Using Automated Machine Learning to Predict the Mortality of Patients With COVID-19: Prediction Model Development Study.
During a pandemic, it is important for clinicians to stratify patients and decide who receives limited medical resources. Machine learning models have been proposed to accurately predict COVID-19 disease severity. Previous studies have typically tested only one machine learning algorithm and limited performance evaluation to area under the curve analysis. To obtain the best results possible, it may be important to test different machine learning algorithms to find the best prediction model. In this study, we aimed to use automated machine learning (autoML) to train various machine learning algorithms. We selected the model that best predicted patients' chances of surviving a SARS-CoV-2 infection. In addition, we identified which variables (ie, vital signs, biomarkers, comorbidities, etc) were the most influential in generating an accurate model. Data were retrospectively collected from all patients who tested positive for COVID-19 at our institution between March 1 and July 3, 2020. We collected 48 variables from each patient within 36 hours before or after the index time (ie, real-time polymerase chain reaction positivity). Patients were followed for 30 days or until death. Patients' data were used to build 20 machine learning models with various algorithms via autoML. The performance of machine learning models was measured by analyzing the area under the precision-recall curve (AUPCR). Subsequently, we established model interpretability via Shapley additive explanation and partial dependence plots to identify and rank variables that drove model predictions. Afterward, we conducted dimensionality reduction to extract the 10 most influential variables. AutoML models were retrained by only using these 10 variables, and the output models were evaluated against the model that used 48 variables. Data from 4313 patients were used to develop the models. The best model that was generated by using autoML and 48 variables was the stacked ensemble model (AUPRC=0.807). The two best independent models were the gradient boost machine and extreme gradient boost models, which had an AUPRC of 0.803 and 0.793, respectively. The deep learning model (AUPRC=0.73) was substantially inferior to the other models. The 10 most influential variables for generating high-performing models were systolic and diastolic blood pressure, age, pulse oximetry level, blood urea nitrogen level, lactate dehydrogenase level, D-dimer level, troponin level, respiratory rate, and Charlson comorbidity score. After the autoML models were retrained with these 10 variables, the stacked ensemble model still had the best performance (AUPRC=0.791). We used autoML to develop high-performing models that predicted the survival of patients with COVID-19. In addition, we identified important variables that correlated with mortality. This is proof of concept that autoML is an efficient, effective, and informative method for generating machine learning-based clinical decision support tools.


Assessment of image quality and dose calculation accuracy on kV CBCT, MV CBCT, and MV CT images for urgent palliative radiotherapy treatments.
A clinical workflow was developed for urgent palliative radiotherapy treatments that integrates patient simulation, planning, quality assurance, and treatment in one 30-minute session. This has been successfully tested and implemented clinically on a linac with MV CBCT capabilities. To make this approach available to all clin-ics equipped with common imaging systems, dose calculation accuracy based on treatment sites was assessed for other imaging units. We evaluated the feasibility of palliative treatment planning using on-board imaging with respect to image quality and technical challenges. The purpose was to test multiple systems using their commercial setup, disregarding any additional in-house development. kV CT, kV CBCT, MV CBCT, and MV CT images of water and anthropomorphic phantoms were acquired on five different imaging units (Philips MX8000 CT Scanner, and Varian TrueBeam, Elekta VersaHD, Siemens Artiste, and Accuray Tomotherapy linacs). Image quality (noise, contrast, uniformity, spatial resolution) was evaluated and compared across all machines. Using individual image value to density calibrations, dose calculation accuracies for simple treatment plans were assessed for the same phantom images. Finally, image artifacts on clinical patient images were evaluated and compared among the machines. Image contrast to visualize bony anatomy was sufficient on all machines. Despite a high noise level and low contrast, MV CT images provided the most accurate treatment plans relative to kV CT-based planning. Spatial resolution was poorest for MV CBCT, but did not limit the visualization of small anatomical structures. A comparison of treatment plans showed that monitor units calculated based on a prescription point were within 5% difference relative to kV CT-based plans for all machines and all studied treatment sites (brain, neck, and pelvis). Local dose differences > 5% were found near the phantom edges. The gamma index for 3%/3 mm criteria was ≥ 95% in most cases. Best dose calculation results were obtained when the treatment isocenter was near the image isocenter for all machines. A large field of view and immediate image export to the treatment planning system were essential for a smooth workflow and were not provided on all devices. Based on this phantom study, image quality of the studied kV CBCT, MV CBCT, and MV CT on-board imaging devices was sufficient for treatment planning in all tested cases. Treatment plans provided dose calculation accuracies within an acceptable range for simple, urgently planned palliative treatments. However, dose calculation accuracy was compromised towards the edges of an image. Feasibility for clinical implementation should be assessed separately and may be complicated by machine specific features. Image artifacts in patient images and the effect on dose calculation accuracy should be assessed in a separate, machine-specific study.


Cripping safe sex : Life Goes On's queer/disabled alliances.
Life Goes On (1989-1993) was the first television series in U.S. history not only to introduce a recurring teenaged HIV-positive character but also to feature an actor with Down syndrome in a leading role. Drawing new connections among disability studies, queer theory, and bioethics, I argue that Life responded to American disability rights activism and the AIDS epidemic of the early 1990s by depicting sex education as disability activism. By portraying fulfilling sexual relationships for its disabled protagonists, Life challenged heteronormative and ableist underpinnings of marriage, sexuality, reproduction, and sex education and imagined transgressive queer/disabled alliances that often surpassed those of activists of its cultural moment. By representing homophobia, AIDS-phobia, and ableism as intertwined oppressions, the series conjured an expansive vision of sexual justice and pleasure, one that included and united teenagers, intellectually disabled people, and seropositive people-populations whose sexualities have generally been regarded as pathological or nonexistent.


