Utilizing the Organizational Power of DNA Scaffolds for New Nanophotonic Applications

AbstractRapid development of DNA technology has provided a feasible route to creating nanoscale materials. DNA acts as a self‐assembled nanoscaffold capable of assuming any three‐dimensional shape. The ability to integrate dyes and new optical materials such as quantum dots and plasmonic nanoparticles precisely onto these architectures provides new ways to exploit their near‐ and far‐field interactions. A fundamental understanding of these optical processes will help drive development of next‐generation photonic nanomaterials. This review is focused on latest progress in DNA‐based photonic materials and highlights DNA scaffolds for rapidly assembling and prototyping nanoscale optical devices. Three areas are discussed including intrinsically active DNA structures displaying chiral properties, DNA scaffolds hosting plasmonic nanomaterials, and fluorophore‐labeled DNAs that engage in Förster resonance energy transfer and give rise to complex molecular photonic wires. An explanation of what is desired from these optical processes when harnessed sets the tone for what DNA scaffolds are providing toward each focus. Examples from the literature illustrate current progress along with a discussion of challenges to overcome for further improvements. Opportunities to integrate diverse classes of optically active molecules including light‐generating enzymes, fluorescent proteins, nanoclusters, and metal–chelates in new structural combinations on DNA scaffolds are also highlighted

Complex genetic diversity patterns of cryptic, sympatric brown trout (Salmo trutta) populations in tiny mountain lakes

publishedVersio

Association between Depression and C-Reactive Protein

Objective. Depression has been associated with increased cardiovascular disease risk, and a depression-related elevation of high sensitivity C-reactive protein (hs-CRP) has been proposed as a possible mechanism. The objective of this paper is to examine association between depression and high sensitivity C-reactive protein (hs-CRP). Methods. Subjects consisted of 508 healthy adults (mean age 48.5 years; 49% women, 88% white) residing in central Massachusetts. Data were collected at baseline and at quarterly intervals over a one-year period per individual. Multivariable linear mixed models were used to assess the association for the entire sample and by gender. Results. The mean Beck Depression Inventory score was 5.8 (standard deviation (SD) 5.4; median 4.3), and average serum hs-CRP was 1.8 mg/L (SD 1.7; median 1.2). Results from the multivariable linear mixed models show that individuals with higher depression scores have higher levels of hs-CRP. Analyses by gender show persistence of an independent association among women, but not among men. Body mass index (BMI = weight(kg)/height(m)2) appears to be a partial mediator of this relationship. Conclusion. Depression score was correlated to hs-CRP levels in women. Further studies are required to elucidate the biological mechanisms underlying these associations and their implications

Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise statedBACKGROUND: Reports on the clinical meaningfulness of outcome measures in spinal muscular atrophy (SMA) are rare. In this two-part study, our aim was to explore patients' and caregivers' views on the clinical relevance of the Hammersmith Functional Motor Scale Expanded- (HFMSE). METHODS: First, we used focus groups including SMA patients and caregivers to explore their views on the clinical relevance of the individual activities included in the HFMSE. Then we asked caregivers to comment on the clinical relevance of possible changes of HFMSE scores over time. As functional data of individual patients were available, some of the questions were tailored according to their functional level on the HFMSE. RESULTS: Part 1: Sixty-three individuals participated in the focus groups. This included 30 caregivers, 25 patients and 8 professionals who facilitated the discussion. The caregivers provided a comparison to activities of daily living for each of the HFMSE items. Part 2: One hundred and forty-nine caregivers agreed to complete the questionnaire: in response to a general question, 72% of the caregivers would consider taking part in a clinical trial if the treatment was expected to slow down deterioration, 88% if it would stop deterioration and 97% if the treatment was expected to produce an improvement. Caregivers were informed of the first three items that their child could not achieve on the HFMSE. In response 75% indicated a willingness to take part in a clinical trial if they could achieve at least one of these abilities, 89% if they could achieve two, and 100% if they could achieve more than 2. CONCLUSIONS: Our findings support the use of the HFMSE as a key outcome measure in SMA clinical trials because the individual items and the detected changes have clear content validity and clinical meaningfulness for patients and their caregivers.Peer reviewedFinal Published versio

Revised Hammersmith Scale for Spinal Muscular Atrophy: : A SMA specific clinical outcome assessment tool

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are 'fit for purpose'. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials.Peer reviewedFinal Published versio

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

An Evaluation of Über den Tellerrand’s Community Events

We worked with Über den Tellerrand, an organization in Berlin, Germany, to improve their program by evaluating the impact that their community events have on both locals and immigrants. The evaluation tool we had developed for the Über den Tellerrand community events was a survey instrument. We tested our survey instrument at many of the community events held by Über den Tellerrand during our time in Berlin, and refined them to capture the most important information. We also supplied the organization with methods to analyze and understand the data. Our program evaluation demonstrated that Über den Tellerrand has reduced prejudices amongst its participants, created a safe space for immigrants and locals to interact, and expanded the participants’ support network

Improving On-Time Delivery at Madera y Metal

Our project goal was to help Madera y Metal, a trophy manufacturing company in Paraguay, reduce the number of orders delivered later than the internal due date. The team used A3 problem-solving to examine root causes and develop solutions. The team guided the implementation of a new software system to track orders and set due dates, analyzed seasonality in demand, and created an order prioritization ranking tool, to allow the company to be more proactive in avoiding late orders

Treatment of MOG-IgG-associated disorder with rituximab: An international study of 121 patients

OBJECTIVE To assess the effect of anti-CD20 B-cell depletion with rituximab (RTX) on relapse rates in myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD). METHODS Retrospective review of RTX-treated MOGAD patients from 29 centres in 13 countries. The primary outcome measure was change in relapse rate after starting rituximab (Poisson regression model). RESULTS Data on 121 patients were analysed, including 30 (24.8%) children. Twenty/121 (16.5%) were treated after one attack, of whom 14/20 (70.0%) remained relapse-free after median (IQR) 11.2 (6.3-14.1) months. The remainder (101/121, 83.5%) were treated after two or more attacks, of whom 53/101 (52.5%) remained relapse-free after median 12.1 (6.3-24.9) months. In this 'relapsing group', relapse rate declined by 37% (95%CI=19-52%, p<0.001) overall, 63% (95%CI=35-79%, p = 0.001) when RTX was used first line (n = 47), and 26% (95%CI=2-44%, p = 0.038) when used after other steroid-sparing immunotherapies (n = 54). Predicted 1-year and 2-year relapse-free survival was 79% and 55% for first-line RTX therapy, and 38% and 18% for second-/third-line therapy. Circulating CD19$^{+}$B-cells were suppressed to <1% of total circulating lymphocyte population at the time of 45/57 (78.9%) relapses. CONCLUSION RTX reduced relapse rates in MOGAD. However, many patients continued to relapse despite apparent B-cell depletion. Prospective controlled studies are needed to validate these results