A dual involvement of Protocadherin 18a in stromal cell development guides the formation of a functional hematopoietic niche.

Hematopoietic stem and progenitor cells emerge from the aorta and migrate to the caudal hematopoietic tissue (CHT) of zebrafish larvae, the hematopoietic equivalent of the mammalian fetal liver, for their proliferation and differentiation. We previously reported that somite-derived stromal cells were a key component of the CHT niche. Here, we found that the cell adhesion protein Protocadherin 18a (Pcdh18a) is expressed in the stromal cell progenitors (SCPs) emigrating from somites toward the future CHT. Deletion of most of the Pcdh18a intracellular domain caused a decrease in the number of SCPs, the directionality of their migration, and the cell-contact mediated repulsion that normally occurs between migrating SCPs. These defects were followed by abnormal morphogenesis of the venous plexus that forms the CHT framework, and the inability of the CHT to function as a niche for hematopoietic stem and progenitor cells. Finally, we found that the extracellular domain of Pcdh18a mediates trans heterophilic adhesion of stromal cells to endothelial cells in vivo and thereby the reticular versus perivascular fate of SCPs. Thus, Pcdh18a expression in SCPs is essential for the proper development of the hematopoietic niche.

Educational programmes for paediatric healthcare professionals in patient- and family-centred care. A scoping review.

To identify and describe educational programmes in patient- and family-centred care for paediatric healthcare professionals. This scoping review was conducted and reported according to the JBI Manual for Evidence Synthesis and the PRISMA guideline. The databases searched included MEDLINE (PubMed), PsycINFO, CINAHL, Scopus, Cochrane, and Embase. Inclusion criteria were experimental, observational and qualitative studies about educational programmes on patient- and family-centred care for paediatric healthcare professionals. Exclusion criteria were reviews and non-peer-reviewed literature. Two reviewers independently screened and extracted the data using Covidence. Of the 13922 records identified, 49 articles met the inclusion criteria. There was a large variety of educational programmes, half of which were interdisciplinary, that mainly targeted nurses and doctors. The median number of participants was 51 (range 7 to 1411). The predominant target population was children with chronic disabilities and neonatal intensive care units, and only one programme specifically targeted adolescents. The median duration was one day (range 5 min to 3.5 years). Development of competencies was the most common objective. We identified 12 different educational content areas. Content mainly focused on communication and relational competencies, including partnership, which involved shared decision-making, mutual agenda setting, and negotiation of a plan. Many kinds of educational strategies were found but experiential learning through simulation and roleplay was used most.   Conclusion: A large variety of educational programmes in paediatric patient- and family-centred care exist. Educational content mainly focused on communication and relational competencies. Experiential learning including roleplay and simulation was the most used educational strategy. What is Known: • Delivery of patient- and family-centred care improves parental satisfaction of care but requires clinicians have a certain attitude towards involving the child and parents in a healthcare partnership as well as advanced triadic communication skills. Little is known about how this attitude, and more broadly, patient- and family-centred care, can be facilitated through education and training. What is New: • This scoping review found a wide array of programmes.. Workshops with simulation or roleplay was the most frequent educational strategy. The programmes, which typically targeted nurses and doctors, chiefly focused on basic and advanced communication and relational competencies, including partnership, which involved shared decision-making and negotiation of plans.

Modern Siberian dog ancestry was shaped by several thousand years of Eurasian-wide trade and human dispersal.

Dogs have been essential to life in the Siberian Arctic for over 9,500 y, and this tight link between people and dogs continues in Siberian communities. Although Arctic Siberian groups such as the Nenets received limited gene flow from neighboring groups, archaeological evidence suggests that metallurgy and new subsistence strategies emerged in Northwest Siberia around 2,000 y ago. It is unclear if the Siberian Arctic dog population was as continuous as the people of the region or if instead admixture occurred, possibly in relation to the influx of material culture from other parts of Eurasia. To address this question, we sequenced and analyzed the genomes of 20 ancient and historical Siberian and Eurasian Steppe dogs. Our analyses indicate that while Siberian dogs were genetically homogenous between 9,500 to 7,000 y ago, later introduction of dogs from the Eurasian Steppe and Europe led to substantial admixture. This is clearly the case in the Iamal-Nenets region (Northwestern Siberia) where dogs from the Iron Age period (∼2,000 y ago) possess substantially less ancestry related to European and Steppe dogs than dogs from the medieval period (∼1,000 y ago). Combined with findings of nonlocal materials recovered from these archaeological sites, including glass beads and metal items, these results indicate that Northwest Siberian communities were connected to a larger trade network through which they acquired genetically distinctive dogs from other regions. These exchanges were part of a series of major societal changes, including the rise of large-scale reindeer pastoralism ∼800 y ago.

