Cognitive changes in spinocerebellar ataxia type 2.
Cognitive disorders and dementia occur in 19 to 42% of patients with spinocerebellar ataxia type 2 (SCA2). Neuropsychological tests can reveal executive dysfunction, impaired visual and verbal memory, tongue and speech impairment, attention disorders and impaired verbal fluency. We performed psychiatric and neuropsychological examinations in 12 patients diagnosed with genetically confirmed SCA2 and 12 healthy volunteers matching the patients in age, gender, and length of education. The level of motor impairment was determined using the brief ataxia rating scale (BARS). The neuropsychological examination focused on testing executive functions, short-term visual and verbal memory, attention, psychomotor tempo, visual motor coordination, learning ability and comprehension ability. The tests were divided into two subgroups according to the difficulty of motor tasks. The cognitive abilities composite score (CACS) was determined by calculating the arithmetic mean of T scores of the respective tests. Patients with SCA2 had significantly lower CACSs (p=0.00005) compared to the healthy volunteers. Patients exhibited impaired performance in both difficult and simple motor tests. The severity of cognitive impairment was related to the age at the onset of the disease (p=0.002) but not to the duration or to the overall BARS score. Compared to healthy volunteers, patients with SCA2 exhibited significantly worse cognitive performance in all areas tested, including the tests of simple motor tasks. Moreover, the cognitive performance of patients worsened as the difficulty of the motor tasks increased.


Mammography use, breast cancer stage at diagnosis, and survival among older women.
Women age 65 years and older account for most newly diagnosed breast cancers and deaths from breast cancer. Yet, older women are least likely to undergo mammography, perhaps because mammography's value is less well demonstrated in older women. To investigate the relationship between prior mammography use, cancer stage at diagnosis, and breast cancer mortality among older women with breast cancer. Retrospective cohort study using the Linked Medicare-Tumor Registry Database. Population-based data from three geographic areas included in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Women aged 67 and older diagnosed with a first primary breast cancer, from 1987 to 1993, residing in Connecticut, metropolitan Atlanta, Georgia, or Seattle-Puget Sound, Washington. Medicare claims were reviewed and women were classified according to their mammography use during the 2 years before diagnosis: nonusers (no prior mammograms), regular users (at least two mammograms at least 10 months apart), or peri-diagnosis users (only mammogram(s) within 3 months before diagnosis). Mammography utilization was linked with SEER data to determine stage at diagnosis and cause of death. Our main outcome variables were (1) stage at diagnosis, classified as early (in situ/Stage I) or late (Stage II or greater), and (2) breast cancer mortality, measured from diagnosis until death from breast cancer or end of the follow-up period (December 31, 1994). Older women who were nonusers of mammography were diagnosed with breast cancer at Stage II or greater more often than regular users (adjusted odds ratio (OR), 3.12; 95% confidence interval (CI), 2.74-3.58). This association was present within each age group studied. Nonusers of mammography were at significantly greater risk of dying from their breast cancer than regular users for all women (adjusted hazard ratio (HR), 3.38; 95% CI, 2.65-4.32) and for women within each age group. Even assuming a lead time of 1.25 years, nonusers of mammography continued to be at increased risk of dying from breast cancer. Our findings remained significant for all women and for the two youngest age groups (67-74 years, 75-85 years), although the benefit was no longer statistically significant for the oldest women (85 years and older). Older women who undergo regular mammography are diagnosed with an earlier stage of disease and are less likely to die from their disease. These data support the use of regular mammography in older women and suggest that mammography can reduce breast cancer mortality in older women, even for women age 85 and older.


A rare complication of spinal surgery: cerebellar hemorrhage.
Remote cerebellar hemorrhage (RCH) after spinal surgery is encountered extremely rarely. A 64 year-old female patient developed symptoms of deteriorating consciousness and diplopia arising on the first postoperative day after recurrent spinal surgery. Cranial CT scan showed cerebral edema and evidence of a cerebellar hemorrhage. Urgent suboccipital decompressive craniectomy and expanded duraplasty were performed. Repeat CT at 24 h revealed hydrocephalus and an external ventricular drain (EVD) was inserted for 20 days. The patient's consciousness deteriorated after withdrawal of the EVD and a ventriculoperitoneal shunt was placed. The patient recovered completely except for gait ataxia and left foot drop. Although the exact cause is unknown iatrogenic dural opening resulting in excessive cerebrospinal fluid (CSF) drainage and secondary development of venous infarction have been suggested to lead to RCH.


Bicycle helmet wearing and the risk of head, face, and neck injury: a French case--control study based on a road trauma registry.
Previous case-control studies on bicycle helmet efficacy are mostly Anglo-Saxon, and based on data from the early 1990s when hard-shell helmets were common. In France, the Rhône county (1.6 million inhabitants) is covered by a road trauma registry that includes emergency department visits, hospital admissions, and fatalities. Over the 1998-2008 period, 13,797 cyclist casualties were identified. The injuries sustained were coded using the Abbreviated Injury Scale (AIS) for injuries to the head (AIS1+ and AIS3+), face (AIS1+), or neck (AIS1+). The study uses a case-control design where the control group includes cyclists injured below the neck-that is, not injured in the region associated with the helmet. We first adjusted for age, gender, and type of crash, as in a previously published Cochrane review. Then we adjusted for injury severity based on non-head, face, or neck injury, and when relevant, for crash location: type of road, urban/rural area. The fully adjusted ORs of helmeted versus unhelmeted cyclists are: for AIS1+ head injuries, 0.69 (95% CI 0.59 to 0.81); for AIS3+ head injuries sustained in urban areas, 0.34 (95% CI 0.15 to 0.65), those sustained in rural areas, 0.07 (95% CI 0.02 to 0.23); for AIS1+ facial injuries, 0.72 (95% CI 0.62 to 0.83); and for AIS1+ neck injuries, 1.18 (95% CI 0.94 to 1.47). This study confirms the protective effect for head and facial injuries, even though soft-shell helmets have now become more common. The reduction of risk is greater for serious head injuries. The study is inconclusive about the risk for neck injuries.


Pathogenic Variation in the Pearl Millet Blast Pathogen Magnaporthe grisea and Identification of Resistance to Diverse Pathotypes.
Blast, also known as leaf spot, caused by Pyricularia grisea (teleomorph: Magnaporthe grisea), has emerged as a serious disease affecting both forage and grain production in pearl millet in India. Pathogenic variation was studied in a greenhouse using 25 M. grisea isolates collected from four major pearl-millet-growing states in India (Rajasthan, Haryana, Maharashtra, and Uttar Pradesh) on 10 pearl millet genotypes (ICMB 02444, ICMB 02777, ICMB 06444, ICMB 93333, ICMB 96666, ICMB 97222, ICMB 99444, 863B, ICMR 06222, and ICMB 95444). Differential reactions to the test isolates were recorded on ICMB 02444, ICMB 93333, ICMB 97222, 863B, and ICMR 06222. The 25 isolates were grouped into five different pathotypes based on their reaction types (virulent = score ≥ 4 and avirulent = score ≤ 3 on a 1-to-9 scale). For the identification of resistance sources, a pearl millet mini-core comprising 238 accessions was evaluated under greenhouse conditions against five M. grisea isolates (Pg118, Pg119, Pg56, Pg53, and Pg45) representing the five pathotypes. Of 238 accessions, 32 were found to be resistant to at least one pathotype. Resistance to multiple pathotypes (two or more) was recorded in several accessions, while three accessions (IP 7846, IP 11036, and IP 21187) exhibited resistance to four of the five pathotypes. Four early-flowering (≤50 days) blast-resistant mini-core accessions (IP 7846, IP 4291, IP 15256, and IP 22449) and four accessions (IP 5964, IP 11010, IP 13636, and IP 20577) having high scores (≥7) for grain and green fodder yield potential and overall plant aspect were found to be promising for utilization in pearl millet improvement programs. Identification of five pathotypes of M. grisea and sources of resistance to these pathotypes will provide a foundation for breeding for blast resistance in pearl millet in India.


Widespread seasonal compensation effects of spring warming on northern plant productivity.
Climate change is shifting the phenological cycles of plants1, thereby altering the functioning of ecosystems, which in turn induces feedbacks to the climate system2. In northern (north of 30° N) ecosystems, warmer springs lead generally to an earlier onset of the growing season3,4 and increased ecosystem productivity early in the season5. In situ6 and regional7-9 studies also provide evidence for lagged effects of spring warmth on plant productivity during the subsequent summer and autumn. However, our current understanding of these lagged effects, including their direction (beneficial or adverse) and geographic distribution, is still very limited. Here we analyse satellite, field-based and modelled data for the period 1982-2011 and show that there are widespread and contrasting lagged productivity responses to spring warmth across northern ecosystems. On the basis of the observational data, we find that roughly 15 per cent of the total study area of about 41 million square kilometres exhibits adverse lagged effects and that roughly 5 per cent of the total study area exhibits beneficial lagged effects. By contrast, current-generation terrestrial carbon-cycle models predict much lower areal fractions of adverse lagged effects (ranging from 1 to 14 per cent) and much higher areal fractions of beneficial lagged effects (ranging from 9 to 54 per cent). We find that elevation and seasonal precipitation patterns largely dictate the geographic pattern and direction of the lagged effects. Inadequate consideration in current models of the effects of the seasonal build-up of water stress on seasonal vegetation growth may therefore be able to explain the differences that we found between our observation-constrained estimates and the model-constrained estimates of lagged effects associated with spring warming. Overall, our results suggest that for many northern ecosystems the benefits of warmer springs on growing-season ecosystem productivity are effectively compensated for by the accumulation of seasonal water deficits, despite the fact that northern ecosystems are thought to be largely temperature- and radiation-limited10.


A hierarchical approach to protein fold prediction.
Fold recognition, assigning novel proteins to known structures, forms an important component of the overall protein structure discovery process. The available methods for protein fold recognition are limited by the low fold-coverage and/or low prediction accuracies. We describe here a new Support Vector Machine (SVM)-based method for protein fold prediction with high prediction accuracy and high fold-coverage. The new method of fold prediction with high fold-coverage was developed by training and testing on a large number of folds in order to make the method suitable for large scale fold predictions. However, presence of large number of folds in the training set made the classification task difficult as a consequence of increased complexity involved in binary classifications of SVMs. In order to overcome this complexity we adopted a hierarchical approach where fold-prediction is made in two steps. At the first step structural class of the query is predicted and at the second step fold is predicted within the predicted structural class. This decreased the complexity of the classification problem and also improved the overall fold prediction accuracy. To the best of our knowledge this is the first taxonomic fold recognition method to cover over 700 protein-folds and gives prediction accuracy of around 70% on a benchmark dataset. Since the new method gives rise to state of the art prediction performance and hence can be very useful for structural characterization of proteins discovered in various genomes.


