CV risk., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Trisomy 21 causes Down syndrome (DS) and is a recognized cause of early-onset Alzheimer's disease (AD)., Objective: The current study sought to determine if premorbid intellectual disability level (ID) was associated with variability in age-trajectories of AD biomarkers and cognitive impairments. General linear mixed models compared the age-trajectory of the AD biomarkers PET Aβ and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type, APOE status, biological sex, and site., Methods: Analyses involved adults with DS from the Alzheimer's Biomarkers Consortium-Down Syndrome. Participants completed measures of memory, mental status, and visuospatial ability. Premorbid ID level was based on IQ or mental age scores prior to dementia concerns. PET was acquired using [11C] PiB for Aβ, and [18F] AV-1451 for tau., Results: Cognitive data was available for 361 participants with a mean age of 45.22 (SD = 9.92) and PET biomarker data was available for 154 participants. There was not a significant effect of premorbid ID level by age on cognitive outcomes. There was not a significant effect of premorbid ID by age on PET Aβ or on tau PET. There was not a significant difference in age at time of study visit of those with mild cognitive impairment-DS or dementia by premorbid ID level., Conclusion: Findings provide robust evidence of a similar time course in AD trajectory across premorbid ID levels, laying the groundwork for the inclusion of individuals with DS with a variety of IQ levels in clinical AD trials.

Purpose of Review: Despite the tremendous advancement in the use of biologics, many patients with inflammatory arthritis do not achieve remission, and the risk of joint damage remains high. A multidimensional approach to treatment is essential. Joint disease in the hands and wrists may prevent patients from performing daily and valued life activities. This review will discuss the role of occupational therapists in inflammatory arthritis, recent updates on joint protection and assistive devices, as well as highlighting adjunctive treatment options for rheumatologists to help patients manage their symptoms., Recent Findings: This article describes the meaningful role of occupational therapy and assistive devices in improving the outcomes for patients with inflammatory arthritis. We describe orthoses, assistive devices and adjunctive therapies utilized in inflammatory arthritis. We provide evidence supporting joint protection and occupational therapy as ways to help with these diseases. A multidisciplinary approach including the entire healthcare provider team, including occupational therapists, is essential to providing individualized treatment focusing on maximizing mobility in each patient's daily routine., Summary: Although larger studies are needed, assessment by hand-certified occupational therapists for instruction in joint protection techniques, assistive devices and customized orthoses and devices are important adjuncts to pharmacologic management in inflammatory arthritis., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Medication access and adherence are important determinants of health outcomes. We investigated factors associated with access and cost-related nonadherence to prescriptions in a population-based cohort of systemic lupus erythematosus (SLE) patients and controls., Methods: Detailed sociodemographic and prescription data were collected by structured interview in 2014-2015 from participants in the Michigan Lupus Epidemiology and Surveillance (MILES) cohort. We compared access between cases and frequency-matched controls and examined associated factors in separate multivariable logistic regression models., Results: A total of 654 participants (462 SLE patients, 192 controls) completed the baseline visit; 584 (89%) were female, 285 (44%) were Black, and the mean age was 53 years. SLE patients and controls reported similar frequencies of being unable to access prescribed medications (12.1% versus 9.4%, respectively; P was not significant). SLE patients were twice as likely as controls to report cost-related prescription nonadherence in the preceding 12 months to save money (21.7% versus 10.4%; P = 0.001) but were also more likely to ask their doctor for lower cost alternatives (23.8% versus 15.6%; P = 0.02). Disparities were found in association with income, race, and health insurance status, but the main findings persisted after adjusting for these and other variables in multivariable models., Conclusion: SLE patients were more likely than controls from the general population to report cost-related prescription nonadherence, including skipping doses, taking less medicine, and delaying filling prescriptions; yet, <1 in 4 patients asked providers for lower cost medications. Consideration of medication costs in patient decision-making could provide a meaningful avenue for improving access and adherence to medications., (© 2020, American College of Rheumatology.)

Background: Acute regression has been reported in some individuals with Down syndrome (DS), typically occurring between the teenage years and mid to late 20s. Characterized by sudden, and often unexplained, reductions in language skills, functional living skills and reduced psychomotor activity, some individuals have been incorrectly diagnosed with Alzheimer's disease (AD)., Methods: This paper compares five individuals with DS who previously experienced acute regression with a matched group of 15 unaffected individuals with DS using a set of AD biomarkers., Results: While the sample was too small to conduct statistical analyses, findings suggest there are possible meaningful differences between the groups on proteomics biomarkers (e.g., NfL, total tau). Hippocampal, caudate and putamen volumes were slightly larger in the regression group, the opposite of what was hypothesized. A slightly lower amyloid load was found on the PET scans for the regression group, but no differences were noted on tau PET., Conclusions: Some proteomics biomarker findings suggest that individuals with DS who experience acute regression may be at increased risk for AD at an earlier age in comparison to unaffected adults with DS. However, due to the age of the group (mean 38 years), it may be too early to observe meaningful group differences on image-based biomarkers.