A Culture of Inquiry: Practice-Based Knowledge for Nurse Leaders.

A culture of inquiry has not traditionally been associated with nursing leadership. As healthcare evolves, leaders must reevaluate barriers to improving healthcare outcomes. One noted barrier has been a need for more inquisitiveness to innovate. Through an American Organization for Nursing Leadership workgroup, the authors advanced the understanding of a "culture of inquiry," applying a practice-based learning approach for knowledge development. Three recommended foundational elements are psychological safety, building connections, and using design thinking at all organizational levels.

Guideline adherence and socioeconomic factors in Danish patients referred to secondary care for low back pain: a cross sectional study.

BACKGROUND: The pre-referral history of patients with low back pain referred to secondary care is poorly documented, and it is unclear whether it complies with clinical guideline recommendations; specifically, whether they have received appropriate treatment in primary care. This study describes the patient population referred to a spine clinic at a Danish hospital and investigates whether they have received an adequate course of treatment in primary care before referral. Furthermore, a possible association between primary care treatment and socioeconomic factors is estimated. METHODS: We examined self-reported data from 1035 patients with low back pain of at least eight weeks duration referred to secondary care at a medical spine clinic using a cross-sectional design. As an approximation to national clinical guidelines, the definition of an adequate course of treatment in primary care was at least five visits to a physiotherapist or chiropractor prior to referral. RESULTS: Patients were on average 53 years old, and 56% were women. The average Oswestry Disability Index score was 36, indicating a moderate level of disability. Nearly half of the patients reported pain for over a year, and 75% reported pain below knee level. Prior to referral, 33% of the patients had not received an adequate course of treatment in primary care. Based on multiple logistic regression with the three socioeconomic variables, age and sex in the model, those who were unemployed had an odds ratio of 2.35 (1.15-4.79) for not receiving appropriate treatment compared to employed patients. Similarly, the odds ratio for patients without vs. with health insurance was 1.71 (1.17-2.50). No significant association was observed with length of education. CONCLUSIONS: Despite national clinical guidelines recommending management for low back pain in primary care, one third of the patients had not received an adequate course of treatment before referral to secondary care. Moreover, the high probability of not having received recommended treatment for patients who were unemployed or lacked health insurance indicates an economic obstacle to adequate care. Therefore, reconsidering the compensation structure for the treatment of back pain patients is imperative to mitigate health inequality within low back pain management.

CVD Bilayer Graphene Spin Valves with 26 µm Spin Diffusion Length at Room Temperature.

We present inverted spin-valve devices fabricated from chemical vapor deposition (CVD)-grown bilayer graphene (BLG) that show more than a doubling in device performance at room temperature compared to state-of-the-art bilayer graphene spin valves. This is made possible by a polydimethylsiloxane droplet-assisted full-dry transfer technique that compensates for previous process drawbacks in device fabrication. Gate dependent Hanle measurements reveal spin lifetimes of up to 5.8 ns and a spin diffusion length of up to 26 µm at room temperature combined with a charge carrier mobility of about 24 000 cm2(V s)-1 for the best device. Our results demonstrate that CVD-grown BLG shows equally good room temperature spin transport properties as both CVD-grown single-layer graphene and even exfoliated single-layer graphene.

Feasibility, safety, and patient-reported outcomes 90 days after same-day total knee arthroplasty: a matched cohort study.