Multivariate computational analysis of biosensor's data for improved CD64 quantification for sepsis diagnosis.
Sepsis, as a leading cause of death worldwide, relies on systemic inflammatory response syndrome (SIRS) criteria for its diagnosis. SIRS is highly non-specific as it relies on monitoring of patients' vitals for sepsis diagnosis, which are known to change with many confounding factors. Changes in leukocyte counts and CD64 expression levels are known specific biomarkers of pro-inflammatory host response at the onset of sepsis. Recently, we have developed a biosensor chip that can enumerate the leukocyte counts and quantify the neutrophil CD64 expression levels from a drop of blood. We were able to show improved sepsis diagnosis and prognosis in clinical studies by measuring these parameters during different times of the patients' stay in hospital. In this paper, we investigated the rate of cell capture with CD64 expression levels and used this in a multivariate computational model using artificial neural networks (ANNs) and showed improved accuracy of quantifying CD64 expression levels from the biosensor (n = 106 whole blood experiments). We found a high coefficient of determination and low error between biosensor- and flow cytometry-based neutrophil CD64 expression levels using multiple ANN training methods in comparison to those of univariate regression commonly employed. This approach can find many applications in biosensor data analytics by utilizing multiple features of the biosensor's data for output determination.


Life cycle risks for human health: a comparison of petroleum versus bio-based production of five bulk organic chemicals.
This article describes the development and application of a generic approach to the comparative assessment of risks related to the production of organic chemicals by petrochemical processes versus white biotechnology. White biotechnology, also referred to as industrial biotechnology, typically uses bio-based feedstocks instead of the fossil raw materials used in the petrochemical sector. The purpose of this study was to investigate whether the production of chemicals by means of white biotechnology has lower conventional risks than their production by petrochemical processes. Conventional risks are the risks of well-established processes, and not those related to genetically modified microorganisms and plants. Our approach combines classical risk assessment methods (largely based on toxicology), as developed by the life cycle assessment (LCA) community, with statistics on technological disasters, accidents, and work-related illnesses. Moreover, it covers the total process chain for both petrochemical and bio-based products from cradle to grave. The approach was applied to five products: the plastics polytrimethylene terephthalate (PTT), polyhydroxyalkanoates (PHA), polyethylene terephthalate (PET), polyethylene (PE), and ethanol. Our results show that the conventional risks related to the white biotechnology products studied are lower than those of the petrochemical products. However, considering the uncertainties with respect to the ranges of input data, the (incomplete) coverage of emissions by the environmental priority strategies (EPS) 2000 method, and the uncertainties of the assumptions made in this study (i.e., large to very large), the differences in results between bio-based and petrochemical products fall into the uncertainty range. Because of this, future research is necessary to decrease the uncertainties before we can conclude that the conventional risks of biotechnologically produced chemicals are lower than those of fossil-fuel-derived chemicals.


Seasonal dynamics and age of stemwood nonstructural carbohydrates in temperate forest trees.
Nonstructural carbohydrate reserves support tree metabolism and growth when current photosynthates are insufficient, offering resilience in times of stress. We monitored stemwood nonstructural carbohydrate (starch and sugars) concentrations of the dominant tree species at three sites in the northeastern United States. We estimated the mean age of the starch and sugars in a subset of trees using the radiocarbon ((14) C) bomb spike. With these data, we then tested different carbon (C) allocation schemes in a process-based model of forest C cycling. We found that the nonstructural carbohydrates are both highly dynamic and about a decade old. Seasonal dynamics in starch (two to four times higher in the growing season, lower in the dormant season) mirrored those of sugars. Radiocarbon-based estimates indicated that the mean age of the starch and sugars in red maple (Acer rubrum) was 7-14 yr. A two-pool (fast and slow cycling reserves) model structure gave reasonable estimates of the size and mean residence time of the total NSC pool, and greatly improved model predictions of interannual variability in woody biomass increment, compared with zero- or one-pool structures used in the majority of existing models. This highlights the importance of nonstructural carbohydrates in the context of forest ecosystem carbon cycling.


A phenomenological study of living with a partner affected with dementia.
Caring for people affected by dementia is a collective effort that involves public health, primary care, and informal care. The third mainly comprises the efforts of spouses. This study aimed to describe spouses' experiences of living with a partner affected with dementia. The study has a descriptive phenomenological approach based on a reflective life-world perspective. Seven in-depth interviews were conducted with spouses of persons affected with dementia. The interviews were audiotaped and analysed using the procedures described by Giorgi (2009) . The essence of living with a partner affected by dementia formed a comprehensive theme: from togetherness to loneliness, which along with three descriptive categories-changes in their partner's behaviour, changes in everyday life, and a changed future-describes the phenomenon. The theme 'From togetherness to loneliness' reflects the spouses' descriptions of their life-world. Daily life changed gradually in line with their partners' personality, and their role became that of a care provider rather than a spouse. Information and knowledge about dementia should be provided at an early stage. Health care has a major responsibility to meet their needs, thus ensuring that all parties are satisfied.


Gene therapy for sickle cell disease.
Sickle cell disease encompasses a group of genetic disorders characterized by the presence of at least one hemoglobin S (Hb S) allele, and a second abnormal allele that could allow abnormal hemoglobin polymerisation leading to a symptomatic disorder.Autosomal recessive disorders (such as sickle cell disease) are good candidates for gene therapy because a normal phenotype can be restored in diseased cells with only a single normal copy of the mutant gene. The objectives of this review are:- to determine whether gene therapy can improve survival and prevent symptoms and complications associated with sickle cell disease;- to examine the risks of gene therapy against the potential long-term gain for people with sickle cell disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises of references identified from comprehensive electronic database searches and searching relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 05 March 2010. All randomised or quasi-randomised clinical trials (including any relevant phase 1, 2 or 3 trials) of gene therapy for all individuals with sickle cell disease, regardless of age or setting. No trials of gene therapy for sickle cell disease were found. No trials of gene therapy for sickle cell disease were reported. No randomised or quasi-randomised clinical trials of gene therapy for sickle cell disease were reported. Thus, no objective conclusions or recommendations in practice can be made on gene therapy for sickle cell disease. This systematic review has identified the need for well-designed, randomised controlled trials to assess the benefits and risks of gene therapy for sickle cell disease.


[Preputial development in Japanese boys].
The natural course of preputial development is still not clearly understood. The preputial retractability was evaluated in 242 Japanese boys. The incidence of having a retractable prepuce gradually increased with age from 0% at age 1 year to 77% by the age of 11 to 15 years. In 48 boys, preputial development was followed up for 2 to 10 years with the self-retract maneuver. Non-retractable prepuce was found in 9 boys, which then became retractable within 2-7 years. The prepuce became retractable in most of the boys with balanoposthitis. In conclusion, forced retraction or circumcision is unnecessary for phimosis in boys with or without balanoposthitis.


A Randomized Encouragement Trial to Increase Mail Order Pharmacy Use and Medication Adherence in Patients with Diabetes.
Mail order pharmacy (MOP) use has been linked to improved medication adherence and health outcomes among patients with diabetes. However, no large-scale intervention studies have assessed the effect of encouraging MOP use on medication adherence. To assess an intervention to encourage MOP services to increase its use and medication adherence. Randomized encouragement trial. 63,012 diabetes patients from three health care systems: Kaiser Permanente Northern California (KPNC), Kaiser Permanente Hawaii (KPHI), and Harvard Pilgrim Health Care (HPHC) who were poorly adherent to at least one class of cardiometabolic medications and had not used MOP in the prior 12 months. Patients were randomized to receive either usual care (control arm) or outreach encouraging MOP use consisting of a mailed letter, secure email message, and automated telephone call outlining the potential benefits of MOP use (intervention arm). HPHC intervention patients received the letter only. We compared the percentages of patients that began using MOP and that became adherent to cardiometabolic medication classes during a 12-month follow-up period. We also conducted a race/ethnicity-stratified analysis. During follow-up, 10.6% of intervention patients began using MOP vs. 9.3% of controls (p < 0.01); the percent of cardiometabolic medication delivered via mail was 42.1% vs. 39.8% (p < 0.01). Metformin adherence improved in the intervention arm relative to control at the two KP sites (52% vs. 49%, p < 0.01). Stratified analyses suggested a significant positive effect of the intervention in White (RR: 1.12, 95% CI: 1.03, 1.22) and Asian (RR: 1.30, 95% CI: 1.17, 1.45) patients. This pragmatic trial showed that simple outreach to encourage MOP modestly increased its use and improved adherence measured by refills to a key class of diabetes medications in some settings. Given its minimal cost, clinicians and health systems should consider outreach interventions to actively promote MOP use among diabetes patients. ClinicalTrials.gov registration number: NCT02621476.


GABA tea attenuates cardiac apoptosis in spontaneously hypertensive rats (SHR) by enhancing PI3K/Akt-mediated survival pathway and suppressing Bax/Bak dependent apoptotic pathway.
Cardiomyocyte apoptosis is the major risk factor for the development of heart failure (HF). The purpose of this study was to evaluate the effects of Gamma-aminobutyric acid (GABA) tea on hypertension-induced cardiac apoptotic pathways in spontaneously hypertensive rats (SHR). In order to reveal the mechanisms, 36 male SHR at eight weeks of age, 200 g were divided into six groups. One group was fed water as a control group. Other rats were administered one of the following treatments: GABA tea at dose 150 and 300 mg/kg/day as low GABA tea (LGT) and high GABA tea (HGT) groups, respectively, pure GABA at dose 150 and 300 mg/kg/day as LG and HG groups, respectively, green tea (GT) as control of LGT and HGT groups. After 12 weeks, cardiac tissues were analyzed by histological analysis, western blotting, and TUNEL assays. GABA tea, GT, and pure GABA decreased hypertension-induced cardiac abnormalities, including abnormal myocardial architecture. In addition, GABA tea, GT, and pure GABA dramatically increased anti-apoptotic protein, Bcl2. Furthermore, GABA tea, GT, and pure GABA also decreased activated-caspase 9 and activated-caspase 3. Additionally, the survival associated protein IGF-I and PI3K/Akt were enhanced in cardiac tissues upon treatment. Our results showed an optimistic anti-apoptotic and pro-survival effects of GABA tea treatment against hypertensive rat hearts.


