The impact of compensation on late mortality after traumatic brain injury: A multi-centre study.
To determine the impact of financial compensation on long-term mortality in adults with severe traumatic brain injury (TBI). An inception cohort of 2545 adults consecutively discharged from three metropolitan, post-acute inpatient rehabilitation services of the NSW Brain Injury Rehabilitation Programme from 1 July 1990 to 1 October 2007. Survival status at 1 October 2009. Compensation data were available for 1851 (73%) participants, with 826 (45%) receiving financial compensation. Yearly standardized mortality ratios remained elevated above general population norms for six to ten years for both groups. Compensation had a protective effect on mortality risk as a univariate predictor. However, when considered in multivariate Cox regression analysis, compensation had minimal effect on mortality risk when modelled with non-modifiable demographic factors and pre-existing medical history. Conversely, compensation trended towards a protective effect when modelled with post-injury variables. Financial compensation had a protective effect against late mortality following rehabilitation for severe TBI through complex interactions with rehabilitation service variables but not with injury-related variables. This finding suggests that wider access to compensation (and hence rehabilitation) through recently implemented schemes (e.g., NSW Lifetime Care and Support) may further improve life expectancy for this clinical population.


Characteristics and spread to the native population of HIV-1 non-B subtypes in two European countries with high migration rate.
Non-B subtypes account for at least 50 % of HIV-1 infections diagnosed in Belgium and Luxembourg. They are considered to be acquired through heterosexual contacts and infect primarily individuals of foreign origin. Information on the extent to which non-B subtypes spread to the local population is incomplete. Pol and env gene sequences were collected from 410 non-subtype B infections. Profound subtyping was performed using 5 subtyping tools and sequences of both pol and env. Demographic information, disease markers (viral load, CD4 count) and viral characteristics (co-receptor tropism) were compared between subtypes. Maximum likelihood phylogenetic trees were constructed and examined for clustering. The majority of non-B infections were diagnosed in patients originating from Africa (55.8 %), individuals born in Western Europe represented 30.5 %. Heterosexual transmission was the most frequently reported transmission route (79.9 %), MSM transmission accounted for 12.2 % and was significantly more frequently reported for Western Europeans (25.7 % versus 4.3 % for individuals originating from other regions; p < 0.001). Subtypes A and C and the circulating recombinant forms CRF01_AE and CRF02_AG were the most represented and were included in the comparative analysis. Native Western Europeans were underrepresented for subtype A (14.5 %) and overrepresented for CRF01_AE (38.6 %). The frequency of MSM transmission was the highest for CRF01_AE (18.2 %) and the lowest for subtype A (0 %). No differences in age, gender, viral load or CD4 count were observed. Prevalence of CXCR4-use differed between subtypes but largely depended on the tropism prediction algorithm applied. Indications for novel intersubtype recombinants were found in 20 patients (6.3 %). Phylogenetic analysis revealed only few and small clusters of local transmission but could document one cluster of CRF02_AG transmission among Belgian MSM. The extent to which non-B subtypes spread in the native Belgian-Luxembourg population is higher than expected, with 30.5 % of the non-B infections diagnosed in native Western Europeans. These infections resulted from hetero- as well as homosexual transmission. Introduction of non-B variants in the local high at risk population of MSM may lead to new sub-epidemics and/or increased genetic variability and is an evolution that needs to be closely monitored.


Discovery and development of differentially methylated regions in human papillomavirus-related oropharyngeal squamous cell carcinoma.
Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) exhibits a different composition of epigenetic alterations. In this study, we identified differentially methylated regions (DMRs) with potential utility in screening for HPV-positive OPSCC. Genome wide DNA methylation was measured using methyl-CpG binding domain protein-enriched genome sequencing (MBD-seq) in 50 HPV-positive OPSCC tissues and 25 normal tissues. Fifty-one DMRs were defined with maximal methylation specificity to cancer samples. The Cancer Genome Atlas (TCGA) methylation array data was used to evaluate the performance of the proposed candidates. Supervised hierarchical clustering of 51 DMRs found that HPV-positive OPSCC had significantly higher DNA methylation levels compared to normal samples, and non-HPV-related head and neck squamous cell carcinoma (HNSCC). The methylation levels of all top 20 DNA methylation biomarkers in HPV-positive OPSCC were significantly higher than those in normal samples. Further confirmation using quantitative methylation specific PCR (QMSP) in an independent set of 24 HPV-related OPSCCs and 22 controls showed that 16 of the 20 candidates had significant higher methylation levels in HPV-positive OPSCC samples compared with controls. One candidate, OR6S1, had a sensitivity of 100%, while 17 candidates (KCNA3, EMBP1, CCDC181, DPP4, ITGA4, BEND4, ELMO1, SFMBT2, C1QL3, MIR129-2, NID2, HOXB4, ZNF439, ZNF93, VSTM2B, ZNF137P and ZNF773) had specificities of 100%. The prediction accuracy of the 20 candidates rang from 56.2% to 99.8% by receiver operating characteristic analysis. We have defined 20 highly specific DMRs in HPV-related OPSCC, which can potentially be applied to molecular-based detection tests and improve disease management.


Estimation of the stress related to conservative scoliosis therapy: an analysis based on BSSQ questionnaires.
Adolescent girls treated with a brace for scoliosis are submitted to prolonged stress related to both the disease and the therapy. Currently proposed quality of life questionnaires are focused on the outcome of therapy. Bad Sobernheim Stress Questionnaire (BSSQ) enables monitoring of patients being under treatment with a brace or exercises. The aim of the study was to assess the stress level in conservatively managed scoliotic girls using BSSQ. 111 girls, aged 14.2 +/- 2.2 years, mean Cobb angle of the primary curve 42.8 degrees +/- 17.0 degrees and mean Bunnell angle of 11.4 degrees +/- 4.5 degrees were examined with two versions of BSSQ (Deformity and Brace). The analysis considered the type of treatment, curve location, correlation of the total score with age, Cobb angle and Bunnell rotation angle. The BSSQ Deformity revealed the median of 17 points in patients managed with exercises (from 4 to 24 points), 18 in patients managed with a brace (from 8 to 24 points) and 12 in patients before surgery (from 3 to 21 points). Braced patients who completed both questionnaires (n = 50) revealed significantly higher score with BSSQ Deformity (median = 18) comparing to BSSQ Brace (median = 9). There was a correlation between the total score of BSSQ Deformity and the Cobb angle (r = -0.34), Bunnell primary curve rotation (r = -0.34) and Bunnell sum of rotation (r = -0.33) but not with the age of patients. Scoliotic adolescents managed with exercises and brace suffered little stress from the deformity. The brace increased the level of stress over the stress induced by the deformity. The stress level correlated with clinical deformity (Bunnell angle), radiological deformity (Cobb angle) and the type of treatment (exercises, bracing, surgery). Bad Sobernheim Stress Questionnaires are simple and helpful in the management of girls treated conservatively for idiopathic scoliosis.


Similar organization of the sigB and spoIIA operons encoding alternate sigma factors of Bacillus subtilis RNA polymerase.
Bacillus subtilis sigma-B is an alternate sigma factor implicated in controlling stationary-phase gene expression. We characterized the genetic organization and regulation of the region containing the sigma-B structural gene (sigB) to learn which metabolic signals and protein factors govern sigma-B function. sigB lay in an operon with four open reading frames (orfs) in the order orfV-orfW-sigB-orfX, and lacZ gene fusions showed that all four frames were translated in vivo. Experiments with primer extension, S1 nuclease mapping, and lacZ transcriptional fusions found that sigB operon transcription initiated early in stationary phase from a site 32 nucleotides upstream of orfV and terminated 34 nucleotides downstream of orfX. Fusion expression was abolished in a strain carrying an in-frame deletion in sigB, suggesting that sigma-B positively regulated its own synthesis, and deletions in the sigB promoter region showed that sequences identical to the sigma-B-dependent ctc promoter were essential for promoter activity. Fusion expression was greatly enhanced in a strain carrying an insertion mutation in orfX, suggesting that the 22-kilodalton (kDa) orfX product was a negative effector of sigma-B expression or activity. Notably, the genetic organization of the sigB operon was strikingly similar to that of the B. subtilis spoIIA operon, which has the gene order spoIIAA-spoIIAB-spoIIAC, with spoIIAC encoding the sporulation-essential sigma-F. The predicted sequence of the 12-kDa orfV product was 32% identical to that of the 13-kDa SpoIIAA protein, and the 18-kDa orfW product was 27% identical to the 16-kDa SpoIIAB protein. On the basis of this clear evolutionary conservation, we speculate these protein pairs regulate their respective sigma factors by a similar molecular mechanism and that the spoIIA and sigB operons might control divergent branches of stationary-phase gene expression.


Atypical perception in autism: A failure of perceptual specialization?
We examined whether reduced perceptual specialization underlies atypical perception in autism spectrum disorder (ASD) testing classifications of stimuli that differ either along integral dimensions (prototypical integral dimensions of value and chroma), or along separable dimensions (prototypical separable dimensions of value and size). Current models of the perception of individuals with an ASD would suggest that on these tasks, individuals with ASD would be as, or more, likely to process dimensions as separable, regardless of whether they represented separable or integrated dimensions. In contrast, reduced specialization would propose that individuals with ASD would respond in a more integral manner to stimuli that differ along separable dimensions, and at the same time, respond in a more separable manner to stimuli that differ along integral dimensions. A group of nineteen adults diagnosed with high functioning ASD and seventeen typically developing participants of similar age and IQ, were tested on speeded and restricted classifications tasks. Consistent with the reduced specialization account, results show that individuals with ASD do not always respond more analytically than typically developed (TD) observers: Dimensions identified as integral for TD individuals evoke less integral responding in individuals with ASD, while those identified as separable evoke less analytic responding. These results suggest that perceptual representations are more broadly tuned and more flexibly represented in ASD. Autism Res 2017, 10: 1510-1522. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.