BACKGROUND AND PURPOSE: Despite increased attention to and acceptance of fast-track procedures, there is a lack of studies concerning discharge on the day of surgery (DOS) following total knee arthroplasty (SD-TKA). We evaluated the feasibility of SD-TKA, and compared safety and patient-reported outcomes (PROs) between patients undergoing SD-TKA and patients undergoing standard TKA. PATIENTS AND METHODS: A SD-TKA group (n = 101) was matched 1:1 to a standard TKA group (n = 101) on age, sex, and ASA score. Feasibility (being discharged on DOS), safety (unplanned contacts and complications evaluated by telephone calls (2 weeks), outpatient visits (2 weeks), and readmission (90 days)) were assessed. Further, Oxford Knee Score (OKS) and Visual Analogue Scale (VAS) (pain at rest and activity) were reported (90 days). RESULTS: 89 of 101 SD-TKA patients were discharged on DOS. The number of telephone calls (≤ 83) and outpatient visits (12) were similar in the 2 groups. The number of readmissions was ≤ 3 in both groups, and only 1 of the readmissions was related to TKA surgery. No differences were found at 90-day follow-up in terms of OKS (34 in both groups) or VAS (rest: SD-TKA = 7 and standard TKA = 8; activity: SD-TKA = 17 and standard TKA = 15). INTERPRETATION: SD-TKA is feasible in a selected group of patients, and safety and PROs are comparable to patients undergoing standard TKA.

Endophilin-A2 functions in membrane scission in clathrin-independent endocytosis.

During endocytosis, energy is invested to narrow the necks of cargo-containing plasma membrane invaginations to radii at which the opposing segments spontaneously coalesce, thereby leading to the detachment by scission of endocytic uptake carriers. In the clathrin pathway, dynamin uses mechanical energy from GTP hydrolysis to this effect, assisted by the BIN/amphiphysin/Rvs (BAR) domain-containing protein endophilin. Clathrin-independent endocytic events are often less reliant on dynamin, and whether in these cases BAR domain proteins such as endophilin contribute to scission has remained unexplored. Here we show, in human and other mammalian cell lines, that endophilin-A2 (endoA2) specifically and functionally associates with very early uptake structures that are induced by the bacterial Shiga and cholera toxins, which are both clathrin-independent endocytic cargoes. In controlled in vitro systems, endoA2 reshapes membranes before scission. Furthermore, we demonstrate that endoA2, dynamin and actin contribute in parallel to the scission of Shiga-toxin-induced tubules. Our results establish a novel function of endoA2 in clathrin-independent endocytosis. They document that distinct scission factors operate in an additive manner, and predict that specificity within a given uptake process arises from defined combinations of universal modules. Our findings highlight a previously unnoticed link between membrane scaffolding by endoA2 and pulling-force-driven dynamic scission.

An Integrated Multidisciplinary Rehabilitation Program Experienced by Patients with Chronic Low Back Pain.

Purpose: To examine how an integrated, multidisciplinary rehabilitation program was experienced by patients with chronic low back pain and to gain insight into how these patients integrated knowledge, skills, and behaviors obtained by the program into their everyday lives.Materials and Methods: A phenomenological hermeneutic design using Ricoeur's interpretation theory was used in the analysis. Data were generated through nine semi-structured interviews in patients with chronic low back pain. The study adhered to the Consolidated criteria for reporting qualitative research (COREQ) checklist.Results: Standardized rehabilitation efforts adapted to individual needs and provided by a highly professional healthcare team in a combination of inpatient stay and home-based activities was experienced as beneficial, because the patients were able to integrate the obtained knowledge, skills, and behaviors into their everyday lives.Conclusions: The findings revealed that the multidisciplinary holistic approach led to higher bodily awareness, greater mental health, and increased social interaction, which improved happiness and quality of life among the patients. This study emphasizes and highlights a rehabilitation approach that promotes home-based activities to provide a base for co-creation across professions regarding rehabilitation initiatives for patients with chronic low back pain.

The effect of an integrated multidisciplinary rehabilitation programme for patients with chronic low back pain: Long-term follow up of a randomised controlled trial.