Episodic encephalopathy due to an occult spinal vascular malformation complicated by superficial siderosis.
Superficial siderosis (SS) of the central nervous system is a rare condition caused by chronic subarachnoid hemorrhage. Clinical manifestations typically include sensorineural hearing loss and cerebellar ataxia. Recurrent episodic encephalopathy in the setting of SS has not been reported. We describe a unique case of SS in a 67-year-old man with an 8-year history of episodic encephalopathy associated with headache and vomiting. The patient also had a history of progressive dementia, ataxia, and myelopathy. A diagnosis of superficial siderosis was made after magnetic resonance gradient-echo images showed diffuse hemosiderin staining over the cerebellum and cerebral convexities. No intracerebral source of hemorrhage was identified. The patient therefore underwent gadolinium-enhanced spinal MRI which suggested a possible vascular malformation. A therapeutic laminectomy subsequently confirmed an arteriovenous fistula which was resected. In SS, there are often long delays between symptom onset and definitive diagnosis. Early identification is facilitated by magnetic resonance imaging with gradient-echo sequences. When no source of hemorrhage is identified intracranially, then total spinal cord imaging is indicated to assess for an occult source of hemorrhage as occurred in our case.


Cerebral autoregulatory performance and the cerebrovascular response to head-of-bed positioning in acute ischaemic stroke.
Cerebrovascular responses to head-of-bed positioning in patients with acute ischaemic stroke are heterogeneous, questioning the applicability of general recommendations on head positioning. Cerebral autoregulation is impaired to various extents after acute stroke, although it is unknown whether this affects cerebral perfusion during posture change. We aimed to elucidate whether the cerebrovascular response to head position manipulation depends on autoregulatory performance in patients with ischaemic stroke. The responses of bilateral transcranial Doppler ultrasound-determined cerebral blood flow velocity (CBFV) and local cerebral blood volume (CBV), assessed by near-infrared spectroscopy of total hemoglobin tissue concentration ([total Hb]), to head-of-bed lowering from 30° to 0° were determined in 39 patients with acute ischaemic stroke and 17 reference subjects from two centers. Cerebrovascular autoregulatory performance was expressed as the phase difference of the arterial pressure-to-CBFV transfer function. Following head-of-bed lowering, CBV increased in the reference subjects only ([total Hb]: + 2.1 ± 2.0 vs. + 0.4 ± 2.6 μM; P < 0.05), whereas CBFV did not change in either group. CBV increased upon head-of-bed lowering in the hemispheres of patients with autoregulatory performance <50th percentile compared with a decrease in the hemispheres of patients with better autoregulatory performance ([total Hb]: +1.0 ± 1.3 vs. -0.5 ± 1.0 μM; P < 0.05). The CBV response was inversely related to autoregulatory performance (r = -0.68; P < 0.001) in the patients, whereas no such relation was observed for CBFV. This study is the first to provide evidence that cerebral autoregulatory performance in patients with acute ischaemic stroke affects the cerebrovascular response to changes in the position of the head.


Trace determination of airborne polyfluorinated iodine alkanes using multisorbent thermal desorption/gas chromatography/high resolution mass spectrometry.
A novel gas chromatography/high resolution mass spectrometry method coupled with multisorbent thermal desorption cartridges has been developed for the determination of volatile neutral polyfluorinated iodine alkanes (PFIs) in airborne samples. It allows, for the first time, simultaneous analysis of four mono-iodized perfluorinated alkanes, three diiodized perfluorinated alkanes and four mono-iodized polyfluorinated telomers in ambient air samples. 3.75 L air sample was passed through a sorbent tube packed with 150 mg of Tenax TA and 200mg of Carbograph 1 TD for analyte adsorption. Important factors during the analysis procedures, such as safe sampling volume, air sampling rate, analyte desorption and transfer strategies, were optimized and good thermal desorption efficiencies were obtained. The method detection limit (MDL) concentration ranged from 0.04 pg/L for 1H,1H,2H,2H-perfluorododecyl iodide to 1.2 pg/L for perfluorohexyl iodide, and instrument response of a seven-point calibration was linear in the range of 10-1000 pg. Travel spike recoveries ranged from 83% to 116%. Small variabilities of less than 36% were obtained near the MDLs and the differences between triplicates were even smaller (2.1-7.3%) at 200 pg spiked level. The method was successfully applied to analyze ambient air samples collected near a point source, and five PFIs were identified (10.8-85.0 pg/L), with none of the analytes detectable at the background site.


Evidence for a role of the genomic region of the gene encoding for the alpha1 chain of type IX collagen (COL9A1) in hip osteoarthritis: A population-based study.
Type IX collagen proteoglycan is an important protein in collagen networks and has been implicated in hip osteoarthritis (OA). We studied 2 COL9A1 markers (509-8B2 and 509-12B1) in relation to radiographic OA, within the framework of the Rotterdam Study, a population-based study of 7,983 subjects ages 55 years and older. We used 2 different designs, as follows: 1) a linkage study of 83 probands with multiple joints affected with radiographic OA and their 221 siblings, yielding 445 sibpairs who participated in the study, and 2) an association study in a series of 71 patients with radiographic hip OA and 269 controls without radiographic OA. All subjects were characterized for the 2 COL9A1 markers, 509-8B2 and 509-12B1. The mean test was used to assess the proportion of alleles shared in concordantly affected and unaffected sibpairs. The chi-square test was used to compare the allele distributions in patients and controls. Affected sibpairs with radiographic hip OA shared alleles identical by descent at markers 8B2 and 12B1 significantly more often than expected (mean +/- SD 0.66 +/- 0.07 and 0.65 +/- 0.08, respectively; P < 0.05). No excess sharing for radiographic OA was observed at other joint sites. When comparing the frequency of marker 8B2 and 12B1 alleles in subjects with radiographic OA and controls, the frequency of 8B2 alleles in subjects with radiographic OA differed significantly(P = 0.01) from that in controls. Our data suggest that susceptibility for hip OA is conferred within or close to the COL9A1 gene in linkage disequilibrium with the COL9A1 509-8B2 marker.


Bi-Force: large-scale bicluster editing and its application to gene expression data biclustering.
The explosion of the biological data has dramatically reformed today's biological research. The need to integrate and analyze high-dimensional biological data on a large scale is driving the development of novel bioinformatics approaches. Biclustering, also known as 'simultaneous clustering' or 'co-clustering', has been successfully utilized to discover local patterns in gene expression data and similar biomedical data types. Here, we contribute a new heuristic: 'Bi-Force'. It is based on the weighted bicluster editing model, to perform biclustering on arbitrary sets of biological entities, given any kind of pairwise similarities. We first evaluated the power of Bi-Force to solve dedicated bicluster editing problems by comparing Bi-Force with two existing algorithms in the BiCluE software package. We then followed a biclustering evaluation protocol in a recent review paper from Eren et al. (2013) (A comparative analysis of biclustering algorithms for gene expressiondata. Brief. Bioinform., 14:279-292.) and compared Bi-Force against eight existing tools: FABIA, QUBIC, Cheng and Church, Plaid, BiMax, Spectral, xMOTIFs and ISA. To this end, a suite of synthetic datasets as well as nine large gene expression datasets from Gene Expression Omnibus were analyzed. All resulting biclusters were subsequently investigated by Gene Ontology enrichment analysis to evaluate their biological relevance. The distinct theoretical foundation of Bi-Force (bicluster editing) is more powerful than strict biclustering. We thus outperformed existing tools with Bi-Force at least when following the evaluation protocols from Eren et al. Bi-Force is implemented in Java and integrated into the open source software package of BiCluE. The software as well as all used datasets are publicly available at http://biclue.mpi-inf.mpg.de.


Predictors and risks for death in a population-based study of persons with IBD in Manitoba.
We aimed to determine the predictors and risk for death among persons with either Crohn's disease (CD) or UC compared with the general population. We used the population-based University of Manitoba IBD Epidemiology Database to calculate HRs and their 95% CIs for cases relative to controls using stratified multivariable Cox proportional hazards regression models, controlling for socioeconomic status and comorbidities. There were 10 788 prevalent cases of CD and UC and 101 860 matched controls. The HR for all-cause mortality in prevalent CD cases was 1.26 (95% CI 1.16 to 1.38) and in prevalent UC cases was 1.04 (95% CI 0.96 to 1.12). Compared with matched controls, CD cases were more likely to die of colorectal cancer, non-Hodgkin's lymphoma, digestive diseases, pulmonary embolism and sepsis and UC cases were more likely to die from colorectal cancer, digestive diseases and respiratory diseases. For incident cases, there were significant effects on mortality by socioeconomic status, comorbidity score and surgery. The greatest risk for death in both CD and UC was within the first 30 days following GI surgery. The first year from diagnosis was associated with increased risk of death in both CD and UC, but persisted after the 1st year only in CD. There is a significantly increased risk of mortality in CD compared with controls while in UC an increased risk for death was only evident in the first year from diagnosis. Surgery poses an increased risk for death in both CD and UC lasting up to 1 year.


Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival.
Based on the hypothesis that features of the molecular program of normal wound healing might play an important role in cancer metastasis, we previously identified consistent features in the transcriptional response of normal fibroblasts to serum, and used this "wound-response signature" to reveal links between wound healing and cancer progression in a variety of common epithelial tumors. Here, in a consecutive series of 295 early breast cancer patients, we show that both overall survival and distant metastasis-free survival are markedly diminished in patients whose tumors expressed this wound-response signature compared to tumors that did not express this signature. A gene expression centroid of the wound-response signature provides a basis for prospectively assigning a prognostic score that can be scaled to suit different clinical purposes. The wound-response signature improves risk stratification independently of known clinico-pathologic risk factors and previously established prognostic signatures based on unsupervised hierarchical clustering ("molecular subtypes") or supervised predictors of metastasis ("70-gene prognosis signature").


