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Cholinergic neurons of the medial forebrain are considered important contributors to brain plasticity and neuromodulation. A reduction of cholinergic innervation can lead to pathophysiological changes of neurotransmission and is observed in Alzheimer’s disease. Here we report on six patients with mild to moderate Alzheimer’s disease (AD) treated with bilateral low-frequency deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM). During a four-week double-blind sham-controlled phase and a subsequent 11-month follow-up open label period, clinical outcome was assessed by neuropsychological examination using the Alzheimer’s Disease Assessment Scale—cognitive subscale as the primary outcome measure. Electroencephalography and [ 18 F]-fluoro-desoxyglucose positron emission tomography were, besides others, secondary endpoints. On the basis of stable or improved primary outcome parameters twelve months after surgery, four of the six patients were considered responders. No severe or non-transitional side effects related to the stimulation were observed. Taking into account all limitations of a pilot study, we conclude that DBS of the NBM is both technically feasible and well tolerated.

Pain is the predominant symptom for people with inflammatory arthritis (IA) and osteoarthritis (OA) mandating the development of evidence-based recommendations for the health professional’s approach to pain management. A multidisciplinary task force including professionals and patient representatives conducted a systematic literature review of systematic reviews to evaluate evidence regarding effects on pain of multiple treatment modalities. Overarching principles and recommendations regarding assessment and pain treatment were specified on the basis of reviewed evidence and expert opinion. From 2914 review studies initially identified, 186 met inclusion criteria. The task force emphasised the importance for the health professional to adopt a patient-centred framework within a biopsychosocial perspective, to have sufficient knowledge of IA and OA pathogenesis, and to be able to differentiate localised and generalised pain. Treatment is guided by scientific evidence and the assessment of patient needs, preferences and priorities; pain characteristics; previous and ongoing pain treatments; inflammation and joint damage; and psychological and other pain-related factors. Pain treatment options typically include education complemented by physical activity and exercise, orthotics, psychological and social interventions, sleep hygiene education, weight management, pharmacological and joint-specific treatment options, or interdisciplinary pain management. Effects on pain were most uniformly positive for physical activity and exercise interventions, and for psychological interventions. Effects on pain for educational interventions, orthotics, weight management and multidisciplinary treatment were shown for particular disease groups. Underpinned by available systematic reviews and meta-analyses, these recommendations enable health professionals to provide knowledgeable pain-management support for people with IA and OA.

This report describes the clinical details of 10 patients who were shown to have been infected with an H5N1 influenzavirus, which normally does not affect humans. The patients had direct contact with fowl a median of three days before they presented with fever, respiratory symptoms, and an acute influenza syndrome, characterized by lymphopenia and marked pulmonary infiltrates on chest radiography. Eight of the patients died, even though none had preexisting medical conditions. This report describes the clinical details of 10 patients who were shown to have been infected with an H5N1 influenzavirus. Eight of the patients died. Influenza A virus infects a variety of animals, including humans and birds. 1 Although the natural reservoir for all known subtypes of influenza A (hemagglutinins H1 through H15 and neuraminidases N1 through N9) is wild waterfowl, only three subtypes are currently circulating among humans (H1N1, H1N2, and H3N2). However, during the past few years, several subtypes of avian influenza A have been shown to cross the species barrier and infect humans. During an outbreak of a highly pathogenic influenza A (H5N1) virus among poultry in Hong Kong in 1997, 6 of 18 people with confirmed infection died. 2 After this outbreak, prevention . . .

While internal climate variability is known to affect climate projections, its influence is often underappreciated and confused with model error. Why? In general, modeling centers contribute a small number of realizations to international climate model assessments [e.g., phase 5 of the Coupled Model Intercomparison Project (CMIP5)]. As a result, model error and internal climate variability are difficult, and at times impossible, to disentangle. In response, the Community Earth System Model (CESM) community designed the CESM Large Ensemble (CESM-LE) with the explicit goal of enabling assessment of climate change in the presence of internal climate variability. All CESM-LE simulations use a single CMIP5 model (CESM with the Community Atmosphere Model, version 5). The core simulations replay the twenty to twenty-first century (1920–2100) 30 times under historical and representative concentration pathway 8.5 external forcing with small initial condition differences. Two companion 1000+-yr-long preindustrial control simulations (fully coupled, prognostic atmosphere and land only) allow assessment of internal climate variability in the absence of climate change. Comprehensive outputs, including many daily fields, are available as single-variable time series on the Earth System Grid for anyone to use. Early results demonstrate the substantial influence of internal climate variability on twentieth- to twenty-first-century climate trajectories. Global warming hiatus decades occur, similar to those recently observed. Internal climate variability alone can produce projection spread comparable to that in CMIP5. Scientists and stakeholders can use CESM-LE outputs to help interpret the observational record, to understand projection spread and to plan for a range of possible futures influenced by both internal climate variability and forced climate change.