OBJECTIVE: To compare the long-term effectiveness of an integrated rehabilitation programme with an existing rehabilitation programme, in terms of back-specific disability, in patients with chronic low back pain. DESIGN: A single-centre, pragmatic, two-arm parallel, randomised controlled trial. SETTING: A rheumatology rehabilitation centre in Denmark. SUBJECTS: A total of 165 adults (aged ⩾ 18 years) with chronic low back pain. INTERVENTIONS: An integrated programme (a pre-admission day, two weeks at home, two weeks inpatient followed by home-based activities, plus two 2-day inpatient booster sessions, and six-month follow-up visit) was compared with an existing programme (four-week inpatient, and six-month follow-up visit). MAIN MEASURE: The primary outcome was disability measured using the Oswestry Disability Index after one year. Secondary outcomes included pain intensity (Numerical Rating Scale), pain self-efficacy (Pain Self-Efficacy Questionnaire), health-related quality of life (EuroQol-5 Domain 5-level (EQ-5D)), and depression (Major Depression Inventory). Analysis was by intention-to-treat, using linear mixed models. RESULTS: 303 patients were assessed for eligibility of whom 165 patients (mean age 50 years (SD 13) with a mean Oswestry Disability Index score of 42 (SD 11)) were randomly allocated (1:1 ratio) to the integrated programme (n = 82) or the existing programme (n = 83). The mean difference (integrated programme minus existing programme) in disability was -0.53 (95% CI -4.08 to 3.02); p = 0.770). No statistically significant differences were found in the secondary outcomes. CONCLUSION: The integrated programme was not more effective in reducing long-term disability in patients with chronic low back pain than the existing programme.

The effect of an integrated multidisciplinary rehabilitation programme alternating inpatient interventions with home-based activities for patients with chronic low back pain: a randomized controlled trial.

OBJECTIVE: To compare the effectiveness of an integrated rehabilitation programme with an existing rehabilitation programme in patients with chronic low back pain. DESIGN: A single-centre, pragmatic, two-arm parallel, randomized controlled trial (1:1 ratio). SETTING: A rheumatology inpatient rehabilitation centre in Denmark. SUBJECTS: A total of 165 adults (aged ⩾ 18 years) with chronic low back pain. INTERVENTIONS: An integrated rehabilitation programme comprising an alternation of three weeks of inpatient stay and 12 weeks of home-based activities was compared with an existing rehabilitation programme of four weeks of inpatient stay. MAIN MEASURES: Patient-reported outcomes were collected at baseline and at the 26-week follow-up. The primary outcome was back-specific disability (Oswestry Disability Index). Secondary outcomes included pain intensity (Numerical Rating Scale), pain self-efficacy (Pain Self-Efficacy Questionnaire), health-related quality of life (EuroQol-5 Domain 5-level (EQ-5D)), and depression (Major Depression Inventory). A complete case analysis was performed. RESULTS: A total of 303 patients were assessed for eligibility of whom 165 (mean age: 50 years (SD 13) and mean Oswestry Disability Index score 42 (SD 11)) were randomized (83 to existing rehabilitation programme and 82 to integrated rehabilitation programme). Overall, 139 patients provided the 26-week follow-up data. Baseline demographic and clinical characteristics were comparable between programmes. The between-group difference in the Oswestry Disability Index score when adjusting for the corresponding baseline score was -0.28 (95% confidence interval (CI): -4.02, 3.45) which was neither statistically nor clinically significant. No significant differences were found in the secondary outcomes. CONCLUSION: An integrated rehabilitation programme was no more effective than an existing rehabilitation programme at the 26-week follow-up.

Not scene learning, but attentional processing is superior in team sport athletes and action video game players.

We tested if high-level athletes or action video game players have superior context learning skills. Incidental context learning was tested in a spatial contextual cueing paradigm. We found comparable contextual cueing of visual search in repeated displays in high-level amateur handball players, dedicated action video game players and normal controls. In contrast, both handball players and action video game players showed faster search than controls, measured as search time per display item, independent of display repetition. Thus, our data do not indicate superior context learning skills in athletes or action video game players. Rather, both groups showed more efficient visual search in abstract displays that were not related to sport-specific situations.

[Occupationally acquired MRSA colonization and occupational dermatological assessments (BK-No. 3101 in the German list of Occupational Diseases) : Analysis of the DGUV documentation and expert opinion on a case with work-related MRSA-triggered atopic dermatitis]. / Beruflich erworbene MRSA-Besiedelung in der berufsdermatologischen Begutachtung (BK-Nr. 3101) : Auswertung der DGUV BK-Dokumentation und Gutachtenfall mit arbeitsbedingter MRSA-getriggerter atopischer Dermatitis.

