School-based interventions are thought to be the most universally applicable and effective way to counteract low physical activity (PA) and fitness although there is controversy about the optimal ...strategy to intervene.
The objective of this review was to summarise recent reviews that aimed to increase PA or fitness in youth and carry out a systematic review of new intervention studies.
Relevant systematic reviews and original controlled and randomised controlled school-based trials with a PA or fitness outcome measure, a duration of ≥12 weeks, a sufficient quality and involvement of a healthy population aged 6-18 years that were published from 2007 to 2010 were included. Results In these reviews, 47-65% of trials were found to be effective. The effect was mostly seen in school-related PA while effects outside school were often not observed or assessed.
The school-based application of multicomponent intervention strategies was the most consistent, promising strategy, while controversy existed regarding the effectiveness of family involvement, focus on healthy populations at increased risk or duration and intensity of the intervention. All 20 trials in the review update showed a positive effect on in-school, out-of-school or overall PA, and 6 of 11 studies showed an increase in fitness. Taking into consideration both assessment quality and public health relevance, multicomponent approaches in children including family components showed the highest level of evidence for increasing overall PA. This review confirms the public health potential of high quality, school-based PA interventions for increasing PA and possibly fitness in healthy youth.
The degree of glaciation of mixed-phase clouds constitutes one of the largest uncertainties in climate prediction. In order to better understand cloud glaciation, cloud spectrometer observations are ...presented in this paper, which were made in the mixed-phase temperature regime between 0 and −38 °C (273 to 235 K), where cloud particles can either be frozen or liquid. The extensive data set covers four airborne field campaigns providing a total of 139 000 1 Hz data points (38.6 h within clouds) over Arctic, midlatitude and tropical regions. We develop algorithms, combining the information on number concentration, size and asphericity of the observed cloud particles to classify four cloud types: liquid clouds, clouds in which liquid droplets and ice crystals coexist, fully glaciated clouds after the Wegener–Bergeron–Findeisen process and clouds where secondary ice formation occurred. We quantify the occurrence of these cloud groups depending on the geographical region and temperature and find that liquid clouds dominate our measurements during the Arctic spring, while clouds dominated by the Wegener–Bergeron–Findeisen process are most common in midlatitude spring. The coexistence of liquid water and ice crystals is found over the whole mixed-phase temperature range in tropical convective towers in the dry season. Secondary ice is found at midlatitudes at −5 to −10 °C (268 to 263 K) and at higher altitudes, i.e. lower temperatures in the tropics. The distribution of the cloud types with decreasing temperature is shown to be consistent with the theory of evolution of mixed-phase clouds. With this study, we aim to contribute to a large statistical database on cloud types in the mixed-phase temperature regime.
Transarterial chemoembolisation (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma, while the multikinase inhibitor sorafenib improves survival in patients ...with advanced disease. We aimed to determine whether TACE with sorafenib improves progression-free survival versus TACE with placebo.
We did a multicentre, randomised, placebo-controlled, phase 3 trial (TACE 2) in 20 hospitals in the UK for patients with unresectable, liver-confined hepatocellular carcinoma. Patients were eligible if they were at least aged 18 years, had Eastern Cooperative Oncology Group performance status of 1 or less, and had Child-Pugh A liver disease. Patients were randomised 1:1 by computerised minimisation algorithm to continuous oral sorafenib (400 mg twice-daily) or matching placebo combined with TACE using drug-eluting beads (DEB-TACE), which was given via the hepatic artery 2–5 weeks after randomisation and according to radiological response and patient tolerance thereafter. Patients were stratified according to randomising centre and serum α-fetoprotein concentration (<400 ng/mL and ≥400 ng/mL). Only the trial coordinator was unmasked to treatment allocation before patient progression during the study. The primary endpoint was progression-free survival defined as the interval between randomisation and progression according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) or death due to any cause, and was analysed by intention-to-treat. Safety was analysed by intention-to-treat. The trial has been completed and the final results are reported. The trial is registered at EudraCT, number 2008-005073-36, and ISRCTN, number ISRCTN93375053.