Risk factors for failure to extend labor epidural analgesia to epidural anesthesia for Cesarean section.
To identify parturients at risk of inability to extend labor epidural analgesia in whom alternative methods of anesthesia should be considered for Cesarean section (CS). For 6 months, we prospectively studied women undergoing a CS with a functioning epidural catheter in place from the delivery ward. All parturients received the same epidural protocol: bolus of bupivacaine 0.1% and fentanyl, then bupivacaine 0.1% and fentanyl (2 microg/ml) 10-15 ml/h and an additional 5 ml of bupivacaine 0.125% top-ups according to patient request. Sixteen millilitres of lidocaine 2%, 1 ml of bicarbonate, and 100 microg of fentanyl were given for CS. Failed epidural analgesia was defined as the need to convert to general anesthesia. Of the 101 parturients studied, 20 (19.8%) required conversion to general anesthesia. In univariate analysis, the likelihood of failed epidural anesthesia was inversely correlated with parturient's age (P = 0.014) and directly correlated with pre-pregnancy weight (P = 0.019), weight at the end of pregnancy (P = 0.003), body mass index (BMI) at the end of pregnancy (P = 0.0004), gestational week (P = 0.008), number of top-ups (P = 0.0004) and visual analog scale (VAS) 2 h before CS (P = 0.03). In multivariate analysis, the number of top-ups in the delivery ward was the best predictor of epidural anesthesia failure (odds ratio 4.39, P = 0.005). Younger, more obese parturients at a higher gestational week, requiring more top-ups during labor, having a higher VAS in the 2 h before CS are at risk of inability to extend labor epidural analgesia to epidural anesthesia for CS.


A genome-wide association study on fish consumption in a Japanese population-the Japan Multi-Institutional Collaborative Cohort study.
Although benefits of fish consumption for health are well known, a significant percentage of individuals dislike eating fish. Fish consumption may be influenced by genetic factors in addition to environmental factors. We conducted a genome-wide association study (GWAS) to find genetic variations that affect fish consumption in a Japanese population. We performed a two-stage GWAS on fish consumption using 13,739 discovery samples from the Japan Multi-Institutional Collaborative Cohort study, and 2845 replication samples from the other population. We used a semi-quantitative food frequency questionnaire to estimate food intake. Association of the imputed variants with fish consumption was analyzed by separate linear regression models per variant, with adjustments for age, sex, energy intake, principal component analysis components 1-10, and alcohol intake (g/day). We also performed conditional analysis. We found 27 single nucleotide polymorphisms (SNPs) located in 12q24 and 14q32.12 that were associated with fish consumption. The 19 SNPs were located at 11 genes including six lead SNPs at the BRAP, ACAD10, ALDH2, NAA25, and HECTD4 regions on 12q24.12-13, and CCDC197 region on 14q32.12. In replication samples, all five SNPs located on chromosome 12 were replicated successfully, but the one on chromosome 14 was not. Conditional analyses revealed that the five lead variants in chromosome 12 were in fact the same signal. We found that new SNPs in the 12q24 locus were related to fish intake in two Japanese populations. The associations between SNPs on chromosome 12 and fish intake were strongly confounded by drinking status.


A Perspective of Immunotherapy for Breast Cancer: Lessons Learned and Forward Directions for All Cancers.
Immunotherapy for cancer has been a focus 50 years ago. At the time, this treatment was developed prior to cloning of the cytokines, no knowledge of regulatory T-cells, and very little information that mesenchymal stem cells (MSCs) (originally colony forming unit-fibroblasts [CFU-F]) could be licensed by the inflammatory microenvironment to suppress an immune response. Given the information available at that time, mononuclear cells from the peripheral blood were activated ex vivo and then replaced in the patients with tumor. The intent was to harness these activated immune cells to target the cancer cells. These studies did not lead to long-term responses because the activated cells when reinfused into the patients were an advantage to the resident MSCs, which can home the tumor and then become suppressive in the presence of the immune cells. The immune suppression caused by MSCs would also expand regulatory T-cells, resulting instead in tumor protection. As time progressed, these different fields converged into a new approach to use immunotherapy for cancer. This article discusses these approaches and also reviews chimeric antigen receptor in the context of future treatments for solid tumors, including breast cancer.


Genetic and serological typing of European infectious haematopoietic necrosis virus (IHNV) isolates.
Infectious haematopoietic necrosis virus (IHNV) causes the lethal disease infectious haematopoietic necrosis (IHN) in juvenile salmon and trout. The nucleocapsid (N) protein gene and partial glycoprotein (G) gene (nucleotides 457 to 1061) of the European isolates IT-217A, FR-32/87, DE-DF 13/98 11621, DE-DF 4/99-8/99, AU-9695338 and RU-FR1 were sequenced and compared with IHNV isolates from the North American genogroups U, M and L. In phylogenetic studies the N gene of the Italian, French, German and Austrian isolates clustered in the M genogroup, though in a different subgroup than the isolates from the USA. Analyses of the partial G gene of these European isolates clustered them in the M genogroup close to the root while the Russian isolate clustered in the U genogroup. The European isolates together with US-WRAC and US-Col-80 were also tested in an enzyme-linked immunosorbent assay (ELISA) using monoclonal antibodies (MAbs) against the N protein. MAbs 136-1 and 136-3 reacted equally at all concentrations with the isolates tested, indicating that these antibodies identify a common epitope. MAb 34D3 separated the M and L genogroup isolates from the U genogroup isolate. MAb 1DW14D divided the European isolates into 2 groups. MAb 1DW14D reacted more strongly with DE-DF 13/98 11621 and RU-FR1 than with IT-217A, FR-32/87, DE-DF 4/99-8/99 and AU-9695338. In the phylogenetic studies, the Italian, French, German and Austrian isolates clustered in the M genogroup, whereas in the serological studies using MAbs, the European M genogroup isolates could not be placed in the same specific group. These results indicate that genotypic and serotypic classification do not correlate.


