Translation of mouse model to human gives insights into periodontitis etiology.
To suggest candidate genes involved in periodontitis, we combined gene expression data of periodontal biopsies from Collaborative Cross (CC) mouse lines, with previous reported quantitative trait loci (QTL) in mouse and with human genome-wide association studies (GWAS) associated with periodontitis. Periodontal samples from two susceptible, two resistant and two lines that showed bone formation after periodontal infection were collected during infection and naïve status. Differential expressed genes (DEGs) were analyzed in a case-control and case-only design. After infection, eleven protein-coding genes were significantly stronger expressed in resistant CC lines compared to susceptible ones. Of these, the most upregulated genes were MMP20 (P = 0.001), RSPO4 (P = 0.032), CALB1 (P = 1.06×10-4), and AMTN (P = 0.05). In addition, human orthologous of candidate genes were tested for their association in a case-controls samples of aggressive (AgP) and chronic (CP) periodontitis (5,095 cases, 9,908 controls). In this analysis, variants at two loci, TTLL11/PTGS1 (rs9695213, P = 5.77×10-5) and RNASE2 (rs2771342, P = 2.84×10-5) suggested association with both AgP and CP. In the association analysis with AgP only, the most significant associations were located at the HLA loci HLA-DQH1 (rs9271850, P = 2.52×10-14) and HLA-DPA1 (rs17214512, P = 5.14×10-5). This study demonstrates the utility of the CC RIL populations as a suitable model to investigate the mechanism of periodontal disease.


Advanced magnetic resonance imaging of cerebral cavernous malformations: part I. High-field imaging of excised human lesions.
We hypothesized that structural details that have not been described previously would be revealed in cerebral cavernous malformations (CCM) through the use of high-field magnetic resonance and confocal microscopy. The structural details of CCMs excised from patients were sought by examination with high-field magnetic resonance imaging (MRI) and correlated with confocal microscopy of the same specimens. Novel features of CCM structure are outlined, including methodological limitations, venues for future research, and possible clinical implications. CCM lesions excised from 4 patients were fixed in 2% paraformaldehyde and subjected to high-resolution MRI at 9.4 or 14.1-T by spin echo and gradient recalled echo methods. Histological validation of angioarchitecture was conducted on thick sections of CCM lesions using fluorescent probes to endothelium under confocal microscopy. Images of excised human CCM lesions were acquired with proton density-weighted, T1-weighted, T2-weighted spin echo, and T2*-weighted gradient recalled echo MRI. These images revealed large "bland" regions with thin-walled caverns and "honeycombed" regions with notable capillary proliferation and smaller caverns surrounding larger caverns. Proliferating capillaries and caverns of various sizes were also associated with the walls of apparent larger blood vessels in the lesions. Similar features were confirmed within thick sections of CCMs by confocal microscopy. MRI relaxation times in different regions of interest suggested the presence of different states of blood breakdown products in areas with apparent angiogenic proliferative activity. High-field MRI techniques demonstrate novel features of CCM angioarchitecture, visible at near histological resolution, including regions with apparently different biological activity. These preliminary observations will motivate future research, correlating lesion biological and clinical activity with features of MRI at higher field strength.


The inhibitory effects of exogenous arachidonic acid on rabbit platelet aggregation and the release reaction.
Although arachidonic acid causes rabbit platelet aggregation and the release of granule contents in suspensions of washed platelets when used in concentrations of approximately 50-300 microM, higher concentrations (500 microM) cause neither aggregation nor release. Suspensions of platelets from rabbits wee exposed to arachidonic acid (250 microM) for 15 min, allowed to recover in the presence of PGE1 for 30 min, washed, and resuspended; in some experiments, the platelets were treated with aspirin before being exposed to arachidonic acid. Aggregation of platelets pretreated with arachidonic acid was inhibited in response to ADP; this effect was greater with the non-aspirin-treated platelets and persisted for at least 4 hr after resuspension. The association of 125I-fibrinogen with the platelets as a result of ADP stimulation was also inhibited. Aggregation and release of granule contents in response to collagen and low concentrations of thrombin was inhibited, but the inhibition could be overcome by higher concentrations. Thrombin induced further release of granule contents from platelets exposed to arachidonic acid without pretreatment with aspirin. Platelets that had been exposed to arachidonic acid, either with or without pretreatment with aspirin, did not aggregate or undergo further release upon stimulation with arachidonic acid after they were washed and resuspended. Inhibition of the lipoxygenase pathway with eicosatetraynoic acid (ETYA) or nordihydroguaiaretic acid (NDGA) did not affect the inhibition caused by arachidonic acid, so it is unlikely that a product of this pathway is responsible for the inhibition. Mixing experiments indicated that the pretreated platelets did not form a thromboxane-A2-like activity, and that they were unresponsive to aggregation and release induced by products formed from arachidonic acid. Experiments with 3H-arachidonic acid showed that after 45 min of incubation with platelets, only 1.1% of the 3H-arachidonic acid remained as free arachidonic acid in the platelets. Although cyclic-AMP was slightly increased 1 min after the addition of arachidonic acid, the cyclic-AMP concentration was the same as that of control platelets after the platelets were washed and resuspended, indicating that increased cyclic-AMP is not likely to be responsible for the persistent inhibitory effect. Thus, the inhibitory effect of pretreatment with arachidonic acid is a general effect on responses to a variety of aggregating agents that act through different mechanisms, and the inhibition is not related to thromboxane-A2 formation. The possibility of membrane perturbation resulting in the unavailability of receptors may explain the persistent inhibitory effect, but the responsible reactions have not been identified.


Does psychopathology at admission predict the length of inpatient stay in psychiatry? Implications for financing psychiatric services.
The debate on appropriate financing systems in inpatient psychiatry is ongoing. In this context, it is important to control resource use in terms of length of stay (LOS), which is the most costly factor in inpatient care and the one that can be influenced most easily. Previous studies have shown that psychiatric diagnoses provide only limited justification for explaining variation in LOS, and it has been suggested that measures such as psychopathology might be more appropriate to predict resource use. Therefore, we investigated the relationship between LOS and psychopathological syndromes or symptoms at admission as well as other characteristics such as sociodemographic and clinical variables. We considered routine medical data of patients admitted to the Psychiatric University Hospital Zurich in the years 2008 and 2009. Complete data on psychopathology at hospital admission were available in 3,220 inpatient episodes. A subsample of 2,939 inpatient episodes was considered in final statistical models, including psychopathology as well as complete datasets of further measures (e.g. sociodemographic, clinical, treatment-related and psychosocial variables). We used multivariate linear as well as logistic regression analysis with forward selection procedure to determine the predictors of LOS. All but two syndrome scores (mania, hostility) were positively related to the length of stay. Final statistical models showed that syndromes or symptoms explained about 5% of the variation in length of stay. The inclusion of syndromes or symptoms as well as basic treatment variables and other factors led to an explained variation of up to 25%. Psychopathological syndromes and symptoms at admission and further characteristics only explained a small proportion of the length of inpatient stay. Thus, according to our sample, psychopathology might not be suitable as a primary indicator for estimating LOS and contingent costs. This might be considered in the development of future costing systems in psychiatry.


Specificity of action representations in the lateral occipitotemporal cortex.
The ability to recognize actions is important for cognitive development and social cognition. Areas in the lateral occipitotemporal cortex show increased activity when subjects view action sequences; however, whether this activity distinguishes between specific actions as necessary for action recognition is unclear. We used a functional magnetic resonance imaging adaptation paradigm to test for brain regions that exhibit action-specific activity. Subjects watched a series of action sequences in which the action performed or the person performing the action could be repeated from a previous scan. Three regions-the superior temporal sulcus (pSTS), human motion-sensitive cortex (MT/MST), and extrastriate body area (EBA)-showed decreased activity for previously seen actions, even when the actions were novel exemplars because the persons involved had not been seen previously. These action-specific adaptation effects provide compelling evidence that representations in the pSTS, MT/MST, and EBA abstract actions from the agents involved and distinguish between different particular actions.


Recovery kinetics following spinal deformity correction: a comparison of isolated cervical, thoracolumbar, and combined deformity morphometries.
The postoperative recovery patterns of cervical deformity patients, thoracolumbar deformity patients, and patients with combined cervical and thoracolumbar deformities, all relative to one another, is not well understood. Clear objective benchmarks are needed to quantitatively define a "good" versus a "bad" postoperative recovery across multiple follow-up visits, varying deformity types, and guide expectations. To objectively define and compare the complete 2-year postoperative recovery process among operative cervical only, thoracolumbar only, and combined deformity patients using area-under-the-curve (AUC) methodology. Retrospective review of 2 prospective, multicenter adult cervical and spinal deformity databases. One hundred seventy spinal deformity patients. Common health-related quality of life (HRQOL) assessments across both databases included the EuroQol 5-Dimension Questionnaire and Numeric Rating Scale (NRS) back pain assessment. In order to compare disability improvements, the Neck Disability Index (NDI) and the Oswestry Disability Index (ODI) were merged into one outcome variable, the ODI-NDI. Both assessments are gauged on the same scale, with minimal question deviation. Sagittal Radiographic Alignment was also assessed at pre- and all postoperative time points. Operative deformity patients >18 years old with baseline (BL) to 2-year HRQOLs were included. Patients were stratified by cervical only (C), thoracolumbar only (T), and combined deformities (CT). HRQOL and radiographic outcomes were compared within and between deformity groups. AUC normalization generated normalized HRQOL scores at BL and all follow-up intervals (6 weeks, 3 months, 1 year, and 2 year). Normalized scores were plotted against follow-up time interval. AUC was calculated for each follow-up interval, and total area was divided by cumulative follow-up length, determining overall, time-adjusted HRQOL recovery (Integrated Health State, IHS). Multiple linear regression models determined significant predictors of HRQOL discrepancies among deformity groups. One hundred seventy patients were included (27 C, 27 T, and 116 CT). Age, BMI, sex, smoking status, osteoporosis, depression, and BL HRQOL scores were similar among groups (p >. 05). T and CT patients had higher comorbidity severities (CCI: C 0.696, T 1.815, CT 1.699, p = .020). Posterior surgical approaches were most common (62.9%) followed by combined (28.8%) and anterior (6.5%). Standard HRQOL analysis found no significant differences among groups until 1-year follow-up, where C patients exhibited comparatively greater NRS back pain (4.88 vs. 3.65 vs. 3.28, p = .028). NRS Back pain differences between groups subsided by 2-years (p>.05). Despite C patients exhibiting significantly faster ODI-NDI minimal clinically important difference (MCID) achievement (33.3% vs. 0% vs. 23.0%, p < .001), all deformity groups exhibited similar ODI-NDI MCID achievement by 2-years (51.9% vs. 59.3% vs. 62.9%, p = 0.563). After HRQOL normalization, similar results were observed relative to the standard analysis (1-year NRS Back: C 1.17 vs. T 0.50 vs. CT 0.51, p < .001; 2-year NRS Back: 1.20 vs. 0.51 vs. 0.69, p = .060). C patients exhibited a worse NRS back normalized IHS (C 1.18 vs. T 0.58 vs. CT 0.63, p = .004), indicating C patients were in a greater state of postoperative back pain for a longer amount of time. Linear regression models determined postoperative distal junctional kyphosis (adjusted beta: 0.207, p = .039) and osteoporosis (adjusted beta: 0.269, p = .007) as the strongest predictors of a poor NRS back IHS (model summary: R2 = 0.177, p = .039). Despite C patients exhibiting a quicker rate of MCID disability (ODI-NDI) improvement, they exhibited a poorer overall recovery of back pain with worse NRS back scores compared with BL status and other deformity groups. Postoperative distal junctional kyphosis and osteoporosis were identified as primary drivers of a poor postoperative NRS back IHS. Utilization of the IHS, a single number adjusting for all postoperative HRQOL visits, in conjunction with predictive modelling may pose as an improved method of gauging the effect of surgical details and complications on a patient's entire recovery process.