In this review we examine, in the context of the amyloid, tau, and neurodegeneration framework, the available evidence and potential alternatives on how to establish tau positivity (T+) for multiple tau-imaging tracers in order to reach a consensus on normal and abnormal tau imaging values that can be universally implemented in clinical research and therapeutic trials., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Patients with rheumatic diseases often have mixed pain states, with varying degrees of nociceptive, neuropathic, and nociplastic mechanisms, which exist on a continuum. When individuals with any chronic pain have a nociplastic component to their symptoms, they are less likely to respond to treatments (eg, injections, surgery, biologics, and opioids) that work better for acute or purely nociceptive pain., Competing Interests: Disclosure D. Minhas has no disclosures. D.J. Clauw has performed consulting for Pfizer, Lilly, Aptinyx, Zynerba, Lundbeck, Tonix, and Samumed and has received research funds from Aptinyx and Lundbeck., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose of Review: Patients with symptomatic hypermobility syndrome such as hypermobile Ehlers-Danlos syndromes (hEDS) and hypermobility spectrum disorders (HSD) commonly present to rheumatologists with joint pain and functional disability. Providers often have difficulty with diagnosis due to a lack of knowledge on the range of associated manifestations and the available therapeutic modalities. This review will discuss recent updates on diagnostic measures and treatment options for rheumatologists to help patients navigate hEDS/HSD., Recent Findings: This article describes newer diagnostic measures and assessment of hEDS/HSD manifestations. Evidence supporting physical therapy and occupational therapy is provided, as well as recent updates on assistive devices, compressive garments, orthoses, and surgical interventions. Given patient heterogeneity specific guidance about the amount and type of therapies required to produce a beneficial effect is lacking. Treatment should be individualized, and many of the studies focus on regional joint complaints rather than a whole-body approach., Summary: Physical therapy and occupational therapy remain the cornerstone of treatment., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Adults with Down syndrome (DS) are at high-risk of revealing Alzheimer's disease (AD) pathology, in part due to the triplication of chromosome 21 encoding the amyloid precursor protein. Adults with DS are uniformly affected by AD pathology by their 30's and have a 70% to 80% chance of clinical dementia by their 60's. Our previous studies have assessed longitudinal changes in amyloid beta (Aβ) accumulation in DS., Objective: The goal of the present study was to assess the presence of brain tau using [ 18 F]AV-1451 positron emission tomography (PET) in DS and to assess the relationship of brain tau pathology to Aβ using Pittsburgh Compound B (PiB)-PET., Design: Cohort study., Setting: Multi-center study., Participants: Participants consisted of a sample of individuals with DS and sibling controls recruited from the community; exclusion criteria included contraindications for magnetic resonance imaging (MRI) and/or a medical or psychiatric condition that impaired cognitive functioning., Exposures: PET brain scans to assess Aβ ([ 11 C]PiB) and tau ([ 18 F]AV-1451) burden., Main Outcomes and Measures: Multiple linear regression models (adjusted for chronological age, sex and performance site) were used to examine associations between regional [ 18 F]AV-1451 standard uptake value ratio (SUVR) (based on regions associated with Braak stages 1-6) and global [ 11 C]PiB SUVR (as both a continuous and dichotomous variable)., Results: A cohort of 156 participants (mean age = 39.05, SD(8.4)) were examined. These results revealed a significant relationship between in vivo Aβ and tau pathology in DS. As a dichotomous variable, [ 18 F]AV-1451 retention was higher in each Braak region in PiB(+) participants. We also found, based on our statistical models, starting with the Braak 3 region of interest (ROI), an acceleration of [ 18 F]AV-1451 SUVR deposition with [ 11 C]PiB SUVR increases., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The development of the striatum dopamine (DA) system through human adolescence, a time of increased sensation seeking and vulnerability to the emergence of psychopathology, has been difficult to study due to pediatric restrictions on direct in vivo assessments of DA. Here, we applied neuroimaging in a longitudinal sample of n = 146 participants aged 12-30. R2', an MR measure of tissue iron which co-localizes with DA vesicles and is necessary for DA synthesis, was assessed across the sample. In the 18-30 year-olds (n = 79) we also performed PET using [11C]dihydrotetrabenazine (DTBZ), a measure of presynaptic vesicular DA storage, and [11C]raclopride (RAC), an indicator of D2/D3 receptor availability. We observed decreases in D2/D3 receptor availability with age, while presynaptic vesicular DA storage (as measured by DTBZ), which was significantly associated with R2' (standardized coefficient = 0.29, 95% CI = [0.11, 0.48]), was developmentally stable by age 18. Our results provide new evidence for maturational specialization of the striatal DA system through adolescence.