Cognitive sequelae of severe malaria with impaired consciousness.
Although cerebral malaria is the most common acute encephalopathy arising in children in Africa little is known of its effect upon the longer-term cognitive development of survivors. In Kenya, we compared the performance of 87 survivors of severe malaria with impaired consciousness to matched community controls on a wide range of tasks, not less than 42 months post illness episode. The presence of cognitive impairment was then related to both the pattern of symptoms at the time of the acute illness and the presence of gross neurological impairment on discharge. Significant group differences were found in areas of cognitive functioning suggestive of widespread impairment in the development of the ability to initiate, plan and carry out tasks (the executive functions). On tasks of more discrete cognitive skills (information processing) there were no significant group differences, although impaired performance was found more frequently in the severe malaria group. The odds ratio associated with the development of cognitive impairment following severe malaria with impaired consciousness was found to be 4.48 (95% CI 1.22, 16.47). A combination of 4 signs (coma, hypoglycaemia, seizures, and absence of hyperpyrexia) proved to have greater accuracy than the presence of gross neurological sequelae in predicting cognitive impairment (95% vs 93% specificity, 67% vs 58% sensitivity).


Effect of sampling duration on the performance evaluation of a stormwater wetland.
In this study, the effect of sampling duration on the performance estimate for a stormwater wetland over both rainy and dry days was evaluated for the appropriate design of sampling duration. As the cumulative percentage volume (Vp), the ratio of cumulative stormwater volume concerning time to the total stormwater volume, varied between 60 and 100%, generally, the inflow total suspended solids, turbidity and total chemical oxygen demand (TCOD) event mean concentrations (EMCs) did not vary significantly, whereas the total nitrogen (TN) and total phosphorus (TP) EMCs were relatively stable. Compared to the inflow, the corresponding outflow EMCs changed much less as Vp changed. And these variations both from inflow and outflow EMCs did not result in significant changes in the removal efficiencies. The investigation during the dry days between two consecutive storm events showed that outflow pollutants did not change to a considerable extent after 1 day of the previous rainfall event. This study identifies the possibility of shortening the rainy sampling duration, because the performance of stormwater wetlands is usually estimated based on removal efficiencies rather than pollutant concentrations. Also, the sampling during dry days should be performed at least 1 day after a rainfall event.


Nothing About Patients Without Patients: More Than Just a Catchphrase!
Health care is sometimes called a "team sport," yet patients were traditionally not considered to be "on the team" in medicine. In 2001, the Institute of Medicine (now National Academy of Medicine) published its seminal book Crossing the Quality Chasm, in which patient-centered care was identified as 1 of 6 quality aims. Many organizations have since included patient-centered care as an important aspect of quality, including The Joint Commission, Centers for Medicare and Medicaid, and many large employers. In the past 10 years, the focus on patient-centered care has expanded in the Kaiser Permanente, Southern California region to include innovative ways for patients to collaborate with health care teams to codesign improvement efforts that are truly patient-centered. We will describe 3 important approaches that have greatly increased the patient-centeredness of our organization: individual patient approaches; adding patients onto health care teams; and effectively utilizing patient and family advisory councils. We will provide examples of how all health care organizations can better partner with their patients to improve their ability to provide higher quality, safer, more equitable, and affordable health care. The slogan "Nothing About Patients Without Patients" was an early rallying cry of the patient engagement movement. It conveyed the idea that as with everything else in our society, patients now expect to have a say in the design and implementation of their care. We show that this is not only possible, but also highly effective and even necessary to improving care.


Role of detection method in predicting breast cancer survival: analysis of randomized screening trials.
Screening mammography detects breast cancers earlier than those detected symptomatically, and so mammographically detected breast cancers tend to have better prognoses. The so-called stage shift that results from screen detection is subject to lead-time and length biases, and so earlier detection may not translate into longer survival. We used data from three large breast cancer screening trials--Health Insurance Plan (HIP) of New York and two Canadian National Breast Cancer Screening Studies (CNBSS)--to investigate survival benefits of breast cancer screening beyond stage shift. We also address whether method of detection is an independent prognostic factor in breast cancer. The HIP trial randomly assigned approximately 62,000 women to screening and control groups. The two CNBSS trial cohorts CNBSS-1 and CNBSS-2 included a total of 44,970 women in the screening group and 44,961 in the control group. After adjusting for stage and other tumor characteristics in a Cox proportional hazards model, survival distributions were compared by method of breast cancer detection with both univariate and multivariable analyses. All P values are two-sided. Breast cancers detected by screening mammography had a shift in stage distribution to earlier stages (for HIP, P < .001; for CNBSS-1, P = .03; and for CNBSS-2, P < .001). After adjusting for tumor size, lymph node status, and disease stage in a Cox proportional hazards model, method of detection was a statistically significant independent predictor of disease-specific survival. Patients with interval cancers had a 53% (95% confidence interval [CI] = 17% to 100%) greater hazard of death from breast cancer than patients with screen-detected cancers, and patients with cancer in the control groups had a 36% (95% CI = 10% to 68%) greater hazard of death than patients with screen-detected cancer. There was an apparent survival benefit beyond stage shift for patients with screen-detected breast cancers compared with patients with breast cancers detected otherwise. Method of detection appears to be an important prognostic factor, even after adjusting for known tumor characteristics. This finding suggests that clinical trialists should routinely collect information about method of detection.


Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer.
Angiogenesis is necessary for the continued growth of solid tumors, invasion and metastasis. Several studies clearly showed that heme oxygenase-1 (HO-1) plays an important role in angiogenesis. In this study, we used the vital microscope system, transparent skinfold model, lung colonization model and transduced pancreatic cancer cell line (Panc-1)/human heme oxygenase-1 (hHO-1) cells, to precisely analyze, for the first time, the effect of hHO-1 gene on tumor growth, angiogenesis and metastasis. Our results revealed that HO-1 stimulates angiogenesis of pancreatic carcinoma in severe combined immune deficient mice. Overexpression of human hHO-1 after its retroviral transfer into Panc-1 cells did not interfere with tumor growth in vitro. While in vivo the development of tumors was accelerated upon transfection with hHO-1. On the other hand, inhibition of heme oxygenase (HO) activity by stannous mesoporphyrin was able transiently to delay tumor growth in a dose dependent manner. Tumor angiogenesis was markedly increased in Panc-1/hHO-1 compared to mock transfected and wild type. Lectin staining and Ki-67 proliferation index confirmed these results. In addition hHO-1 stimulated in vitro tumor angiogenesis and increased endothelial cell survival. In a lung colonization model, overexpression of hHO-1 increased the occurrence of metastasis, while inhibition of HO activity by stannous mesoporphyrin completely inhibited the occurrence of metastasis. In conclusion, overexpression of HO-1 genes potentiates pancreatic cancer aggressiveness, by increasing tumor growth, angiogenesis and metastasis and that the inhibition of the HO system may be of useful benefit for the future treatment of the disease.


Pathogenomics of Emerging Campylobacter Species.
Campylobacter is among the four main causes of gastroenteritis worldwide and has increased in both developed and developing countries over the last 10 years. The vast majority of reported Campylobacter infections are caused by Campylobacter jejuni and, to a lesser extent, C. coli; however, the increasing recognition of other emerging Campylobacter pathogens is urgently demanding a better understanding of how these underestimated species cause disease, transmit, and evolve. In parallel to the enhanced clinical awareness of campylobacteriosis due to improved diagnostic protocols, the application of high-throughput sequencing has increased the number of whole-genome sequences available to dozens of strains of many emerging campylobacters. This has allowed for comprehensive comparative pathogenomic analyses for several species, such as C. fetus and C. concisus These studies have started to reveal the evolutionary forces shaping their genomes and have brought to light many genomic features related to pathogenicity in these neglected species, promoting the development of new tools and approaches relevant for clinical microbiology. Despite the need for additional characterization of genomic diversity in emerging campylobacters, the increasing body of literature describing pathogenomic studies on these species deserves to be discussed from an integrative perspective. This review compiles the current knowledge and highlights future work toward deepening our understanding about genome dynamics and the mechanisms governing the evolution of pathogenicity in emerging Campylobacter species, which is urgently needed to develop strategies to prevent or control the spread of these pathogens.


Shaping the optical components of solitary threewave weakly coupled states in a two-mode waveguide.
Temporal Bragg solitary waves in the form of collinear threewave weakly coupled states are studied theoretically and experimentally in a two-mode optical waveguide, exhibiting square-law nonlinearity. The dynamics of shaping their optical components, bright and dark, is studied, and the roles of localizing pulse width and phase mismatch are revealed.


Automatic assignment of NOESY cross peaks and determination of the protein structure of a new world scorpion neurotoxin using NOAH/DIAMOD.
The 3D NMR structures of the scorpion neurotoxin, CsE-v5, were determined from the same NOESY spectra with NOAH/DIAMOD, an automated assignment and 3D structure calculation software package, and with a conventional manual assignment combined with a distance geometry/simulated annealing (X-PLOR) refinement method. The NOESY assignments and the 3D structures obtained from the two independent methods were compared in detail. The NOAH/DIAMOD program suite uses feedback filtering and self-correcting distance geometry methods to automatically assign NOESY spectra and to calculate the 3D structure of a protein. NOESY cross peaks were automatically picked using a standard software package and combined with 74 manually assigned NOESY peaks to start the NOAH/DIAMOD calculations. After 63 NOAH/DIAMOD cycles, using REDAC procedures in the last 8 cycles, and final FANTOM constrained energy minimization, a bundle of 20 structures with the smallest target functions has a RMSD of 0.81 A for backbone atoms and 1.11 A for all heavy atoms to the mean structure. Despite some missing chemical shifts of side chain protons, 776 (including 74 manually assigned) of 1130 NOE peaks were unambiguously assigned, 150 peaks have more than one possible assignment compatible with the bundle structures, and only 30 peaks could not be assigned within the given chemical shift tolerance ranges in either the D1 or the D2 dimension. The remaining 174, mainly weak NOE peaks were not compatible with the final 20 best bundle structures at the last NOAH/DIAMOD cycle. The automatically determined structures agree well with the structures determined independently using the conventional method and the same NMR spectra, with the mean RMSD in well-defined regions of 0.84 A for bb and 1.48 A for all heavy atoms from residues 2-5, 18-26, 32-36, and 39-45. This study demonstrates the potential of the NOAH/DIAMOD program suite to automatically assign NMR data for proteins and determine their structure.