Accelerated healing of laser-injured rabbit retina by basic fibroblast growth factor.
To improve the outcome of injured retina, human recombinant basic fibroblast growth factor (bFGF) was examined for its ability to accelerate healing in laser-injured New Zealand Red rabbits. A multi-line argon laser (454 to 514 nm) was used to produce lesions near subretinal hemorrhaging levels. Within 30 minutes after irradiation, eyes were intravitreally injected directly above the lesions with 10 microliters vehicle or 10 micrograms of bFGF in 10 microliters of vehicle. Lesions were evaluated by funduscopy and fluorescein angiography. After 4 days of treatment, animals were killed and eyes examined histologically. On subsequent days, bFGF-treated lesions were less opaque, smaller in diameter, and less leaky to fluorescein than lesions in the control eyes. Eyes treated with bFGF exhibited reduction in lesion diameter (P < or = 0.001) and in the lesion periphery, decreased loss of photoreceptors (P < or = 0.001), and greater numbers of pigmented epithelial cells, compared to controls. By bromodeoxyuridine incorporation, increased proliferation occurred in fibroblasts, retinal pigmented epithelial cells, and inner retinal glial cells. These results indicate that bFGF both accelerated ocular tissue repair and also prevented photoreceptor loss. The rescue of photoreceptors by bFGF may occur through direct action on the photoreceptors, or indirectly through effects on other cells in the retina.


A survey of TWIST for mutations in craniosynostosis reveals a variable length polyglycine tract in asymptomatic individuals.
The human TWIST gene encodes a 202 amino acid transcription factor characterized by a highly conserved basic-helix-loop-helix motif in the C-terminal half, and a less conserved N-terminal half that has binding activity toward the histone acetyltransferase p300. Between these domains is a repeat region of unknown function that encodes the glycine-rich sequence (Gly)5Ala(Gly)5. Heterozygous mutations of TWIST were previously described in Saethre-Chotzen craniosynostosis syndrome [El Ghouzzi et al., 1997; Howard et al., 1997]. During a search for TWIST mutations in patients with craniosynostosis, we identified, in addition to 11 novel and one previously described bona fide mutations, several individuals with rearrangements of the glycine-rich region, involving either deletion of 18 nucleotides or insertion of three, 15, or 21 nucleotides. None of these rearrangements was consistently associated with clinical disease and we conclude that they are at most weakly pathogenic. The glycine stretch may serve as a flexible linker between the functional domains of the TWIST protein, and as such may be subject to reduced evolutionary constraint.


miR-202 Diminishes TGFβ Receptors and Attenuates TGFβ1-Induced EMT in Pancreatic Cancer.
Previous studies in our laboratory identified that 3-deazaneplanocin A (DZNep), a carbocyclic adenosine analog and histone methyl transferase inhibitor, suppresses TGFβ-induced epithelial-to-mesenchymal (EMT) characteristics. In addition, DZNep epigenetically reprograms miRNAs to regulate endogenous TGFβ1 levels via miR-663/4787-mediated RNA interference (Mol Cancer Res. 2016 Sep 13. pii: molcanres.0083.2016) (1). Although DZNep also attenuates exogenous TGFβ-induced EMT response, the mechanism of this inhibition was unclear. Here, DZNep induced miR-202-5p to target both TGFβ receptors, TGFBR1 and TGFBR2, for RNA interference and thereby contributes to the suppression of exogenous TGFβ-induced EMT in pancreatic cancer cells. Lentiviral overexpression of miR-202 significantly reduced the protein levels of both TGFβ receptors and suppressed TGFβ signaling and EMT phenotypic characteristics of cultured parenchymal pancreatic cancer cells. Consistently, transfection of anti-miRNAs against miR-202-5p resulted in increased TGFBR1 and TGFBR2 protein expressions and induced EMT characteristics in these cells. In stellate pancreatic cells, miR-202 overexpression slowed growth as well as reduced stromal extracellular membrane matrix protein expression. In orthotopic pancreatic cancer mouse models, both immunodeficient and immunocompetent, miR-202 reduced tumor burden and metastasis. Together, these findings demonstrate an alternative mechanism of DZNep in suppressing TGFβ signaling at the receptor level and uncover the EMT-suppressing role of miR-202 in pancreatic cancer.Implications: These findings support the possibility of combining small molecule-based (e.g., DZNep analogs) or large molecule-based (e.g., miRNAs) epigenetic modifiers with conventional nucleoside analogs (e.g., gemcitabine, capecitabine) to improve the antimetastatic potential of current pancreatic cancer therapy. Mol Cancer Res; 15(8); 1029-39. ©2017 AACR.


Impact of Chemotherapy and Radiotherapy on Management of Early Stage Clear Cell and Papillary Serous Carcinoma of the Uterus.
The aim of the study was to assess interaction of lymph node dissection (LND), adjuvant chemotherapy (CT), and radiotherapy (RT) in stage I uterine papillary serous carcinoma (UPSC) and uterine clear cell carcinoma (UCC). The National Cancer Data Base was queried for women diagnosed with International Federation of Gynecology and Obstetrics stage I UPSC and UCC from 1998 to 2012. Overall survival (OS) was estimated for combinations of RT and CT by the Kaplan-Meier method stratified by histology and LND. Multivariate Cox proportional hazard models were generated. Uterine papillary serous carcinoma: 5432 women with UPSC were identified. Uterine papillary serous carcinoma had the highest 5-year OS with CT + RT with (83%) or without LND (76%). On multivariate analyses, CT [hazard ratio (HR), 0.77; P = 0.01] and vaginal cuff brachytherapy (HR, 0.68; P = 0.003) with LND were independently associated with OS. Without LND, vaginal cuff brachytherapy (HR, 0.53; P = 0.03), but not CT (HR, 1.21; P = 0.92), was associated with OS. Uterine clear cell carcinoma: 2516 women with UCC were identified. Uterine clear cell carcinoma with and without LND had comparable 5-year OS for all combinations of CT and RT on univariate and multivariate analyses. In stage I papillary serous uterine cancer, brachytherapy and CT were associated with increased survival; however, the benefit of chemotherapy was limited to those with surgical staging. In contrast, no adjuvant therapy was associated with survival in stage I uterine clear cell carcinoma, and further investigation to identify more effective therapies is warranted.


Complexity and anisotropy in host morphology make populations less susceptible to epidemic outbreaks.
One of the challenges in epidemiology is to account for the complex morphological structure of hosts such as plant roots, crop fields, farms, cells, animal habitats and social networks, when the transmission of infection occurs between contiguous hosts. Morphological complexity brings an inherent heterogeneity in populations and affects the dynamics of pathogen spread in such systems. We have analysed the influence of realistically complex host morphology on the threshold for invasion and epidemic outbreak in an SIR (susceptible-infected-recovered) epidemiological model. We show that disorder expressed in the host morphology and anisotropy reduces the probability of epidemic outbreak and thus makes the system more resistant to epidemic outbreaks. We obtain general analytical estimates for minimally safe bounds for an invasion threshold and then illustrate their validity by considering an example of host data for branching hosts (salamander retinal ganglion cells). Several spatial arrangements of hosts with different degrees of heterogeneity have been considered in order to separately analyse the role of shape complexity and anisotropy in the host population. The estimates for invasion threshold are linked to morphological characteristics of the hosts that can be used for determining the threshold for invasion in practical applications.


Affibody molecules for epidermal growth factor receptor targeting in vivo: aspects of dimerization and labeling chemistry.
Noninvasive detection of epidermal growth factor receptor (EGFR) expression in malignant tumors by radionuclide molecular imaging may provide diagnostic information influencing patient management. The aim of this study was to evaluate a novel EGFR-targeting protein, the ZEGFR:1907 Affibody molecule, for radionuclide imaging of EGFR expression, to determine a suitable tracer format (dimer or monomer) and optimal label. An EGFR-specific Affibody molecule, ZEGFR:1907, and its dimeric form, (ZEGFR:1907)2, were labeled with 111In using benzyl-diethylenetriaminepentaacetic acid and with 125I using p-iodobenzoate. Affinity and cellular retention of conjugates were evaluated in vitro. Biodistribution of radiolabeled Affibody molecules was compared in mice bearing EGFR-expressing A431 xenografts. Specificity of EGFR targeting was confirmed by comparison with biodistribution of non-EGFR-specific counterparts. Head-to-tail dimerization of the Affibody molecule improved the dissociation rate. In vitro, dimeric forms demonstrated superior cellular retention of radioactivity. For both molecular set-ups, retention was better for the 111In-labeled tracer than for the radioiodinated counterpart. In vivo, all conjugates accumulated specifically in xenografts and in EGFR-expressing tissues. The retention of radioactivity in tumors was better in vivo for dimeric forms; however, the absolute uptake values were higher for monomeric tracers. The best tracer, 111In-labeled ZEGFR:1907, provided a tumor-to-blood ratio of 100 (24 h after injection). The radiometal-labeled monomeric Affibody molecule ZEGFR:1907 has a potential for radionuclide molecular imaging of EGFR expression in malignant tumors.


The Bipolar Affective Disorder Dimension Scale (BADDS)--a dimensional scale for rating lifetime psychopathology in bipolar spectrum disorders.
Current operational diagnostic systems have substantial limitations for lifetime diagnostic classification of bipolar spectrum disorders. Issues include: (1) It is difficult to operationalize the integration of diverse episodes of psychopathology, (2) Hierarchies lead to loss of information, (3) Boundaries between diagnostic categories are often arbitrary, (4) Boundaries between categories usually require a major element of subjective interpretation, (5) Available diagnostic categories are relatively unhelpful in distinguishing severity, (6) "Not Otherwise Specified (NOS)" categories are highly heterogeneous, (7) Subclinical cases are not accommodated usefully within the current diagnostic categories. This latter limitation is particularly pertinent in the context of the increasing evidence for the existence of a broader bipolar spectrum than has been acknowledged within existing classifications. We have developed a numerical rating system, the Bipolar Affective Disorder Dimension Scale, BADDS, that can be used as an adjunct to conventional best-estimate lifetime diagnostic procedures. The scale definitions were informed by (a) the current concepts of mood syndrome recognized within DSMIV and ICD10, (b) the literature regarding severity of episodes, and (c) our own clinical experience. We undertook an iterative process in which we initially agreed scale definitions, piloted their use on sets of cases and made modifications to improve utility and reliability. BADDS has four dimensions, each rated as an integer on a 0 - 100 scale, that measure four key domains of lifetime psychopathology: Mania (M), Depression (D), Psychosis (P) and Incongruence (I). In our experience it is easy to learn, straightforward to use, has excellent inter-rater reliability and retains the key information required to make diagnoses according to DSMIV and ICD10. Use of BADDS as an adjunct to conventional categorical diagnosis provides a richer description of lifetime psychopathology that (a) can accommodate sub-clinical features, (b) discriminate between illness severity amongst individuals within a single conventional diagnostic category, and (c) demonstrate the similarity between the illness experience of individuals who have been classified into different disease categories but whose illnesses both fall near the boundaries between the two categories. BADDS may be useful for researchers and clinicians who are interested in description and classification of lifetime psychopathology of individuals with disorders lying on the bipolar spectrum.