An inability to reliably predict quantitative behaviors for novel combinations of genetic elements limits the rational engineering of biological systems. We developed an expression cassette architecture for genetic elements controlling transcription and translation initiation in Escherichia coli: transcription elements encode a common mrnA start, and translation elements use an overlapping genetic motif found in many natural systems. We engineered libraries of constitutive and repressor-regulated promoters along with translation initiation elements following these definitions. We measured activity distributions for each library and selected elements that collectively resulted in expression across a 1,000-fold observed dynamic range. We studied all combinations of curated elements, demonstrating that arbitrary genes are reliably expressed to within twofold relative target expression windows with ~93% reliability. We expect the genetic element definitions validated here can be collectively expanded to create collections of public-domain standard biological parts that support reliable forward engineering of gene expression at genome scales. One main goal of synthetic biology is to make the engineering of biology easier 1,2. DNA synthesis and assembly has progressed to the point where entire metabolic pathways, chromosomes and genomes can now be synthesized and transplanted 3-5. However, our capacity to rationally design increasingly complicated genetic systems as enabled by improvements in DNA construction methods has not kept pace 2,6. One of the greatest claimed barriers to efficient and scalable genetic design is the lack of standard parts that can be reused reliably in novel combinations 6,7. Many examples instead highlight, even within well-studied organisms such as E. coli, how seemingly simple genetic functions behave differently in different settings 8,9. For example, a prokaryotic ribosome-binding site (RBS) element that initiates translation for one coding sequence might not function at all with another coding sequence 10. If the genetic elements that encode control of central cellular processes such as transcription and translation cannot be reliably reused, then there is little chance that higher-order objects encoded from such basic elements will be reliable in larger-scale systems 6,11. Standard biological parts could, in theory, enable hierarchical abstraction of biological functions 1,2,12,13. The behavior of integrated genetic systems could then be represented via simpler models of individual elements and ultimately mapped to underlying genetic sequences whose encoded functions are dependent on a limited number of measurable or calculable intrinsic variables. Such abstraction of function seems necessary to manage biological complexity and to allow the engineering of increasingly sophisticated genetic systems 6,12,14. We engineered ~500 transcription and translation initiation elements that are compatible within a standardized genetic context, or expression operating unit (EOU), that enables predictable forward engineering of gene expression over a wide dynamic range. We characterized representative parts for each type by testing more than 1,200 part-part combinations to establish and validate functional composition rules while quantifying scores for part activity. From this data we also estimated the 'quality' of each part, a second-order statistic that represents the extent to which the activity of a part varies across changes in context 15. Our results demonstrate how, when combined with standardized transcription control elements, a more physically complex design for the control of translation initiation creates simply modeled parts enabling reliable forward engineering of gene expression. results Prioritizing part composition puzzles In related work, we systematically assembled and tested all combinations of frequently used prokaryotic transcription and translation control elements to quantify average part activities and also variation in activities as parts are reused in novel combinations 15. Here we focus on developing rules for a genetic layout architecture underlying gene expression cassettes that eliminate

Individuals with the red hair/fair skin phenotype usually carry a polymorphism in the gene encoding the melanocortin 1 receptor ( Mc1r ) that results in the production of pigment containing a high pheomelanin-to-eumelanin ratio; here it is shown in a mouse model that inactivation of Mc1r promotes melanoma formation in the presence of the Braf oncogene, thus suggesting that pheomelanin synthesis is carcinogenic by an ultraviolet-radiation-independent mechanism. Linkage of melanoma risk and red hair Individuals with a 'redhead' phenotype — who typically have pale skin, red hair and an inability to tan — often carry a polymorphism in the gene encoding the melanocortin 1 receptor ( Mc1r ) that reduces its ability to stimulate the production of the black/brown pigment eumelanin from the red/yellow pigment pheomelanin. David Fisher and colleagues report that in a mouse model, inactivation of Mc1r promotes melanoma formation in the presence of BRAF V600E , the most common melanoma oncoprotein, independently of exposure to ultraviolet radiation. They find that it is pheomelanin synthesis per se that promotes melanoma formation, through an increase in oxidative damage, because abrogation of all pigment production in the mice abolishes the effects. In practical terms this suggests that further protective strategies, in addition to avoiding sunlight, could be of benefit in at-risk individuals. People with pale skin, red hair, freckles and an inability to tan—the ‘red hair/fair skin’ phenotype—are at highest risk of developing melanoma, compared to all other pigmentation types 1 . Genetically, this phenotype is frequently the product of inactivating polymorphisms in the melanocortin 1 receptor ( MC1R ) gene. MC1R encodes a cyclic AMP-stimulating G-protein-coupled receptor that controls pigment production. Minimal receptor activity, as in red hair/fair skin polymorphisms, produces the red/yellow pheomelanin pigment, whereas increasing MC1R activity stimulates the production of black/brown eumelanin 2 . Pheomelanin has weak shielding capacity against ultraviolet radiation relative to eumelanin, and has been shown to amplify ultraviolet-A-induced reactive oxygen species 3 , 4 , 5 . Several observations, however, complicate the assumption that melanoma risk is completely ultraviolet-radiation-dependent. For example, unlike non-melanoma skin cancers, melanoma is not restricted to sun-exposed skin and ultraviolet radiation signature mutations are infrequently oncogenic drivers 6 . Although linkage of melanoma risk to ultraviolet radiation exposure is beyond doubt, ultraviolet-radiation-independent events are likely to have a significant role 1 , 7 . Here we introduce a conditional, melanocyte-targeted allele of the most common melanoma oncoprotein, BRAF V600E , into mice carrying an inactivating mutation in the Mc1r gene (these mice have a phenotype analogous to red hair/fair skin humans). We observed a high incidence of invasive melanomas without providing additional gene aberrations or ultraviolet radiation exposure. To investigate the mechanism of ultraviolet-radiation-independent carcinogenesis, we introduced an albino allele, which ablates all pigment production on the Mc1r e/e background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1r e/e mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino- Mc1r e/e mouse skin. These data suggest that the pheomelanin pigment pathway produces ultraviolet-radiation-independent carcinogenic contributions to melanomagenesis by a mechanism of oxidative damage. Although protection from ultraviolet radiation remains important, additional strategies may be required for optimal melanoma prevention.