Performance Evaluation and Optimal Detection of Relay-Assisted Diffusion-Based Molecular Communication With Drift.
In this paper, we consider a decode-and-forward (DF) relay-assisted diffusion-based molecular communication system inside one of the blood vessels of a human body with positive drift from transmitter to receiver. We use the normal approximation to the distribution of the number of received molecules and derive a closed-form expression for the end-to-end bit error probability of the system. We then propose an optimization problem that aims at minimizing the bit error probability of the system and solve it at the receiver nanomachine by an algorithm based on the bisection method to determine the optimal detection threshold. Furthermore, we study the impact of the system parameters, such as drift velocity, position of the relay node and number of allocated molecules on the performance of the system. The numerical results show that with a constant molecular budget, DF relying strategy can considerably improve the system performance.


Of chloroquine and COVID-19.
Recent publications have brought attention to the possible benefit of chloroquine, a broadly used antimalarial drug, in the treatment of patients infected by the novel emerged coronavirus (SARS-CoV-2). The scientific community should consider this information in light of previous experiments with chloroquine in the field of antiviral research.


Time-dependent statistical failure of fiber networks.
Numerical simulations of time-dependent stochastic failure of fiber network have been performed by using a central-force, triangular lattice model. This two-dimensional (2D) network can be seen as the next level of structural hierarchy to fiber bundles, which have been investigated for many years both theoretically and numerically. Unlike fiber bundle models, the load sharing of the fiber network is determined by the network mechanics rather than a preassigned rule, and its failure is defined as the point of avalanche rather than the total fiber failure. We have assumed that the fiber in the network follows Coleman's probabilistic failure law [B. D. Coleman, J. Appl. Phys. 29, 968 (1958)] with the Weibull shape parameter β=1 (memory less fiber). Our interests are how the fiber-level probabilistic failure law is transformed into the one for the network and how the failure characteristics and disorders on the fiber level influence the network failure response. The simulation results showed that, with increasing the size of the network (N), weakest-link scaling (WLS) appeared and each lifetime distribution at a given size approximately followed Weibull distribution. However, the scaling behavior of the mean and the Weibull shape parameter clearly deviate from what we can predict from the WLS of Weibull distribution. We have found that a characteristic distribution function has, in fact, a double exponential form, not Weibull form. Accordingly, for the 2D network system, Coleman's probabilistic failure law holds but only approximately. Comparing the fiber and network failure properties, we found that the network structure induces an increase of the load sensitivity factor ρ (more brittle than fiber) and Weibull shape parameter β (less uncertainty of lifetime). Superimposed disorders on the fiber level reduce all these properties for the network.


On the origin of oscillopsia during pedunculopontine stimulation.
We report a case of induced oscillopsia caused by deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN). Recent reports have described involuntary oscillopsia during DBS of the PPN that patients have described as trembling vision. Here we substantiate this observation using infra-red eye tracking. It has been suggested that this phenomenon might be used as an indicator of accurate targeting of the PPN with DBS. Our observations suggest that this phenomenon may not be related to a constricted anatomical structure and therefore such practise may be unwise. Scrutiny has led us to believe that the oscillopsia in our patient is not caused by direct stimulation of the oculomotor nerve as suggested in a previous report, but by stimulation of fibres in the uncinate fasciculus of the cerebellum and the superior cerebellar peduncle, which in turn stimulate the saccadic pre-motor neurones in the brainstem.


Code labs: expediting laboratory test results during a code.
BACKGROUND Knowing a patient's "laboratory picture" is crucial in any code blue situation. Having no streamlined method for collecting and processing laboratory specimens during codes leads to staff frustration and critical delays in patient care. OBJECTIVE To simplify collection and testing of laboratory specimens during codes. METHODS Staff nurses led an initiative through which (1) code laboratory tests were placed in a computerized order set, thereby simplifying ordering; (2) prepackaged bags of supplies for the new order set were placed in each code cart; (3) the laboratory department supervisor began carrying a code pager to ensure that laboratory staff are prepared for incoming "code labs"; (4) a protocol was created for laboratory staff to follow after receiving code labs; and (5) processes were developed for units that are not integrated in the organization's electronic ordering system. RESULTS The mean turnaround time (the time from when laboratory tests are ordered to when results are posted) was reduced from 52.0 minutes to 31.3 minutes (P = .002). Laboratory staff improved their processing time (the time from when specimens are received by laboratory staff to when results are posted) from 34.9 minutes to 21.5 minutes (P = .01). Survey responses indicated that staff across disciplines were significantly more satisfied with the new process. CONCLUSIONS Because the changes are basic, they can be implemented easily in any hospital setting to improve turnaround time for laboratory tests during codes.