Between Nov 4, 2010, and Dec 7, 2015, the trial enrolled 399 patients and was terminated after a planned interim futility analysis. 86 patients failed screening and 313 remaining patients were randomly assigned: 157 to sorafenib and 156 to placebo. The median daily dose was 660 mg (IQR 389·2–800·0) sorafenib versus 800 mg (758·2–800·0) placebo, and median duration of therapy was 120·0 days (IQR 43·0–266·0) for sorafenib versus 162·0 days (70·0–323·5) for placebo. There was no evidence of difference in progression-free survival between the sorafenib group and the placebo group (hazard ratio HR 0·99 95% CI 0·77–1·27, p=0·94); median progression-free survival was 238·0 days (95% CI 221·0–281·0) in the sorafenib group and 235·0 days (209·0–322·0) in the placebo group. The most common grade 3–4 adverse events were fatigue (29 18% of 157 patients in the sorafenib group vs 21 13% of 156 patients in the placebo group), abdominal pain (20 13% vs 12 8%), diarrhoea (16 10% vs four 3%), gastrointestinal disorders (18 11% vs 12 8%), and hand–foot skin reaction (12 8% and none). At least one serious adverse event was reported in 65 (41%) of 157 patients in the sorafenib group and 50 (32%) of 156 in the placebo group, and 181 serious adverse events were reported in total, 95 (52%) in the sorafenib group and 86 (48%) in the placebo group. Three deaths occurred in each group that were attributed to DEB-TACE. Four deaths were attributed to study drug; three in the sorafenib group and one in the placebo group.
The addition of sorafenib to DEB-TACE does not improve progression-free survival in European patients with hepatocellular carcinoma. Alternative systemic therapies need to be assessed in combination with TACE to improve patient outcomes.
Bayer PLC and BTG PLC.
Although pertussis disease is vaccine preventable, Washington State experienced a substantial rise in pertussis incidence beginning in 2011. By June 2012, the reported cases reached 2,520 (37.5 cases ...per 100,000 residents), a 1,300% increase compared with the same period in 2011. We assessed the molecular epidemiology of this statewide epidemic using 240 isolates collected from case patients reported from 19 of 39 Washington counties during 2012 to 2013. The typing methods included pulsed-field gel electrophoresis (PFGE), multilocus variable number tandem repeat analysis (MLVA), multilocus sequence typing (MLST), and pertactin gene (prn) mutational analysis. Using the scheme PFGE-MLVA-MLST-prn mutations-Prn deficiency, the 240 isolates comprised 65 distinct typing profiles. Thirty-one PFGE types were found, with the most common types, CDC013 (n = 51), CDC237 (n = 44), and CDC002 (n = 42), accounting for 57% of them. Eleven MLVA types were observed, mainly comprising type 27 (n = 183, 76%). Seven MLST types were identified, with the majority of the isolates typing as prn2-ptxP3-ptxA1-fim3-1 (n = 157, 65%). Four different prn mutations accounted for the 76% of isolates exhibiting pertactin deficiency. PFGE provided the highest discriminatory power (D = 0.87) and was found to be a more powerful typing method than MLVA and MLST combined (D = 0.67). This study provides evidence for the continued predominance of MLVA 27 and prn2-ptxP3-ptxA1 alleles, along with the reemergence of the fim3-1 allele. Our results indicate that the Bordetella pertussis population causing this epidemic was diverse, with a few molecular types predominating. The PFGE, MLVA, and MLST profiles were consistent with the predominate types circulating in the United States and other countries. For prn, several mutations were present in multiple molecular types.
Wearable sensors have the potential to facilitate remote monitoring for patients recovering from knee replacement surgery. Using IMU sensors attached to the patients’ leg, knee flexion can be ...monitored while the patients are recovering in their home environment. Ideally, these flexion angle measurements will have an accuracy and repeatability at least on par with current clinical standards. To validate the clinical accuracy of a two-sensor IMU system, knee flexion angles were measured in eight subjects post-TKA and compared with other in-clinic angle measurement techniques. These sensors are aligned to the patients’ anatomy by taking a pose resting their operated leg on a box; an initial goniometer measurement defines the patients’ knee flexion while taking that pose. The repeatability and accuracy of the system was subsequently evaluated by comparing knee flexion angles against goniometer readings and markerless optical motion capture data. The alignment pose was repeatable with a mean absolute error of 1.6 degrees. The sensor accuracy through the range of motion had a mean absolute error of 2.6 degrees. In conclusion, the presented sensor system facilitates a repeatable and accurate measurement of the knee flexion, holding the potential for effective remote monitoring of patients recovering from knee replacement surgery.