Global lessons learned from COVID-19 mass casualty incidents.
With healthcare systems rapidly becoming overwhelmed and occupied by patients during a pandemic, effective and safe care for patients is easily compromised. During the course of the current pandemic, numerous treatment guidelines have been developed and published that have improved care for patients with COVID-19. Certain lessons have only been learned during the course of the outbreak, from which we can learn for future pandemics. This editorial aims to raise awareness about the importance of timely stockpiling of sufficient amounts of personal protection equipment and medications, adequate oxygen supplies, uninterrupted electricity, and fair locally adapted triage strategies.


Diet and human mobility from the lapita to the early historic period on Uripiv island, Northeast Malakula, Vanuatu.
Vanuatu was first settled ca. 3000 years ago by populations associated with the Lapita culture. Models of diet, subsistence practices, and human interaction for the Lapita and subsequent occupation periods have been developed mainly using the available archaeological and paleoenvironmental data. We test these models using stable (carbon, nitrogen, and sulfur) and radiogenic (strontium) isotopes to assess the diet and childhood residency of past communities that lived on the small (<1 km2) island of Uripiv, located off the northeast coast of Malakula, Vanuatu. The burials are from the initial Lapita occupation of the island (ca. 2800-2600 BP), the subsequent later Lapita (LL, ca. 2600-2500 BP) and post-Lapita (PL, ca. 2500-2000 BP) occupations, in addition to a late prehistoric/historic (LPH, ca. 300-150 BP) occupation period. The human stable isotope results indicate a progressively more terrestrial diet over time, which supports the archaeological model of an intensification of horticultural and arboricultural systems as local resources were depleted, populations grew, and cultural situations changed. Pig diets were similar and included marine foods during the Lapita and PL periods but were highly terrestrial during the LPH period. This dietary pattern indicates that there was little variation in animal husbandry methods during the first 800 years of prehistory; however, there was a subsequent change as animal diets became more controlled in the LPH period. After comparison with the local bioavailable 87Sr/86Sr baseline, all of the Lapita and LPH individuals appeared to be 'local', but three of the PL individuals were identified as "non-local." We suggest that these "non-locals" moved to the island after infancy or childhood from one of the larger islands, supporting the model of a high level of regional interaction during the post-Lapita period.


Evidence of nNOS and ChAT positive phenotypes in nervous ganglia of the retrostyloid space.
The cholinergic and nitrergic phenotypes in human fetal ganglia (inferior) of the glossopharyngeal and vagus nerves were overlooked in basic research. Lack of a positive neuronal NO synthase (nNOS) phenotype in the inferior vagal fetal ganglion was recently suggested to be an individually variable phenotype. Choline acetyltransferase (ChAT) was not evaluated previously in ontogenesis. We aimed to evaluate these phenotypes in human midterm fetuses. Samples from five specimens with gestational ages varying from 4 to 6 months were used. Immunohistochemistry for nNOS, ChAT, neurofilaments, and S100 protein was performed. Neuronal somata were positively stained for nNOS, ChAT and neurofilaments in the inferior glossopharyngeal and vagal ganglia. S100 protein distinctively labelled the satellite glial cells ensheating the respective neurons. In human midterm fetuses vagal and glossopharyngeal inferior ganglia are nitrergic and cholinergic. To evaluate a functional role of these phenotypes in ontogenesis, the specific anatomic circuits should be further checked. Differences in immune labelling should be evaluated by use of similar antibodies from different manufacturers.


Reduction in Glycated Hemoglobin and Daily Insulin Dose Alongside Circadian Clock Upregulation in Patients With Type 2 Diabetes Consuming a Three-Meal Diet: A Randomized Clinical Trial.
In type 2 diabetes, insulin resistance and progressive β-cell failure require treatment with high insulin doses, leading to weight gain. Our aim was to study whether a three-meal diet (3Mdiet) with a carbohydrate-rich breakfast may upregulate clock gene expression and, as a result, allow dose reduction of insulin, leading to weight loss and better glycemic control compared with an isocaloric six-meal diet (6Mdiet). Twenty-eight volunteers with diabetes (BMI 32.4 ± 5.2 kg/m2 and HbA1c 8.1 ± 1.1% [64.5 ± 11.9 mmol/mol]) were randomly assigned to 3Mdiet or 6Mdiet. Body weight, glycemic control, continuous glucose monitoring (CGM), appetite, and clock gene expression were assessed at baseline, after 2 weeks, and after 12 weeks. 3Mdiet, but not 6Mdiet, led to a significant weight loss (-5.4 ± 0.9 kg) (P < 0.01) and decreased HbA1c (-12 mmol/mol [-1.2%]) (P < 0.0001) after 12 weeks. Fasting glucose and daily and nocturnal glucose levels were significantly lower on the 3Mdiet. CGM showed a significant decrease in the time spent in hyperglycemia only on the 3Mdiet. Total daily insulin dose was significantly reduced by 26 ± 7 units only on the 3Mdiet. There was a significant decrease in the hunger and cravings only in the 3Mdiet group. Clock genes exhibited oscillation, increased expression, and higher amplitude on the 3Mdiet compared with the 6Mdiet. A 3Mdiet, in contrast to an isocaloric 6Mdiet, leads to weight loss and significant reduction in HbA1c, appetite, and overall glycemia, with a decrease in daily insulin. Upregulation of clock genes seen in this diet intervention could contribute to the improved glucose metabolism.


Comparison of breast and bowel cancer screening uptake patterns in a common cohort of South Asian women in England.
Inequalities in uptake of cancer screening by ethnic minority populations are well documented in a number of international studies. However, most studies to date have explored screening uptake for a single cancer only. This paper compares breast and bowel cancer screening uptake for a cohort of South Asian women invited to undertake both, and similarly investigates these women's breast cancer screening behaviour over a period of fifteen years. Screening data for rounds 1, 2 and 5 (1989-2004) of the NHS breast cancer screening programme and for round 1 of the NHS bowel screening pilot (2000-2002) were obtained for women aged 50-69 resident in the English bowel screening pilot site, Coventry and Warwickshire, who had been invited to undertake breast and bowel cancer screening in the period 2000-2002. Breast and bowel cancer screening uptake levels were calculated and compared using the chi-squared test. 72,566 women were invited to breast and bowel cancer screening after exclusions. Of these, 3,539 were South Asian and 69,027 non-Asian; 18,730 had been invited to mammography over the previous fifteen years (rounds 1 to 5). South Asian women were significantly less likely to undertake both breast and bowel cancer screening; 29.9% (n = 1,057) compared to 59.4% (n = 40,969) for non-Asians (p < 0.001). Women in both groups who consistently chose to undertake breast cancer screening in rounds 1, 2 and 5 were more likely to complete round 1 bowel cancer screening. However, the likelihood of completion of bowel cancer screening was still significantly lower for South Asians; 49.5% vs. 82.3% for non-Asians, p < 0.001. South Asian women who undertook breast cancer screening in only one round were no more likely to complete bowel cancer screening than those who decided against breast cancer screening in all three rounds. In contrast, similar women in the non-Asian population had an increased likelihood of completing the new bowel cancer screening test. The likelihood of continued uptake of mammography after undertaking screening in round 1 differed between South Asian religio-linguistic groups. Noticeably, women in the Muslim population were less likely to continue to participate in mammography than those in other South Asian groups. Culturally appropriate targeted interventions are required to reduce observed disparities in cancer screening uptakes.


The knee meniscus: structure-function, pathophysiology, current repair techniques, and prospects for regeneration.
Extensive scientific investigations in recent decades have established the anatomical, biomechanical, and functional importance that the meniscus holds within the knee joint. As a vital part of the joint, it acts to prevent the deterioration and degeneration of articular cartilage, and the onset and development of osteoarthritis. For this reason, research into meniscus repair has been the recipient of particular interest from the orthopedic and bioengineering communities. Current repair techniques are only effective in treating lesions located in the peripheral vascularized region of the meniscus. Healing lesions found in the inner avascular region, which functions under a highly demanding mechanical environment, is considered to be a significant challenge. An adequate treatment approach has yet to be established, though many attempts have been undertaken. The current primary method for treatment is partial meniscectomy, which commonly results in the progressive development of osteoarthritis. This drawback has shifted research interest toward the fields of biomaterials and bioengineering, where it is hoped that meniscal deterioration can be tackled with the help of tissue engineering. So far, different approaches and strategies have contributed to the in vitro generation of meniscus constructs, which are capable of restoring meniscal lesions to some extent, both functionally as well as anatomically. The selection of the appropriate cell source (autologous, allogeneic, or xenogeneic cells, or stem cells) is undoubtedly regarded as key to successful meniscal tissue engineering. Furthermore, a large variation of scaffolds for tissue engineering have been proposed and produced in experimental and clinical studies, although a few problems with these (e.g., byproducts of degradation, stress shielding) have shifted research interest toward new strategies (e.g., scaffoldless approaches, self-assembly). A large number of different chemical (e.g., TGF-β1, C-ABC) and mechanical stimuli (e.g., direct compression, hydrostatic pressure) have also been investigated, both in terms of encouraging functional tissue formation, as well as in differentiating stem cells. Even though the problems accompanying meniscus tissue engineering research are considerable, we are undoubtedly in the dawn of a new era, whereby recent advances in biology, engineering, and medicine are leading to the successful treatment of meniscal lesions.