Alveolar hemorrhage and kidney disease: characteristics and therapy.
Anti-neutrophil cytoplasmic antibody-associated vasculitis and Goodpasture's glomerular basement membrane disease are the most common causes of diffuse alveolar hemorrhage, a life-threatening disease. Systemic lupus erythematosus and the antiphospholipid syndrome are also causes of alveolar hemorrhage. We retrospectively reviewed 15 cases of diffuse alveolar hemorrhage (DAH) associated with renal diseases. Diagnosis of DAH was based on the presence of bloody bronchoalveolar lavage fluid. There were three men and 12 women, with a mean age of 50.5 years (extremes: 24-74 years). Proteinuria and hematuria were observed, respectively, in 15 and 14 cases. Six patients revealed arterial hypertension. Crescentic glomerulonephritis was diagnosed with kidney biopsies in ten cases. The etiology of renal disease was microscopic polyangiitis (MPA) in seven cases, Wegener disease in four cases, systemic lupus erythematous in one case, cryoglobulinemia in one case, myeloma in one case and propyl-thiouracil-induced MPA in one case. Hemoptysis occurred in 14 cases. The mean serum level of hemoglobin was 7.1 g/dL (5.1-10 g/dL). The mean serum creatinine concentration was 7.07 mg/dL (2.4-13.7 mg/dL). Gas exchange was severely compromised, with an oxygenation index <80 mmHg in 14 patients and <60 mmHg in seven patients. Bronchoalveolar lavage was performed in 11 cases, and had positive findings for hemorrhage in all. Methylprednisolone pulses and cyclophosphamide were used in 14 patients. Plasmapheresis was performed in three cases. One patient received cycles of Dexamethasome-Melphalan. Three patients died as a result of DAH. The mortality rate in our study was 20%.


Timing and pattern of cell fate restrictions in the neural crest lineage.
The trunk neural crest of vertebrate embryos is a transient collection of precursor cells present along the dorsal aspect of the neural tube. These cells migrate on two distinct pathways and give rise to specific derivatives in precise embryonic locations. One group of crest cells migrates early on a ventral pathway and generates neurons and glial cells. A later-dispersing group migrates laterally and gives rise to melanocytes in the skin. These observations raise the possibility that the appearance of distinct derivatives in different embryonic locations is a consequence of lineage restrictions specified before or soon after the onset of neural crest cell migration. To test this notion, we have assessed when and in what order distinct cell fates are specified during neural crest development. We determined the proportions of different types of precursor cells in cultured neural crest populations immediately after emergence from the neural tube and at intervals as development proceeds. We found that the initial neural crest population was a heterogeneous mixture of precursors almost half of which generated single-phenotype clones. Distinct neurogenic and melanogenic sublineages were also present in the outgrowth population almost immediately, but melanogenic precursors dispersed from the neural tube only after many neurogenic precursors had already done so. A discrete fate-restricted neuronal precursor population was distinguished before entirely separate fate-restricted melanocyte and glial precursor populations were present, and well before initial neuronal differentiation. Taken together, our results demonstrate that lineage-restricted subpopulations constitute a major portion of the initial neural crest population and that neural crest diversification occurs well before overt differentiation by the asynchronous restriction of distinct cell fates. Thus, the different morphogenetic and differentiative behavior of neural crest subsets in vivo may result from earlier cell fate-specification events that generate developmentally distinct subpopulations that respond differentially to environmental cues.


Glycosylation is an Androgen-Regulated Process Essential for Prostate Cancer Cell Viability.
Steroid androgen hormones play a key role in the progression and treatment of prostate cancer, with androgen deprivation therapy being the first-line treatment used to control cancer growth. Here we apply a novel search strategy to identify androgen-regulated cellular pathways that may be clinically important in prostate cancer. Using RNASeq data, we searched for genes that showed reciprocal changes in expression in response to acute androgen stimulation in culture, and androgen deprivation in patients with prostate cancer. Amongst 700 genes displaying reciprocal expression patterns we observed a significant enrichment in the cellular process glycosylation. Of 31 reciprocally-regulated glycosylation enzymes, a set of 8 (GALNT7, ST6GalNAc1, GCNT1, UAP1, PGM3, CSGALNACT1, ST6GAL1 and EDEM3) were significantly up-regulated in clinical prostate carcinoma. Androgen exposure stimulated synthesis of glycan structures downstream of this core set of regulated enzymes including sialyl-Tn (sTn), sialyl Lewis(X) (SLe(X)), O-GlcNAc and chondroitin sulphate, suggesting androgen regulation of the core set of enzymes controls key steps in glycan synthesis. Expression of each of these enzymes also contributed to prostate cancer cell viability. This study identifies glycosylation as a global target for androgen control, and suggests loss of specific glycosylation enzymes might contribute to tumour regression following androgen depletion therapy.


Oxford brain health clinic: protocol and research database.
Despite major advances in the field of neuroscience over the last three decades, the quality of assessments available to patients with memory problems in later life has barely changed. At the same time, a large proportion of dementia biomarker research is conducted in selected research samples that often poorly reflect the demographics of the population of patients who present to memory clinics. The Oxford Brain Health Clinic (BHC) is a newly developed clinical assessment service with embedded research in which all patients are offered high-quality clinical and research assessments, including MRI, as standard. Here we describe the BHC protocol, including aligning our MRI scans with those collected in the UK Biobank. We evaluate rates of research consent for the first 108 patients (data collection ongoing) and the ability of typical psychiatry-led NHS memory-clinic patients to tolerate both clinical and research assessments. Our ethics and consenting process enables patients to choose the level of research participation that suits them. This generates high rates of consent, enabling us to populate a research database with high-quality data that will be disseminated through a national platform (the Dementias Platform UK data portal).


Gallstone Disease and the Risk of Type 2 Diabetes.
Gallstone disease (GSD) is related to several diabetes risk factors. The present study was to examine whether GSD was independently associated with type 2 diabetes in the China Kadoorie Biobank study. After excluding participants with prevalent diabetes and prior histories of cancer, heart disease, and stroke at baseline, 189,154 men and 272,059 women aged 30-79 years were eligible for analysis. The baseline prevalence of GSD was 5.7% of the included participants. During 4,138,687 person-years of follow-up (median, 9.1 years), a total of 4,735 men and 7,747 women were documented with incident type 2 diabetes. Compared with participants without GSD at baseline, the multivariate-adjusted hazard ratios (HRs) for type 2 diabetes for those with GSD were 1.09 (95% CI: 0.96-1.24; P = 0.206), 1.21 (95% CI: 1.13-1.30; P < 0.001), and 1.17 (95% CI: 1.10-1.25; P < 0.001) in men, women, and the whole cohort respectively. There was no statistically significant heterogeneity between men and women (P = 0.347 for interaction). The association between GSD and type 2 diabetes was strongest among participants who reported ≥5 years since the first diagnosis and were still on treatment at baseline (HR = 1.48; 95% CI: 1.16-1.88; P = 0.001). The present study highlights the importance of developing a novel prevention strategy to mitigate type 2 diabetes through improvement of gastrointestinal health.


Phosphorylation of the beta-amyloid precursor protein at the cell surface by ectocasein kinases 1 and 2.
The beta-amyloid precursor protein (betaAPP) is one of the rare proteins known to be phosphorylated within its ectodomain. We have shown previously that betaAPP can be phosphorylated within secretory vesicles and at the cell surface (Walter, J., Capell, A., Hung, A. Y. , Langen, H., Schnölzer, M., Thinakaran, G., Sisodia, S. S., Selkoe, D. J., and Haass, C. (1997) J. Biol. Chem. 272, 1896-1903). We have now specifically characterized the phosphorylation of cell surface-located betaAPP and identified two ectoprotein kinases that phosphorylate betaAPP at the outer face of the plasma membrane. By using selective protein kinase inhibitors and by investigating the usage of ATP and GTP as cosubstrates, we demonstrate that membrane-bound betaAPP as well as secreted forms of betaAPP can be phosphorylated by casein kinase (CK) 1- and CK2-like ectoprotein kinases. The ectodomain of betaAPP was also phosphorylated by purified CK1 and CK2 in vitro, but not by protein kinases A and C. Phosphorylation of betaAPP by ectoprotein kinases and by purified CK1 and CK2 occurred within an acidic domain in the N-terminal half of the protein. Heparin strongly inhibited the phosphorylation of cell-surface betaAPP by ecto-CK1 and ecto-CK2, indicating a regulatory role of this extracellular matrix component in betaAPP phosphorylation.