BACKGROUND: Person-to-person transmitted infectious diseases can cause occupational diseases (OD). These are subsumed as BK-No. 3101 in the German list of OD which applies for individuals with a considerably higher risk for infection as a consequence of their professional activity compared to the general population. OBJECTIVES: The special medical and insurance law aspects of a work-related MRSA colonization are presented using the example of an expert opinion case and an evaluation of the BK reports of suspected occupational disease (BK No. 3101) of the German Social Accident Insurance (DGUV). PATIENTS AND METHODS: The BK documentation of the DGUV from 2007-2012 and the patient cohort from the Department of Dermatology, University Hospital Erlangen, presenting for expert assessment from 2007-2012 were retrospectively analysed for human-to-human transmitted infectious diseases of the skin (BK-No. 3101). RESULTS: Person-to-person transmission of infectious diseases of the skin is rare in the field of occupational dermatology. In the DGUV cohort, suspected BK-No. 3101cases amounted to 2.6% of all notified cases; recognized BK-No. 3101 cases accounted for 4.2% of all recognized cases, amongst which 9 were caused by MRSA. In contrast to a symptomatic infection, an asymptomatic MRSA colonization is not being recognized as BK-No. 3101. Bacterial superantigens can trigger atopic dermatitis (AD). In particular cases, occupationally acquired MRSA can elicit AD and may justify classification as an OD (BK-No. 3101). CONCLUSIONS: Early detection of MRSA colonization and eradication are necessary for rehabilitation. Management of skin diseases due to infectious diseases within the framework of OD is presented.

Specialized sledge dogs accompanied Inuit dispersal across the North American Arctic.

Domestic dogs have been central to life in the North American Arctic for millennia. The ancestors of the Inuit were the first to introduce the widespread usage of dog sledge transportation technology to the Americas, but whether the Inuit adopted local Palaeo-Inuit dogs or introduced a new dog population to the region remains unknown. To test these hypotheses, we generated mitochondrial DNA and geometric morphometric data of skull and dental elements from a total of 922 North American Arctic dogs and wolves spanning over 4500 years. Our analyses revealed that dogs from Inuit sites dating from 2000 BP possess morphological and genetic signatures that distinguish them from earlier Palaeo-Inuit dogs, and identified a novel mitochondrial clade in eastern Siberia and Alaska. The genetic legacy of these Inuit dogs survives today in modern Arctic sledge dogs despite phenotypic differences between archaeological and modern Arctic dogs. Together, our data reveal that Inuit dogs derive from a secondary pre-contact migration of dogs distinct from Palaeo-Inuit dogs, and probably aided the Inuit expansion across the North American Arctic beginning around 1000 BP.

Prediction of 2-year work participation in sickness absentees with neck or shoulder pain: the contribution of demographic, patient-reported, clinical and imaging information.

BACKGROUND: In cases of neck and shoulder pain, the responsibility for assessing work prognosis is held by clinicians with access to different domains of information. One of these domains is magnetic resonance imaging (MRI), and although MRI is increasingly used, it is unknown which domains of information contribute the most to the prediction of work prognosis. This retrospective cohort study explored the contribution of demographic, patient-reported, clinical, and MRI information to the prediction of work participation in sickness absentees with neck or shoulder pain. METHODS: From a secondary care setting, 168 sickness absentees with neck or shoulder pain were included. Based on registry data, a successful work outcome was defined as ≥50% work participation score (WPS) from Weeks 1 to 104 after enrolment. Prognostic variables were categorized into four domains (demographic, patient-reported, clinical, and MRI) resembling the order of information obtained in a clinical setting. Crude logistic regression analyses were used to identify prognostic variables for each domain (p < 0.2). This was followed by multivariable analyses including the identified variables in a domain-wise order. For each added domain, the probability of successful WPS was dichotomized leaving two possible classifications: ≥ 50% chance of successful WPS or not. In cross-tabulations of chance and the actual WPS outcome, positive and negative predictive values (PPV and NPV), sensitivity, specificity and area under the curve (AUC) were calculated. RESULTS: The combination of demographic and patient-reported variables yielded an NPV of 0.72 and a PPV of 0.67, while specificity was 0.82, sensitivity 0.54 and AUC 0.77. None of these values improved notably by adding clinical and MRI variables as predictors of successful WPS. CONCLUSIONS: These results suggest that - among sickness absentees with neck or shoulder pain - clinical and MRI variables provide no additional information for the prediction of work participation compared with only demographic and patient-reported information.