A systems approach to achieving CarerNet--an integrated and intelligent telecare system.
The system requirements for an integrated telecare system are presented by using a modification of the CORE methodology. The resulting system model uses viewpoint analysis to establish the needs and requirements of both the client and the care providers within a system context and discusses the implications for a user-centered, technology-based solution referred to as "CarerNet." The implementation of CarerNet is considered in terms of the enabling technologies required within the local environment of the client and identifies the monitoring, networking requirements, and system intelligence necessary to the provision of a comprehensive telecare service. A hypothetical case study based on patient aftercare following discharge from the hospital is presented to illustrate the points discussed.


Transforming health care delivery through consumer engagement, health data transparency, and patient-generated health information.
Address current topics in consumer health informatics. Literature review. Current health care delivery systems need to be more effective in the management of chronic conditions as the population turns older and experiences escalating chronic illness that threatens to consume more health care resources than countries can afford. Most health care systems are positioned poorly to accommodate this. Meanwhile, the availability of ever more powerful and cheaper information and communication technology, both for professionals and consumers, has raised the capacity to gather and process information, communicate more effectively, and monitor the quality of care processes. Adapting health care systems to serve current and future needs requires new streams of data to enable better self-management, improve shared decision making, and provide more virtual care. Changes in reimbursement for health care services, increased adoption of relevant technologies, patient engagement, and calls for data transparency raise the importance of patient-generated health information, remote monitoring, non-visit based care, and other innovative care approaches that foster more frequent contact with patients and better management of chronic conditions.


Novel POC1A mutation in primordial dwarfism reveals new insights for centriole biogenesis.
POC1A encodes a WD repeat protein localizing to centrioles and spindle poles and is associated with short stature, onychodysplasia, facial dysmorphism and hypotrichosis (SOFT) syndrome. These main features are related to the defect in cell proliferation of chondrocytes in growth plate. In the current study, we aimed at identifying the molecular basis of two patients with primordial dwarfism (PD) in a single family through utilization of whole-exome sequencing. A novel homozygous p.T120A missense mutation was detected in POC1A in both patients, a known causative gene of SOFT syndrome, and confirmed using Sanger sequencing. To test the pathogenicity of the detected mutation, primary fibroblast cultures obtained from the patients and a control individual were used. For evaluating the global gene expression profile of cells carrying p.T120A mutation in POC1A, we performed the gene expression array and compared their expression profiles to those of control fibroblast cells. The gene expression array analysis showed that 4800 transcript probes were significantly deregulated in cells with p.T120A mutation in comparison to the control. GO term association results showed that deregulated genes are mostly involved in the extracellular matrix and cytoskeleton. Furthermore, the p.T120A missense mutation in POC1A caused the formation of abnormal mitotic spindle structure, including supernumerary centrosomes, and changes in POC1A were accompanied by alterations in another centrosome-associated WD repeat protein p80-katanin. As a result, we identified a novel mutation in POC1A of patients with PD and showed that this mutation causes the formation of multiple numbers of centrioles and multipolar spindles with abnormal chromosome arrangement.


Monoclonal antibodies to ethanol-induced rat liver cytochrome P-450 that metabolizes aniline and nitrosamines.
Hybridomas were prepared from mouse myeloma cells and spleen cells derived from female BALB/c mice that had been immunized with a partially purified ethanol-induced rat liver cytochrome P-450 (P-450et). Monoclonal antibodies (MAbs) produced by the hybridomas were screened for binding to P-450et with a radioimmunoassay. Thirty-one independent hybrid clones produced MAbs that had a high affinity for P-450et. Each clone produced MAbs of a single subclass of the mouse immunoglobulins IgG1, IgG2a, IgM, or IgA. Ten of the 31 MAbs also immunoprecipitated P-450et as determined by Ouchterlony double-immunodiffusion analyses. One of the MAbs was tested for cross-reactivity with other rabbit and rat liver cytochromes P-450 and was found not to cross-react with rat liver P-450 induced by either phenobarbital, beta-naphthoflavone, or rabbit liver P-450LM2 or P-450LM4. Nine of the MAbs were tested for cross-reactivity with rat liver clofibrate-induced P-450, rat liver pregnenolone-16-alpha-carbonitrile-induced P-450, and a human liver P-450. All the MAbs showed no cross-reactivity except for one MAb which cross-reacted with both pregnenolone-16-alpha-carbonitrile and human P-450 and three MAbs which cross-reacted with human P-450. Three antigen-precipitating MAbs and four nonprecipitating MAbs were tested for their effects on the aniline p-hydroxylase activity of liver microsomes of untreated rats and from rats treated with acetone, pyrazole, methylpyrazole, or imidazole. One of the seven MAbs tested, 1-91-3, inhibited enzyme activity of acetone-, pyrazole-, or methylpyrazole-induced microsomes by 54, 47, and 48%, respectively. This indicates that at least 50% of microsomal cytochrome P-450 aniline p-hydroxylase activity in the latter is a function of a P-450 enzyme that contained the epitope to which the MAb 1-91-3 is directed. With untreated and imidazole-induced microsomes, 32 and 21% inhibition of the enzyme activity was observed. In reconstituted systems containing phospholipid and NADPH-cytochrome P-450 reductase, MAb 1-91-3 inhibited aniline p-hydroxylase activity of purified ethanol-induced P-450et and acetone-induced P-450 by more than 90%. Nitrosodimethylamine demethylase activity of acetone-induced rat microsomes was inhibited by the various MAbs up to 77% and the activity of the purified acetone-induced P-450 was inhibited up to 92%.(ABSTRACT TRUNCATED AT 400 WORDS)


Determinants of neurologic deterioration and stroke-free survival after spontaneous cervicocranial dissections: a multicenter study.
Patients with spontaneous cervicocranial dissection (SCCD) may experience new or recurrent ischemic events despite antiplatelet or anticoagulant therapy. Treatment with stent placement is an available option; however, the literature on patient selection is limited. Thus, identifying patients at high risk for neurologic deterioration after SCCD is of critical importance. The present study examined the rate of neurologic deterioration in medically treated patients with SCCD and evaluated demographic, clinical, and radiologic factors affecting this deterioration. We retrospectively identified consecutive patients with SCCD over a 7-year period from 3 medical institutions, and evaluated the relationships between demographic data, clinical characteristics, and angiographical findings and subsequent neurologic outcomes. Neurologic deterioration was defined as transient ischemic attack (TIA), ischemic stroke, or death occurring during hospitalization or within 1 year of diagnosis. Kaplan-Meier curves were used to determine neurologic event-free survival up to 12 months. A total of 69 patients (mean age, 47.8 ± 14 years; 45 males) with SCCD were included in the study. Eleven patients (16%) experienced in-hospital neurologic deterioration (TIA in 9, ischemic stroke in 1) or death (1 patient). An additional 8 patients developed neurologic deterioration within 1 year after discharge (TIA in 5, ischemic stroke in 2, and death in 1). The overall 1-year event-free survival rate was 72%. Women (P = .046), patients with involvement of both vertebral arteries (P = .02), and those with intracranial arterial involvement (P = .018) had significantly higher rates of neurologic deterioration. Our findings indicate that neurologic deterioration is relatively common after SCCD despite medical treatment in women, patients with bilateral vertebral artery involvement, and those with intracranial vessel involvement.


Lassa fever clinical course and setting a standard of care for future randomized trials: A protocol for a cohort study of Lassa-infected patients in Nigeria (LASCOPE).
Lassa Fever (LF), is a severe viral disease prevalent in Western Africa. It is classified as a priority disease by the World Health Organization (WHO). Ribavirin is the recommended therapy despite weak evidence of its efficacy. Promising therapeutic agents are becoming available for evaluation in human. Before launching therapeutic trials, we need data on the evolution of the disease under the best possible conditions of care. We have initiated a prospective study in Nigeria to better understand the clinical course and prognostic factors of LF while implementing high quality standardized care. Inclusion criteria are: suspected or confirmed LF and informed consent. Participants are followed 60 days from admission and receive free of charge standardized supportive care and biological monitoring, as well as intravenous ribavirin for those with confirmed LF. Data are collected using standardized case report forms (CRF). Primary and secondary outcomes are fatality and severe morbidity, with special focus on acute kidney dysfunction and pregnancy complications. Factors associated with outcomes will be investigated. The cohort is planned for 3 years. Inclusions started in April 2018 at the Federal Medical Center Owo in Ondo State. A second site will open in Nigeria in 2020 and discussions are underway to open a site in Benin. 150 to 200 new participants are expected per year. This cohort will: provide evidence to standardize LF case management; provide key inputs to design future clinical trials of novel therapeutics; and establish clinical research teams capable of conducting such trials in LF-endemic areas. The LASCOPE study was registered on ClinicalTrial.gov (NCT03655561).


The foraging and antipredator behaviour of growth-enhanced transgenic Atlantic salmon.
Growth rate has been established as a key parameter influencing foraging decisions involving the risk of predation. Through genetic manipulation, transgenic salmon bred to contain and transmit a growth hormone transgene are able to achieve growth rates significantly greater than those of unmanipulated salmon. Using such growth-enhanced transgenic Atlantic salmon, we directly tested the hypothesis that relative growth rates should be correlated with willingness to risk exposure to a predator. We used size-matched transgenic and control salmon in two experiments where these fish could either feed in safety, or in the presence of the predator. The first experiment constrained the predator behind a Plexiglas partition (no risk of mortality), the second required the fish to feed in the same compartment as the predator (a finite risk of mortality). During these experiments, transgenic salmon had rates of consumption that were approximately five times that of the control fish and rates of movement approximately double that of controls. Transgenic salmon also spent significantly more time feeding in the presence of the predator, and consumed absolutely more food at that location. When there was a real risk of mortality, control fish almost completely avoided the dangerous location. Transgenic fish continued to feed at this location, but at a reduced level. These data demonstrate that the growth enhancement associated with the transgenic manipulation increases the level of risk these fish are willing to incur while foraging. If the genetic manipulation necessary to increase growth rates is achievable through evolutionary change, these experiments suggest that growth rates of Atlantic salmon may be optimized by the risk of predation. Copyright 1999 The Association for the Study of Animal Behaviour.