Lack of effect of the glucagon-like peptide-1 receptor agonist liraglutide on psoriasis in glucose-tolerant patients--a randomized placebo-controlled trial.
It has been proposed that glucagon-like peptide-1 receptor (GLP-1R) agonists used for the treatment of patients with type 2 diabetes might also improve their psoriasis. To assess the efficacy and safety of the GLP-1R agonist liraglutide in glucose-tolerant patients with plaque psoriasis. A total of 20 obese (body mass index > 25 kg/m(2)), glucose-tolerant patients with plaque psoriasis (psoriasis area and severity index (PASI) of at least 8) were randomized 1:1 to once-daily subcutaneous injections with liraglutide or placebo for an 8-week period. The primary end points were improvement in PASI and dermatology life quality index (DLQI). Secondary end points included changes in weight and high sensitive C-reactive protein (hsCRP) levels, as well as adverse events. After 8 weeks of treatment, no significant change in PASI was found in the liraglutide group (mean±standard deviation: -2.6 ± 2.1) compared with the placebo group (-1.3 ± 2.4) (P = 0.228). No difference in DLQI was observed between the groups [-2.5 ± 4.4 (liraglutide) vs. -3.7 ± 4.8 (placebo); P = 0.564]. HsCRP did not change in any of the groups (0.26 ± 1 (placebo) vs. 0.25 ± 2.2 (liraglutide); P = 0.992). Liraglutide treatment resulted in a bodyweight loss of 4.7 ± 2.5 kg compared with 1.6 ± 2.7 kg in the placebo group (P = 0.014) accompanied by decreased cholesterol levels. No serious adverse events occurred during the 8-week observation period. The most common complaint was transient nausea, which occurred in 45% of the liraglutide-treated patients but in none from the placebo group. Liraglutide treatment for 8 weeks did not significantly change PASI, DLQI, or hsCRP in a small group of glucose-tolerant obese patients with plaque psoriasis compared with placebo. A significant weight loss and decrease in cholesterol levels was observed in liraglutide-treated patients.


Proinsulin and somatostatin from the islet organ of the southern-hemisphere lamprey Geotria australis.
An extract of the islet organ of the southern-hemisphere lamprey Geotria australis contained a high concentration of somatostatin-like immunoreactivity (34 nmol/g) but only trace amounts of insulin-like immunoreactivity. The primary structure of Geotria somatostatin-33 (AVQEAGGAAM10PPPGQRDRKA20GCKNFFWKTF30SSC) shows almost no similarity to somatostatins from the holarctic lampreys Petromyzon marinus and Lampetra fluviatilis in the N-terminal region but the functionally important C-terminal region, including the substitution Thr31 --> Ser, is the same. Insulin was not identified in the extract but proinsulin and an incompletely processed form with an intact A-chain/C-peptide junction were purified and partially characterized. The primary structure of the insulin region of Geotria proinsulin was established as A-chain; GIVEKCCHNR10CSIYQ MESYC20N; B-chain: SALTGSGGNY10LCGSYLVDAL20YLACGPRGFF30YTSTPV. This sequence contains 17 amino acid substitutions compared with the identical insulins from P. marinus and L. fluviatilis but the unusual extension to the N-terminus of the B-chain (SALTG) is present. Compared with mammalian insulins, Geotria insulin contains several substitutions of strongly conserved residues such as Gln(A5) --> Lys in the putative receptor-binding region, Glu(B26) --> Pro important in dimerization, and Leu(A13) --> Ile, His(B10) --> Tyr, and His(B21) --> Tyr important in hexamerization. Geotria proinsulin contains an Arg-Arg processing site at the B-chain/C-peptide junction but we speculate either that the Lys-Arg processing site at the C-peptide/A-chain junction is absent or that the Geotria pancreas is unable to synthesize a SPC2-type prohormone convertase. Our results are consistent with the view that G. australis and holarctic lampreys arose from a common stock but have been separated for a considerable period.


The Effects of Mexican origin family structure on parental monitoring and pre-adolescent substance use expectancies and substance use.
Substance use among Mexican origin, low-income youths is a serious, but under-studied problem. This study examines the relationship between the structure of Mexican origin families (i.e. nuclear, single-parent, blended or extended), and the parental monitoring, substance use expectancies, and substance use reported by pre-adolescents. Family structure did not differentiate the substance use prevalence, expectancies or parental monitoring among the 1224 low-income, Mexican-origin fifth grade participants. Parents from all family types demonstrated similar levels of parental monitoring. More importantly, family composition was not related to pre-adolescents' substance use. Other analyses showed that the relationship between substance use and certain demographic variables (e.g. gender, country of birth, language use) did not differ across family structures. The report concludes by discussing possible developmental and resiliency factors in Mexican origin families that would account for these findings.


Effect of TTP488 in patients with mild to moderate Alzheimer's disease.
TTP488, an antagonist at the Receptor for Advanced Glycation End products, was evaluated as a potential treatment for patients with mild-to-moderate Alzheimer's disease (AD). A previous report describes decreased decline in ADAS-cog (delta = 3.1, p = 0.008 at 18 months, ANCOVA with multiple imputation), relative to placebo, following a 5 mg/day dose of TTP488. Acute, reversible cognitive worsening was seen with a 20 mg/day dose. The present study further evaluates the efficacy of TTP488 by subgroup analyses based on disease severity and concentration effect analysis. 399 patients were randomized to one of two oral TTP488 doses (60 mg for 6 days followed by 20 mg/day; 15 mg for 6 days followed by 5 mg/day) or placebo for 18 months. Pre-specified primary analysis, using an ITT population, was on the ADAS-cog11. Secondary analyses included as a key secondary variable the Clinical Dementia Rating-Sum of Boxes (CDR-SB), and another secondary variable of the ADCS-ADL. On-treatment analysis demonstrated numerical differences favoring 5 mg/day over placebo, with nominal significance at Month 18 (delta = 2.7, p = 0.03). Patients with mild AD, whether defined by MMSE or ADAS-cog, demonstrated significant differences favoring 5 mg/day on ADAS-cog and trends on CDR-sb and ADCS-ADL at Month 18. TTP488 plasma concentrations of 7.6-16.8 ng/mL were associated with a decreased decline in ADAS-cog over time compared to placebo. Worsening on the ADAS-cog relative to placebo was evident at 46.8-167.0 ng/mL. Results of these analyses support further investigation of 5 mg/day in future Phase 3 trials in patients with mild AD.