Proximal tubule epithelial cell specific ablation of the spermidine/spermine N1-acetyltransferase gene reduces the severity of renal ischemia/reperfusion injury.
Expression and activity of spermidine/spermine N1-acetyltransferase (SSAT) increases in kidneys subjected to ischemia/reperfusion (I/R) injury, while its ablation reduces the severity of such injuries. These results suggest that increased SSAT levels contribute to organ injury; however, the role of SSAT specifically expressed in proximal tubule epithelial cells, which are the primary targets of I/R injury, in the mediation of renal damage remains unresolved. Severity of I/R injury in wt and renal proximal tubule specific SSAT-ko mice (PT-SSAT-Cko) subjected to bilateral renal I/R injury was assessed using cellular and molecular biological approaches. Severity of the loss of kidney function and tubular damage are reduced in PT-SSAT-Cko- compared to wt-mice after I/R injury. In addition, animals treated with MDL72527, an inhibitor of polyamine oxidases, had less severe renal damage than their vehicle treated counter-parts. The renal expression of HMGB 1 and Toll like receptors (TLR) 2 and 4 were also reduced in PT-SSAT-Cko- compared to wt mice after I/R injury. Furthermore, infiltration of neutrophils, as well as expression of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) transcripts were lower in the kidneys of PT-SSAT-Cko compared to wt mice after I/R injury. Finally, the activation of caspase3 was more pronounced in the wt compared to PT-SSAT-Cko animals. Enhanced SSAT expression by proximal tubule epithelial cells leads to tubular damage, and its deficiency reduces the severity of renal I/R injury through reduction of cellular damage and modulation of the innate immune response.


Spirometric diagnosis of upper airway obstruction.
We evaluated the results of routine spirometry in patients with well-documented upper airway obstruction (UAO) to determine if this readily available form of pulmonary function testing could reliably identify patients with this abnormality. Our results indicate that, although individual standard spirometric indexes could not identify these patients, ratios derived from these indexes provided excellent discrimination between patients with UAO and patients with a variety of lung diseases. A ratio of maximal voluntary ventilation to forced expiratory volume in 1 s of less than 25 was present in ten (66%) of 15 patients with UAO and only one (1%) of 100 comparison patients. A ratio of forced inspiratory flow between 25% and 75% of the vital capacity to forced expiratory flow between 25% and 75% of the vital capacity of less than 1 was found in 12 (80%) of 15 patients with UAO, but in only four (4%) of 100 comparison patients. All patients with UAO had one ratio abnormal. We conclude that spirometry remains a valuable procedure in the diagnosis of UAO.


Ghrelin directly stimulates glucagon secretion from pancreatic alpha-cells.
Previous work has demonstrated that the peptide hormone ghrelin raises blood glucose. Such has been attributed to ghrelin's ability to enhance GH secretion, restrict insulin release, and/or reduce insulin sensitivity. Ghrelin's reported effects on glucagon have been inconsistent. Here, both animal- and cell-based systems were used to determine the role of glucagon in mediating ghrelin's effects on blood glucose. The tissue and cell distribution of ghrelin receptors (GHSR) was evaluated by quantitative PCR and histochemistry. Plasma glucagon levels were determined following acute acyl-ghrelin injections and in pharmacological and/or transgenic mouse models of ghrelin overexpression and GHSR deletion. Isolated mouse islets and the α-cell lines αTC1 and InR1G9 were used to evaluate ghrelin's effects on glucagon secretion and the role of calcium and ERK in this activity. GHSR mRNA was abundantly expressed in mouse islets and colocalized with glucagon in α-cells. Elevation of acyl-ghrelin acutely (after sc administration, such that physiologically relevant plasma ghrelin levels were achieved) and chronically (by slow-releasing osmotic pumps and as observed in transgenic mice harboring ghrelinomas) led to higher plasma glucagon and increased blood glucose. Conversely, genetic GHSR deletion was associated with lower plasma glucagon and reduced fasting blood glucose. Acyl-ghrelin increased glucagon secretion in a dose-dependent manner from mouse islets and α-cell lines, in a manner requiring elevation of intracellular calcium and phosphorylation of ERK. Our study shows that ghrelin's regulation of blood glucose involves direct stimulation of glucagon secretion from α-cells and introduces the ghrelin-glucagon axis as an important mechanism controlling glycemia under fasting conditions.


Glutamatergic plasticity by synaptic delivery of GluR-B(long)-containing AMPA receptors.
Activity-driven delivery of AMPA receptors is proposed to mediate glutamatergic synaptic plasticity, both during development and learning. In hippocampal CA1 principal neurons, such trafficking is primarily mediated by the abundant GluR-A subunit. We now report a study of GluR-B(long), a C-terminal splice variant of the GluR-B subunit. GluR-B(long) synaptic delivery is regulated by two forms of activity. Spontaneous synaptic activity-driven GluR-B(long) transport maintains one-third of the steady-state AMPA receptor-mediated responses, while GluR-B(long) delivery following the induction of LTP is responsible for approximately 50% of the resulting potentiation at the hippocampal CA3 to CA1 synapses at the time of GluR-B(long) peak expression-the second postnatal week. Trafficking of GluR-B(long)-containing receptors thus mediates a GluR-A-independent form of glutamatergic synaptic plasticity in the juvenile hippocampus.


Physiotherapy Commenced Within the First Four Weeks Post-Spinal Surgery Is Safe and Effective: A Systematic Review and Meta-Analysis.
To determine whether physiotherapy commenced within the first 4 weeks post-spinal surgery is safe and effective. Electronic databases CINAHL, MEDLINE, AMED, PubMed, Embase, and PEDro were searched from the earliest date possible through May 2015. An additional trial was identified through reference list scanning. Controlled trials evaluating comprehensive physiotherapy rehabilitation commenced within 4 weeks postoperatively compared with a control group receiving no physiotherapy, standard postoperative care, rest, less active physiotherapy, or sham physiotherapy after spinal surgery of a musculoskeletal etiology. Two reviewers independently applied inclusion and exclusion criteria, with disagreements discussed until consensus could be reached. Searching identified 3162 potentially relevant articles, of which 4 trials with 250 participants met the inclusion criteria. Data were extracted using a predefined data extraction form. Methodological quality of trials was assessed independently by 2 reviewers using the Downs and Black checklist. Pooled analyses were performed using a random-effects model with inverse variance methods to calculate risk differences and 95% confidence intervals (CIs) (dichotomous outcomes), and standardized mean differences (SMDs) and 95% CIs (continuous outcomes). When compared with no or sham physiotherapy, early comprehensive physiotherapy did not increase the risk of adverse events (risk difference, -.01; 95% CI, -.07 to .05; I(2)=0%). In addition, there is moderate-quality evidence demonstrating a reduction in pain by a moderate and significant amount at 12 weeks (SMD=-.38; 95% CI, -.66 to -.10; I(2)=0%) and at 12+ months (SMD=-.30; 95% CI, -.59 to -.02; I(2)=0%). Early comprehensive physiotherapy commenced within the first 4 weeks post-spinal surgery does not increase the potential for an adverse event and leads to a moderate, statistically significant reduction in pain when compared with a control group.


Exposure to pesticides or solvents and risk of Parkinson disease.
To investigate the risk of Parkinson disease (PD) associated with exposure to pesticides and solvents using meta-analyses of data from cohort and case-control studies. Prospective cohort and case-control studies providing risk and precision estimates relating PD to exposure to pesticides or solvents or to proxies of exposure were considered eligible. The heterogeneity in risk estimates associated with objective study quality was also investigated. A total of 104 studies/3,087 citations fulfilled inclusion criteria for meta-analysis. In prospective studies, study quality was not a source of heterogeneity. PD was associated with farming and the association with pesticides was highly significant in the studies in which PD diagnosis was self-reported. In case-control studies, study quality appeared to be a source of heterogeneity in risk estimates for some exposures. Higher study quality was frequently associated with a reduction in heterogeneity. In high-quality case-control studies, PD risk was increased by exposure to any-type pesticides, herbicides, and solvents. Exposure to paraquat or maneb/mancozeb was associated with about a 2-fold increase in risk. In high-quality case-control studies including an appreciable number of cases (>200), heterogeneity remained significantly high (>40%) only for insecticides, organochlorines, organophosphates, and farming; also, the risk associated with rural living was found to be significant. The literature supports the hypothesis that exposure to pesticides or solvents is a risk factor for PD. Further prospective and high-quality case-control studies are required to substantiate a cause-effect relationship. The studies should also focus on specific chemical agents.


Efficacy and Safety of Vamorolone in Duchenne Muscular Dystrophy: A 30-Month Nonrandomized Controlled Open-Label Extension Trial.
Vamorolone is a synthetic steroidal drug with potent anti-inflammatory properties. Initial open-label, multiple ascending dose-finding studies of vamorolone among boys with Duchenne muscular dystrophy (DMD) found significant motor function improvement after 6 months treatment in higher-dose (ie, ≥2.0 mg/kg/d) groups. To investigate outcomes after 30 months of open-label vamorolone treatment. This nonrandomized controlled trial was conducted by the Cooperative International Neuromuscular Research Group at 11 US and non-US study sites. Participants were 46 boys ages 4.5 to 7.5 years with DMD who completed the 6-month dose-finding study. Data were analyzed from July 2020 through November 2021. Participants were enrolled in a 24-month, long-term extension (LTE) study with vamorolone dose escalated to 2.0 or 6.0 mg/kg/d. Change in time-to-stand (TTSTAND) velocity from dose-finding baseline to end of LTE study was the primary outcome. Efficacy assessments included timed function tests, 6-minute walk test, and NorthStar Ambulatory Assessment (NSAA). Participants with DMD treated with glucocorticoids from the Duchenne Natural History Study (DNHS) and NorthStar United Kingdom (NSUK) Network were matched and compared with participants in the LTE study receiving higher doses of vamorolone. Among 46 boys with DMD who completed the dose-finding study, 41 boys (mean [SD] age, 5.33 [0.96] years) completed the LTE study. Among 21 participants treated with higher-dose (ie, ≥2.0 mg/kg/d) vamorolone consistently throughout the 6-month dose-finding and 24-month LTE studies with data available at 30 months, there was a decrease in mean (SD) TTSTAND velocity from baseline to 30 months (0.206 [0.070] rises/s vs 0.189 (0.124) rises/s), which was not a statistically significant change (-0.011 rises/s; CI, -0.068 to 0.046 rises/s). There were no statistically significant differences between participants receiving higher-dose vamorolone and matched participants in the historical control groups receiving glucocorticoid treatment (75 patients in DNHS and 110 patients in NSUK) over a 2-year period in NSAA total score change (0.22 units vs NSUK; 95% CI, -4.48 to 4.04]; P = .92), body mass index z score change (0.002 vs DNHS SD/mo; 95% CI, -0.006 to 0.010; P = .58), or timed function test change. Vamorolone at doses up to 6.0 mg/kg/d was well tolerated, with 5 of 46 participants discontinuing prematurely and for reasons not associated with study drug. Participants in the DNHS treated with glucocorticoids had significant growth delay in comparison with participants treated with vamorolone who had stable height percentiles (0.37 percentile/mo; 95% CI, 0.23 to 0.52 percentile/mo) over time. This study found that vamorolone treatment was not associated with a change in TTSTAND velocity from baseline to 30 months among boys with DMD aged 4 to 7 years at enrollment. Vamorolone was associated with maintenance of muscle strength and function up to 30 months, similar to standard of care glucocorticoid therapy, and improved height velocity compared with growth deceleration associated with glucocorticoid treatment, suggesting that vamorolone may be an attractive candidate for treatment of DMD. ClinicalTrials.gov Identifier: NCT03038399.