Fast molecular tracking maps nanoscale dynamics of plasma membrane lipids.
We describe an optical method capable of tracking a single fluorescent molecule with a flexible choice of high spatial accuracy (approximately 10-20 nm standard deviation or approximately 20-40 nm full-width-at-half-maximum) and temporal resolution (< 1 ms). The fluorescence signal during individual passages of fluorescent molecules through a spot of excitation light allows the sequential localization and thus spatio-temporal tracking of the molecule if its fluorescence is collected on at least three separate point detectors arranged in close proximity. We show two-dimensional trajectories of individual, small organic dye labeled lipids diffusing in the plasma membrane of living cells and directly observe transient events of trapping on < 20 nm spatial scales. The trapping is cholesterol-assisted and much more pronounced for a sphingo- than for a phosphoglycero-lipid, with average trapping times of approximately 15 ms and < 4 ms, respectively. The results support previous STED nanoscopy measurements and suggest that, at least for nontreated cells, the transient interaction of a single lipid is confined to macromolecular dimensions. Our experimental approach demonstrates that fast molecular movements can be tracked with minimal invasion, which can reveal new important details of cellular nano-organization.


Neurosurgery simulation in residency training: feasibility, cost, and educational benefit.
The effort required to introduce simulation in neurosurgery academic programs and the benefits perceived by residents have not been systematically assessed. To create a neurosurgery simulation curriculum encompassing basic and advanced skills, cadaveric dissection, cranial and spine surgery simulation, and endovascular and computerized haptic training. A curriculum with 68 core exercises per academic year was distributed in individualized sets of 30 simulations to 6 neurosurgery residents. The total number of procedures completed during the academic year was set to 180. The curriculum includes 79 simulations with physical models, 57 cadaver dissections, and 44 haptic/computerized sessions. Likert-type evaluations regarding self-perceived performance were completed after each exercise. Subject identification was blinded to junior (postgraduate years 1-3) or senior resident (postgraduate years 4-6). Wilcoxon rank testing was used to detect differences within and between groups. One hundred eighty procedures and surveys were analyzed. Junior residents reported proficiency improvements in 82% of simulations performed (P < .001). Senior residents reported improvement in 42.5% of simulations (P < .001). Cadaver simulations accrued the highest reported benefit (71.5%; P < .001), followed by physical simulators (63.8%; P < .001) and haptic/computerized (59.1; P < .001). Initial cost is $341,978.00, with $27,876.36 for annual operational expenses. The systematic implementation of a simulation curriculum in a neurosurgery training program is feasible, is favorably regarded, and has a positive impact on trainees of all levels, particularly in junior years. All simulation forms, cadaver, physical, and haptic/computerized, have a role in different stages of learning and should be considered in the development of an educational simulation program.


An experimental demonstration of Fisher's principle: evolution of sexual proportion by natural selection.
Most sexually reproducing species have sexual proportions around 1:1. This major biological phenomenon remained unexplained until 1930, when FISHER proposed that it results from a mechanism of natural selection. Here we report the first experimental test of his model that obeys all its assumptions. We used a naturally occurring X-Y meiotic drive system--the sex-ratio trait of Drosophila mediopunctat--to generate female-biased experimental populations. As predicted by FISHER, these populations evolved toward equal sex proportions due to natural selection, by accumulation of autosomal alleles that direct the parental reproductive effort toward the rare sex. Classical Fisherian evolution is a rather slow mechanism: despite a very large amount of genetic variability, the experimental populations evolved from 16% of males to 32% of males in 49 generations and would take 330 generations (29 years) to reach 49%. This slowness has important implications for species potentially endangered by skewed sexual proportions, such as reptiles with temperature sex determination.


Leishmania amazonensis Subverts the Transcription Factor Landscape in Dendritic Cells to Avoid Inflammasome Activation and Stall Maturation.
Leishmania parasites are the causative agents of human leishmaniases. They infect professional phagocytes of their mammalian hosts, including dendritic cells (DCs) that are essential for the initiation of adaptive immune responses. These immune functions strictly depend on the DC's capacity to differentiate from immature, antigen-capturing cells to mature, antigen-presenting cells-a process accompanied by profound changes in cellular phenotype and expression profile. Only little is known on how intracellular Leishmania affects this important process and DC transcriptional regulation. Here, we investigate these important open questions analyzing phenotypic, cytokine profile and transcriptomic changes in murine, immature bone marrow-derived DCs (iBMDCs) infected with antibody-opsonized and non-opsonized Leishmania amazonensis (L.am) amastigotes. DCs infected by non-opsonized amastigotes remained phenotypically immature whereas those infected by opsonized parasites displayed a semi-mature phenotype. The low frequency of infected DCs in culture led us to use DsRed2-transgenic parasites allowing for the enrichment of infected BMDCs by FACS. Sorted infected DCs were then subjected to transcriptomic analyses using Affymetrix GeneChip technology. Independent of parasite opsonization, Leishmania infection induced expression of genes related to key DC processes involved in MHC Class I-restricted antigen presentation and alternative NF-κB activation. DCs infected by non-opsonized parasites maintained an immature phenotype and showed a small but significant down-regulation of gene expression related to pro-inflammatory TLR signaling, the canonical NF-kB pathway and the NLRP3 inflammasome. This transcriptomic profile was further enhanced in DCs infected with opsonized parasites that displayed a semi-mature phenotype despite absence of inflammasome activation. This paradoxical DC phenotype represents a Leishmania-specific signature, which to our knowledge has not been observed with other opsonized infectious agents. In conclusion, systems-analyses of our transcriptomics data uncovered important and previously unappreciated changes in the DC transcription factor landscape, thus revealing a novel Leishmania immune subversion strategy directly acting on transcriptional control of gene expression. Our data raise important questions on the dynamic and reciprocal interplay between trans-acting and epigenetic regulators in establishing permissive conditions for intracellular Leishmania infection and polarization of the immune response.


Inhalational drug delivery from seven different spacer devices.
A study was performed to determine in vitro the difference in drug output of seven currently available spacer devices when used with different inhaled medications. A glass multistage liquid impinger (MSLI) was used to determine the amount of disodium cromoglycate (DSCG, 5 mg), salbutamol (100 micrograms), or budesonide (200 micrograms) obtained in various particle size ranges from metered dose inhalers (MDIs) actuated directly into the MSLI or via one of seven different spacer devices; the Fisonair, Nebuhaler, Volumatic, Inspirease, Aerochamber, Aerosol Cloud Enhancer, and Dynahaler. In particles smaller than 5 microns in diameter the dose of DSCG recovered from the Fisonair and Nebuhaler was 118% and 124%, respectively, of that recovered using the MDI alone. The dose recovered from the smaller volume spacers was 90% (Inspirease), 36% (Aerochamber), 33% (Aerosol Cloud Enhancer), and 21% (Dynahaler) of that from the MDI alone. The Volumatic increased the amount of salbutamol in particles smaller than 5 microns to 117% of that from the MDI, and the Inspirease and Aerochamber spacers decreased it by nearly 50%. The amount of budesonide in small particles recovered after use of the Nebuhaler, Inspirease, and the Aerochamber was 92%, 101%, and 78%, respectively, of that from the MDI alone. Under the test conditions used, large volume spacers such as the Fisonair, Nebuhaler, and Volumatic delivered significantly more DSCG and salbutamol than the smaller spacers tested. The differences between spacers were less for budesonide than the other medications studied. This study shows that there are significant differences in the amount of drug available for inhalation when different spacers are used as inhalational aids with different drugs. Spacer devices need to be fully evaluated for each drug prescribed for them.


A mutation-resistant deoxyribozyme OR gate for highly selective detection of viral nucleic acids.
Highly selective probes hybridize only to fully complementary DNA or RNA sequences and, therefore, often fail to recognize mutated viral genomes. Here we designed a probe that possesses two seemingly incompatible properties: it tolerates some point mutations in genome, while it remains selective towards others. An OR deoxyribozyme logic gate was designed to fluorescently report the sequences of enterovirus 71 (EV71) covering ∼90% of all known EV71 strains. Importantly, sequences of closely related coxsackieviruses that differed by single nucleotides were reliably differentiated in 7 out of 8 cases.


Fine Mapping for Identification of Citrus Alternaria Brown Spot Candidate Resistance Genes and Development of New SNP Markers for Marker-Assisted Selection.
Alternaria brown spot (ABS) is a serious disease affecting susceptible citrus genotypes, which is a strong concern regarding citrus breeding programs. Resistance is conferred by a recessive locus (ABSr) previously located by our group within a 3.3 Mb genome region near the centromere in chromosome III. This work addresses fine-linkage mapping of this region for identifying candidate resistance genes and develops new molecular markers for ABS-resistance effective marker-assisted selection (MAS). Markers closely linked to ABSr locus were used for fine mapping using a 268-segregating diploid progeny derived from a heterozygous susceptible × resistant cross. Fine mapping limited the genomic region containing the ABSr resistance gene to 366 kb, flanked by markers at 0.4 and 0.7 cM. This region contains nine genes related to pathogen resistance. Among them, eight are resistance (R) gene homologs, with two of them harboring a serine/threonine protein kinase domain. These two genes along with a gene encoding a S-adenosyl-L-methionine-dependent-methyltransferase protein, should be considered as strong candidates for ABS-resistance. Moreover, the closest SNP was genotyped in 40 citrus varieties, revealing very high association with the resistant/susceptible phenotype. This new marker is currently used in our citrus breeding program for ABS-resistant parent and cultivar selection, at diploid, triploid and tetraploid level.