Rheumatic diseases are a leading cause of chronic, noncancer pain. Systemic lupus erythematosus (SLE) is a chronic autoimmune rheumatic disease characterized by periodic flares that can result in irreversible target organ damage, including end-stage renal disease. Both intermittent and chronic musculoskeletal pain, as well as fibromyalgia (considered a centralized pain disorder due to dysregulation of pain processing in the central nervous system), are common in SLE. Opioids are generally not indicated for long-term management of musculoskeletal pain or centralized pain (fibromyalgia) because of lack of efficacy, safety issues ranging from adverse medical effects to overdose, and risk for addiction (1,2). In this study of 462 patients with SLE from the population-based Michigan Lupus Epidemiology and Surveillance (MILES) Cohort and 192 frequency-matched persons without SLE, nearly one third (31%) of SLE patients were using prescription opioids during the study period (2014-2015), compared with 8% of persons without SLE (p<0.001). Among the SLE patients using opioids, 97 (68%) were using them for >1 year, and 31 (22%) were concomitantly on two or more opioid medications. Among SLE patients, those using the emergency department (ED) were approximately twice as likely to use prescription opioids (odds ratio [OR] = 2.1; 95% confidence interval [CI] = 1.3-3.6; p = 0.004). In SLE, the combined contributions of underlying disease and adverse effects of immunosuppressive and glucocorticoid therapies already put patients at higher risk for some known adverse effects attributed to long-term opioid use. Addressing the widespread and long-term use of opioid therapy in SLE will require strategies aimed at preventing opioid initiation, tapering and discontinuation of opioids among patients who are not achieving treatment goals of reduced pain and increased function, and consideration of nonopioid pain management strategies., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Afton Hassett reports personal fees from AbbVie outside the submitted work. Siobán Harlow reports personal fees from American Reagent, outside the submitted work. Chad Brummett serves on the advisory board for Recro Pharma Inc. and Heron Therapeutics, and receives grants from the Michigan Department of Health and Human Services (Sub K Michigan OPEN), NIDA (Centralized Pain Opioid Non-Responsiveness R01 DA038261-05), the University of Michigan Genomics Initiative, during the conduct of the study. In addition, Dr. Brummett has a patent for Peripheral Perineural Dexmedetomidine (no royalties) Application number 12/791,506; Issue Date 4/2/13; licensed. No other potential conflicts of interest were disclosed.

Objective: Few studies have examined ankylosing spondylitis (AS) patients' concerns about and perceptions of biologic therapies, apart from traditional surveys. In this study, we used social media data to examine the knowledge, attitudes, and beliefs of AS patients regarding biologic therapies., Methods: We collected posts published on 601 social media sites between January 1, 2016 and April 26, 2017. In each post, both an AS keyword and a biologic were mentioned. To explore themes within the collection of posts in an unsupervised manner, a latent Dirichlet allocation topic model was fit to the data set. Each discovered topic was represented as a discrete distribution over the words in the collection, similar to a word cloud. The topics were manually reviewed to identify themes, which were confirmed using thematic data analysis., Results: We examined 27,416 social media posts and identified 112 themes. The majority of themes (n = 67 [60%]) focused on discussions related to AS treatment. Other themes, including the psychological impact of AS, reporting of medical literature, and AS disease consequences, accounted for the remaining 40% (n = 45). In discussions regarding AS treatment, most topics involved biologics, and most subthemes involved side effects (e.g., fatigue, allergic reactions), biologic treatment attributes (e.g., dosing, frequency), and concerns about use of biologics (e.g., increased cancer risk). Additional implicit patient needs (e.g., support) were identified using qualitative analyses., Conclusion: Social media revealed a dynamic range of themes governing AS patients' experience with and choice of biologic agents. The complexity of selecting biologics from among many such agents and navigating their risk/benefit profiles suggests the merit of creating online tools tailored to support patients' decision-making with regard to biologic therapies for AS., (© 2018, American College of Rheumatology.)