Perceptions and Practices Regarding Sleep in the Intensive Care Unit. A Survey of 1,223 Critical Care Providers.
Poor sleep affects a majority of critically ill patients and is believed to be associated with adverse intensive care unit (ICU) outcomes such as delirium. While recent guidelines recommend sleep promotion efforts to improve delirium and other ICU outcomes, little is known about critical care providers' beliefs regarding sleep in the ICU. To evaluate providers' perceptions and practices regarding sleep in the ICU. From April to July 2014, the Sleep in the ICU Survey was disseminated to ICU providers via institutional e-mail lists and four international critical care society distribution lists. A total of 1,223 surveys were completed by providers from 24 countries. Respondents were primarily nurses (59%) or physicians (39%). Most respondents indicated that ICU patients experienced "poor" or "very poor" sleep (75%) and that poor sleep could affect the ICU recovery process (88%). Respondents also felt that poor sleep was associated with negative ICU outcomes such as the development of delirium (97%), longer length of stay (88%), poor participation in physical therapy (87%), and delayed liberation from mechanical ventilation (83%). The minority (32%) of providers had sleep-promoting protocols; these providers tended to believe their patients slept longer and experienced better sleep quality. Though most clinicians believe that sleep in the ICU is poor and adversely affects patient outcomes, a minority of the ICUs represented by our respondents have sleep promotion protocols. These findings highlight discordant provider perceptions and practices surrounding sleep in the ICU, as well as a possible lack of available evidence-based guidelines for promoting sleep in the ICU.


Electronic feedback in a diet- and physical activity-based lifestyle intervention for weight loss: a randomized controlled trial.
The SenseWear™ Armband (SWA) (BodyMedia, Inc. Pittsburgh, PA) is a physical activity and lifestyle monitor that objectively and accurately measures free-living energy balance and sleep and includes software for self-monitoring of daily energy expenditure and energy intake. The real-time feedback of the SWA can improve individual self-monitoring and, therefore, enhance weight loss outcomes. We recruited 197 sedentary overweight or obese adults (age, 46.8 ± 10.8 y; body mass index (BMI), 33.3 ± 5.2 kg/m(2); 81% women, 32% African-American) from the greater Columbia, South Carolina area. Participants were randomized into 1 of 4 groups, a self-directed weight loss program via an evidence-based weight loss manual (Standard Care, n = 50), a group-based behavioral weight loss program (GWL, n = 49), the armband alone (SWA-alone, n = 49), or the GWL plus the armband (GWL+SWA, n = 49), during the 9-month intervention. The primary outcome was change in body weight and waist circumference. A mixed-model repeated-measures analysis compared change in the intervention groups to the standard care group on weight and waist circumference status after adjusting for age, sex, race, education, energy expenditure, and recruitment wave. Body weight was available for 62% of participants at 9 months (52% standard care, 70% intervention). There was significant weight loss in all 3 intervention groups (GWL, 1.86 kg, P = 0.05; SWA-alone, 3.55 kg, P = 0.0002; GWL+SWA, 6.59 kg, P < 0.0001) but not in the Standard Care group (0.89 kg, P = 0.39) at month 9. Only the GWL+SWA group achieved significant weight loss at month 9 compared to the Standard Care group (P = 0.04). Significant waist circumference reductions were achieved in all 4 groups at month 9 (Standard Care, 3.49 cm, P = 0.0004; GWL, 2.42 cm, P = 0.008; SWA-alone, 3.59 cm, P < 0.0001; GWL+SWA, 6.77 cm, P < 0.0001), but no intervention group had significantly reduced waist circumference compared to the Standard Care group. Continuous self-monitoring from wearable technology with real-time feedback may be particularly useful to enhance lifestyle changes that promote weight loss in sedentary overweight or obese adults. This strategy, combined with a group-based behavioral intervention, may yield optimal weight loss.


Acute occupational disinfectant-related illness among youth, 1993-1998.
Working youths face many safety and health risks. Among these risks are those posed by disinfectant exposures. In this study we describe acute occupational disinfectant-related illness among youth. Data on U.S. children younger than 18 years with acute occupational disinfectant-related illnesses between 1993 and 1998 were collected from the Toxic Exposure Surveillance System and from the California Department of Pesticide Regulation. We analyzed data from persons with exposures who met the case definition for acute occupational disinfectant-related illness. The case definition required onset of new adverse health effects that were both temporally related to a disinfectant exposure and consistent with the known toxicology of the disinfectant. We calculated incidence rates of acute occupational disinfectant-related illness among youths 15-17 years old and incidence rate ratios to compare these rates with those of adults 25-44 years old. We found 307 children with disinfectant-related illnesses. The average annual incidence rate was 16.8/billion hours worked with a relative risk compared with adults of 4.14 (95% confidence interval, 3.66-4.68). Most illnesses were of mild severity (78%). There were no fatalities. Hypochlorites (e.g., bleach) were responsible for 45% of the illnesses. Among the 206 cases where the responsible disinfectant's U.S. Environmental Protection Agency toxicity category was known, 80% were in category I (highest toxicity level). These findings suggest the need for greater efforts to prevent adolescent acute occupational disinfectant-related illness. This may require strengthening regulations and enforcement as well as increased educational efforts directed at employers, youths, parents, school officials, and physicians. Better mechanisms for reporting and tracking chemical illnesses among working adolescents are also needed.


Invasive species threat: parasite phylogenetics reveals patterns and processes of host-switching between non-native and native captive freshwater turtles.
One of the major threats to biodiversity involves biological invasions with direct consequences on the stability of ecosystems. In this context, the role of parasites is not negligible as it may enhance the success of invaders. The red-eared slider, Trachemys scripta elegans, has been globally considered among the worst invasive species. Since its introduction through the pet trade, T. s. elegans is now widespread and represents a threat for indigenous species. Because T. s. elegans coexists with Emys orbicularis and Mauremys leprosa in Europe, it has been suggested it may compete with the native turtle species and transmit pathogens. We examined parasite transfer from American captive to the two native species that co-exist in artificial pools of a Turtle Farm in France. As model parasite species we used platyhelminth worms of the family Polystomatidae (Monogenea) because polystomes have been described from American turtles in their native range. Phylogenetic relationships among polystomes parasitizing chelonian host species that are geographically widespread show patterns of diversification more complex than expected. Using DNA barcoding to identify species from adult and/or polystome eggs, several cases of host switching from exotic to indigenous individuals were illustrated, corroborating that parasite transmission is important when considering the pet trade and in reintroduction programmes to reinforce wild populations of indigenous species.


Trends in incidence, treatment and survival of aggressive B-cell lymphoma in the Netherlands 1989-2010.
Only a small number of patients with aggressive B-cell lymphoma take part in clinical trials, and elderly patients in particular are under-represented. Therefore, we studied data of the population-based nationwide Netherlands Cancer Registry to determine trends in incidence, treatment and survival in an unselected patient population. We included all patients aged 15 years and older with newly diagnosed diffuse large B-cell lymphoma or Burkitt lymphoma in the period 1989-2010 and mantle cell lymphoma in the period 2001-2010, with follow up until February 2013. We examined incidence, first-line treatment and survival. We calculated annual percentage of change in incidence and carried out relative survival analyses. Incidence remained stable for diffuse large B-cell lymphoma (n=23,527), while for mantle cell lymphoma (n=1,634) and Burkitt lymphoma (n=724) incidence increased for men and remained stable for women. No increase in survival for patients with aggressive B-cell lymphoma was observed during the period 1989-1993 and the period 1994-1998 [5-year relative survival 42% (95%CI: 39%-45%) and 41% (38%-44%), respectively], but increased to 46% (43%-48%) in the period 1999-2004 and to 58% (56%-61%) in the period 2005-2010. The increase in survival was most prominent in patients under 65 years of age, while there was a smaller increase in patients over 75 years of age. However, when untreated patients were excluded, patients over 75 years of age had a similar increase in survival to younger patients. In the Netherlands, survival for patients with aggressive B-cell lymphoma increased over time, particularly in younger patients, but also in elderly patients when treatment had been initiated. The improvement in survival coincided with the introduction of rituximab therapy and stem cell transplantation into clinical practice.


Fibronectin-Grafted Titanium Dental Implants: An In Vivo Study.
Modification of the physiochemical properties of titanium surfaces using glow discharge plasma (GDP) and fibronectin coating has been shown to enhance the surface hydrophilicity, surface roughness, cell adhesion, migration, and proliferation. This in vivo study aimed to evaluate the bone integration efficacy of a biologically modified implant surface. Two different surface-modified implants (Ar-GDP and GDP-fib) were placed in the mandibular premolar area of six beagle dogs for 2-8 weeks. Three techniques [histologic evaluation, resonance frequency analysis (RFA), and microcomputed tomography (micro-CT) evaluation] were used to detect the implant stability and bone-implant contact. The implant stability quotient values of GDP-fib implants were significantly greater than the Ar-GDP implants at 2 and 4 weeks (P < 0.01). The bone volume/total volume ratio of GDP-fib implants was greater than the Ar-GDP implants in micro-CT evaluation. A high positive correlation was observed between RFA and micro-CT measurements. At 2 weeks, osteoblasts were seen to line the implant surface, and multinuclear osteoclasts could be seen on the surface of old parent bone. After 8 weeks, a majority of the space in the wound chamber appeared to be replaced by bone. Enhancement of the stability of biologically modified implants was proved by the results of RFA, micro-CT, and histological analysis. This enhanced stability may help fasten treatment and be clinically beneficial.