The Sano study: justification and detailed description of a multidisciplinary biopsychosocial rehabilitation programme in patients with chronic low back pain.

OBJECTIVE:: To justify and describe an integrated rehabilitation programme for patients with chronic low back pain prior to evaluation in a randomized controlled trial. METHOD:: The Template for Intervention Description and Replication (TIDieR) checklist was used as a structural framework for the description of the integrated rehabilitation programme. As a part of the description, the Medical Research Council guidance, 'Developing and evaluating complex interventions', was used as a framework to justify the integrated rehabilitation programme. INTERVENTION DESCRIPTION:: The integrated rehabilitation programme adopts a participatory biopsychosocial approach integrating inpatient activities supported by a multidisciplinary team and learning located within the patient's own environment. The integrated rehabilitation programme comprises 3 weeks of inpatient stay and 11 weeks of home-based activities. The inpatient part of the programme consists of 38 clinical activities, some of them delivered more than once. The 38 clinical activities were described in an activity sheet developed for this purpose, combining five items from the TIDieR. CONCLUSION:: An integrated rehabilitation programme for patients with chronic low back pain has been justified and described. The intervention description is currently being used for successful structuring and standardization of the content and delivery of the integrated rehabilitation programme in a randomized controlled trial. TRAIL REGISTRATION:: ClinicalTrials.gov: NCT02884466.

First four years of operation of a municipal acute bed unit in rural Norway.

OBJECTIVE: To evaluate the use of a small municipality acute bed unit (MAU) in rural Norway resulting from the Coordination reform regarding occupancy-rate, patient characteristics and healthcare provided during the first four years of operation. Further, to investigate whether implementation of the new municipal service avoided acute hospital admissions. DESIGN: Observational study. SETTING: A two-bed municipal acute bed unit. SUBJECTS: All patients admitted to the unit between 2013 and 2016. MAIN OUTCOME MEASURES: Demographics, comorbidity, main diagnoses and level of municipal care on admission and discharge, diagnostic and therapeutic initiatives, MAU occupancy rate, and acute hospital admission rate. RESULTS: Altogether, 389 admissions occurred, 215 first-time admissions and 174 readmissions. The mean MAU bed occupancy rate doubled from of 0.26 in 2013 to 0.50 in 2016, while acute hospital admission rates declined. The patients (median age 84.0 years, 48.9% women at first time admission) were most commonly admitted for infections (28.0%), observation (22.1%) or musculoskeletal symptoms (16.2%). Some 52.7% of the patients admitted from home were discharged to a higher care level; musculoskeletal problems as admission diagnosis predicted this (RR =1.43, 95% CI 1.20-1.71, adjusted for age and sex). CONCLUSION: Admission rates to MAU increased during the first years of operation. In the same period, there was a reduction in acute hospital admissions. Patient selection was largely in accordance with national and local criteria, including observational stays. Half the patients admitted from home were discharged to nursing home, suggesting that the unit was used as pathway to a higher municipal care level. Key Points Evaluation of the first four years of operation of a municipality acute bed unit (MAU) in rural Norway revealed: • Admission rates to MAU increased, timely coinciding with decreased acute admission rates to hospital medical wards. • Most patients were old and had complex health problems. • Only half the patients were discharged back home; musculoskeletal symptoms were associated with discharge to a higher care level.

6q12 and 11p14 variants are associated with postnatal exhaled nitric oxide levels and respiratory symptoms.