Amyloid-β (Aβ) accumulation is a hallmark of Alzheimer's disease, although Aβ alone may be insufficient to cause impairments. Modifiable health factors, including sleep, may mitigate functional symptoms of neurodegeneration. We assessed whether sleep moderated the relationship between Aβ and cognitive performance in 41 older adults, mean age 83 years. Sleep measures included actigraphy-assessed wake after sleep onset and total sleep time. Cognitive performance was assessed with memory recall, cognitive flexibility, and verbal fluency. Memory recall was assessed with the Rey-Osterrieth Complex Figure task, cognitive flexibility with the Trail Making test, and verbal fluency with FAS word generation. Aβ was assessed with a global measure of Pittsburgh Compound B. Wake after sleep onset moderated the relationship between Aβ and memory, with a stronger positive association for Aβ and forgetting in those with poorer sleep. These results suggest a possible protective role of sleep in preclinical Alzheimer's disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Several studies have investigated how lifetime cognitive engagement affects levels of amyloid-beta (Aβ) deposition in the brain. However, there has been some disagreement, leaving the relationship of cognitive activity (CA) to Aβ a largely open question. The present study investigated the relationship between CA, Aβ deposition, and glucose metabolism. One hundred nine cognitively normal participants underwent Pittsburgh Compound-B (PiB) and [ 18 F]fluorodeoxyglucose-positron emission tomography and completed a questionnaire designed to measure current CA. Statistical analyses revealed significant differences in PiB retention between those in the high and low CA groups. Linear regression models revealed a significant negative relationship between PiB retention and CA and a significant positive relationship between glucose metabolism and CA. These data suggest that CA may have a direct beneficial effect on the pathophysiology of AD or reflect another underlying process that results in both higher CA and lower AD pathophysiology., (Copyright © 2018 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

The chloroplast ATP synthase catalyzes the light-driven synthesis of ATP and is activated in the light and inactivated in the dark by redox-modulation through the thioredoxin system. It has been proposed that this down-regulation is important for preventing wasteful hydrolysis of ATP in the dark. To test this proposal, we compared the effects of extended dark exposure in Arabidopsis lines expressing the wild-type and mutant forms of ATP synthase that are redox regulated or constitutively active. In contrast to the predictions of the model, we observed that plants with wild-type redox regulation lost photosynthetic capacity rapidly in darkness, whereas those expressing redox-insensitive form were far more stable. To explain these results, we propose that in wild-type plants, down-regulation of ATP synthase inhibits ATP hydrolysis, leading to dissipation of thylakoid proton motive force (pmf) and subsequent inhibition of protein transport across the thylakoid through the twin arginine transporter (Tat)-dependent and Sec-dependent import pathways, resulting in the selective loss of specific protein complexes. By contrast, in mutants with a redox-insensitive ATP synthase, pmf is maintained by ATP hydrolysis, thus allowing protein transport to maintain photosynthetic activities for extended periods in the dark. Hence, a basal level of Tat-dependent, as well as, Sec-dependent import activity, in the dark helps replenishes certain components of the photosynthetic complexes and thereby aids in maintaining overall complex activity. However, the influence of a dark pmf on thylakoid protein import, by itself, could not explain all the effects we observed in this study. For example, we also observed in wild type plants a large transient buildup of thylakoid pmf and nonphotochemical exciton quenching upon sudden illumination of dark adapted plants. Therefore, we conclude that down-regulation of the ATP synthase is probably not related to preventing loss of ATP per se . Instead, ATP synthase redox regulation may be impacting a number of cellular processes such as (1) the accumulation of chloroplast proteins and/or ions or (2) the responses of photosynthesis to rapid changes in light intensity. A model highlighting the complex interplay between ATP synthase regulation and pmf in maintaining various chloroplast functions in the dark is presented. Significance Statement: We uncover an unexpected role for thioredoxin modulation of the chloroplast ATP synthase in regulating the dark-stability of the photosynthetic apparatus, most likely by controlling thylakoid membrane transport of proteins and ions.