Differences in cortical thickness in healthy controls, subjects with mild cognitive impairment, and Alzheimer's disease patients: a longitudinal study.
In this study, we analyzed differences in cortical thickness (CTH) between healthy controls (HC), subjects with stable mild cognitive impairment (S-MCI), progressive MCI (P-MCI), and Alzheimer's disease (AD), and assessed correlations between CHT and clinical disease severity, education, and apolipoprotein E4 (APOE) genotype. Automated CTH analysis was applied to baseline high-resolution structural MR images of 145 subjects with a maximum followup time of 7.4 years pooled from population-based study databases held in the University of Kuopio. Statistical differences in CTH between study groups and significant correlations between CTH and clinical and demographic factors were assessed and displayed on a cortical surface model. Compared to HC group (n = 26), the AD (n = 21) group displayed significantly reduced CTH in several areas of frontal and temporal cortices of the right hemisphere. Higher education and lower MMSE scores were correlated with reduced CTH in the AD group, whereas no significant correlation was found between CDR-SB scores or APOE genotype and CTH. The P-MCI group demonstrated significantly reduced CTH compared to S-MCI in frontal, temporal and parietal cortices even after statistically adjusting for all confounding variables. Ultimately, analysis of CTH can be used to detect cortical thinning in subjects with progressive MCI several years before conversion and clinical diagnosis of AD dementia, irrespective of their cognitive performance, education level, or APOE genotype.


The Choice of Conduits in Coronary Artery Bypass Surgery.
Coronary artery bypass grafting is the most common cardiac surgery operation performed worldwide. It is the most effective revascularization method for several categories of patients affected by coronary artery disease. Although coronary artery bypass grafting has been performed for more than 40 years, no detailed guidelines on the choice of coronary artery bypass grafting conduits have been published and the choice of the revascularization strategy remains more a matter of art than of science. Moreover, there is a clear contradiction between the proven benefits of arterial grafting and its very limited use in everyday clinical practice. In the hope of encouraging wider diffusion of arterial revascularization and to provide a guide for clinicians, we discuss current evidence for the use of different conduits in coronary artery bypass surgery and propose an evidence-based algorithm for the choice of the second conduit during coronary artery bypass operations.


Surgical approaches and long-term outcomes of intramedullary spinal cord cavernous malformations: a single-center consecutive series of 219 patients.
Optimal surgical strategies for intramedullary spinal cord cavernous malformations (ISCCMs) are not optimized and remain problematic. In this study the authors identify rational surgical strategies for ISCCMs and predictors of outcomes after resection. A single-center study was performed with 219 consecutive surgically treated patients who presented from 2002 to 2017 and were analyzed retrospectively. The American Spinal Injury Association (ASIA) Impairment Scale was used to evaluate neurological functions. Patient characteristics, surgical approaches, and immediate and long-term postoperative outcomes were identified. The average ISCCM size was 10.5 mm. The spinal level affected was cervical in 24.8% of patients, thoracic in 73.4%, and lumbar in 1.8%. The locations of the lesions in the horizontal plane were 30.4% ventral, 41.6% dorsal, and 28.0% central. Of the 214 patients included in the cohort for operative evaluation, 62.6% had superficially located lesions, while 37.4% were embedded. Gross-total resection was achieved in 98.1% of patients. The immediate postoperative neurological condition worsened in 10.3% of the patients. Multivariate logistic regression identified mild preoperative function (p = 0.014, odds ratio [OR] 4.5, 95% confidence interval [CI] 1.4-14.8) and thoracolumbar-level lesions (p = 0.01, OR 15.7, 95% CI 1.9-130.2) as independent predictors of worsening. The mean follow-up duration in 187 patients was 45.9 months. Of these patients, 63.1% were stable, 33.2% improved, and 3.7% worsened. Favorable outcomes were observed in 86.1% of patients during long-term follow-up and were significantly associated with preoperative mild neurological and disability status (p = 0.000) and cervically located lesions (p = 0.009). The depths of the lesions were associated with worse long-term outcomes (p = 0.001), and performing myelotomy directly through a yellowish abnormal surface in moderate-depth lesions was an independent predictor of worsening (p = 0.023, OR 35.3, 95% CI 1.6-756.3). Resection performed with an individualized surgical approach remains the primary therapeutic option in ISCCMs. Performing surgery in patients with mild symptoms at the thoracolumbar level and embedded located lesions requires more discretion.


Chemoprophylaxis trial designs in epidemics: insights from a systematic review of COVID-19 study registrations.
Chemoprophylactics against emerging epidemic and pandemic infectious diseases offer potential for prevention but require efficacy and safety analysis before widespread use can be recommended. Chemoprophylaxis with repurposed drugs enables deployment ahead of development of novel vaccines. It may have particular utility as a stopgap ahead of vaccine deployment or when vaccines become less effective on virus variants, in countries where there may be structural inaccessibility to vaccines or in specific risk-groups. Rapid implementation of robust trial designs is a persistent challenge in epidemics. We systematically reviewed SARS-CoV-2 and COVID-19 chemoprophylaxis trial registrations from the first 21 weeks of the pandemic to critically appraise significant design features and alignment of study populations to clinical and public health uses, and describe candidate chemoprophylactic agents. We searched online international trial databases from 31 Dec 2019 to 26 May 2020 using keywords "proph*" or "prevention". Trial protocols assessing efficacy of chemoprophylactic agents for COVID-19 were included. Trial components were screened for eligibility and relevant studies extracted. Key trial design features were assessed. We found 76 chemoprophylaxis study registrations, proposing enrolment of 208,367 people with median size of 490 (IQR 262-1710). A randomised design was specified for 63 trials, 61 included a control group and total proposed enrolment size was 197,010, median 600 (IQR 236-1834). Four protocols provided information on effect size sought. We estimate that for a control group attack rate of 10%, 66% of trials would be underpowered to detect a 50% effect size, and 97% of trials would be underpowered to detect a 30% effect size (at the 80% level). We found evidence of adaptive design in one trial registration only. Laboratory-confirmed infection with or without symptoms was the most common primary outcome. Polymerase chain reaction testing alone was used in 46% of trials, serological testing in 6.6% and 14.5% used both testing methods. Healthcare workers were the target population in 52/79 (65.8%) trials: 49 pre-exposure prophylaxis (PrEP) and 3 post-exposure prophylaxis (PEP). Sixteen trials (20.3%) planned PEP in close contacts. Five studies (6.3%) considered chemoprophylaxis in clinical-risk patients. Older adults were the focus of recruitment in only 3 (3.8%) studies (all long-term care facilities). Two (2.5%) studies of PrEP in the general population included older adults. Hydroxychloroquine was the most common candidate agent in 55/79 trials (69.6%), followed by chloroquine (4/79, 5.0%) and lopinavir/ritonavir (3/79, 3.8%). Many registered COVID-19 chemoprophylaxis efficacy trials were underpowered to detect clinically meaningful protection at epidemiologically informed attack rates. This, compounded with the time that has taken to organise these trials as compared to the rapid development of COVID-19 vaccines, has rendered these trials of marginal importance. International coordination mechanisms and collaboration is required. Supporting the design of feasible chemoprophylaxis trials, large enough to generate strong evidence, early on in an epidemic using adaptive platform trial designs will allow structured entry and exit of candidate agents and rapid stand-up of trial infrastructure. Our protocol is registered at https://www.osf.io/vp56f on May 20, 2020.


DNA binding properties of the yeast Msh2-Msh6 and Mlh1-Pms1 heterodimers.
We describe here our recent studies of the DNA binding properties of Msh2-Msh6 and Mlh1-Pms1, two protein complexes required to repair mismatches generated during DNA replication. Mismatched DNA binding by Msh2-Msh6 was probed by mutagenesis based on the crystal structure of the homologous bacterial MutS homodimer bound to DNA. The results suggest that several amino acid side chains inferred to interact with the DNA backbone near the mismatch are critical for repair activity. These contacts, which are different in Msh2 and Msh6, likely facilitate stacking and hydrogen bonding interactions between side chains in Msh6 and the mismatched base, thus stabilizing a kinked DNA conformation that permits subsequent repair steps coordinated by the Mlh1-Pms1 heterodimer. Mlh1-Pms1 also binds to DNA, but independently of a mismatch. Mlh1-Pms1 binds short DNA substrates with low affinity and with a slight preference for single-stranded DNA. It also binds longer duplex DNA molecules, but with a higher affinity indicative of cooperative binding. Indeed, imaging by atomic force microscopy reveals cooperative DNA binding and simultaneous interaction with two DNA duplexes. The novel DNA binding properties of Mlh1-Pms1 may be relevant to signal transduction during DNA mismatch repair and to recombination, meiosis and cellular responses to DNA damage.


Pathogen-induced accumulation of an ellagitannin elicits plant defense response.
In an incompatible interaction between Colletotrichum fragariae and strawberry plants, the accumulation of phenolic compounds in plant leaves was observed. A particularly abundant penta-esterified ellagitannin that accumulated in response to pathogen attack was identified as 1-0-galloyl-2,3;4,6-bis-hexahydroxydiphenoyl-β-d-glucopyranose (HeT) by mass spectroscopy and nuclear magnetic resonance. Foliar application of purified HeT prior to inoculation with a virulent pathogen was shown to increase resistance toward C. acutatum in strawberry plants and to Xanthomonas citri subsp. citri in lemon plants. The induced resistance in strawberry was associated with a rapid oxidative burst, callose deposition, a transient increase of salicylic acid in phloem, and induction of gene expression responsive to salicylic acid. Results obtained suggested that HeT could be a common plant defense response molecule capable of inducing pathogen resistance in different plant species.


Unique structural and stabilizing roles for the individual pseudouridine residues in the 1920 region of Escherichia coli 23S rRNA.
The synthesis of a 5'-O-BzH-2'- O -ACE-protected pseudouridine phosphoramidite is reported [BzH, benzhydryloxy-bis(trimethylsilyloxy)silyl; ACE, bis(2-acetoxyethoxy)methyl]. The availability of the phosphoramidite allows for reliable and efficient syntheses of hairpin RNAs containing single or multiple pseudouridine modifications in the stem or loop regions. Five 19-nt hairpin RNAs representing the 1920-loop region (G(1906)-C(1924)) of Escherichia coli 23S rRNA were synthesized with pseudouridine residues located at positions 1911, 1915 and 1917. Thermodynamic parameters, circular dichroism spectra and NMR data are presented for all five RNAs. Overall, three different structural contexts for the pseudouridine residues were examined and compared with the unmodified RNA. Our main findings are that pseudouridine modifications exhibit a range of effects on RNA stability and structure, depending on their locations. More specifically, pseudouridines in the single-stranded loop regions of the model RNAs are slightly destabilizing, whereas a pseudo-uridine at the stem-loop junction is stabilizing. Furthermore, the observed effects on stability are approximately additive when multiple pseudouridine residues are present. The possible relationship of these results to RNA function is discussed.