Conducting sexualities research: an outline of emergent issues and case studies from ten Wellcome-funded projects.
This letter seeks to synthesise methodological challenges encountered in a cohort of Wellcome Trust-funded research projects focusing on sexualities and health. The ten Wellcome Trust projects span a diversity of gender and sexual orientations and identities, settings; institutional and non-institutional contexts, lifecourse stages, and explore a range of health-related interventions. As researchers, we originate from a breadth of disciplinary traditions, use a variety of research methods and data sources. Despite this breadth, four common themes are found across the projects: (i) inclusivity, representations and representativeness, (ii) lumping together of diverse groups, (iii) institutions and closed settings (iv) ethical and governance barriers.


Tracing the Distribution of European Lactase Persistence Genotypes Along the Americas.
In adulthood, the ability to digest lactose, the main sugar present in milk of mammals, is a phenotype (lactase persistence) observed in historically herder populations, mainly Northern Europeans, Eastern Africans, and Middle Eastern nomads. As the -13910∗T allele in the MCM6 gene is the most well-characterized allele responsible for the lactase persistence phenotype, the -13910C > T (rs4988235) polymorphism is commonly evaluated in lactase persistence studies. Lactase non-persistent adults may develop symptoms of lactose intolerance when consuming dairy products. In the Americas, there is no evidence of the consumption of these products until the arrival of Europeans. However, several American countries' dietary guidelines recommend consuming dairy for adequate human nutrition and health promotion. Considering the extensive use of dairy and the complex ancestry of Pan-American admixed populations, we studied the distribution of -13910C > T lactase persistence genotypes and its flanking haplotypes of European origin in 7,428 individuals from several Pan-American admixed populations. We found that the -13910∗T allele frequency in Pan-American admixed populations is directly correlated with allele frequency of the European sources. Moreover, we did not observe any overrepresentation of European haplotypes in the -13910C > T flanking region, suggesting no selective pressure after admixture in the Americas. Finally, considering the dominant effect of the -13910∗T allele, our results indicate that Pan-American admixed populations are likely to have higher frequency of lactose intolerance, suggesting that general dietary guidelines deserve further evaluation across the continent.


Extra-pulmonary and smear-negative forms of tuberculosis are associated with treatment delay and hospitalisation.
Adult patients with tuberculosis (TB) recruited at the chest clinic of the University Teaching Hospital in Lusaka, Zambia, from 2003 to 2004. To identify factors associated with delayed treatment or hospitalisation. A cross-sectional survey of newly identified adult patients with TB. A total of 223 patients were included in the analysis. Patients with smear-negative disease were 2.6 times more likely to be hospitalised than those with smear-positive disease (95%CI 1.28-5.30), while patients with extra-pulmonary disease were 3.42 times more likely to be hospitalised than those with pulmonary disease (95%CI 1.75-6.66). Patients with smear-negative disease were 2.81 times more likely to have experienced overall delay than those with smear-positive disease (95%CI 1.20-6.66). This analysis has demonstrated that patients with extra-pulmonary or smear-negative disease are significantly more likely to be hospitalised. Patients with smear-negative disease are also more likely to have experienced treatment delay. These data reinforce the urgent need for more robust diagnostic tests, particularly for smear-negative and extra-pulmonary disease. As these forms of disease are more likely to be associated with the human immunodeficiency virus (HIV), the data support earlier diagnosis and treatment of HIV infection.


ATF2 partly mediated the expressions of proliferative factors and inhibited pro-inflammatory factors' secretion in arsenite-treated human uroepithelial cells.
Inorganic arsenic (iAs) could induce the expression of activating transcription factor-2 (ATF2) in the human urinary bladder epithelial cell line (SV-HUC-1 cells). ATF2, as a member of the bZIP transcription factor family, has been implicated in a transcriptional response leading to cell growth, migration and malignant tumor progression. However, little is known about the effects of ATF2 on proliferative factors in iAs treated human urothelial cells. In this study, ATF2 siRNA was employed to investigate the relationship between ATF2 activation and the expressions of proliferative factors, such as BCL2, cyclin D1, COX-2, MMP1 and PCNA, and pro-inflammatory factors (TNFα, TGFα and IL-8) in SV-HUC-1 cells. The results showed that low concentration arsenite increased the expressions of proliferative factors BCL2, cyclin D1, COX-2, MMP1 and PCNA in SV-HUC-1 cells, and ATF2 siRNA partly decreased the expressions of BCL2, cyclin D1, and COX-2. A neutralizing antibody of IL-8 was used for attenuating the levels of IL-8 and neutralizing antibody of IL-8 did not relieve the expressions of ATF2 and proliferative factors induced by arsenite in SV-HUC-1 cells. In addition, ATF2 knockdown did not decrease the expressions of pro-inflammatory cytokines induced by arsenite in SV-HUC-1 cells, but dramatically increased mRNA expressions of TNFα, TGFα and IL-8 under arsenite and non-arsenite conditions. In conclusion, our present study indicated that ATF2, but not IL-8, played a partial role in the expressions of proliferative factors induced by arsenite in human uroepithelial cells.


Neuroprotective Effect of Caffeic Acid Phenethyl Ester in A Mouse Model of Alzheimer's Disease Involves Nrf2/HO-1 Pathway.
Alzheimer's disease (AD) is a progressive pathology, where dementia symptoms gradually worsen over a number of years. The hallmarks of AD, such as amyloid β-peptide (Aβ) in senile plaque and neurofibrillary tangles, are strongly intertwined with oxidative stress, which is considered one of the common effectors of the cascade of degenerative events. The endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) is the "master regulator" of the antioxidant response and it is known as an indicator and regulator of oxidative stress. The present study aimed to determine the potential neuroprotective activity of caffeic acid phenethyl ester (CAPE), a polyphenolic compound abundant in honeybee, against the neurotoxicity of Aβ1-42 oligomers (AβO) in mice. An intracerebroventricular (i.c.v.) injection of AβO into the mouse brain triggered increased reactive oxygen species levels, neurodegeneration, neuroinflammation, and memory impairment. In contrast, the intraperitoneal administration of CAPE (10 mg/kg) after i.c.v. AβO-injection counteracted oxidative stress accompanied by an induction of Nrf2 and heme oxygenase-1 via the modulation of glycogen synthase kinase 3β in the hippocampus of mice. Additionally, CAPE treatment decreased AβO-induced neuronal apoptosis and neuroinflammation, and improved learning and memory, protecting mice against the decline in spatial cognition. Our findings demonstrate that CAPE could potentially be considered as a promising neuroprotective agent against progressive neurodegenerative diseases such as AD.


What Do People Know and Believe about Vitamin D?
People have been exposed to a lot of information regarding vitamin D, with evidence suggesting that vitamin D may be involved in numerous health conditions, subsequently creating concerns about vitamin D insufficiency. As a result, what do people really know or believe about this topic? In this cross-sectional study, we assessed vitamin D-related knowledge and beliefs in 59,273 French adults (NutriNet-Santé cohort) using a specific questionnaire. Answers to this questionnaire were weighted according to the French sociodemographic distribution and compared across individual characteristics, using χ²-tests. Physicians and media were identified as key information providers. Participants did not always accurately cite vitamin D sources (e.g., 72% only for sun exposure, fatty fish: 61%) or established health effects (e.g., bone health: 62%-78%). Conversely, they mentioned incorrect sources and health effects for which there is no consensus yet (e.g., skin cancer). These findings were modulated by age/generational and socioeconomic factors. A strong inconsistency was also observed between participants' true vitamin D status (plasma 25-hydroxyvitamin D concentration) and their opinion about it. This study, the first in Europe with such a large sample, stresses the need for simple and up-to-date supports of communication for the public and healthcare professionals regarding sources and health effects of vitamin D.


'Designer babies' almost thirty years on.
The first pregnancies and live births following in vitro fertilisation (IVF) and preimplantation genetic testing (PGT), formerly known as preimplantation genetic diagnosis, were reported in 1990, almost 30 years ago, in several couples at risk of X-linked inherited conditions, which typically only affect boys inheriting the X chromosome with the affected gene from their carrier mothers. At that time, it was only possible to identify the sex of the embryo by amplifying a Y-linked repeat sequence in single cells biopsied at cleavage stages and avoid the transfer of males, half of which would be affected. The extensive publicity surrounding these cases and the perceived risk of using IVF and PGT for desirable characteristics not related to health, such as sex selection, led to the epithet of 'designer babies' which continues to resonate to this day. Here, I briefly reflect on how the technology of PGT has evolved over the decades and whether it deserves this reputation. With efficient methods for whole genome amplification and the genomic revolution, we now have highly accurate universal tests that combine marker-based diagnosis of almost any monogenic disorder with the detection of aneuploidy. PGT is now clinically well established and is likely to remain a valuable alternative for couples at risk of having affected children.


Percutaneous transhepatic gall bladder drainage: a better initial therapeutic choice for patients with gall bladder perforation in the emergency department.
To investigate clinical features and outcomes in patients with acute cholecystitis with gall bladder perforation receiving open cholecystectomy or percutaneous transhepatic gall bladder drainage in the emergency department. From 1996 through 2005, 33 patients with non-traumatic gall bladder perforation, among 585 patients with acute cholecystitis, were enrolled. Patients were divided into two groups: open cholecystectomy in 16 patients and percutaneous transhepatic gall bladder drainage in 17 patients. Medical records, including demographic data, past history of systemic diseases or gallbladder stones, initial clinical presentations, laboratory data, physical status, therapeutic interventions, and outcomes, were analysed. Mean patient age was 72.6 years (range 54-92 years). 28 patients (84.8%) were male. Median time of symptom onset before emergency department diagnosis was 5 days (range 0.5-30 days). Estimated incidence of gall bladder perforation was 5.6% (33/585). 27 patients (81.8%) had gallstones operatively or in image studies. All patients had either right upper quadrant pain/tenderness or epigastric pain/tenderness. Only 9 (27.3%) patients had positive Murphy's sign. Six patients in the percutaneous transhepatic gall bladder drainage group received further open cholecystectomy. Overall mortality was 24.2% (8/33). The direct cause of death was disease related sepsis in all patients. Patients receiving percutaneous transhepatic gall bladder drainage had a higher survival rate than those receiving open cholecystectomy (100% vs 50%, p<0.001). No differences in complications and length of hospital stay of survivors were observed between groups. In this study, we delineated clinical features of patients with gall bladder perforation. Better clinical outcome is observed for percutaneous transhepatic gall bladder drainage, and this is suggested as an initial therapeutic choice, especially in high risk patients who are likely to need surgery.