Hydrophobic residue contributions to sequence-specific DNA binding by the bovine papillomavirus helicase E1.
Previously, mutational analyses of the DNA binding domain of the bovine papillomavirus E1 protein (E1DBD) identified several hydrophobic residues that are critical for DNA binding activity (M. West, D. Flanery, K. Woytek, D. Rangasamy, and V. G. Wilson, 2001, J. Virol. 75, 11948-11960). Hydrophobic interactions of nonpolar amino acid side chains can contribute to the function of DNA binding proteins through both conformational effects and direct interaction with nucleotides. To further investigate the role of hydrophobic residues in E1DBD function, a more extensive site-directed mutational analysis of hydrophobic amino acids was conducted. Alanine substitutions were made at residues V196, F197, F217, F, 237, V246, L249, and F276, and the mutants were tested for DNA binding activity in vitro and in vivo. The E1 F237A and F276A mutants were completely defective for site-specific DNA binding, while the other mutants retained partial to full wild-type binding activity. Consistent with their DNA binding defect, the F237A and F276A mutants were severely impaired for the ability to support transient in vivo replication of an origin plasmid. Combined with our previous study, five critical hydrophobic residues have been identified: F175, V193, F237, V246, and F276. These five residues localize to two internal clusters in the E1DBD structure designated hydrophobic clusters A (HCA; includes F175, V193, and F276) and B (HCB; includes F237 and V246). Amino acid side chains from residues in HCA and HCB have little surface accessibility and it is unlikely that they are involved in direct contact with DNA. HCA is distal to the DNA binding surface and presumably contributes to global conformational organization of the E1DBD. HCB is positioned beneath the DNA contact surface and we propose that it serves as an anchor or platform device to stabilize the DNA-binding element. A comparable hydrophobic cluster is present in the corresponding position in the T antigen DBD and likely serves a similar function.


Design and fabrication of nano-sinusoid LSPR devices.
Applications of LSPR nano-particles in various areas of solar cells, LSPR biosensors, and SERS biosensors, based on interaction of light with noble metal nano-particles is increasing. Therefore, design and nano-fabrication of the LSPR devices is a key step in developing such applications. Design of nano-structures with desirable spectral properties using numerical techniques such as finite difference time domain (FDTD) is the first step in this work. A new structure called nano-sinusoid, satisfying the some desirable LSPR characteristics, is designed and simulated using the FDTD method. In the next stage, analytical method of electro static eigen mode method is used to validate the simulation results. The, nano-fabrications method of electron beam lithography (EBL) is implemented to fabricate the proposed profile with high precision. Finally, atomic force microscopy (AFM) is used to investigate the shape of the fabricated nano-particles, and the dark field microscopy is employed to demonstrate the particular spectral characteristics of the proposed nano-sinusoids.


Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat.
We asked whether the well known starvation-induced impairment of glucose-stimulated insulin secretion (GSIS) seen in isolated rat pancreas preparations also applies in vivo. Accordingly, fed and 18-24-h-fasted rats were subjected to an intravenous glucose challenge followed by a hyperglycemic clamp protocol, during which the plasma-insulin concentration was measured. Surprisingly, the acute (5 min) insulin response was equally robust in the two groups. However, after infusion of the antilipolytic agent, nicotinic acid, to ensure low levels of plasma FFA before the glucose load, GSIS was essentially ablated in fasted rats, but unaffected in fed animals. Maintenance of a high plasma FFA concentration by coadministration of Intralipid plus heparin to nicotinic acid-treated rats (fed or fasted), or further elevation of the endogenous FFA level in nonnicotinic acid-treated fasted animals by infusion of etomoxir (to block hepatic fatty acid oxidation), resulted in supranormal GSIS. The in vivo findings were reproduced in studies with the perfused pancreas from fed and fasted rats in which GSIS was examined in the absence and presence of palmitate. The results establish that in the rat, the high circulating concentration of FFA that accompanies food deprivation is a sine qua non for efficient GSIS when a fast is terminated. They also serve to underscore the powerful interaction between glucose and fatty acids in normal beta cell function and raise the possibility that imbalances between the two fuels in vivo could have pathological consequences.


Complex-decorated surfactant-encapsulated clusters (CD-SECs) as novel multidynamic hybrid materials.
Generation of well-defined organic-inorganic hybrid materials with controllable size and morphology is challenging and an active area of modern research in view of their unique properties and thus multifunctional applications. Specifically polyoxometalates (POMs) were recognized as a very promising group for the construction of those systems, nonetheless there are domains where the profound understanding of hierarchical mutual interactions and assembly are lacking. We present an efficient approach towards the synthesis of a novel group of POM-based nanocomposites that we name Complex-Decorated Surfactant Encapsulated-Clusters (CD-SECs). In the investigated system the organic surfactant may behave as a metal-coordinating agent, thus allowing for derivatization of the synthesized SECs via utilization of the non-covalent interactions. We demonstrate possibilities and limitations of three types of hybrid systems (H1-H3) generated via seven distinct constructing approaches (routes A-G). These systems have the potential to exhibit multiresponsive functions depending on the nature of their building blocks and could find many potential applications in biology or materials science.