Evaluation of community based education and service courses for undergraduate radiography students at Makeree University, Uganda.
The Faculty of Medicine, Makerere University, is the oldest health professionals' training institution in East Africa. It has been training health professionals since 1924. In 2001, a bachelors degree in radiography commenced. After a curriculum review, the university's longstanding traditional curriculum was converted to a problem based learning curriculum with a focus on Community Based Education and Service (COBES). As a component of COBES, radiography, medical, nursing, dentistry and pharmacy students are sent to community health facilities where they are expected to participate in community services and other primary healthcare activities. This study was designed to obtain radiography teachers' and students' opinions of the significance and relevance of this community based training to radiography training. Cross-sectional descriptive study. Both students and teachers (91.4%) affirmed the community training to be significant and relevant to radiography training. In total, 71.4% of the students had participated in X-ray services and 39.2% in ultrasound services during COBES; and 68.6% of the students reported the need to be better prepared for the COBES training. Both students and teachers confirmed COBES to be relevant to Ugandan radiography training.


Detection of viral hemorrhagic septicemia virus by quantitative reverse transcription polymerase chain reaction from two fish species at two sites in Lake Superior.
Viral hemorrhagic septicemia virus (VHSV) was first detected in the Laurentian Great Lakes in 2005 during a mortality event in the Bay of Quinte, Lake Ontario. Subsequent analysis of archived samples determined that the first known isolation of VHSV in the Laurentian Great Lakes was from a muskellunge Esox masquinongy collected in Lake St. Clair in 2003. By the end of 2008, mortality events and viral isolations had occurred in all of the Laurentian Great Lakes except Lake Superior. In 2009, a focused disease surveillance program was designed to determine whether VHSV was also present in Lake Superior. In this survey, 874 fish from 7 sites along the U.S. shoreline of Lake Superior were collected during June 2009. Collections were focused on nearshore species known to be susceptible to VHSV. All fish were dissected individually by using aseptic techniques and were tested for the presence of VHSV genetic material by use of a quantitative reverse transcription (qRT) polymerase chain reaction (PCR) targeting the viral nucleoprotein gene. Seventeen fish from two host species at two different sites tested positive at low levels for VHSV. All attempts to isolate virus in cell culture were unsuccessful. However, the presence of viral RNA was confirmed independently in five fish by using a nested PCR that targeted the glycoprotein (G) gene. Partial G gene sequences obtained from three fish were identical to the corresponding sequence from the original 2003 VHSV isolate (MI03) from muskellunge. These detections represent the earliest evidence for the presence of VHSV in Lake Superior and illustrate the utility of the highly sensitive qRT-PCR assay for disease surveillance in aquatic animals.


William Taylor, Peninsular War surgeon and deputy inspector of hospitals at Waterloo.
William Taylor was a British army surgeon remembered for his role as deputy inspector of hospitals (DIH) at Waterloo serving under Sir James Grant MD (1778-1852). No biography of Taylor exists beyond his entry in Drew's records of commissioned officers in the medical services of the British Army. Taylor appears to have been a Scotsman and is first noted as a hospital mate in 1795. He joined the 10th Royal Dragoons (Hussars from 1806) as an assistant surgeon in 1797. He is recorded at Guildford (1800) and Brighton (1803). He was made surgeon in August 1803. A further reference to Taylor, deduced from the title of "regimental surgeon," is documented at Lewes, Sussex, in 1808. Taylor served with the 10th Hussars in the Peninsular and Challis' roll call records his service at the Battles of Sahagún (21 December 1808) and Benavente (29 December 1808). Taylor was transferred to the staff on 20 June 1811 and made DIH on 25 July 1811. He was put on half-pay before being reinstated for Waterloo. Taylor retired on half-pay in February 1816 and died at Turnham Green on 9 January 1820. His Waterloo medal was sold in 2006.


Medically inoperable peripheral lung cancer treated with stereotactic body radiation therapy.
Lung cancer is the most frequent cause of cancer-related death in North America. There is wide variation between patients who are medically inoperable and those managed surgically. The use of stereotactic body radiotherapy (SBRT) has narrowed the gap in survival rates between operative and non-operative management for those with early stage disease. This retrospective study reports outcomes for the treatment of peripheral non-small cell lung carcinoma (NSCLC) with SBRT from a single community practice. Sixty-seven consecutive patients (pts) with inoperable, untreated peripheral lung tumors were treated from 2010 through 2012 and included in this study. Stereotactic targeting was facilitated by either spine or lung-based image guidance, either with or without fiducial marker tracking with a frameless robotic radiosurgery system. Peripheral tumors received a median biological effective dose (BED) of 105.6 Gy10 or in terms of a median physical dose, 48 Gy delivered over 4 daily fractions. Survival was measured using the Kaplan-Meier method to determine rates of local control, progression of disease and overall survival. The Cox proportional hazards regression model was used to study the effects of tumor size, stage, histology, patient age, tumor location (lobe), tracking method, and BED on the survival distributions. The median follow-up for this cohort was 24.5 months (range: 2.4-50.3) with an overall (OS) 3-year survival of 62.4 % (95 % CI: 74.3-47.3). The median progression-free survival was 28.5 months (95 % CI: 15.8 months to not reached). Local control (LC), defined as a lack of FDG uptake on PET/CT or the absence of tumor growth was achieved in 60 patients (90.9 %) at the time of first follow-up (median 3 months, range: 1-6). Local control at one year for the entire cohort was 81.8 % (95 % CI, 67.3-90.3). The one-year OS probability among those who achieved local control at first follow-up was 86.2 % (95 % CI, 74.3-92.9) but no patients who did not achieve LC at first follow-up survived one year. Of the 60 pts that achieved initial LC, 16 have died. The rates of local control, progression-free survival and overall survival were not statistically different for patients treated using a fiducial target tracking system versus non-invasive guidance. (p = 0.44, p = 0.97 and p = 0.66, respectively). No National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE-4) grade 3 or greater toxicity was observed. SBRT is an effective treatment for medically inoperable NSCLC patients with peripherally located tumors. This therapy appears to be well tolerated with low toxicity, and patient outcomes when using non-invasive tumor tracking systems are not inferior to traditional fiducial-based techniques.


Promiscuous, non-catalytic, tandem carbohydrate-binding modules modulate the cell-wall structure and development of transgenic tobacco (Nicotiana tabacum) plants.
We have compared heterologous expression of two types of carbohydrate binding module (CBM) in tobacco cell walls. These are the promiscuous CBM29 modules (a tandem CBM29-1-2 and its single derivative CBM29-2), derived from a non-catalytic protein1, NCP1, of the Piromyces equi cellulase/hemicellulase complex, and the less promiscuous tandem CBM2b-1-2 from the Cellulomonas fimi xylanase 11A. CBM-labelling studies revealed that CBM29-1-2 binds indiscriminately to every tissue of the wild-type tobacco stem whereas binding of CBM2b-1-2 was restricted to vascular tissue. The promiscuous CBM29-1-2 had much more pronounced effects on transgenic tobacco plants than the less promiscuous CBM2b-1-2. Reduced stem elongation and prolonged juvenility, resulting in delayed flower development, were observed in transformants expressing CBM29-1-2 whereas such growth phenotypes were not observed for CBM2b-1-2 plants. Histological examination and electron microscopy revealed layers of collapsed cortical cells in the stems of CBM29-1-2 plants whereas cellular deformation in the stem cortical cells of CBM2b-1-2 transformants was less severe. Altered cell expansion was also observed in most parts of the CBM29-1-2 stem whereas for the CBM2b-1-2 stem this was observed in the xylem cells only. The cellulose content of the transgenic plants was not altered. These results support the hypothesis that CBMs can modify cell wall structure leading to modulation of wall loosening and plant growth.


The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries.
This population-based registry was designed to provide robust and updated information on the characteristics and the epidemiology of chronic myeloid leukemia (CML). All cases of newly diagnosed Philadelphia positive, BCR-ABL1+ CML that occurred in a sample of 92.5 million adults living in 20 European countries, were registered over a median period of 39 months. 94.3% of the 2904 CML patients were diagnosed in chronic phase (CP). Median age was 56 years. 55.5% of patients had comorbidities, mainly cardiovascular (41.9%). High-risk patients were 24.7% by Sokal, 10.8% by EURO, and 11.8% by EUTOS risk scores. The raw incidence increased with age from 0.39/100,000/year in people 20-29 years old to 1.52 in those >70 years old, and showed a maximum of 1.39 in Italy and a minimum of 0.69 in Poland (all countries together: 0.99). The proportion of Sokal and Euro score high-risk patients seen in many countries indicates that trial patients were not a positive selection. Thus from a clinical point of view the results of most trials can be generalized to most countries. The incidences observed among European countries did not differ substantially. The estimated number of new CML cases per year in Europe is about 6370.


In Vitro Modeling of the Bipolar Disorder and Schizophrenia Using Patient-Derived Induced Pluripotent Stem Cells with Copy Number Variations of PCDH15 and RELN.
Bipolar disorder (BP) and schizophrenia (SCZ) are major psychiatric disorders, but the molecular mechanisms underlying the complicated pathologies of these disorders remain unclear. It is difficult to establish adequate in vitro models for pathological analysis because of the heterogeneity of these disorders. In the present study, to recapitulate the pathologies of these disorders in vitro, we established in vitro models by differentiating mature neurons from human induced pluripotent stem cells (hiPSCs) derived from BP and SCZ patient with contributive copy number variations, as follows: two BP patients with PCDH15 deletion and one SCZ patient with RELN deletion. Glutamatergic neurons and GABAergic neurons were induced from hiPSCs under optimized conditions. Both types of induced neurons from both hiPSCs exhibited similar phenotypes of MAP2 (microtubule-associated protein 2)-positive dendrite shortening and decreasing synapse numbers. Additionally, we analyzed isogenic PCDH15- or RELN-deleted cells. The dendrite and synapse phenotypes of isogenic neurons were partially similar to those of patient-derived neurons. These results suggest that the observed phenotypes are general phenotypes of psychiatric disorders, and our in vitro models using hiPSC-based technology may be suitable for analysis of the pathologies of psychiatric disorders.


When do negative and positive emotions modulate working memory performance?
The present study investigated when emotion modulates working memory from the perspective of neural activation. Using fMRI, we measured brain activity during the encoding and retrieval phases of a reading span test (RST) that used emotional contexts. The emotional RST required participants to read sentences that elicited negative, neural or positive emotional states while they were memorizing target words from the sentences. Compared with the neutral RST, the negative RST activated the right amygdala during the reading phase. Significant activation was also found in the parahippocampal gyrus, albeit only after activation of the amygdala became comparable to that in the neutral RST. In contrast, the positive RST activated the substantia nigra during the reading phase relative to the neutral RST. These findings suggest that negative and positive emotions modulate working memory through distinctive neural circuits. We also discuss possible relationships between emotional modulation and working memory capacity.