Endovascular treatment of fusiform cerebral aneurysms with the Pipeline Embolization Device.
Despite advances in surgical and endovascular techniques, fusiform aneurysms remain a therapeutic challenge. Introduction of flow-diverting stents has revolutionized the treatment of aneurysms with wide necks and of complex morphology. The authors report their experience with the endovascular treatment of fusiform aneurysms using the Pipeline Embolization Device. A retrospective review of 146 patients with cerebral aneurysms treated with the Pipeline Embolization Device between June 2011 and January 2013 was performed. Twenty-four patients were identified as having fusiform aneurysms. Twenty-four aneurysms in these 24 patients were treated. The mean patient age was 59 years. There were 9 men and 15 women. Angiographic and clinical data (including the modified Rankin Scale [mRS] score) were recorded at the time of treatment and at follow-up. The aneurysms were located in the internal carotid artery in 8 patients (33.3%), middle cerebral artery in 8 patients (33.3%), anterior cerebral artery in 1 patient (4%), and vertebrobasilar circulation in 7 patients (29%). The aneurysms were smaller than 10 mm in 3 patients, 10-25 mm in 16 patients, and larger than 25 mm in 5 patients. The mean largest dimension diameter was 18 mm. Stent deployment was successful in all cases. The minor procedural morbidity was 4% (1 case). Morbidity and mortality related to aneurysm treatment were 4.2% and 4.2%, respectively. The mean mRS scores preoperatively and at clinical follow-up (median 6.0 months, mean 6.9 months) were 0.71 and 1.2, respectively (91.7% presented with an mRS score of 2 or better, and 79.2% had an mRS score of 2 or better at the 6.0-month follow-up). At clinical follow-up, 82.6% of patients were stable or had improved, 13.0% worsened, and 4.2% had died. Twenty-two (91.7%) of 24 patients had follow-up angiography available (mean follow-up time 6.3 months); 59% had excellent angiographic results (> 95% or complete occlusion), 31.8% had complete aneurysm occlusion, 27.3% had greater than 95% aneurysm occlusion, 18.2% had a moderate decrease in size (50%-95%), 4.5% had a minimal decrease in size (< 50%), 13.6% had not changed, and 4.5% had an increase in size. This series demonstrates that endovascular treatment of fusiform cerebral aneurysms with flow diversion was a safe and effective treatment. Procedural complications were low. Long-term morbidity and mortality rates were acceptable given the complex nature of these lesions.


Further evidence for the influence of photoperiod at birth on chronotype in a sample of German adolescents.
Individuals differ in their circadian preferences (chronotype). There is evidence in the literature to support a season-of-birth effect on chronotype but the evidence is not convincing. In part, the relationship is obscured by a number of methodological differences between studies, including the measures used to define morningness, the way in which the seasons were categorized, and the sample size. This study adds to the literature in several ways. First, we adopt a new approach to categorizing the photoperiod rather than the calendar season; thus we prefer to use the term photoperiod at birth. Second, we used two measures of morningness. Third, we used a large and homogeneous German sample. The results show that adolescents (n = 2905) born during the increasing photoperiod (Feb-Apr) had a significantly later midpoint of sleep (MSFsc) than those born during the decreasing photoperiod (Aug-Oct). A similar pattern was found for the Composite Scale of Morningness (CSM). Furthermore, both measures of chronotype demonstrated a significant quadratic function over a 1-yr cycle. When looking at each of six consecutive years separately, the Composite Scale of Morningness suggests a cosine rhythm linked to increasing and decreasing photoperiods that becomes weaker in amplitude with increasing age. Despite the strengths in our study, the effect of photoperiod at birth on chronotype remains small. Future studies may require larger sample sizes, may need to explore how neonatal light exposure modulates chronotype, and may need to track how puberty and adolescent lifestyle habits mask the photoperiod effect.


Reporting guidelines for clinical trial reports for interventions involving artificial intelligence: the CONSORT-AI extension.
The CONSORT 2010 statement provides minimum guidelines for reporting randomized trials. Its widespread use has been instrumental in ensuring transparency in the evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate impact on health outcomes. The CONSORT-AI (Consolidated Standards of Reporting Trials-Artificial Intelligence) extension is a new reporting guideline for clinical trials evaluating interventions with an AI component. It was developed in parallel with its companion statement for clinical trial protocols: SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials-Artificial Intelligence). Both guidelines were developed through a staged consensus process involving literature review and expert consultation to generate 29 candidate items, which were assessed by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed upon in a two-day consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants). The CONSORT-AI extension includes 14 new items that were considered sufficiently important for AI interventions that they should be routinely reported in addition to the core CONSORT 2010 items. CONSORT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention is integrated, the handling of inputs and outputs of the AI intervention, the human-AI interaction and provision of an analysis of error cases. CONSORT-AI will help promote transparency and completeness in reporting clinical trials for AI interventions. It will assist editors and peer reviewers, as well as the general readership, to understand, interpret and critically appraise the quality of clinical trial design and risk of bias in the reported outcomes.


Reactions to UV damage in the model archaeon Sulfolobus solfataricus.
Mechanisms involved in DNA repair and genome maintenance are essential for all organisms on Earth and have been studied intensively in bacteria and eukaryotes. Their analysis in extremely thermophilic archaea offers the opportunity to discover strategies for maintaining genome integrity of the relatively little explored third domain of life, thereby shedding light on the diversity and evolution of these central and important systems. These studies might also reveal special adaptations that are essential for life at high temperature. A number of investigations of the hyperthermophilic and acidophilic crenarchaeote Sulfolobus solfataricus have been performed in recent years. Mostly, the reactions to DNA damage caused by UV light have been analysed. Whole-genome transcriptomics have demonstrated that a UV-specific response in S. solfataricus does not involve the transcriptional induction of DNA-repair genes and it is therefore different from the well-known SOS response in bacteria. Nevertheless, the UV response in S. solfataricus is impressively complex and involves many different levels of action, some of which have been elucidated and shed light on novel strategies for DNA repair, while others involve proteins of unknown function whose actions in the cell remain to be elucidated. The present review summarizes and discusses recent investigations on the UV response of S. solfataricus on both the molecular biological and the cellular levels.


Subjective and objective outcomes of strabismus surgery in children.
The negative psychosocial impact of strabismus in adults has been well documented. Despite the increasingly recognized importance of outcomes research, parents' satisfaction with strabismus treatment in childhood and their assessment of its functional impact and "quality of life" impact have not been investigated. A survey instrument was designed to assess parents' perceptions of preoperative, surgical, and postoperative phases of the clinical experience, including the long-term impact of surgery on their children. Overall satisfaction with the surgical result was rated "good" or "very good" in 85% of 77 children under age 6. The correlation between subjective satisfaction and objective alignment within 10 prism diopters (delta) of orthophoria was significant (P < .001). Parents of children under age 4 noted improved eye contact (61%) and appearance (94%). Parents of older children noted improved interactions with others (47%) and self-esteem (55%). Coordination was considered improved in 56% of the entire group. Subjective satisfaction and psychosocial benefits often occurred even in cases deemed objectively unsuccessful. Surgical correction of strabismus in childhood is clearly perceived by parents to be both successful and important to them and their children.


Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
This chapter about the recognition, treatment, and prevention of heparin-induced thrombocytopenia (HIT) is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices. Among the key recommendations in this chapter are the following: For patients receiving heparin in whom the clinician considers the risk of HIT to be > 1.0%, we recommend platelet count monitoring over no platelet count monitoring (Grade 1C). For patients who are receiving heparin or have received heparin within the previous 2 weeks, we recommend investigating for a diagnosis of HIT if the platelet count falls by >/= 50%, and/or a thrombotic event occurs, between days 5 and 14 (inclusive) following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia has occurred (Grade 1C). For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, we recommend use of an alternative, nonheparin anticoagulant (danaparoid [Grade 1B], lepirudin [Grade 1C], argatroban [Grade 1C], fondaparinux [Grade 2C], or bivalirudin [Grade 2C]) over the further use of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) therapy or initiation/continuation of vitamin K antagonists (VKAs) [Grade 1B]. The guidelines include specific recommendations for nonheparin anticoagulant dosing that differ from the package inserts. For patients with strongly suspected or confirmed HIT, we recommend against the use of vitamin K antagonist (VKA) [coumarin] therapy until after the platelet count has substantially recovered (usually, to at least 150 x 10(9)/L) over starting VKA therapy at a lower platelet count (Grade 1B); that VKA therapy be started only with low maintenance doses (maximum, 5 mg of warfarin or 6 mg of phenprocoumon) over higher initial doses (Grade 1B); and that the nonheparin anticoagulant (eg, lepirudin, argatroban, danaparoid) be continued until the platelet count has reached a stable plateau, the international normalized ratio (INR) has reached the intended target range, and after a minimum overlap of at least 5 days between nonheparin anticoagulation and VKA therapy rather than a shorter overlap (Grade 1B). For patients receiving VKAs at the time of diagnosis of HIT, we recommend use of vitamin K (10 mg po or 5 to 10 mg IV) [Grade 1C].


Prostaglandin E2 activates Src signaling in lung adenocarcinoma cell via EP3.
Accumulating evidence suggests that overproduction of prostaglandin (PG) E2 attributable to induction of cyclooxygenase-2 plays an important role in the development of lung adenocarcinoma. Recently, we have reported that a PGE2 receptor, EP3 is involved in appearance of malignant phenotype of a lung adenocarcinoma cell (A549 cell). In line with our previous study, here we investigated if Src signaling could be involved in PGE2-stimulated growth of A549 cells via EP3. PGE2-dependent cell growth in A549 cell positively related to the activation of Src. A specific antagonist against EP3 abrogated the cell growth and Src activation in the cells stimulated with PGE2. Also, the inhibition of Src activity suppressed its downstream signaling related to cell growth as well as the cell growth in the cells treated with PGE2. These results indicate that PGE2-dependent activation of Src signaling via EP3 plays an important role in growth of A549 cells.