We describe a new member of the class of mutants in Arabidopsis exhibiting high rates of cyclic electron flow around photosystem I (CEF), a light-driven process that produces ATP but not NADPH. High cyclic electron flow 2 ( hcef2 ) shows strongly increased CEF activity through the NADPH dehydrogenase complex (NDH), accompanied by increases in thylakoid proton motive force ( pmf ), activation of the photoprotective q E response, and the accumulation of H 2 O 2 . Surprisingly, hcef2 was mapped to a non-sense mutation in the TADA1 (tRNA adenosine deaminase arginine) locus, coding for a plastid targeted tRNA editing enzyme required for efficient codon recognition. Comparison of protein content from representative thylakoid complexes, the cytochrome bf complex, and the ATP synthase, suggests that inefficient translation of hcef2 leads to compromised complex assembly or stability leading to alterations in stoichiometries of major thylakoid complexes as well as their constituent subunits. Altered subunit stoichiometries for photosystem I, ratios and properties of cytochrome bf hemes, and the decay kinetics of the flash-induced thylakoid electric field suggest that these defect lead to accumulation of H 2 O 2 in hcef2 , which we have previously shown leads to activation of NDH-related CEF. We observed similar increases in CEF, as well as increases in H 2 O 2 accumulation, in other translation defective mutants. This suggests that loss of coordination in plastid protein levels lead to imbalances in photosynthetic energy balance that leads to an increase in CEF. These results taken together with a large body of previous observations, support a general model in which processes that lead to imbalances in chloroplast energetics result in the production of H 2 O 2 , which in turn activates CEF. This activation could be from either H 2 O 2 acting as a redox signal, or by a secondary effect from H 2 O 2 inducing a deficit in ATP.

The thylakoid proton motive force ( pmf ) generated during photosynthesis is the essential driving force for ATP production; it is also a central regulator of light capture and electron transfer. We investigated the effects of elevated pmf on photosynthesis in a library of Arabidopsis thaliana mutants with altered rates of thylakoid lumen proton efflux, leading to a range of steady-state pmf extents. We observed the expected pmf- dependent alterations in photosynthetic regulation, but also strong effects on the rate of photosystem II (PSII) photodamage. Detailed analyses indicate this effect is related to an elevated electric field (Δ ψ ) component of the pmf , rather than lumen acidification, which in vivo increased PSII charge recombination rates, producing singlet oxygen and subsequent photodamage. The effects are seen even in wild type plants, especially under fluctuating illumination, suggesting that Δ ψ -induced photodamage represents a previously unrecognized limiting factor for plant productivity under dynamic environmental conditions seen in the field., Competing Interests: DMK: Founder and stock holder in Phenometrics, Inc. and a founder of the PhotosynQ.org project, these entities manufacture and distribute instrumentation for plant and algal phenotyping. However, neither of these technologies are used in the current work. The other authors declare that no competing interests exist.

Introduction: Twitter channels are increasingly popular at medical conferences. Many groups, including healthcare providers and third party entities (e.g., pharmaceutical or medical device companies) use these channels to communicate with one another. These channels are unregulated and can allow third party commercial entities to exert an equal or greater amount of Twitter influence than healthcare providers. Third parties can use this influence to promote their products or services instead of sharing unbiased, evidence-based information. In this investigation we quantified the Twitter influence that third party commercial entities had in 13 major medical conferences., Methods: We analyzed tweets contained in the official Twitter hashtags of thirteen medical conferences from 2011 to 2013. We placed tweet authors into one of four categories based on their account profile: healthcare provider, third party commercial entity, none of the above and unknown. We measured Twitter activity by the number of tweet authors per category and the tweet-to-author ratio by category. We measured Twitter influence by the PageRank of tweet authors by category., Results: We analyzed 51159 tweets authored by 8778 Twitter account holders in 13 conferences that were sponsored by 5 medical societies. A quarter of all authors identified themselves as healthcare providers, while only 18% could be identified as third party commercial entities. Healthcare providers had a greater tweet-to-author ratio than their third party commercial entity counterparts (8.98 versus 6.93 tweets). Despite having less authors and composing less tweets, third party commercial entities had a statistically similar PageRank as healthcare providers (0.761 versus 0.797)., Conclusion: The Twitter influence of third party commercial entities (PageRank) is similar to that of healthcare providers. This finding is interesting because the number of tweets and third party commercial entity authors required to achieve this PageRank is far fewer than that needed by healthcare providers. Without safety mechanisms in place, the Twitter channels of medical conferences can devolve into a venue for the spread of biased information rather than evidence-based medical knowledge that is expected at live conferences. Continuing to measure the Twitter influence that third parties exert can help conference organizers develop reasonable guidelines for Twitter channel activity., Competing Interests: TD is an employee of the United States Government. TD is the creator of Nephrology On-Demand. This affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials. Aabid Shariff is an employee of Monsanto. He has no other relevant declarations to make. His employment with Monsanto does not alter our adherence to PLOS ONE policies on sharing data and materials.