High conversion efficiency, high energy terahertz pulses by optical rectification in cryogenically cooled lithium niobate.
We demonstrate highly efficient terahertz (THz) generation by optical rectification (OR) of near-optimum pump pulses centered at 1.03 μm in cryogenically cooled lithium niobate. Using a close to optimal pulse duration of 680 fs and a pump energy of 1.2 mJ, we report conversion efficiencies above 3.8±0.4%, which is more than an order of magnitude higher than previously reported. The results confirm the advantage of using cryogenic cooling of the lithium niobate crystal that significantly reduces the THz absorption, enabling the scaling of THz pulse energies to the millijoule level via OR.


An evaluation of circulating activated TAFI in septic DIC: a case series and review of the literature.
Administration of recombinant human soluble thrombomodulin (rTM) is often used in Japan to treat septic disseminated intravascular coagulation (DIC). Thrombin-activatable fibrinolysis inhibitor (TAFI) is a fibrinolysis inhibitor activated by the thrombin-thrombomodulin complex, however, it is unknown whether circulating activated TAFI is increased after rTM administration in patients with DIC. Furthermore, the relationship between TAFI activation and the prognosis of septic DIC is not defined yet. We report a series of 8 patient's TAFI activation with septic DIC treated by rTM. We sought to investigate the effect of rTM on TAFI activation and the association of plasma activated TAFI (TAFIa/ai) levels with the prognosis of septic DIC. Using plasma samples from clinical studies conducted from May 2016-March 2017 on eight patients with septic DIC at Kagoshima University Hospital, we measured plasma levels of total TAFI, TAFIa/ai, thrombin-antithrombin complex (TAT), prothrombin fragment 1 + 2 (F1 + 2), soluble fibrin (SF), antithrombin (AT), protein C (PC), protein S (PS), and plasminogen activator inhibitor-1 (PAI-1) before and after intravenous rTM administration. Then, we evaluated the relationship of these marker levels to prognosis. The thrombin-rTM complex activated TAFI in vitro in plasma from a healthy volunteer. However, TAFIa/ai levels did not significantly increase over baseline in the septic DIC patients after intravenous rTM administration. Baseline TAFIa/ai levels in non-survivors were significantly higher than those in survivors. Plasma TAFIa/ai did not increase with rTM administration. Elevated baseline TAFIa/ai concentration may be a negative prognostic indicator in septic DIC. Larger studies are needed to confirm the in vivo effect of rTM on TAFI activation.


Global Is Local: Does Formal Resident Global Health Medical Education Improve Clinical Care in the United States?
We administered a standardized 41-item questionnaire to a convenience sample of graduates of five residency programs with formal global health pathways and compared findings to a national cohort of practicing physicians to evaluate the comparative effectiveness of an overarching global health pathway on residency program graduates. Compared with the national cohort database, global health pathway graduates self-reported that they felt better prepared to treat immigrants, refugees, patients with limited English proficiency (LEP), racial/ethnic minorities, those with non-Western health beliefs, international travelers, and military veterans (P < 0.05). They were more likely to report using best practices when working with lesbian, gay, bisexual, transgender, queer/questioning patients, immigrant and refugee patients, patients with non-Western health beliefs, patients with LEP, and patients communicating via American Sign Language (P < 0.05). They also reported being more familiar with 11 of 14 high-impact or common infections encountered in travelers, immigrants, and military personnel (P < 0.05). Our findings suggest that formal postgraduate training focused on global health improves knowledge, attitudes, and self-reported medical practices when caring for diverse and marginalized populations in the United States.


Absence of 5 alpha-reductase activity in the gubernaculum during descent of the fetal pig testis.
To evaluate the hypothesis that testicular descent is mediated by the action of high local concentrations of dihydrotestosterone in the gubernaculum, testis, or epididymis, we obtained tissues from 30 male pig fetuses between 63 and 101 days of gestation. We assayed the 5 alpha-reductase activity in homogenates of pooled tissue by following the conversion of (3H)testosterone to (3H)dihydrotestosterone. The 5 alpha-reductase activity in the urethra and prostate increased prior to and during, but decreased after, the period of testicular descent. The 5 alpha-reductase activity in the gubernaculum remained constant throughout gestation and was not significantly higher than the background activity found in umbilical cord, testis plus epididymis, striated thigh muscle and heat inactivated samples of prostate and urethra. Prior to testicular descent, the 5 alpha-reductase activity was approximately 60 to 300 times higher in the urethra than in the gubernaculum, and approximately 20 to 55 times higher in the prostate than in the gubernaculum. These findings indicate that local conversion of testosterone to dihydrotestosterone in the gubernaculum or epididymis does not play a role in the mediation of testicular descent in the pig fetus.


New optical frequency domain differential mode delay measurement method for a multimode optical fiber.
A novel mode analysis method and differential mode delay (DMD) measurement technique for a multimode optical fiber based on optical frequency domain reflectometry has been proposed for the first time. We have used a conventional OFDR with a tunable external cavity laser and a Michelson interferometer. A few-mode optical multimode fiber was prepared to test our proposed measurement technique. We have also compared the OFDR measurement results with those obtained using a traditional time-domain measurement method.


Auditory priming within and across modalities: evidence from positron emission tomography.
Previous neuroimaging studies of perceptual priming have reported priming-related decreases in the extrastriate cortex. However, because these experiments have used visual stimuli, it is unclear whether the observed decreases are associated specifically with some aspect of visual perceptual processing or with more general aspects of priming. We studied within- and cross-modality priming using an auditory word stem completion paradigm. Positron emission tomography (PET) images were obtained during stem completion and a fixation task. Within-modality auditory priming was associated with blood flow decreases in the extrastriate cortex (bilateral), medial/right anterior prefrontal cortex, right angular gyrus, and precuneus. In cross-modality priming, the study list was presented visually, and subjects completed auditory word stems. Cross-modality priming was associated with trends for blood flow decreases in the left angular gyrus and increases in the medial/right anterior prefrontal cortex. Results thus indicate that reduced activity in the extrastriate cortex accompanies within-modality priming in both visual and auditory modalities.


Surgical Trends in Breast Cancer in Turkey: An Increase in Breast-Conserving Surgery.
Breast cancer is the most frequent cancer in women, and there is a great variability in surgical practice for treating that cancer in different countries. The aims of this study were to analyze the effect of guidelines from the Turkish Federation of Breast Diseases Societies on academic institutions that have breast centers and to evaluate surgical practice in Turkey in 2018. Between January and March 2019, a survey was sent to breast surgeons who were working in breast centers in academic institutions. The sampling frame included 24 academic institutions with breast centers in 18 cities in Turkey to evaluate interdisciplinary differences among breast centers and seven regions in Turkey regarding patients' choices, surgical approaches, and academic institutions. All surgeons responded to the survey, and all 4,381 patients were included. Most of the surgeons (73.9%) were working in a breast center. Multidisciplinary tumor boards were performed in 87% of the breast centers. The average time between clinical evaluation and initiation of treatment was 29 days; the longest time was in Southeast Anatolia (66 days). Only 6% of patients had ductal carcinoma in situ. Sentinel lymph node biopsy was available in every region across the country and was performed in 64.5% of the patients. In 2018, the overall breast-conserving surgery rate was 57.3% in Turkey, and it varied from 72.2% in the Black Sea region to 33.5% in Central Anatolia (P < .001). Oncoplastic breast surgery options were available at all breast centers. However, 25% of the breast centers from the Black Sea region and half the breast centers from Eastern Anatolia and the Mediterranean region did not perform this type of surgery. Increasing rates of nonpalpable breast cancer and decreasing rates of locoregional recurrences favored breast-conserving surgery, especially in developed countries. Guidelines from the Turkish Federation of Breast Diseases Societies resulted in more comprehensive breast centers and improved breast health in Turkey.


Genetic analysis of defecation in Caenorhabditis elegans.
Defecation in the nematode Caenorhabditis elegans is achieved by a cyclical stereotyped motor program. The first step in each cycle is contraction of a set of posterior body muscles (pBoc), followed by contraction of a set of anterior body muscles (aBoc), and finally contraction of specialized anal muscles that open the anus and expel intestinal contents (Exp). By testing existing behavioral mutants and screening for new mutants that become constipated due to defects in defecation, I have identified 18 genes that are involved in defecation. Mutations in 16 of these genes affect specific parts of the motor program: mutations in two genes specifically affect the pBoc step; mutations in four genes affect the aBoc step; mutations in four genes affect the Exp step; and mutations in six genes affect both aBoc and Exp. Mutations in two other genes affect the defecation cycle period but have a normal motor program. Sensory inputs that regulate the cycle timing in the wild type are also described. On the basis of the phenotypes of the defecation mutants and of double mutants, I suggest a formal genetic pathway for the control of the defecation motor program.


3D multi-spectrum sensor system with face recognition.
This paper presents a novel three-dimensional (3D) multi-spectrum sensor system, which combines a 3D depth sensor and multiple optical sensors for different wavelengths. Various image sensors, such as visible, infrared (IR) and 3D sensors, have been introduced into the commercial market. Since each sensor has its own advantages under various environmental conditions, the performance of an application depends highly on selecting the correct sensor or combination of sensors. In this paper, a sensor system, which we will refer to as a 3D multi-spectrum sensor system, which comprises three types of sensors, visible, thermal-IR and time-of-flight (ToF), is proposed. Since the proposed system integrates information from each sensor into one calibrated framework, the optimal sensor combination for an application can be easily selected, taking into account all combinations of sensors information. To demonstrate the effectiveness of the proposed system, a face recognition system with light and pose variation is designed. With the proposed sensor system, the optimal sensor combination, which provides new effectively fused features for a face recognition system, is obtained.


Generation and Analysis of Chromosomal Contact Maps of Yeast Species.
Genome-wide derivatives of the chromosome conformation capture (3C) technique are now well-established approaches to study the multiscale average organization of chromosomes from bacteria to mammals. However, the experimental parameters of the protocol have to be optimized for different species, and the downstream experimental products (i.e., pair-end sequences) are influenced by these parameters. Here, we describe a complete pipeline to generate 3C-seq libraries and compute chromosomal contact maps of yeast species.