BACKGROUND: Exhaled nitric oxide (eNO) is a biomarker of airway inflammation and seems to precede respiratory symptoms, such as asthma, in childhood. Identifying genetic determinants of postnatal eNO levels might aid in unraveling the role of eNO in epithelial function or airway inflammation and disease. OBJECTIVE: We sought to identify genetic determinants of early postnatal eNO levels and subsequent respiratory symptoms during the first year of life. METHODS: Within a population-based birth cohort, eNO levels were measured in healthy term infants aged 5 weeks during quiet tidal breathing in unsedated sleep. We assessed associations of single nucleotide polymorphisms with eNO levels in a genome-wide association study and subsequent symptoms of lower respiratory tract infections during the first year of life and asked whether this was modified by prenatal and early-life environmental factors. RESULTS: We identified thus far unknown determinants of infant eNO levels: rs208515 (P = 3.3 × 10-8), which is located at 6q12, probably acting in "trans" and explaining 10.3% of eNO level variance, and rs1441519 (P = 1.6 × 10-6), which is located at 11p14, potentially affecting nitric oxide synthase 3 (NOS3) expression, as shown by means of in vitro functional analyses. Moreover, the 6q12 locus was inversely associated with subsequent respiratory symptoms (P < .05) and time to recovery after first respiratory symptoms during the first year of life (P < .05). CONCLUSION: The identification of novel genetic determinants of infant eNO levels might implicate that postnatal eNO metabolism in healthy infants before first viral infections and sensitization is related to mechanisms other than those associated with asthma, atopy, or increased risk thereof later in life.

[Adult ADHD and borderline personality disorder: A pilot study on differences in attachment and early traumatization]. / ADHS im Erwachsenenalter und Borderline-Persönlichkeitsstörung: Eine Pilotstudie zu den Unterschieden im Bindungsstil und frühkindlichen Traumatisierungen.

Adult ADHD and borderline personality disorder: A pilot study on differences in attachment and early traumatization Objective: Attention-deficit/hyperactivity disorder (ADHD) in adulthood and borderline personality disorder (BPD) share commondiagnostic criteria.The present study examined how ADHD in adulthood can be distinguished from BPDregarding attachment style and traumatic experiences. METHOD: The sample consists of N = 30 persons with 50% (n = 15) ADHD patients and 50% (n = 15) BPD patients. The patients were asked to fill out different questionnaires to investigate the criteria for specific symptoms. RESULTS: The results show that most of the patients are insecurely attached. In addition, 80% of both the ADHD and BPD sample claimed traumatic experiences in their childhood or adolescence. Most frequently, patients reported traumatisation following emotional neglect and emotional abuse. No group-specific differences concerning traumatic experiences and the individual attachment style were determined. CONCLUSION: The etiological factors attachment style and traumatic experiences are not suitable for differentiating ADHD in adulthood and BPD.

Quantitative projection of human brain penetration of the H3 antagonist PF-03654746 by integrating rat-derived brain partitioning and PET receptor occupancy.

1. Unbound brain drug concentration (Cb,u), a valid surrogate of interstitial fluid drug concentration (CISF), cannot be directly determined in humans, which limits accurately defining the human Cb,u:Cp,u of investigational molecules. 2. For the H3R antagonist (1R,3R)-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-lmethyl)phenyl]cyclobutane-1-carboxamide (PF-03654746), we interrogated Cb,u:Cp,u in humans and nonhuman primate (NHP). 3. In rat, PF-03654746 achieved net blood-brain barrier (BBB) equilibrium (Cb,u:Cp,u of 2.11). 4. In NHP and humans, the PET receptor occupancy-based Cp,u IC50 of PF-03654746 was 0.99 nM and 0.31 nM, respectively, which were 2.1- and 7.4-fold lower than its in vitro human H3 Ki (2.3 nM). 5. In an attempt to understand this higher-than-expected potency in humans and NHP, rat-derived Cb,u:Cp,u of PF-03654746 was integrated with Cp,u IC50 to identify unbound (neuro) potency of PF-03654746, nIC50. 6. The nIC50 of PF-03654746 was 2.1 nM in NHP and 0.66 nM in human which better correlated (1.1- and 3.49-fold lower) with in vitro human H3 Ki (2.3 nM). 7. This correlation of the nIC50 and in vitro hH3 Ki suggested the translation of net BBB equilibrium of PF-03654746 from rat to NHP and humans, and confirmed the use of Cp,u as a reliable surrogate of Cb,u. 8. Thus, nIC50 quantitatively informed the human Cb,u:Cp,u of PF-03654746.