Importance: Cerebral microbleeds (CMBs) are collections of blood breakdown products that are a common incidental finding in magnetic resonance imaging of elderly individuals. Cerebral microbleeds are associated with cognitive deficits, but the mechanism is unclear. Studies show that individuals with CMBs related to symptomatic cerebral amyloid angiopathy have abnormal vascular reactivity and cerebral blood flow (CBF), but, to our knowledge, abnormalities in cerebral blood flow have not been reported for healthy individuals with incidental CMBs., Objective: To evaluate the association of incidental CMBs with resting-state CBF, cerebral metabolism, cerebrovascular disease, β-amyloid (Aβ), and cognition., Design, Setting, and Participants: A cross-sectional study of 55 cognitively normal individuals with a mean (SD) age of 86.8 (2.7) years was conducted from May 1, 2010, to May 1, 2013, in an academic medical center in Pittsburgh; data analysis was performed between June 10, 2013, and April 9, 2015., Interventions: 3-Tesla magnetic resonance imaging was performed with susceptibility-weighted imaging or gradient-recalled echo to assess CMBs, arterial spin labeling for CBF, and T1- and T2-weighted imaging for atrophy, white matter hyperintensities, and infarcts. Positron emission tomography was conducted with fluorodeoxyglucose to measure cerebral metabolism and Pittsburgh compound B for fibrillar Aβ. Neuropsychological evaluation, including the Clinical Dementia Rating scale, was performed., Main Outcomes and Measures: Magnetic resonance images were rated for the presence and location of CMBs. Lobar CMBs were subclassified as cortical or subcortical. Measurements of CBF, metabolism, and Aβ were compared with the presence and number of CMBs with voxelwise and region-of-interest analyses., Results: The presence of cortical CMBs was associated with significantly reduced CBF in multiple regions on voxelwise and region-of-interest analyses (percentage difference in global CBF, -25.3%; P = .0003), with the largest reductions in the parietal cortex (-37.6%; P < .0001) and precuneus (-31.8%; P = .0006). Participants with any CMBs showed a nonsignificant trend toward reduced CBF. Participants with cortical CMBs had a significant association with greater prevalence of infarcts (24% vs 6%; P = .047) and demonstrated a trend to greater prevalence of deficits demonstrated on the Clinical Dementia Rating scale (45% vs 19%; P = .12). There was no difference in cortical amyloid (measured by Pittsburgh compound B positron emission tomography) between participants with and without CMBs (P = .60)., Conclusions and Relevance: In cognitively normal elderly individuals, incidental CMBs in cortical locations are associated with widespread reductions in resting-state CBF. Chronic hypoperfusion may put these people at risk for neuronal injury and neurodegeneration. Our results suggest that resting-state CBF is a marker of CMB-related small-vessel disease.