Controlling the activity of quorum sensing autoinducers with light.
Bacteria use a communication system, called quorum sensing (QS), to organize into communities and synchronize gene expression to promote virulence and secure survival. Here we report on a proof-of-principle for externally interfering with this bacterial communication system, using light. By employing photoswitchable small molecules, we were able to photocontrol the QS-related bioluminescence in an Escherichia coli reporter strain, and the expression of target QS genes and pyocyanin production in Pseudomonas aeruginosa.


The mycotoxin, deoxynivalenol, delays gastric emptying through serotonin-3 receptors in rodents.
The effects of the trichotecene mycotoxin, deoxynivalenol, on gastric emptying and intestinal propulsion in mice and rats and gastrointestinal myoelectrical activity in rats were investigated. Gastric emptying and intestinal transit were evaluated after gavage with a milk meal containing a marker (51CrO4Na2) and radio-activity was counted in the stomach and 10 segments of the small intestine. The myoelectrical activity of the antrum, duodenum and jejunum was assessed by implanting electrodes for long-term electromyographic recordings. Deoxynivalenol given orally (50-1000 micrograms/kg) but not i.c.v. (5 micrograms/kg) 10 min before the test meal inhibited gastric emptying in a dose-related manner. Intestinal propulsion was reduced for the highest dose (1000 micrograms/kg) only. The inhibition of gastric emptying induced by deoxynivalenol was antagonized by ondansetron and granisetron given s.c. (50 micrograms/kg) but not by ondansetron i.c.v. (10 micrograms/kg). Metoclopramide, domperidone (1 mg/kg s.c.), methysergide, ritanserin and cisapride (2 mg/kg s.c.) did not modify the deoxynivalenol-induced inhibition of gastric emptying. In rats, gavage with a 2.5-ml milk meal increased the frequency of antral spike bursts from 1.9 +/- 0.9/min in the fasted state to 4.7 +/- 0.4/min and disrupted intestinal migrating motor complexes for 84.9 +/- 10.8 min. Oral administration of deoxynivalenol (50-100 micrograms/kg) 10 min before the meal did not modify the frequency of antral spike bursts but induced migrating motor complexes on the small intestine after the meal. This effect was reversed by ondansetron (10 micrograms/kg s.c.). It was concluded that, in rodents, deoxynivalenol inhibits gastric emptying by inducing intestinal migrating motor complexes through a peripheral action at the serotonin-3 receptors.


Cardiac transplantation for endstage heart disease.
Orthotopic heart transplantation (OHT), first accomplished in 1967, is currently performed in over 2000 patients per year at hundreds of centers worldwide. Selection criteria include end-stage heart failure with a limited life expectancy, intractable angina due to inoperable coronary artery disease, malignant ventricular arrhythmias refractory to maximal therapy, and unresectable cardiac tumors. While early immunosuppression was based on azathioprine and steroids, the current success of OHT is based on the addition of cyclosporine A (CyA) to this regimen. At Columbia-Presbyterian Medical Center, steroids and azathioprine are given perioperatively, and cyclosporine (OKT3 in patients with renal dysfunction) begun postoperatively. Survival rates at our institution parallel those reported by other centers, with 1- and 5-year actuarial survival of 85% and 70%, respectively. The most frequent causes of early mortality are allograft rejection and infection, while graft coronary artery disease (CAD) is responsible for most deaths occurring after the first post-transplant year. Regular endomyocardial biopsy is used to monitor for rejection, which occurs in 55% of patients within the first year. Mild or asymptomatic rejection is managed with oral steroids, followed by intravenous steroids and/or OKT3 or anti-thymocyte globulin (ATG) in refractory cases. Graft CAD occurs in 45% of patients surviving 3 years, and may require retransplantation. Heart transplantation is a proven, effective form of cardiac replacement. The recent trend of increasingly critically ill transplant candidates, however, has driven the costs of OHT to unprecedented levels. This issue, as well as the continuing organ short-age and current developments in mechanical cardiac assistance and xenotransplantation will undoubtedly assure a continually evolving role for cardiac transplantation in the treatment of endstage heart disease.


The Role of Mitochondrial DNA Variation in Age-Related Decline in Gait Speed Among Older Men Living With Human Immunodeficiency Virus.
Age-related gait speed decline is accelerated in men with human immunodeficiency virus (HIV). Mitochondrial genetic variation is associated with frailty and mortality in the general population and may provide insight into mechanisms of functional decline in people aging with HIV. Gait speed was assessed semiannually in the Multicenter AIDS Cohort Study. Mitochondrial DNA (mtDNA) haplogroups were extracted from genome-wide genotyping data, classifying men aged ≥50 years into 5 groups: mtDNA haplogroup H, J, T, Uk, and other. Differences in gait speed by haplogroups were assessed as rate of gait speed decline per year, probability of slow gait speed (<1.0 m/s), and hazard of slow gait using multivariable linear mixed-effects models, mixed-effects logistic regression models, and the Andersen-Gill model, controlling for hepatitis C virus infection, previous AIDS diagnosis, thymidine analogues exposure, education, body composition, smoking, and peripheral neuropathy. Age was further controlled for in the mixed-effects logistic regression models. A total of 455 HIV-positive white men aged ≥50 years contributed 3283 person-years of follow-up. Among them, 70% had achieved HIV viral suppression. In fully adjusted models, individuals with haplogroup J had more rapid decline in gait speed (adjusted slopes, 0.018 m/s/year vs 0.011 m/s/year, pinteraction = 0.012) and increased risk of developing slow gait (adjusted odds ratio, 2.97; 95% confidence interval, 1.24-7.08) compared to those with other haplogroups. Among older, HIV-infected men, mtDNA haplogroup J was an independent risk factor for more rapid age-related gait speed decline.


Carbohydrate hydrolysis and transport in the extreme thermoacidophile Sulfolobus solfataricus.
Extremely thermoacidophilic microbes, such as Sulfolobus solfataricus, are strict chemoheterotrophs despite their geologic niche. To clarify their ecophysiology, the overlapping roles of endoglucanases and carbohydrate transporters were examined during growth on soluble cellodextrins as the sole carbon and energy source. Strain-specific differences in genome structure implied a unique role for one of three endogenous endoglucanases. Plasmid-based endoglucanase expression promoted the consumption of oligosaccharides, including cellohexaose (G6) through cellonanaose (G9). Protein transporters required for cellodextrin uptake were identified through mutagenesis and complementation of an ABC transporter cassette, including a putative oligosaccharide binding protein. In addition, ablation of the binding protein compromised growth on glucose and alpha-linked oligosaccharides while inactivation of a previously described glucose transporter had no apparent impact. These data demonstrate that S. solfataricus employs a redundant mechanism for soluble cellodextrin catabolism having both substrate uptake and extracytoplasmic hydrolytic components.


Establishment of cell type by compartmentalized activation of a transcription factor.
Early in the process of spore formation in Bacillus subtilis a septum is formed that partitions the sporangium into daughter cells called the forespore and the mother cell. The daughter cells each have their own chromosome but follow dissimilar programs of gene expression. Differential gene expression in the forespore is now shown to be established by the compartmentalized activity of the transcription factor sigma F. The sigma F factor is produced prior to septation, but is active only in the forespore compartment of the post-septation sporangium. The sigma F factor is controlled by the products of sporulation operons spoIIA and spoIIE, which may be responsible for confining its activity to one of the daughter cells.


Nanocrystals in compression: unexpected structural phase transition and amorphization due to surface impurities.
We report an unprecedented surface doping-driven anomaly in the compression behaviors of nanocrystals demonstrating that the change of surface chemistry can lead to an interior bulk structure change in nanoparticles. In the synchrotron-based X-ray diffraction experiments, titania nanocrystals with low concentration yttrium dopants at the surface are found to be less compressible than undoped titania nanocrystals. More surprisingly, an unexpected TiO2(ii) phase (α-PbO2 type) is induced and obvious anisotropy is observed in the compression of yttrium-doped TiO2, in sharp contrast to the compression behavior of undoped TiO2. In addition, the undoped brookite nanocrystals remain with the same structure up to 30 GPa, whereas the yttrium-doped brookite amorphizes above 20 GPa. The abnormal structural evolution observed in yttrium-doped TiO2 does not agree with the reported phase stability of nano titania polymorphs, thus suggesting that the physical properties of the interior of nanocrystals can be controlled by the surface, providing an unconventional and new degree of freedom in search for nanocrystals with novel tunable properties that can trigger applications in multiple areas of industry and provoke more related basic science research.


Combining Individual Phenotypes of Feed Intake With Genomic Data to Improve Feed Efficiency in Sea Bass.
Measuring individual feed intake of fish in farms is complex and precludes selective breeding for feed conversion ratio (FCR). Here, we estimated the individual FCR of 588 sea bass using individual rearing under restricted feeding. These fish were also phenotyped for their weight loss at fasting and muscle fat content that were possibly linked to FCR. The 588 fish were derived from a full factorial mating between parental lines divergently selected for high (F+) or low (F-) weight loss at fasting. The pedigree was known back to the great grand-parents. A subset of 400 offspring and their ancestors were genotyped for 1,110 SNPs which allowed to calculate the genomic heritability of traits. Individual FCR and growth rate in aquarium were both heritable (genomic h2 = 0.47 and 0.76, respectively) and strongly genetically correlated (-0.98) meaning that, under restricted feeding, faster growing fish were more efficient. FCR and growth rate in aquariums were also significantly better for fish with both parents from F- (1.38), worse for fish with two parents F+ (1.51) and intermediate for cross breed fish (F+/F- or F-/F+ at 1.46). Muscle fat content was positively genetically correlated to growth rate in aquarium and during fasting. Thus, selecting for higher growth rate in aquarium, lower weight loss during fasting and fatter fish could improve FCR in aquarium. Improving these traits would also improve FCR of fish in normal group rearing conditions, as we showed experimentally that groups composed of fish with good individual FCR were significantly more efficient. The FCR of groups was also better when the fish composing the groups had, on average, lower estimated breeding values for growth rate during fasting (losing less weight). Thus, improving FCR in aquarium and weight loss during fasting is promising to improve FCR of fish in groups but a selection response experiment needs to be done. Finally, we showed that the reliability of estimated breeding values was higher (from+10% up to +125%) with a genomic-based BLUP model than with a traditional pedigree-based BLUP, showing that genomic data would enhance the accuracy of the prediction of EBV of selection candidates.


