An intact C-terminal end of albumin is required for its long half-life in humans.

Albumin has an average plasma half-life of three weeks and is thus an attractive carrier to improve the pharmacokinetics of fused therapeutics. The half-life is regulated by FcRn, a cellular receptor that protects against intracellular degradation. To tailor-design the therapeutic use of albumin, it is crucial to understand how structural alterations in albumin affect FcRn binding and transport properties. In the blood, the last C-terminal residue (L585) of albumin may be enzymatically cleaved. Here we demonstrate that removal of the L585 residue causes structural stabilization in regions of the principal FcRn binding domain and reduces receptor binding. In line with this, a short half-life of only 3.5 days was measured for cleaved albumin lacking L585 in a patient with acute pancreatitis. Thus, we reveal the structural requirement of an intact C-terminal end of albumin for a long plasma half-life, which has implications for design of albumin-based therapeutics

A human endothelial cell-based recycling assay for screening of FcRn targeted molecules.

Albumin and IgG have remarkably long serum half-lives due to pH-dependent FcRn-mediated cellular recycling that rescues both ligands from intracellular degradation. Furthermore, increase in half-lives of IgG and albumin-based therapeutics has the potential to improve their efficacies, but there is a great need for robust methods for screening of relative FcRn-dependent recycling ability. Here, we report on a novel human endothelial cell-based recycling assay (HERA) that can be used for such pre-clinical screening. In HERA, rescue from degradation depends on FcRn, and engineered ligands are recycled in a manner that correlates with their half-lives in human FcRn transgenic mice. Thus, HERA is a novel cellular assay that can be used to predict how FcRn-binding proteins are rescued from intracellular degradation. Nat Commun 2018 Feb 12; 9(1):621

Physical inactivity is associated with chronic musculoskeletal complaints 11 years later: results from the Nord-Trøndelag Health Study

Background Physical inactivity is associated with several diseases, but studies evaluating the association between chronic musculoskeletal complaints (MSCs) and physical exercise have shown conflicting results. The aim of this large-scale prospective population-based study was to investigate the association between self-reported physical exercise at baseline and the prevalence of chronic musculoskeletal complaints (MSCs) 11 years later. Methods The results are based upon two consecutive public health studies conducted within the county of Nord-Trøndelag, Norway (The HUNT studies). A total of 39,520 (83%) out of 47,556 adults who participated in HUNT 1 and HUNT 2 responded to questions about physical exercise at baseline in 1984–86, and to questions about musculoskeletal complaints 11 years later (1995–97). Chronic MSCs was defined as MSCs ≥ 3 months during the past year, and chronic widespread MSCs such as pain ≥ 15 days during the last month from the axial region, above the waist, and below the waist. Associations were assessed using multiple logistic regression, estimating prevalence odds ratio (OR) with 95% confidence intervals (CIs). All the final analyses were adjusted for age, gender, body mass index, smoking and education level. Results At follow-up 20,223 (51%) reported chronic MSCs, and among these 2,318 (5.9%) reported chronic widespread MSCs. Individuals who exercised at baseline were less likely to report chronic MSCs 11 years later (OR 0.91, 95% CI 0.85–0.97) than inactive persons. Among individuals who exercised more than three times per week, chronic widespread MSCs were 28% less common (OR 0.72, 95% CI 0.59–0.88) compared to inactive individuals. Conclusion In this large-scale population-based study, physical exercise was associated with lower prevalence of chronic MSCs, in particular chronic widespread MSCs. Future studies should try to clarify whether chronic MSCs are a cause or a consequence of inactivity

Come Get A Taste of our PB and J: Positive Behavior Journey

Established in 1971, Seaborn Lee has long been known as a place parents can confidently send their children. However, as times changed, Seaborn Lee started to experience challenges in behavior, discipline, and how the staff responded to those challenges. Prior to implementing School Wide Positive Behavioral Interventions and Support (SWPBIS), students were missing more days of class than there were school days in the year. In 2012-2013, administrators reported nearly 300 behavior incidents that led to students missing instruction and 421 days in which students were suspended or in office time out. The types of behaviors which were leading to the suspensions were disruption, defiance, fighting, and bullying. Principal Kine’ Geathers recognized the need to implement additional support, which came in the form of an early learning climate prototype. This was developed by the Metropolitan Regional educational service Agency (MRESA) in partnership with Fulton County Schools thanks to funding from the David, Helen, and Marian Woodward Fund-Atlanta. All staff were trained on an aligned SWPBIS framework that helped us address creating a positive learning climate and, most importantly, equipped us with social-emotional and developmentally appropriate strategies to address challenging student behavior. We also identified our school-wide PBIS leadership team and designed resources for implementation. Our main goal was properly defining major versus minor behaviors, how they would be handled, who would handle them, and how the data would be tracked. We created a behavior matrix that complemented our school mascot: a bulldog. Our theme is P.A.W.S. (Be Prepared, Act Respectfully, Work Together, and Stay Safe), and these principles guide teachers and students in behavioral expectations. The strategies and framework the students learn at school can also be used by parents at home to positively reinforce the behaviors they wish to see in their children