We integrated five sets of proteomics data profiling the constituents of cerebrospinal fluid (CSF) derived from Huntington disease (HD)-affected and -unaffected individuals with genomics data ...profiling various human and mouse tissues, including the human HD brain. Based on an integrated analysis, we found that brain-specific proteins are 1.8 times more likely to be observed in CSF than in plasma, that brain-specific proteins tend to decrease in HD CSF compared with unaffected CSF, and that 81% of brain-specific proteins have quantitative changes concordant with transcriptional changes identified in different regions of HD brain. The proteins found to increase in HD CSF tend to be liver-associated. These protein changes are consistent with neurodegeneration, microgliosis, and astrocytosis known to occur in HD. We also discuss concordance between laboratories and find that ratios of individual proteins can vary greatly, but the overall trends with respect to brain or liver specificity were consistent. Concordance is highest between the two laboratories observing the largest numbers of proteins.
Equine sarcoids are highly recurrent bovine papillomavirus (BPV)-induced fibroblastic neoplasms that are the most common skin tumours in horses. In order to facilitate the study of potential equine ...sarcoid prophylactics or therapeutics, which can be a slow and costly process in equines, a murine model for BPV-1 protein-expressing equine sarcoid-like tumours was developed in mice through stable transfection of BPV-1 E5 and E6 in a murine fibroblast tumour cell line (K-BALB). Like equine sarcoids, these murine tumour cells (BPV-KB) were of fibroblast origin, were tumorigenic and expressed BPV-1 proteins. As an initial investigation of the preclinical potential of this tumour model for equine sarcoids prophylactics, mice were immunized with BPV-1 E5E6 Venezuelan equine encephalitis virus replicon particles, prior to BPV-KB challenge, which resulted in an increased tumour-free period compared with controls, indicating that the BPV-KB murine model may be a valuable preclinical alternative to equine clinical trials.
Nuclear lamins are nucleus-specific intermediate filaments (IF) found at the inner nuclear membrane (INM) of the nuclear envelope (NE). Together with nuclear envelope transmembrane proteins, they ...form the nuclear lamina and are crucial for gene regulation and mechanical robustness of the nucleus and the whole cell. Recently, we characterized
NE81 as an evolutionarily conserved lamin-like protein, both on the sequence and functional level. Here, we show on the structural level that the
NE81 is also capable of assembling into filaments, just as metazoan lamin filament assemblies. Using field-emission scanning electron microscopy, we show that NE81 expressed in
oocytes forms filamentous structures with an overall appearance highly reminiscent of
lamin B2. The in vitro assembly properties of recombinant His-tagged NE81 purified from
extracts are very similar to those of metazoan lamins. Super-resolution stimulated emission depletion (STED) and expansion microscopy (ExM), as well as transmission electron microscopy of negatively stained purified NE81, demonstrated its capability of forming filamentous structures under low-ionic-strength conditions. These results recommend
as a non-mammalian model organism with a well-characterized nuclear envelope involving all relevant protein components known in animal cells.
Smad4 is a tumor suppressor gene primarily involved in carcinogenesis of the pancreas and colon. The functional inactivation of Smad4 is a late step genetically. In pancreatic carcinogenesis, loss of ...Smad4 marks the transition to invasive growth. In colorectal cancers, the frequency of Smad4 inactivation is markedly increased in metastatic cancers. We have established cell biological models, re‐expressing Smad4 in deficient human cancer cells, in which we could show that Smad4 is adequate to suppress tumor growth through suppression of angiogenic and invasive properties. Thus, pairs of Smad4‐re‐expressing and Smad4‐deficient cells are prone to model the progression from premalignant stages to carcinomas in the carcinogenic process and may provide access to Smad4 targets of high clinical relevance. We present here a “differential secretome analysis”, comparing all the proteins released in vitro from the Smad4‐deficient and Smad4‐re‐expressing SW480 human colon carcinoma cells. The differential secretome catalog comprises more than 25 proteins including proteases and protease inhibitors, as well as established tumor biomarkers. In conclusion, this approach proved to be a sensitive tool to specifically detect Smad4 targets relevant for tumor‐stroma interactions. It is also able to reflect complex alterations of cellular physiology. Moreover, the results support our hypothesis that human tumor markers detectable in serum may be identified through differential secretome analyses.
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