Biogeochemistry of "pristine" freshwater stream and lake systems in the western Canadian Arctic.
Climate change poses a substantial threat to the stability of the Arctic terrestrial carbon (C) pool as warmer air temperatures thaw permafrost and deepen the seasonally-thawed active layer of soils and sediments. Enhanced water flow through this layer may accelerate the transport of C and major cations and anions to streams and lakes. These act as important conduits and reactors for dissolved C within the terrestrial C cycle. It is important for studies to consider these processes in small headwater catchments, which have been identified as hotspots of rapid mineralisation of C sourced from ancient permafrost thaw. In order to better understand the role of inland waters in terrestrial C cycling we characterised the biogeochemistry of the freshwater systems in a c. 14 km2 study area in the western Canadian Arctic. Sampling took place during the snow-free seasons of 2013 and 2014 for major inorganic solutes, dissolved organic and inorganic C (DOC and DIC, respectively), carbon dioxide (CO2) and methane (CH4) concentrations from three water type groups: lakes, polygonal pools and streams. These groups displayed differing biogeochemical signatures, indicative of contrasting biogeochemical controls. However, none of the groups showed strong signals of enhanced permafrost thaw during the study seasons. The mean annual air temperature in the region has increased by more than 2.5 °C since 1970, and continued warming will likely affect the aquatic biogeochemistry. This study provides important baseline data for comparison with future studies in a warming Arctic.


Risk analysis on infection caused by peripherally inserted central catheter for bone tumor patients.
The aim of this study is to explore the related factors affecting infection risk caused by peripherally inserted central catheter (PICC) for bone tumor patients. A retrospective analysis was performed for 223 bone tumor patients who received PICC and were admitted to our hospital from 2004 to 2017. A total of 18 cases (infection group) with PICC catheter-related infections and 205 cases without infection (noninfection group) were studied. First, factor analysis of variance or Chi-square test was applied to compare independent risk factors for PICC catheter-related infections, between bone tumor patients with catheter-related infections and those without catheter-related infections. This retrospective analysis involved a total of 18 patients with PICC infections and 205 patients without infections. The infection rate was 8.07%. Factor analysis of variance showed that many factors were related to PICC catheter-related infections, including experience of operator (χ2 = 3.48, P < 0.05), catheter retention time (χ2 = 7.478, P < 0.05), receiving chemotherapy or not (χ2 = 2.43, P < 0.05), Karnofsky Performance Scale scores (χ2 = 2.19, P < 0.05) and the frequency of replacing pad pasting on the point of puncture (χ2 = 2.23). Logistic regression analysis showed that PICC catheter retention time (odds ratio [OR] = 4.21, P < 0.05) and operator experience (OR = 2.80, P < 0.05) were independent factors affected PICC catheter-related infections. Catheter-related infections were related to experience of PICC operatorand length of catheter retention time.


Remission and low disease activity in psoriatic arthritis publications: a systematic literature review with meta-analysis.
Remission (REM) or low disease activity (LDA) is the treatment target in psoriatic arthritis (PsA). The objective of this study was to assess the reporting and prevalence of REM/LDA in published studies of PsA. This was a systematic literature review of all clinical papers published in PubMed, EMBASE or Cochrane database in English between 2012 and 2019 in the field of PsA. Data were collected regarding reporting of REM/LDA by very low disease activity/minimal disease activity (VLDA/MDA), Disease Activity index for Psoriatic Arthritis (DAPSA), or Disease Activity Score 28 joints (DAS28). The pooled rates of REM and LDA by each definition were calculated by random effect meta-analysis. In all, 258 publications (corresponding to 114 651 patients), of which 81 (31%) were randomized controlled trials, were analysed: patients' mean age was 49.4 ( 4.4) years; with a mean disease duration of 8.5 ( 3.8) years. REM/LDA was reported in 91/258 (35.3%) publications. VLDA/MDA was used in 61/91 (67.0%) studies, DAPSA in 27/91 (29.6%) and DAS28 in 28/91 (30.7%), with 40/91 (43.9%) papers reporting several of these definitions. The pooled prevalence (lower-upper limits) of REM was 13.1% (10.9-15.4), 23.1% (16.8-30.1) and 42.1% (33.9-50.4) using VLDA, DAPSA-REM and DAS28, respectively. For LDA the pooled prevalence was 36.3% (32.3-40.5), 52.8% (41.8-63.6) and 60.4% (52.5-68.0) using MDA, DAPSA-LDA and DAS28, respectively. REM/LDA status was reported in only1/3 of recent studies on PsA, with important variations in the frequency of these outcomes according to the definition used: 13.1-42.1% for REM, and 36.3-60.4% for LDA. This highlights the need for consensus.


Development assistance for health: what criteria do multi- and bilateral funders use?
After years of unprecedented growth in development assistance for health (DAH), the system is challenged on several fronts: by the economic downturn and stagnation of DAH, by the epidemiological transition and increase in non-communicable diseases, and by the economic transition and rise of the middle-income countries. This raises questions about which countries should receive DAH and how much, and, fundamentally, what criteria that promote fair and effective allocation. Yet, no broad comparative assessment exists of the criteria used today. We reviewed the allocation criteria stated by five multilateral and nine bilateral funders of DAH. We found that several funders had only limited information about concrete criteria publicly available. Moreover, many funders not devoted to health lacked specific criteria for DAH or criteria directly related to health, and no funder had criteria directly related to inequality. National income per capita was emphasised by many funders, but the associated eligibility thresholds varied considerably. These findings and the broad overview of criteria can assist funders in critically examining and revising the criteria they use, and inform the wider debate about what the optimal criteria are.


Assessing the Impact of Early Learning Programs in Africa.
We present results from early learning programs in six African countries: Ethiopia, Kenya, Liberia, Malawi, Tanzania, and Uganda. In partnership with ministries of education, RTI International has worked within government systems to support the design and deployment of locally contextualized materials, training, and assessment tools, with the goal of improving outcomes for early learners in primary schools, and in Kenya and Tanzania preprimary as well. Here we report on the experience and evidence of impact from specific programs in each country, including summary assessment results when available. In several countries with completed impact evaluations, there are significant and important learning gains of between 0.2 and 2.57 SD in effect size; in one case the percentage of students reaching grade-level reading proficiency increased from 12% to 47%. In the context of increased urgency surrounding what UNESCO has called a "global learning crisis," these experiences provide useful lessons for policymakers and practitioners alike.


Overlapping and distinct mechanisms regulating IRF-3 and IRF-7 function.
Recent molecular, biochemical, and gene disruption studies have demonstrated the essential role of interferon (IFN) regulatory factor-3, (IRF-3) and IRF-7 in the activation of type I IFN gene expression and the induction of the antiviral state. Both transcription factors share structural and functional properties, as well as a common mechanism of activation through C-terminal phosphorylation. The purpose of this review is to summarize recent investigations indicating that similar signalling pathways are likely involved in the activation of IRF-3 and IRF-7. Moreover, unique biochemical events, such as coactivator association and differential recognition of cis-acting elements, also illustrate the capacity of IRF-3 and IRF-7 to selectively regulate type I IFN and IFN-stimulated gene (ISG) expression.


Two distinct populations of Chiari I malformation based on presence or absence of posterior fossa crowdedness on magnetic resonance imaging.
OBJECTIVE A subset of patients with Chiari I malformation demonstrate patent subarachnoid spaces around the cerebellum, indicating that reduced posterior fossa volume alone does not account for tonsillar descent. The authors distinguish two subsets of Chiari I malformation patients based on the degree of "posterior fossa crowdedness" on MRI. METHODS Two of the coauthors independently reviewed the preoperative MR images of 49 patients with Chiari I malformation and categorized the posterior fossa as "spacious" or "crowded." Volumetric analysis of posterior fossa structures was then performed using open-source DICOM software. The preoperative clinical and imaging features of the two groups were compared. RESULTS The posterior fossae of 25 patients were classified as spacious and 20 as crowded by both readers; 4 were incongruent. The volumes of the posterior fossa compartment, posterior fossa tissue, and hindbrain (posterior fossa tissue including herniated tonsils) were statistically similar between the patients with spacious and crowed subtypes (p = 0.33, p = 0.17, p = 0.20, respectively). However, patients in the spacious and crowded subtypes demonstrated significant differences in the ratios of posterior fossa tissue to compartment volumes as well as hindbrain to compartment volumes (p = 0.001 and p = 0.0004, respectively). The average age at surgery was 29.2 ± 19.3 years (mean ± SD) and 21.9 ± 14.9 years for spacious and crowded subtypes, respectively (p = 0.08). Syringomyelia was more prevalent in the crowded subtype (50% vs 28%, p = 0.11). CONCLUSIONS The authors' study identifies two subtypes of Chiari I malformation, crowded and spacious, that can be distinguished by MRI appearance without volumetric analysis. Earlier age at surgery and presence of syringomyelia are more common in the crowded subtype. The presence of the spacious subtype suggests that crowdedness alone cannot explain the pathogenesis of Chiari I malformation in many patients, supporting the need for further investigation.


Local adaptation limits lifetime reproductive success of dispersers in a wild salmon metapopulation.
Demographic and evolutionary dynamics in wild metapopulations are critically affected by the balance between dispersal and local adaptation. Where populations are demographically interconnected by migration, gene flow is often assumed to prevent local adaptation. However, reduced fitness of immigrants may limit gene flow between populations adapted to distinct habitat types, although direct quantification of the lifetime reproductive success of immigrants in the wild is lacking. Here, we show that dispersers between stream-spawning populations of sockeye salmon (Oncorhynchus nerka) had similar reproductive success to those that spawned in their natal stream, whereas dispersers from a different habitat (nearby lake beaches) produced half as many offspring. The stream- and beach-spawning ecotypes exhibited striking morphological differences despite their close spatial proximity, yet dispersal from the beach to the streams was more common than dispersal between streams, presenting empirical evidence that variation in immigrant reproductive success is important for the maintenance of intraspecific biodiversity.