Complete determination of the Pin1 catalytic domain thermodynamic cycle by NMR lineshape analysis.
The phosphorylation-specific peptidyl-prolyl isomerase Pin1 catalyzes the isomerization of the peptide bond preceding a proline residue between cis and trans isomers. To best understand the mechanisms of Pin1 regulation, rigorous enzymatic assays of isomerization are required. However, most measures of isomerase activity require significant constraints on substrate sequence and only yield rate constants for the cis isomer, [Formula: see text] and apparent Michaelis constants, [Formula: see text]. By contrast, NMR lineshape analysis is a powerful tool for determining microscopic rates and populations of each state in a complex binding scheme. The isolated catalytic domain of Pin1 was employed as a first step towards elucidating the reaction scheme of the full-length enzyme. A 24-residue phosphopeptide derived from the amyloid precurser protein intracellular domain (AICD) phosphorylated at Thr668 served as a biologically-relevant Pin1 substrate. Specific (13)C labeling at the Pin1-targeted proline residue provided multiple reporters sensitive to individual isomer binding and on-enzyme catalysis. We have performed titration experiments and employed lineshape analysis of phosphopeptide (13)C-(1)H constant time HSQC spectra to determine [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text] for the catalytic domain of Pin1 acting on this AICD substrate. The on-enzyme equilibrium value of [E·trans]/[E·cis] = 3.9 suggests that the catalytic domain of Pin1 is optimized to operate on this substrate near equilibrium in the cellular context. This highlights the power of lineshape analysis for determining the microscopic parameters of enzyme catalysis, and demonstrates the feasibility of future studies of Pin1-PPIase mutants to gain insights on the catalytic mechanism of this important enzyme.


Diverse Vectors and Mechanisms Spread New Delhi Metallo-β-Lactamases among Carbapenem-Resistant Enterobacteriaceae in the Greater Boston Area.
New Delhi metallo-beta-lactamases (NDMs) are an uncommon but emerging cause of carbapenem resistance in the United States. Genomic factors promoting their domestic spread remain poorly characterized. A prospective genomic surveillance program among Boston-area hospitals identified multiple new occurrences of NDM-carrying strains of Escherichia coli and Enterobacter cloacae complex in inpatient and outpatient settings, representing the first occurrences of NDM-mediated resistance since initiating genomic surveillance in 2011. Cases included domestic patients with no international exposures. PacBio sequencing of isolates identified strain characteristics, resistance genes, and the complement of mobile vectors mediating spread. Analyses revealed a common 3,114-bp region containing the blaNDM gene, with carriage of this conserved region among unique strains by diverse transposon and plasmid backbones. Functional studies revealed a broad capacity for blaNDM transmission by conjugation, transposition, and complex interplasmid recombination events. NDMs represent a rapidly spreading form of drug resistance that can occur in inpatient and outpatient settings and in patients without international exposures. In contrast to Tn4401-based spread of Klebsiella pneumoniae carbapenemases (KPCs), diverse transposable elements mobilize NDM enzymes, commonly with other resistance genes, enabling naive strains to acquire multi- and extensively drug-resistant profiles with single transposition or plasmid conjugation events. Genomic surveillance provides effective means to rapidly identify these gene-level drivers of resistance and mobilization in order to inform clinical decisions to prevent further spread.


Dipicolylamine as a unique structural switching element for helical peptides.
Developing novel methods for metal-induced switching of peptide structures expands the design principles of functional biomolecules and biomaterials. Here, a simple method for on-resin synthesis of dipicolylamine (Dpa)-containing peptides was developed. Whereas addition of divalent metal ions such as Fe(ii) and Cu(ii) to a peptide bearing a pair of Dpa moieties at the i and i + 4 positions led to the formation of a 1:1 complex of Dpa with metals, addition of Ni(ii) yielded a cross-linked structure of Dpa-metal (2:1). This feature was utilized for the selective detection of Ni(ii) using the peptide-Fe(ii) complex. Repeated switching of the helical structure was also achieved by multiple additions of divalent metal ions to the peptide.


Bidentate nitroxide ligands stable toward oxidative redox cycling and their complexes with cerium and lanthanum.
We report the synthesis of 1,3-bis[(2′-tertbutyl)hydroxyaminophenyl]benzene (H2arene-diNOx) and its metal complexes, Ce(arene-diNOx)2 (1) and [(py)2K(18-crown-6)][La(arene-diNOx)2] (2). Electrochemical studies demonstrated that the H2arene-diNOx, bidentate nitroxide ligands significantly stabilized the Ce(IV/III) redox couple to −1.74 V versus Fc/Fc(+). Moreover, a reversible oxidation wave was observed for 1 at −0.37 V, leading to a novel, stable redox-active nitroxide ligand. DFT calculations confirmed that the observed oxidation is assignable to one of the nitroxide groups.


Learning a sparse code for temporal sequences using STDP and sequence compression.
A spiking neural network that learns temporal sequences is described. A sparse code in which individual neurons represent sequences and subsequences enables multiple sequences to be stored without interference. The network is founded on a model of sequence compression in the hippocampus that is robust to variation in sequence element duration and well suited to learn sequences through spike-timing dependent plasticity (STDP). Three additions to the sequence compression model underlie the sparse representation: synapses connecting the neurons of the network that are subject to STDP, a competitive plasticity rule so that neurons specialize to individual sequences, and neural depolarization after spiking so that neurons have a memory. The response to new sequence elements is determined by the neurons that have responded to the previous subsequence, according to the competitively learned synaptic connections. Numerical simulations show that the model can learn sets of intersecting sequences, presented with widely differing frequencies, with elements of varying duration.


Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging.
Elevated plasma total homocysteine concentration may be a risk factor for cognitive decline and Alzheimer disease, but data from prospective studies are limited. Further, high homocysteine levels are associated with low vitamin status, and it is unknown whether it is homocysteine toxicity or vitamin insufficiency that is responsible for the observed cognitive dysfunction. We performed cross-sectional and longitudinal analyses of a cohort of 499 high-functioning community-dwelling persons aged 70 to 79 years to determine the effect of homocysteine and related vitamin plasma concentrations on cognitive function and cognitive decline. Nonfasting plasma concentrations of homocysteine, folate, vitamin B(6), and vitamin B(12) were measured at baseline. Summary measures of cognitive function were created from tests of multiple cognitive domains administered at baseline and again after 7 years. In cross-sectional analyses investigating each variable separately, subjects with elevated homocysteine levels, or low levels of folate or vitamin B(6), demonstrated worse baseline cognitive function. In longitudinal analyses, after adjusting for multiple covariates, including homocysteine, those in the bottom quartile of folate had a 1.6-fold increased risk (95% confidence interval: 1.01 to 2.31; P =0.04) of being in the worst quartile of 7-year cognitive decline. Low folate levels largely accounted for a trend towards greater cognitive decline with elevated homocysteine level. In high-functioning older adults, low folate levels appear to be a risk factor for cognitive decline. The risk of developing cognitive decline might be reduced through dietary folate intake.


Non-vigorous physical activity and all-cause mortality: systematic review and meta-analysis of cohort studies.
Although previous studies have found physical activity to be associated with lower mortality, the dose-response relationship remains unclear. In this systematic review and meta-analysis we quantify the dose-response relationship of non-vigorous physical activity and all-cause mortality. We aimed to include all cohort studies in adult populations with a sample size of more than 10 000 participants that estimated the effect of different levels of light or moderate physical activity on all-cause mortality. We searched Medline, Embase, Cochrane (DARE), Web of Science and Global Health (June 2009). We used dose-response meta-regression models to estimate the relation between non-vigorous physical activity and mortality. We identified 22 studies that met our inclusion criteria, containing 977 925 (334 738 men and 643 187 women) people. There was considerable variation between the studies in their categorization of physical activity and adjustment for potential confounders. We found that 2.5 h/week (equivalent to 30 min daily of moderate intensity activity on 5 days a week) compared with no activity was associated with a reduction in mortality risk of 19% [95% confidence interval (CI) 15-24], while 7 h/week of moderate activity compared with no activity reduced the mortality risk by 24% (95% CI 19-29). We found a smaller effect in studies that looked at walking alone. Being physically active reduces the risk of all-cause mortality. The largest benefit was found from moving from no activity to low levels of activity, but even at high levels of activity benefits accrue from additional activity.


Efficiency and shrinking in evolving networks.
Characterizing the spatio-temporal evolution of networks is a central topic in many disciplines. While network expansion has been studied thoroughly, less is known about how empirical networks behave when shrinking. For transportation networks, this is especially relevant on account of their connection with the socio-economical substrate, and we focus here on the evolution of the French railway network from its birth in 1840 to 2000, in relation to the country's demographic dynamics. The network evolved in parallel with technology (e.g. faster trains) and under strong constraints, such as preserving a good population coverage and balancing cost and efficiency. We show that the shrinking phase that started in 1930 decreased the total length of the network while preserving efficiency and population coverage: efficiency and robustness remained remarkably constant while the total length of the network shrank by 50% between 1930 and 2000, and the total travel time and time-diameter decreased by more than 75% during the same period. Moreover, shrinking the network did not affect the overall accessibility with an average travel time that decreases steadily since its formation. This evolution leads naturally to an increase in transportation multimodality (such as a massive use of cars) and shows the importance of considering together transportation modes acting at different spatial scales. More generally, our results suggest that shrinking is not necessarily associated with a decay in performance and functions but can be beneficial in terms of design goals and can be part of the natural evolution of an adaptive network.


Shifts in alcohol consumption during the COVID-19 pandemic: early indications from Australia.
The effect of the COVID-19 pandemic on alcohol consumption is currently unclear. This study aimed to provide early estimates of how stress and demographics will interact with shifts in harmful alcohol consumption from before the COVID-19 outbreak to 2 months into social distancing. Cross-sectional convenience sample. Australia. A total of 1684 Australians aged 18-65 years who drink at least monthly. Items from the Alcohol Use Disorders Identification Test (AUDIT) and the stress subscale of the Depression Anxiety and Stress Scale (DASS). Overall, harmful drinking decreased during social distancing measures in our sample [2019 score = 8.2, 95% confidence interval (CI) = 7.9-8.4; during the pandemic = 7.3, 95% CI = 7.1-7.6]. Younger drinkers, particularly young women, decreased their consumption the most, but there was a small increase in consumption in middle-aged women. Drinkers experiencing high levels of stress also reported a relatively higher shift in harmful consumption compared with those with low levels of stress (β = 0.65, P = 0.003), despite reporting a small decrease overall. The closure of licensed premises and social distancing measures in Australia in response to the COVID-19 outbreak appear to have reduced harmful alcohol consumption in younger drinkers, particularly young women.