Combining multi-population datasets for joint genome-wide association and meta-analyses: The case of bovine milk fat composition traits.
In genome-wide association studies (GWAS), sample size is the most important factor affecting statistical power that is under control of the investigator, posing a major challenge in understanding the genetics underlying difficult-to-measure traits. Combining data sets available from different populations for joint or meta-analysis is a promising alternative to increasing sample sizes available for GWAS. Simulation studies indicate statistical advantages from combining raw data or GWAS summaries in enhancing quantitative trait loci (QTL) detection power. However, the complexity of genetics underlying most quantitative traits, which itself is not fully understood, is difficult to fully capture in simulated data sets. In this study, population-specific and combined-population GWAS as well as a meta-analysis of the population-specific GWAS summaries were carried out with the objective of assessing the advantages and challenges of different data-combining strategies in enhancing detection power of GWAS using milk fatty acid (FA) traits as examples. Gas chromatography (GC) quantified milk FA samples and high-density (HD) genotypes were available from 1,566 Dutch, 614 Danish, and 700 Chinese Holstein Friesian cows. Using the joint GWAS, 28 additional genomic regions were detected, with significant associations to at least 1 FA, compared with the population-specific analyses. Some of these additional regions were also detected using the implemented meta-analysis. Furthermore, using the frequently reported variants of the diacylglycerol acyltransferase 1 (DGAT1) and stearoyl-CoA desaturase (SCD1) genes, we show that significant associations were established with more FA traits in the joint GWAS than the remaining scenarios. However, there were few regions detected in the population-specific analyses that were not detected using the joint GWAS or the meta-analyses. Our results show that combining multi-population data set can be a powerful tool to enhance detection power in GWAS for seldom-recorded traits. Detection of a higher number of regions using the meta-analysis, compared with any of the population-specific analyses also emphasizes the utility of these methods in the absence of raw multi-population data sets to undertake joint GWAS.


Interactions of Airy beams, nonlinear accelerating beams, and induced solitons in Kerr and saturable nonlinear media.
We investigate numerically interactions between two in-phase or out-of-phase Airy beams and nonlinear accelerating beams in Kerr and saturable nonlinear media in one transverse dimension. We discuss different cases in which the beams with different intensities are launched into the medium, but accelerate in opposite directions. Since both the Airy beams and nonlinear accelerating beams possess infinite oscillating tails, we discuss interactions between truncated beams, with finite energies. During interactions we see solitons and soliton pairs generated that are not accelerating. In general, the higher the intensities of interacting beams, the easier to form solitons; when the intensities are small enough, no solitons are generated. Upon adjusting the interval between the launched beams, their interaction exhibits different properties. If the interval is large relative to the width of the first lobes, the generated soliton pairs just propagate individually and do not interact much. However, if the interval is comparable to the widths of the maximum lobes, the pairs strongly interact and display varied behavior.


Ectopic sphenoid sinus pituitary adenoma (ESSPA) with normal anterior pituitary gland: a clinicopathologic and immunophenotypic study of 32 cases with a comprehensive review of the english literature.
Ectopic sphenoid sinus pituitary adenoma (ESSPA) may arise from a remnant of Rathke's pouch. These tumors are frequently misdiagnosed as other neuroendocrine or epithelial neoplasms which may develop in this site (olfactory neuroblastoma, neuroendocrine carcinoma, sinonasal undifferentiated carcinoma, paraganglioma, melanoma). Thirty-two patients with ESSPA identified in patients with normal pituitary glands (intact sella turcica) were retrospectively retrieved from the consultation files of the authors' institutions. Clinical records were reviewed with follow-up obtained. An immunohistochemical panel was performed on available material. Sixteen males and 16 females, aged 2-84 years (mean, 57.1 years), presented with chronic sinusitis, headache, obstructive symptoms, and visual field defects, although several were asymptomatic (n = 6). By definition, the tumors were centered within the sphenoid sinus and demonstrated, by imaging studies or intraoperative examination, a normal sella turcica without a concurrent pituitary adenoma. A subset of tumors showed extension into the nasal cavity (n = 5) or nasopharynx (n = 9). Mean tumor size was 3.4 cm. The majority of tumors were beneath an intact respiratory epithelium (n = 22), arranged in many different patterns (solid, packets, organoid, pseudorosette-rosette, pseudopapillary, single file, glandular, trabecular, insular). Bone involvement was frequently seen (n = 21). Secretions were present (n = 16). Necrosis was noted in 8 tumors. The tumors showed a variable cellularity, with polygonal, plasmacytoid, granular, and oncocytic tumor cells. Severe pleomorphism was uncommon (n = 5). A delicate, salt-and-pepper chromatin distribution was seen. In addition, there were intranuclear cytoplasmic inclusions (n = 25) and multinucleated tumor cells (n = 18). Mitotic figures were infrequent, with a mean of 1 per 10 HPFs and a <1% proliferation index (Ki-67). There was a vascularized to sclerotic or calcified stroma. Immunohistochemistry highlighted the endocrine nature of the tumors, with synaptophysin (97%), CD56 (91%), NSE (76%) and chromogranin (71%); while pan-cytokeratin was positive in 79%, frequently with a dot-like Golgi accentuation (50%). Reactivity with pituitary hormones included 48% reactive for 2 or more hormones (plurihormonal), and 33% reactive for a single hormone, with prolactin seen most frequently (59%); 19% of cases were non-reactive. The principle differential diagnosis includes olfactory neuroblastoma, neuroendocrine carcinoma, melanoma, and meningioma. All patients were treated with surgery. No patients died from disease, although one patient died with persistent disease (0.8 months). Surgery is curative in the majority of cases, although recurrence/persistence was seen in 4 patients (13.8%). In conclusion, ESSPAs are rare, affecting middle aged patients with non-specific symptoms, showing characteristic light microscopy and immunohistochemical features of their intrasellar counterparts. When encountering a tumor within the sphenoid sinus, ectopic pituitary adenoma must be considered, and pertinent imaging, clinical, and immunohistochemical evaluation undertaken to exclude tumors within the differential diagnosis. This will result in accurate classification, helping to prevent the potentially untoward side effects or complications of incorrect therapy.


Kainate receptor-mediated synaptic transmissions in the adult rodent insular cortex.
Kainate (KA) receptors are expressed widely in the central nervous system and regulate both excitatory and inhibitory synaptic transmission. KA receptors play important roles in fear memory, anxiety, and pain. However, little is known about their function in synaptic transmission in the insular cortex (IC), a critical region for taste, memory, and pain. Using whole cell patch-clamp recordings, we have shown that KA receptors contribute to fast synaptic transmission in neurons in all layers of the IC. In the presence of the GABA(A) receptor antagonist picrotoxin, the NMDA receptor antagonist AP-5, and the selective AMPA receptor antagonist GYKI 53655, KA receptor-mediated excitatory postsynaptic currents (KA EPSCs) were revealed. We found that KA EPSCs are ~5-10% of AMPA/KA EPSCs in all layers of the adult mouse IC. Similar results were found in adult rat IC. KA EPSCs had a significantly slower rise time course and decay time constant compared with AMPA receptor-mediated EPSCs. High-frequency repetitive stimulations at 200 Hz significantly facilitated the summation of KA EPSCs. In addition, genetic deletion of GluK1 or GluK2 subunit partially reduced postsynaptic KA EPSCs, and exposure of GluK2 knockout mice to the selective GluK1 antagonist UBP 302 could significantly reduce the KA EPSCs. These data suggest that both GluK1 and GluK2 play functional roles in the IC. Our study may provide the synaptic basis for the physiology and pathology of KA receptors in the IC-related functions.


Preclinical and clinical studies of peptide receptor radionuclide therapy.
In the 1980s, the (111)In-labeled somatostatin analog OctreoScan (Covidien, Hazelwood, MO) was developed for imaging of somatostatin receptor subtype 2 (sst(2)) overexpressing tumors. On the basis of this success, peptide receptor radionuclide therapy (PRRT) was developed using similar somatostatin analogs with different therapeutic radionuclides. Clinical application of PRRT demonstrated impressive results on tumor response, overall survival, and quality of life in patients with gastroenteropancreatic neuroendocrine tumors. The peptides 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), Tyr(3)-octreotate (DOTATATE) and DOTA, Tyr(3)-octreotide (DOTATOC) (brand name Onalta), predominantly targeting sst(2), have been granted Orphan Drug status by the European Medicines Agency and the US Food and Drug Administration for application in PRRT. Besides somatostatin receptor-targeting peptides, multiple other radiopeptide analogs were developed targeting several other receptors overexpressed on various tumors. Some of these peptide analogs, including cholecystokinin, gastrin, gastrin-releasing peptide, arginine-glycine-aspartate (RGD)-peptides, and glucagon-like peptide 1 analogs appeared very promising in preclinical and clinical imaging and PRRT studies. Although the success of PRRT with radiolabeled somatostatin analogs has been established, there is still room for improvement. The therapeutic window of PRRT could be enlarged by the use of new and improved targeting compounds, of which new antagonists with excellent tumor to background ratios are very promising. Furthermore, locoregional administration, improved healthy tissue protection, and combination treatment can be applied to increase the effectiveness of PRRT. Combination treatment might include cocktails of different peptide analogs of different therapeutic radionuclides and of radiolabeled peptides with chemotherapeutic or radiosensitizing agents. This review summarizes results of PRRT and describes clinical and preclinical studies regarding PRRT optimizing strategies.