Can Intestinal Pseudo-Obstruction Drive Recurrent Stroke-Like Episodes in Late-Onset MELAS Syndrome? A Case Report and Review of the Literature.
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disorder that is most commonly caused by the m. 3243A>G mutation in the MT-TL1 mitochondrial DNA gene, resulting in impairment of mitochondrial energy metabolism. Although childhood is the typical age of onset, a small fraction (1-6%) of individuals manifest the disease after 40 years of age and usually have a less aggressive disease course. The clinical manifestations are variable and mainly depend on the degree of heteroplasmy in the patient's tissues and organs. They include muscle weakness, diabetes, lactic acidemia, gastrointestinal disturbances, and stroke-like episodes, which are the most commonly observed symptom. We describe the case of a 50-year-old male patient who presented with relapsing intestinal pseudo-obstruction (IPO) episodes, which led to a late diagnosis of MELAS. After diagnosis, he presented several stroke-like episodes in a short time period and developed a rapidly progressive cognitive decline, which unfortunately resulted in his death. We describe the variable clinical manifestations of MELAS syndrome in this atypical and relatively old patient, with a focus on paralytic ileus and stroke-like episodes; the first symptom may have driven the others, leading to a relentless decline. Moreover, we provide a brief revision of previous reports of IPO occurrence in MELAS patients with the m.3243A>G mutation, and we investigate its relationship with stroke-like episodes. Our findings underscore the importance of recognizing gastrointestinal disturbance to prevent neurological comorbidities.


Expansion of gene clusters, circular orders, and the shortest Hamiltonian path problem.
Clusters of paralogous genes such as the famous HOX cluster of developmental transcription factors tend to evolve by stepwise duplication of its members, often involving unequal crossing over. Gene conversion and possibly other mechanisms of concerted evolution further obfuscate the phylogenetic relationships. As a consequence, it is very difficult or even impossible to disentangle the detailed history of gene duplications in gene clusters. In this contribution we show that the expansion of gene clusters by unequal crossing over as proposed by Walter Gehring leads to distinctive patterns of genetic distances, namely a subclass of circular split systems. Furthermore, when the gene cluster was left undisturbed by genome rearrangements, the shortest Hamiltonian paths with respect to genetic distances coincide with the genomic order. This observation can be used to detect ancient genomic rearrangements of gene clusters and to distinguish gene clusters whose evolution was dominated by unequal crossing over within genes from those that expanded through other mechanisms.


Co-morbidities, complications and causes of death among people with femoral neck fracture - a three-year follow-up study.
The poor outcome after a hip fracture is not fully understood. The aim of the study was to describe the prevalence of co-morbidities, complications and causes of death and to investigate factors that are able to predict mortality in old people with femoral neck fracture. Data was obtained from a randomized, controlled trial with a 3-year follow-up at Umeå University Hospital, Sweden, which included 199 consecutive patients with femoral neck fracture, aged ≥70 years. The participants were assessed during hospitalization and in their homes 4, 12 and 36 months after surgery. Medical records and death certificates were analysed. Multivariate analysis revealed that cancer, dependence in P-ADL (Personal Activities of Daily Living), cardiovascular disease, dementia at baseline or pulmonary emboli or cardiac failure during hospitalization were all independent predictors of 3-year mortality. Seventy-nine out of 199 participants (40 %) died within 3 years. Cardiovascular events (24 %), dementia (23 %), hip-fracture (19 %) and cancer (13 %) were the most common primary causes of death. In total, 136 participants suffered at least one urinary tract infection; 114 suffered 542 falls and 37 sustained 56 new fractures, including 13 hip fractures, during follow-up. Old people with femoral neck fracture have multiple co-morbidities and suffer numerous complications. Thus randomized intervention studies should focus on prevention of complications that might be avoidable such as infections, heart diseases, falls and fractures.


Engagement in the electoral processes: scaling laws and the role of political positions.
We report on a statistical analysis of the engagement in the electoral processes of all Brazilian cities by considering the number of party memberships and the number of candidates for mayor and councillor. By investigating the relationships between the number of party members and the population of voters, we have found that the functional forms of these relationships are well described by sublinear power laws (allometric scaling) surrounded by a multiplicative log-normal noise. We have observed that this pattern is quite similar to those we previously reported for the relationships between the number of candidates (mayor and councillor) and population of voters [Europhys. Lett. 96, 48001 (2011)], suggesting that similar universal laws may be ruling the engagement in the electoral processes. We also note that the power-law exponents display a clear hierarchy, where the more influential is the political position the smaller is the value of the exponent. We have also investigated the probability distributions of the number of candidates (mayor and councillor), party memberships, and voters. The results indicate that the most influential positions are characterized by distributions with very short tails, while less influential positions display an intermediate power-law decay before showing an exponential-like cutoff. We discuss the possibility that, in addition to the political power of the position, limitations in the number of available seats can also be connected with this changing of behavior. We further believe that our empirical findings point out to an under-representation effect, where the larger the city is, the larger are the obstacles for more individuals to become directly engaged in the electoral process.


Combining Cystatin C and Creatinine Yields a Reliable Glomerular Filtration Rate Estimation in Older Adults in Contrast to β-Trace Protein and β2-Microglobulin.
The glomerular filtration rate (GFR) is the most important measure of kidney function and chronic kidney disease (CKD). This study aims to validate commonly used equations for estimated GFR (eGFR) based on creatinine (cr), cystatin C (cys), β-trace protein (BTP), and β2-microglobulin (B2M) in older adults. We conducted a validation study with 126 participants aged between 72 and 98 with a mean measured GFR (mGFR) by iohexol clearance of 54 mL/min/1.73 m2. The eGFR equations (CKD-Epidemiology collaboration [CKD-EPI], Berlin Initiative Study [BIS], Full Age Spectrum [FAS], Modification of Diet in Renal Disease [MDRD]cr, Caucasian-Asian-Pediatric-Adult [CAPA]cys, Lund-Malmö Revised [LM-REV]cr, and MEAN-LM-CAPAcr-cys), were assessed in terms of bias (median difference: eGFR-mGFR), precision (interquartile range of the differences), and accuracy (P30: percentage of estimates ±30% of mGFR). The equations were compared to a benchmark equation: CKD-EPIcr-cys. All cystatin C-based equations underestimated the GFR compared to mGFR, whereas bias was mixed for the equations based only on creatinine. Accuracy was the highest for CKD-EPIcr-cys (98%) and lowest for MDRD (82%). Below mGFR 45 mL/min/1.73 m2 only equations incorporating cystatin C reached P30 accuracy >90%. CKD-EPIcr-cys was not significantly more accurate than the other cystatin C-based equations. In contrast, CKD-EPIcr-cys was significantly more accurate than all creatinine-based equations except LM-REVcr. This study confirms that it is reasonable to use equations incorporating cystatin C and creatinine in older patients across a wide spectrum of GFR. However, the results call into question the use of creatinine alone below mGFR 45 mL/min/1.73 m2. B2M and BTP do not demonstrate additional value in eGFR determination in older adults.


Relationship between a three-month physical conditioning "posture-balance-motricity and health education" (PBM-HE) program on postural and balance capacities of sedentary older adults: influence of initial motor profile.
The aims of this study were (i) to define the relationship between a physical reconditioning cycle using balance exercises and muscular-articular stress and the balance capabilities of sedentary older adults and (ii) to assess whether older adults with weaker equilibrium abilities have a significantly limited progression. Our sample consisted of 338 people (263 women, 75 men) with an age, weight and height of 74.4 years (+/- 8.6), 67 kg (+/- 13.6) and 161.4 cm (+/- 8) and with a body mass index of 25.6 (+/- 4.3). The functional evaluations consisted of individual motor profile tests, monopodal eyes open and eyes closed for 30 s, a Timed Up and Go test (TUG) and stabilometric measurements on hard ground with eyes open for a duration of 25.6 s. The physical repackaging protocol was based on the 12-week Posture-Balance-Motricity and Health Education (PBM-ES) method with two 90-min weekly group sessions. The evolution of the "posture" and "balance" variables was significantly associated with the equilibration capacities (p < 0.001). For unipedal stance with open eyes on the dominant and non-dominant sides, respectively, the progressions were significant for the profiles of middle (OR: 4.78 and 2.42) and low levels (OR: 4.34 and 1.66). Eyes-closed progressions were non-significant for the low-level balance profiles. For the COP Surface and Length variables, compared to those with high levels of balance, respectively, the progressions were significant for the middle- (OR: 1.41 and 2.98) and low-level (OR: 2.91 and 3.28) profiles. After a 3-month bi-weekly PBM-HE program, we observed that sedentary older adults with the lowest initial level of balance progressed significantly more than high-level individuals, but only for basic motor abilities. It turns out that even among the most deconditioned people and older adults, very significant progress can be made. This increase requires an individualized training content focused on initial mobilizable capacities.


Deleterious CHEK2 1100delC and L303X mutants identified among 38 human breast cancer cell lines.
The CHEK2 protein plays a major role in the regulation of DNA damage response pathways. Mutations in the CHEK2 gene, in particular 1100delC, have been associated with increased cancer risks, but the precise function of CHEK2 mutations in carcinogenesis is not known. Human cancer cell lines with CHEK2 mutations are therefore of main interest. Here, we have sequenced 38 breast cancer cell lines for mutations in the CHEK2 gene and identified two cell lines with deleterious CHEK2 mutations. Cell line UACC812 has a nonsense truncating mutation in the CHEK2 kinase domain (L303X) and cell line SUM102PT has the well-known oncogenic CHEK2 1100delC founder mutation. Immunohistochemical analysis revealed that the two CHEK2 mutant cell lines expressed neither CHEK2 nor P-Thr(68) CHEK2 proteins, implying abrogation of normal CHEK2 DNA repair functions. Cell lines UACC812 and SUM102PT thus are the first human CHEK2 null cell lines reported and should therefore be a major help in further unraveling the function of CHEK2 mutations in carcinogenesis.


Diet mediates the relationship between longevity and reproduction in mammals.
The disposable soma hypothesis posits a negative correlation between longevity and reproduction, presumably because these aspects of fitness compete for a limited pool of nutrients. However, diet, which varies widely among animals, could affect the availability of key nutrients required for both reproduction and longevity, especially protein. We used a comparative database of mammal life history data to test the hypothesis that carnivores experience less of a negative relationship between reproduction and longevity than herbivores. Annual reproduction and adult mass were significant predictors of longevity among all mammals; although, the relative importance of reproduction and mass for explaining longevity varied among trophic levels. In herbivores, reproduction was a stronger predictor of longevity than mass. Carnivores showed the opposite pattern with reproduction explaining much less of the variation in longevity. Omnivores showed an intermediate pattern with mass and reproduction explaining similar amounts of variation in longevity. In addition, longevity and reproduction were significantly higher in omnivores than herbivores and carnivores, which were not different from each other. Higher dietary protein at higher trophic levels may allow mammals to avoid potential conflicts between reproduction and longevity. However, there may be potential costs of carnivorous diets that limit the overall performance of carnivores and explain the peak in reproduction and longevity for omnivores.