Background: The biomarker model of Alzheimer's disease postulates a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline as an individual progresses from preclinical Alzheimer's disease to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed., Methods: For this prospective cohort study, carriers of autosomal dominant Alzheimer's disease mutations (aged ≥21 years) were recruited from across the USA through referrals by physicians or from affected families. People with mutations in PSEN1, PSEN2, or APP were assessed at the University of Pittsburgh Alzheimer's Disease Research Center every 1-2 years, between March 23, 2003, and Aug 1, 2014. We measured global cerebral amyloid β (Aβ) load using (11)C-Pittsburgh Compound-B PET, posterior cortical metabolism with (18)F-fluorodeoxyglucose PET, hippocampal volume (age and sex corrected) with T1-weighted MRI, verbal memory with the ten-item Consortium to Establish a Registry for Alzheimer's Disease Word List Learning Delayed Recall Test, and general cognition with the Mini Mental State Examination. We estimated overall biomarker trajectories across estimated years from symptom onset using linear mixed models, and compared these estimates with cross-sectional data from cognitively normal control individuals (age 65-89 years) who were negative for amyloidosis, hypometabolism, and hippocampal atrophy. In the mutation carriers who had the longest follow-up, we examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition to identify progressive within-individual changes (a significant change was defined as an increase or decrease of more than two Z scores standardised to controls)., Findings: 16 people with mutations in PSEN1, PSEN2, or APP, aged 28-56 years, completed between two and eight assessments (a total of 83 assessments) over 2-11 years. Significant differences in mutation carriers compared with controls (p<0·01) were detected in the following order: increased amyloidosis (7·5 years before expected onset), decreased metabolism (at time of expected onset), decreased hippocampal volume and verbal memory (7·5 years after expected onset), and decreased general cognition (10 years after expected onset). Among the seven participants with longest follow-up (seven or eight assessments spanning 6-11 years), three individuals had active amyloidosis without progressive neurodegeneration or cognitive decline, two amyloid-positive individuals showed progressive neurodegeneration and cognitive decline without further progressive amyloidosis, and two amyloid-positive individuals showed neither active amyloidosis nor progressive neurodegeneration or cognitive decline., Interpretation: Our results support amyloidosis as the earliest component of the biomarker model in autosomal dominant Alzheimer's disease. Our within-individual examination suggests three sequential phases in the development of autosomal dominant Alzheimer's disease-active amyloidosis, a stable amyloid-positive period, and progressive neurodegeneration and cognitive decline-indicating that Aβ accumulation is largely complete before progressive neurodegeneration and cognitive decline occur. These findings offer supportive evidence for efforts to target early Aβ deposition for secondary prevention in individuals with autosomal dominant Alzheimer's disease., Funding: National Institutes of Health and Howard Hughes Medical Institute., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Rationale: Differences in brain function in cocaine users can occur even when frank deficits are not apparent, indicating neuroadaptive consequences of use. Using monkeys to investigate altered metabolic activity following chronic cocaine self-administration allows an assessment of altered function due to cocaine use, without confounding pre-existing differences or polysubstance use often present in clinical studies., Objectives: To evaluate alterations in metabolic function during a working memory task in the prefrontal cortex and the cerebellum following 1 year of chronic cocaine self-administration followed by a 20 month drug-free period., Methods: Fluorodeoxyglucose ((18)F) PET imaging was used to evaluate changes in relative regional metabolic activity associated with a delayed match to sample working memory task. Chronic cocaine animals were compared to a control group, and region of interest analyses focused on the dorsolateral prefrontal cortex (DLPFC) and cerebellum., Results: Despite no differences in task performance, in the cocaine group, the cerebellum showed greater metabolic activity during the working memory task (relative to the control task) compared to the control group. There was also a trend toward a significant difference between the groups in DLPFC activity (p = 0.054), with the cocaine group exhibiting lower DLPFC metabolic activity during the delay task (relative to the control task) than the control group., Conclusion: The results support clinical indications of increased cerebellar activity associated with chronic cocaine exposure. Consistent with evidence of functional interactions between cerebellum and prefrontal cortex, these changes may serve to compensate for potential impairments in functionality of DLPFC.

Medical educators and patients are turning to YouTube to teach and learn about medical conditions. These videos are from authors whose credibility cannot be verified & are not peer reviewed. As a result, studies that have analyzed the educational content of YouTube have reported dismal results. These studies have been unable to exclude videos created by questionable sources and for non-educational purposes. We hypothesize that medical education YouTube videos, authored by credible sources, are of high educational value and appropriately suited to educate the public. Credible videos about cardiovascular diseases were identified using the Mayo Clinic's Center for Social Media Health network. Content in each video was assessed by the presence/absence of 7 factors. Each video was also evaluated for understandability using the Suitability Assessment of Materials (SAM). User engagement measurements were obtained for each video. A total of 607 videos (35 hours) were analyzed. Half of all videos contained 3 educational factors: treatment, screening, or prevention. There was no difference between the number of educational factors present & any user engagement measurement (p NS). SAM scores were higher in videos whose content discussed more educational factors (p<0.0001). However, none of the user engagement measurements correlated with higher SAM scores. Videos with greater educational content are more suitable for patient education but unable to engage users more than lower quality videos. It is unclear if the notion "content is king" applies to medical videos authored by credible organizations for the purposes of patient education on YouTube.

Objectives: We sought to provide a systematic review of the determinants of success in scaling up and sustaining community health worker (CHW) programs in low- and middle-income countries (LMICs)., Methods: We searched 11 electronic databases for academic literature published through December 2010 (n = 603 articles). Two independent reviewers applied exclusion criteria to identify articles that provided empirical evidence about the scale-up or sustainability of CHW programs in LMICs, then extracted data from each article by using a standardized form. We analyzed the resulting data for determinants and themes through iterated categorization., Results: The final sample of articles (n = 19) present data on CHW programs in 16 countries. We identified 23 enabling factors and 15 barriers to scale-up and sustainability, which were grouped into 3 thematic categories: program design and management, community fit, and integration with the broader environment., Conclusions: Scaling up and sustaining CHW programs in LMICs requires effective program design and management, including adequate training, supervision, motivation, and funding; acceptability of the program to the communities served; and securing support for the program from political leaders and other health care providers.