Cinnamon treatment upregulates neuroprotective proteins Parkin and DJ-1 and protects dopaminergic neurons in a mouse model of Parkinson's disease.
Upregulation and/or maintenance of Parkinson's disease (PD)-related beneficial proteins such as Parkin and DJ-1 in astrocytes during neurodegenerative insults may have therapeutic efficacy in PD. Cinnamon is a commonly used natural spice and flavoring material throughout the world. Here we have explored a novel use of cinnamon in upregulating Parkin and DJ-1 and protecting dopaminergic neurons in MPTP mouse model of PD. Recently we have delineated that oral feeding of cinnamon (Cinnamonum verum) powder produces sodium benzoate (NaB) in blood and brain of mice. Proinflammatory cytokine IL-1β decreased the level of Parkin/DJ-1 in mouse astrocytes. However, cinnamon metabolite NaB abrogated IL-1β-induced loss of these proteins. Inability of TNF-α to produce nitric oxide (NO) and decrease the level of Parkin/DJ-1 in wild type (WT) astrocytes, failure of IL-1β to reduce Parkin/DJ-1 in astrocytes isolated from iNOS (-/-) mice, and decrease in Parkin/DJ-1 in WT astrocytes by NO donor DETA-NONOate suggest that NO is a negative regulator of Parkin/DJ-1. Furthermore, suppression of IL-1β-induced expression of iNOS in astrocytes by NaB and reversal of NaB-mediated protection of Parkin/DJ-1 by DETA-NONOate in astrocytes indicate that NaB protects Parkin/DJ-1 in activated astrocytes via suppressing iNOS. Similarly MPTP intoxication also increased the level of iNOS and decreased the level of Parkin/DJ-1 in vivo in the nigra. However, oral treatment of MPTP-intoxicated mice with cinnamon powder and NaB reduced the expression of iNOS and protected Parkin/DJ-1 in the nigra. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions by cinnamon in MPTP-intoxicated mice. These results suggest that cinnamon may be beneficial for PD patients.


The role of type I interferons in the differentiation and function of Th1 and Th2 cells.
T-helper cells are compartmentalized according to the cytokines they are able to produce. T-helper 1 cells produce interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), and develop following priming with IL-12. T-helper 2 cells produce IL-4, IL-5, and IL-10, and IL-4 is necessary to induce the differentiation of these cells. Type I IFNs have no direct effects on T-helper cell differentiation, but may regulate, especially in humans, the expression of the IL-12 receptor and thus influence T-helper 1 differentiation. On the other hand, type I IFNs can have inhibitory effects on the cytokine production by differentiated T-helper 1 cells. This suggests an important regulatory role for type I IFNs in adaptive immunity.


The 'healthy brothel': the context of clinical services for sex workers in Hillbrow, South Africa.
Conventional health services often present barriers to sex workers seeking health care resulting in untreated sexually transmitted infections (STI) and increased risk of HIV infection. A brothel-based clinic was established to provide STI treatment for sex workers who worked in the inner city suburb of Hillbrow, South Africa. Qualitative research demonstrated that the clinic was acceptable to women in terms of service quality, accessibility, and efficacy, and positively influenced health-seeking behaviours, health awareness, and condom use. The intervention also transformed the image of the hotels from sites of 'dirt and disease' into 'healthy brothels'. The paper concludes that clinical services offered on site are a viable alternative to the provision of conventional clinical services.


Suboptimal Maternal Iodine Intake Is Associated with Impaired Child Neurodevelopment at 3 Years of Age in the Norwegian Mother and Child Cohort Study.
Background: Severe iodine deficiency in pregnancy has major effects on child neurodevelopment, but less is known about the potential consequences of mild-to-moderate deficiency and iodine supplement use.Objective: We explored the associations between maternal iodine intake and child neurodevelopment at 3 y of age and the potential impact of maternal intake of iodine from supplements on the same outcomes.Methods: This population-based prospective observational study included 48,297 mother-child pairs recruited during pregnancy from 2002 to 2008. Maternal iodine intake was calculated based on a validated food-frequency questionnaire answered during midpregnancy that covered mean intake since the beginning of pregnancy. Associations between iodine intake and maternal-reported child language and motor development and behavior problems were explored by multivariable regression analyses.Results: In 33,047 mother-child pairs, excluding iodine supplement users, maternal iodine intake was associated with child language delay (P = 0.024), externalizing and internalizing behavior problems (both P < 0.001), and fine motor skills (P = 0.002) but not gross motor skills or the risk of not walking unaided at 17 mo of age. In 74% of the participants who had an iodine intake <160 μg/d (Estimated Average Requirement), suboptimal iodine intake was estimated to account for ∼5% (95% CI: -5%, 14%) of the cases of language delay, 16% (95% CI: 0%, 21%) of the cases of externalizing behavior problems >1.5 SD, and 16% (95% CI: 10%, 21%) of the cases of internalizing behavior problems >1.5 SD. In 48,297 mother-child pairs, including iodine supplement users, we found no protective effects of supplemental iodine during pregnancy on neurodevelopment.Conclusions: Maternal iodine intake below the Estimated Average Requirement during pregnancy was associated with symptoms of child language delay, behavior problems, and reduced fine motor skills at 3 y of age. The results showed no evidence of a protective effect of iodine supplementation during pregnancy.


The Escherichia coli RNA processing and degradation machinery is compartmentalized within an organized cellular network.
Bacterial RNA processing and degradation involves the co-ordinated action of a large number of RNases, RNA helicases and other proteins. It is not known how this functional network is organized within the cell nor how it is co-ordinated or regulated. In the present study, we show that multiple components of the RNA degradation and processing network of Escherichia coli are localized within extended cellular structures that appear to coil around the periphery of the cell. These include Orn, Hfq, PAP I, RNase III, RppH, RraA and RraB in addition to the previously reported proteins RNase II and RNaseE. Double-label localization studies of several of the proteins showed co-localization of the proteins within the observed structures. Assembly of the proteins into the structures was independent of the MreBCD or MinCDE cytoskeletal systems, RNA synthesis, or nucleoid positioning within the cell. Our results indicate that the components of the RNA processing and degradation network are compartmentalized within the cell rather than diffusely distributed in the cytoplasm. This sequestration provides the cell with a possible mechanism to control access to RNA substrates and to functionally co-ordinate the multiple players of the RNA processing and degradation pathways.


The spatial epidemiology of sickle-cell anaemia in India.
Sickle-cell anaemia (SCA) is a neglected chronic disorder of increasing global health importance, with India estimated to have the second highest burden of the disease. In the country, SCA is particularly prevalent in scheduled populations, which comprise the most socioeconomically disadvantaged communities. We compiled a geodatabase of a substantial number of SCA surveys carried out in India over the last decade. Using generalised additive models and bootstrapping methods, we generated the first India-specific model-based map of sickle-cell allele frequency which accounts for the district-level distribution of scheduled and non-scheduled populations. Where possible, we derived state- and district-level estimates of the number of SCA newborns in 2020 in the two groups. Through the inclusion of an additional 158 data points and 1.3 million individuals, we considerably increased the amount of data in our mapping evidence-base compared to previous studies. Highest predicted frequencies of up to 10% spanned central India, whilst a hotspot of ~12% was observed in Jammu and Kashmir. Evidence was heavily biased towards scheduled populations and remained limited for non-scheduled populations, which can lead to considerable uncertainties in newborn estimates at national and state level. This has important implications for health policy and planning. By taking population composition into account, we have generated maps and estimates that better reflect the complex epidemiology of SCA in India and in turn provide more reliable estimates of its burden in the vast country. This work was supported by European Union's Seventh Framework Programme (FP7//2007-2013)/European Research Council [268904 - DIVERSITY]; and the Newton-Bhabha Fund [227756052 to CH].


Association Between Serum Folate Levels and Caffeinated Beverage Consumption in Pregnant Women in Chiba: The Japan Environment and Children's Study.
Several studies have reported the adverse effects of caffeine intake during pregnancy on fetal health. However, the effects of caffeine intake from green and oolong teas has not been investigated, despite the considerable consumption of these teas in Japan and the potential inhibitory effects of catechins-chemicals present at relatively high levels in green and oolong teas-on folic acid absorption. The potential associations of serum folate levels with caffeinated beverage consumption and catechin levels remain largely unstudied. The present study aimed to determine these associations in pregnant Japanese women. Pregnant women (n = 2,701) not receiving folate supplementation were enrolled at the Chiba Unit Center, a regional site of the Japan Environment and Children's Study (JECS). Serum folate levels were measured using an Access folate assay kit, and nutrient and caffeine intakes were assessed using a self-administered food frequency questionnaire that was previously evaluated in Japanese populations. The low and normal serum folate groups reported caffeine intakes of 42.3 mg/1,000 kcal and 34.4 mg/1,000 kcal, respectively, and tannin intakes of 40.8 mg/1,000 kcal and 36.3 mg/1,000 kcal, respectively. Multiple regression analyses revealed negative associations of serum folate levels with caffeine and tannin intakes and a positive association between serum folate levels and dietary folate intake. Considering the negative associations of caffeine and tannin levels with serum folate levels, pregnant women should consume caffeinated beverages, such as coffee and green/oolong teas, with caution.


Towards systematic identification of Plasmodium essential genes by transposon shuttle mutagenesis.
After the deciphering of the genome sequences of several Plasmodium species, efforts must turn to elucidating gene function and identifying essential gene products. However, random approaches are lacking and gene targeting is inefficient in Plasmodium. Here, we established shuttle transposon mutagenesis in Plasmodium berghei. We constructed a mini-Tn5 derivative that can transpose into parasite genes cloned in Escherichia coli, providing an efficient means of generating knockout fragments. A 10(4)-fold increase in frequencies of double-crossover homologous recombination in the parasite using a new electroporation technology permits to reproducibly generate pools of distinct mutants after transfection with mini-Tn5-interrupted sequences. The procedure opens the way to the systematic identification of essential genes in Plasmodium.


The impact of antiretroviral therapy on population-level virulence evolution of HIV-1.
In HIV-infected patients, an individual's set point viral load (SPVL) strongly predicts disease progression. Some think that SPVL is evolving, indicating that the virulence of the virus may be changing, but the data are not consistent. In addition, the widespread use of antiretroviral therapy (ART) has the potential to drive virulence evolution. We develop a simple deterministic model designed to answer the following questions: what are the expected patterns of virulence change in the initial decades of an epidemic? Could administration of ART drive changes in virulence evolution and, what is the potential size and direction of this effect? We find that even without ART we would not expect monotonic changes in average virulence. Transient decreases in virulence following the peak of an epidemic are not necessarily indicative of eventual evolution to avirulence. In the short term, we would expect widespread ART to cause limited downward pressure on virulence. In the long term, the direction of the effect is determined by a threshold condition, which we define. We conclude that, given the surpassing benefits of ART to the individual and in reducing onward transmission, virulence evolution considerations need have little bearing on how we treat.