Phosphodiesterases (PDEs) and PDE inhibitors for treatment of LUTS.
Lower urinary tract (LUT) smooth muscle can be relaxed by drugs that increase intracellular concentrations of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both of these substances are degraded by phosphodiesterases (PDEs), which play a central role in the regulation of smooth muscle tone. The distribution and functional significance of PDE enzymes vary in different tissues of the LUT. Targeting specific PDE isoenzymes should thus allow organ selectivity. PDE 4 and 5 appear to predominate in the prostate, PDE 1 and 4 are thought to influence detrusor smooth muscle function, and PDE 5 may be functionally important in the urethra and vasculature. Studies on the use of PDE inhibitors to treat various LUT symptoms (LUTS), have yielded favorable results. Thus, positive effects of the PDE 5 inhibitors sildenafil and tadalafil on symptoms and quality of life in men with LUTS, erectile dysfunction, and BPH have also been demonstrated. These effects may be due to effects on cGMP signaling and/or modification of afferent input from bladder, urethral, and prostate tissue. This review gives an update on the distribution of PDEs in structures relevant for LUT function, and discusses how inhibition of these enzymes can contribute to beneficial effects on LUTS. Information for the review was obtained from searches of the PubMed database, and from the authors' files.


Mobile diagnostics: next-generation technologies for in vitro diagnostics.
The emergence of a wide range of applications of smartphones along with advances in 'liquid biopsy' has significantly propelled medical research particularly in the field of in vitro diagnostics (IVD). Herein, we have presented a detailed analysis of IVD, its associated critical concerns and probable solutions. It also demonstrates the transition in terms of analytes from minimally invasive (blood) to non-invasive (urine, saliva and sweat) and depicts how the different features of a smartphone can be integrated for specific diagnostic purposes. This review basically highlights recent advances in the applications of smartphone-based biosensors in IVD taking into account the following factors: accuracy and portability; quantitative and qualitative analysis; and centralization and decentralization tests. Furthermore, the critical concerns and future direction of diagnostics based on smartphones are also discussed.


Trends in suicide methods in Switzerland from 1969 to 2018: an observational study.
Suicide is a serious societal and health problem. We examined changes in rates of completed suicides in Switzerland between 1969-2018 with particular regard to different methods of suicide used in different subgroups of the resident population. We used data of the Swiss cause of death statistics and Poisson regression models to analyse annual incidence rates and calendar time trends of specific suicide methods used in population subgroups by sex (men vs women), age (10-29, 30-64, >64 years), and nationality (Swiss vs other citizenship). There were 64,996 registered suicides between 1969 and 2018. Across these 5 decades, the overall suicide rate was higher in men than in women (incidence rate ratio [IRR] 2.62, 95% confidence interval [CI] 2.58-2.67), in Swiss citizens than in foreigners (IRR 2.02; 95% CI 1.97-2.07), and in older residents (>64 years) than in the age groups 30-64 years (IRR 1.35, 95% CI 1.32-1.37) and 10-29 years (IRR 2.37, 95% CI 2.32-2.43). After peaking in the 1980s, the overall suicide rate had declined in all of these population subgroups, with flattening trends over most recent years. The most common specific methods of suicide were hanging (accounting for 26.7% of all suicides) and firearms (23.6%). The rates of the specific suicide methods were usually higher in men, in Swiss citizens and in older residents, and they had typically declined over most recent decades in the population subgroups examined. However, some methods diverged from this general pattern, at least in some population subgroups. For instance, railway suicides most recently increased in younger and in male residents whereas suicides by gas and by drowning were only at a low level after rapid declines in the last millennium. Restricting access to lethal means (e.g., detoxification of domestic gas), improvements in health care and media guidelines for responsible reporting of suicides are possible explanations for the generally declining suicide rates in Switzerland. Whereas some methods (e.g., poisoning by gases or drowning) had become rare, others continue to account for many suicides every year, at least in some population subgroups (e.g., firearms in older Swiss men or railway suicides in younger and in male residents). As different methods of suicide are chosen by different people or subgroups of the population, preventive efforts should include differentiated strategies and targeted measures to further reduce suicides in Switzerland and elsewhere.


Transmission-reducing immunity is inversely related to age in Plasmodium falciparum gametocyte carriers.
Immunity to the sexual stages of Plasmodium falciparum is induced during natural infections and can significantly reduce the transmission of parasites to mosquitoes (transmission reducing activity; TRA) but little is known about how these responses develop with increasing age/exposure to malaria. Routinely TRA is measured in the standard membrane feeding assay (SMFA). Sera were collected from a total of 199 gametocyte carriers (median age 4 years, quartiles 2 and 9 years) near Ifakara, Tanzania; 128 samples were tested in the SMFA and generated TRA data classified as a reduction of > 50% and > 90% of transmission. TRA of > 50% was highest in young children (aged 1-2) with a significant decline with age (chi(2) trend = 5.79, P = 0.016) and in logistic regression was associated with prevalence of antibodies to both Pfs230 and Pfs48/45 (OR 4.03, P = 0.011 and OR 2.43 P = 0.059, respectively). A TRA of > 90% reduction in transmission was not age related but was associated with antibodies to Pfs48/45 (OR 2.36, P = 0.055). Our data confirm that antibodies are an important component of naturally induced TRA. However, whilst a similar but small proportion of individuals at all ages have TRA > 90%, the gradual deterioration of TRA > 50% with age suggests decreased antibody concentration or affinity. This may be due to decreased exposure to gametocytes, probably as a result of increased asexual and/or gametocyte specific immunity.


Chronic leptin administration decreases fatty acid uptake and fatty acid transporters in rat skeletal muscle.
Chronic leptin administration reduces triacylglycerol content in skeletal muscle. We hypothesized that chronic leptin treatment, within physiologic limits, would reduce the fatty acid uptake capacity of red and white skeletal muscle due to a reduction in transport protein expression (fatty acid translocase (FAT/CD36) and plasma membrane-associated fatty acid-binding protein (FABPpm)) at the plasma membrane. Female Sprague-Dawley rats were infused for 2 weeks with leptin (0.5 mg/kg/day) using subcutaneously implanted miniosmotic pumps. Control and pair-fed animals received saline-filled implants. Leptin levels were significantly elevated (approximately 4-fold; p < 0.001) in treated animals, whereas pair-fed treated animals had reduced serum leptin levels (approximately -2-fold; p < 0.01) relative to controls. Palmitate transport rates into giant sarcolemmal vesicles were reduced following leptin treatment in both red (-45%) and white (-84%) skeletal muscle compared with control and pair-fed animals (p < 0.05). Leptin treatment reduced FAT mRNA (red, -70%, p < 0.001; white, -48%, p < 0.01) and FAT/CD36 protein expression (red, -32%; p < 0.05) in whole muscle homogenates, whereas FABPpm mRNA and protein expression were unaltered. However, in leptin-treated animals plasma membrane fractions of both FAT/CD36 and FABPpm protein expression were significantly reduced in red (-28 and -34%, respectively) and white (-44 and -56%, respectively) muscles (p < 0.05). Across all experimental treatments and muscles, palmitate uptake by giant sarcolemmal vesicles was highly correlated with the plasma membrane FAT/CD36 protein (r = 0.88, p < 0.01) and plasma membrane FABPpm protein (r = 0.94, p < 0.01). These studies provide the first evidence that protein-mediated long chain fatty acid transport is subject to long term regulation by leptin.


A study of warning letters issued to institutional review boards by the United States Food and Drug Administration.
This study explores the ethical issues contained in warning letters (WLs) issued to institutional review boards (IRBs) by the United States Food and Drug Administration (FDA). The online FDA Warning Letter Index was reviewed for letters issued to IRBs in the United States under the violation categories "Institutional Review Board" and "IRB" for the period January 1997 through July 2004. The resultant letters were evaluated for violations in 4 regulatory themes: having and following written procedures for research review; documentation of research review; IRB membership and conflict of interest; and informed consent. Fifty-two (52) FDA WLs were issued to IRBs during this period. Hospital/medical centre IRBs received the most letters (n = 34), followed by university IRBs (n = 9) and private IRBs (n = 9). The most common regulatory violations were failure to have and follow adequate written procedures about how the review of research is conducted (50 WLs); failure to prepare and maintain adequate documentation of IRB activities (47 WLs); and failure to provide adequate continuing review of approved studies (36 WLs). Nineteen WLs were issued for consent form issues. Warning letters are informative with regard to clinical research regulations and research subject protection. The content of these letters consistently indicates weaknesses in review and documentation activities of audited IRBs, potentially signalling similar issues among IRBs across the United States. Our findings, in a setting of overburdened IRBs who, in general, passively monitor studies, raise concerns about study oversight and optimal protection of research subjects.


Surface crystallization in a liquid AuSi alloy.
X-ray measurements reveal a crystalline monolayer at the surface of the eutectic liquid Au82Si18, at temperatures above the alloy's melting point. Surface-induced atomic layering, the hallmark of liquid metals, is also found below the crystalline monolayer. The layering depth, however, is threefold greater than that of all liquid metals studied to date. The crystallinity of the surface monolayer is notable, considering that AuSi does not form stable bulk crystalline phases at any concentration and temperature and that no crystalline surface phase has been detected thus far in any pure liquid metal or nondilute alloy. These results are discussed in relation to recently suggested models of amorphous alloys.


KAP1 promotes proliferation and metastatic progression of breast cancer cells.
KAP1 (TRIM28) is a transcriptional regulator in embryonic development that controls stem cell self-renewal, chromatin organization, and the DNA damage response, acting as an essential corepressor for KRAB family zinc finger proteins (KRAB-ZNF). To gain insight into the function of this large gene family, we developed an antibody that recognizes the conserved zinc fingers linker region (ZnFL) in multiple KRAB-ZNF. Here, we report that the expression of many KRAB-ZNF along with active SUMOlyated KAP1 is elevated widely in human breast cancers. KAP1 silencing in breast cancer cells reduced proliferation and inhibited the growth and metastasis of tumor xenografts. Conversely, KAP1 overexpression stimulated cell proliferation and tumor growth. In cells where KAP1 was silenced, we identified multiple downregulated genes linked to tumor progression and metastasis, including EREG/epiregulin, PTGS2/COX2, MMP1, MMP2, and CD44, along with downregulation of multiple KRAB-ZNF proteins. KAP1-dependent stabilization of KRAB-ZNF required direct interactions with KAP1. Together, our results show that KAP1-mediated stimulation of multiple KRAB-ZNF contributes to the growth and metastasis of breast cancer.