Breastfeeding (BF) promotion is one of the most cost-effective interventions to advance mother-child health. Evidence-based frameworks and models to promote the effective scale up and sustainability of BF programs are still lacking. A systematic review of peer-reviewed and gray literature reports was conducted to identify key barriers and facilitators for scale up of BF programs in low- and middle-income countries. The review identified BF programs located in 28 countries in Africa, Latin America and the Caribbean, and Asia. Study designs included case studies, qualitative studies, and observational quantitative studies. Only 1 randomized, controlled trial was identified. A total of 22 enabling factors and 15 barriers were mapped into a scale-up framework termed "AIDED" that was used to build the parsimonious breastfeeding gear model (BFGM). Analogous to a well-oiled engine, the BFGM indicates the need for several key "gears" to be working in synchrony and coordination. Evidence-based advocacy is needed to generate the necessary political will to enact legislation and policies to protect, promote, and support BF at the hospital and community levels. This political-policy axis in turn drives the resources needed to support workforce development, program delivery, and promotion. Research and evaluation are needed to sustain the decentralized program coordination "gear" required for goal setting and system feedback. The BFGM helps explain the different levels of performance in national BF outcomes in Mexico and Brazil. Empirical research is recommended to further test the usefulness of the AIDED framework and BFGM for global scaling up of BF programs.

Background: Many family health innovations that have been shown to be both efficacious and cost-effective fail to scale up for widespread use particularly in low-income and middle-income countries (LMIC). Although individual cases of successful scale-up, in which widespread take up occurs, have been described, we lack an integrated and practical model of scale-up that may be applicable to a wide range of public health innovations in LMIC., Objective: To develop an integrated and practical model of scale-up that synthesises experiences of family health programmes in LMICs., Data Sources: We conducted a mixed methods study that included in-depth interviews with 33 key informants and a systematic review of peer-reviewed and grey literature from 11 electronic databases and 20 global health agency web sites., Study Eligibility Criteria, Participants and Interventions: We included key informants and studies that reported on the scale up of several family health innovations including Depo-Provera as an example of a product innovation, exclusive breastfeeding as an example of a health behaviour innovation, community health workers (CHWs) as an example of an organisational innovation and social marketing as an example of a business model innovation. Key informants were drawn from non-governmental, government and international organisations using snowball sampling. An article was excluded if the article: did not meet the study's definition of the innovation; did not address dissemination, diffusion, scale up or sustainability of the innovation; did not address low-income or middle-income countries; was superficial in its discussion and/or did not provide empirical evidence about scale-up of the innovation; was not available online in full text; or was not available in English, French, Spanish or Portuguese, resulting in a final sample of 41 peer-reviewed articles and 30 grey literature sources., Study Appraisal and Synthesis Methods: We used the constant comparative method of qualitative data analysis to extract recurrent themes from the interviews, and we integrated these themes with findings from the literature review to generate the proposed model of scale-up. For the systematic review, screening was conducted independently by two team members to ensure consistent application of the predetermined exclusion criteria. Data extraction from the final sample of peer-reviewed and grey literature was conducted independently by two team members using a pre-established data extraction form to list the enabling factors and barriers to dissemination, diffusion, scale up and sustainability., Results: The resulting model-the AIDED model-includes five non-linear, interrelated components: (1) assess the landscape, (2) innovate to fit user receptivity, (3) develop support, (4) engage user groups and (5) devolve efforts for spreading innovation. Our findings suggest that successful scale-up occurs within a complex adaptive system, characterised by interdependent parts, multiple feedback loops and several potential paths to achieve intended outcomes. Failure to scale up may be attributable to insufficient assessment of user groups in context, lack of fit of the innovation with user receptivity, inability to address resistance from stakeholders and inadequate engagement with user groups., Limitations: The inductive approach used to construct the AIDED model did not allow for simultaneous empirical testing of the model. Furthermore, the literature may have publication bias in which negative studies are under-represented, although we did find examples of unsuccessful scale-up. Last, the AIDED model did not address long-term, sustained use of innovations that are successfully scaled up, which would require longer-term follow-up than is common in the literature., Conclusions and Implications of Key Findings: Flexible strategies of assessment, innovation, development, engagement and devolution are required to enable effective change in the use of family health innovations in LMIC.