The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18-65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR)=0.76, 95% confidence interval (95% CI) of 0.65-0.89, P=0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR=0.89, 95% CI: 0.74-1.08, P=0.24). The incidence of SPM were similar between the two arms (7% each, P=0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size [egs]10%) and renal impairment at baseline (serum creatinine >2 mg dl-1 ) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR=1.02, P=0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.

Background Overweight among adolescents is worldwide still considered a serious public health problem. Although both parents influence children’s energy balance-related behavior, most studies have predominantly focused on mothers and white populations. Therefore, in this study, we contribute to the research by exploring the perceptions and needs of Dutch fathers with a migration background on parenting, specifically regarding promoting healthy energy balance-related behaviors among their children, and what motivates fathers to participate in parenting programs focused on these behaviors. Methods We used a qualitative research design. Informal conversations ( n  = 2), semi-structured interviews ( n  = 11) and one focus group ( n  = 13) were conducted with professionals specialized in intercultural pedagogy and fathers participating in a parenting program organized by these professionals. Interviews and focus group were audio-recorded and transcribed. Atlas.ti 8 was used for theme detection, categorization, and classification using inductive and deductive approaches. The data was analyzed using grounded theory analysis. Results Fathers joined parenting programs to improve their parenting skills and knowledge and address health and socio-cultural challenges. Furthermore, intergenerational differences were evident: second-generation fathers were more proactive in tackling parenting challenges related to healthy lifestyles. Fathers highlighted challenges related to parenting in two cultures. Although participating in the parenting program facilitated fathers in adopting a healthier lifestyle for both themselves and their families, improving communication with family members, and experiencing changes regarding gender dynamics within their household, influencing their teenage children, to adopt healthier habits remained a challenge, especially in comparison to younger children. Conclusions A deeper understanding of the needs, perceptions, and experiences of migrant populations concerning parenting regarding the promotion of healthy energy balance-related behaviors among their children can lead to better-tailored health promotion programs that prioritize cultural and linguistic inclusivity.

Leukapheresis is a potentially life-saving therapy for children with symptomatic hyperleukocytosis. However, the standard centrifugation-based approach exposes pediatric patients to significant complications due to its large extracorporeal volume, high flow rates, and considerable platelet loss. Here, we tested whether performing cell separation with a high-throughput microfluidic technology could alleviate these limitations. In vitro, our microfluidic devices removed ~85% of large leukocytes and ~90% of spiked leukemic blasts from undiluted human whole blood, while minimizing platelet losses. Multiplexed devices connected in parallel allowed for faster, clinically relevant flow rates in vitro with no difference in leukocyte collection efficiency. When connected to Sprague-Dawley rats, the devices removed large leukocytes with ~80% collection efficiency, reducing the leukocyte count in recirculating blood by nearly half after a 3-hour procedure. Evaluation of plasma biomarkers and end-organ histology revealed no adverse effects compared to sham control. Overall, our study suggests that microfluidics-based leukapheresis is safe and effective at selectively removing leukocytes from circulation, with separation performance sufficiently high to ultimately enable low extracorporeal volume leukapheresis in children. Leukapheresis is prohibitive in newborns due to the large extracorporeal volume. Here, the authors develop a microfluidic device to perform leukapheresis on whole blood at clinically relevant flow rates and show its safety and efficacy in animals.