Tilførselsprogrammet: 2010 Passive air and water sampling at Andøya, Bjørnøya and Jan Mayen, 2009-2010

As part of the Climate and Pollution Agency (Klif) monitoring programme on fluxes of contaminants in the Barents Sea, Norwegian Sea and North Sea, passive sampling was undertaken at Andøya, Bjørnøya and Jan Mayen to measure levels of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), organochlorines (OCs) and polybrominated diphenylethers (PBDEs) in air and water. Semipermeable membrane devices and silicone strips were deployed in water for periods of 10-12 months. PAH levels in water were low, but mostly quantifiable. PCB levels were mostly below limits of detection (LOD), the latter being in the low picogram/litre range. LODs were adequate for pentachlorobenzene and hexachlorobenzene, while concentrations of hexachlorocyclohexane isomers (-HCH and -HCH) and p,p’-DDE were closer to the LOD. PBDE-47 and PBDE-99 were consistently detected. For certain compounds, it was possible to compare dissolved water concentrations to levels in the sediment and in cod liver. Results from polyurethane foam samplers (PUFs) deployed in the air are broadly consistent with results from past findings and active air samplers, yet also revealed difficulties when applying passive sampling methods in the harsh Arctic climatic conditions. Contaminant levels in air were successfully measured at the three sites using PUF air samplers. Some recommendations regarding further work are provided

Combining a deconvolution and a universal library search algorithm for the nontarget analysis of data-independent acquisition mode liquid chromatography-high-resolution mass spectrometry results

Nontarget analysis is considered one of the most comprehensive tools for the identification of unknown compounds in a complex sample analyzed via liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Due to the complexity of the data generated via LC-HRMS, the data-dependent acquisition mode, which produces the MS2 spectra of a limited number of the precursor ions, has been one of the most common approaches used during nontarget screening. However, data-independent acquisition mode produces highly complex spectra that require proper deconvolution and library search algorithms. We have developed a deconvolution algorithm and a universal library search algorithm (ULSA) for the analysis of complex spectra generated via data-independent acquisition. These algorithms were validated and tested using both semisynthetic and real environmental data. A total of 6000 randomly selected spectra from MassBank were introduced across the total ion chromatograms of 15 sludge extracts at three levels of background complexity for the validation of the algorithms via semisynthetic data. The deconvolution algorithm successfully extracted more than 60% of the added ions in the analytical signal for 95% of processed spectra (i.e., 3 complexity levels multiplied by 6000 spectra). The ULSA ranked the correct spectra among the top three for more than 95% of cases. We further tested the algorithms with 5 wastewater effluent extracts for 59 artificial unknown analytes (i.e., their presence or absence was confirmed via target analysis). These algorithms did not produce any cases of false identifications while correctly identifying similar to 70% of the total inquiries. The implications, capabilities, and the limitations of both algorithms are further discussed

Cost-effective management of women with minor cervical lesions: Revisiting the application of HPV DNA testing.

Background Lack of consensus in management guidelines for women with minor cervical lesions, coupled with novel screening approaches, such as human papillomavirus (HPV) genotyping, necessitate revisiting prevention policies. We evaluated the cost-effectiveness and resource trade-offs of alternative triage strategies to inform cervical cancer prevention in Norway. Methods We used a decision-analytic model to compare the lifetime health and economic consequences associated with ten novel candidate approaches to triage women with minor cervical lesions. Candidate strategies varied by: 1) the triage test(s): HPV testing in combination with cytology, HPV testing alone with or without genotyping for HPV-16 and -18, and immediate colposcopy, and 2) the length of time between index and triage testing (i.e., 6, 12 or 18 months). Model outcomes included quality-adjusted life-years (QALYs), lifetime societal costs, and resource use (e.g., colposcopy referrals). Results The current Norwegian guidelines were less effective and more costly than candidate strategies. Given a commonly-cited willingness-to-pay threshold in Norway of $100,000 per QALY gained, the preferred strategy involved HPV genotyping with immediate colposcopy referral for HPV-16 or -18 positive and repeat HPV testing at 12 months for non-HPV-16 or -18 positive ($78,010 per QALY gained). Differences in health benefits among candidate strategies were small, while resource use varied substantially. More effective strategies required a moderate increase in colposcopy referrals (e.g., a 9% increase for the preferred strategy) compared with current levels. Conclusion New applications of HPV testing may improve management of women with minor cervical lesions, yet are accompanied by a trade-off of increased follow-up procedures