Temporal course of depressive symptoms during the development of Alzheimer disease.
To characterize change in depressive symptoms before and after the onset of dementia in Alzheimer disease (AD). We used data from the Chicago Health and Aging Project, a longitudinal cohort study of risk factors for AD in a geographically defined population of old people. Two subsets were analyzed. In 357 individuals who developed incident AD during the study, self-report of depressive symptoms (Center for Epidemiologic Studies Depression Scale) was obtained at 3-year intervals for a mean of 8 to 9 years. In 340 individuals who agreed to annual data collection, informant report of depressive symptoms (Hamilton Depression Rating Scale) was obtained for a mean of 3 years after a diagnosis of AD (n = 107), mild cognitive impairment (n = 81), or no cognitive impairment (n = 152). The incident AD group reported a barely perceptible increase in depressive symptoms during 6 to 7 years of observation before the diagnosis (0.04 symptoms per year) and no change during 2 to 3 years of observation after the diagnosis except for a slight decrease in positive affect. In those with annual follow-up, neither AD nor its precursor, mild cognitive impairment, was associated with change in informant report of depressive symptoms during a mean of 3 years of observation. Depressive symptoms show little change during the development and progression of AD to a moderate level of dementia severity.


Effects of cannabis on neurocognitive functioning: recent advances, neurodevelopmental influences, and sex differences.
Decades of research have examined the effects of cannabis on neurocognition. Recent advances in this field provide us with a better understanding of how cannabis use influences neurocognition both acutely (during intoxication) and non-acutely (after acute effects subside). Evidence of problems with episodic memory is one of the most consistent findings reported; however, several other neurocognitive domains appear to be adversely affected by cannabis use under various conditions. There is significant variability in findings across studies, thus a discussion of potential moderators is increasingly relevant. The purpose of this review was to 1) provide an update on research of cannabis' acute and non-acute effects on neurocognition, with a focus on findings since 2007 and 2) suggest and discuss how neurodevelopmental issues and sex differences may influence cannabis effects on neurocognition. Finally we discuss how future investigations may lead to better understanding of the complex interplay among cannabis, stages of neurodevelopment, and sex on neurocognitive functioning.


Prevention of mother-to-child transmission of HIV programme: low vertical transmission in KwaZulu-Natal, South Africa.
To describe the operational effectiveness of the prevention of mother-to-child transmission (PMTCT) of HIV programme at McCord Hospital during the period 1 March 2004 - 31 August 2005. Observational cohort study. McCord Hospital, Durban, South Africa. Antenatal patients attending the PMTCT clinic. During the 18 months all 2 624 women (100%) attending the antenatal clinic received HIV counselling, resulting in 91% (2 388) being tested for HIV. The prevalence of HIV in the total cohort was 13% (95% confidence interval (CI) 11.6 - 14.2). Of the HIV-positive mothers 302 (89%) completed their pregnancy at the hospital, and in this group there were 3 intrauterine deaths, 1 miscarriage, 1 maternal death (with the baby in utero) and 297 live births with 1 early neonatal death. Only 11% (36 out of 338) were lost to follow-up. A quarter (668) of the partners of all women attending the antenatal clinic were tested for HIV. Delivery in 70% (209) of live births was by caesarean section. Nevirapine was administered to 98% (290) of live babies and 75% (224) received zidovudine (AZT) as well. The 6-week polymerase chain reaction (PCR) baby test uptake was 81% (239 out of 296 live babies). Of those tested, 2.9% (95% CI 1.3 - 6.2) tested HIV positive. Despite challenges faced by PMTCT providers in a resource-constrained setting, this state-aided hospital provides a comprehensive and integrated service and has achieved outcomes that compare favourably with those in the developed world.


Ammonium alters creatine transport and synthesis in a 3D culture of developing brain cells, resulting in secondary cerebral creatine deficiency.
Hyperammonemic disorders in pediatric patients lead to poorly understood irreversible effects on the developing brain that may be life-threatening. We showed previously that some of these NH4+-induced irreversible effects might be due to impairment of axonal growth that can be protected under ammonium exposure by creatine co-treatment. The aim of the present work was thus to analyse how the genes of arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), allowing creatine synthesis, as well as of the creatine transporter SLC6A8, allowing creatine uptake into cells, are regulated in rat brain cells under NH4+ exposure. Reaggregated brain cell three-dimensional cultures exposed to NH4Cl were used as an experimental model of hyperammonemia in the developing central nervous system (CNS). We show here that NH4+ exposure differentially alters AGAT, GAMT and SLC6A8 regulation, in terms of both gene expression and protein activity, in a cell type-specific manner. In particular, we demonstrate that NH4+ exposure decreases both creatine and its synthesis intermediate, guanidinoacetate, in brain cells, probably through the inhibition of AGAT enzymatic activity. Our work also suggests that oligodendrocytes are major actors in the brain in terms of creatine synthesis, trafficking and uptake, which might be affected by hyperammonemia. Finally, we show that NH4+ exposure induces SLC6A8 in astrocytes. This suggests that hyperammonemia increases blood-brain barrier permeability for creatine. This is normally limited due to the absence of SLC6A8 from the astrocyte feet lining microcapillary endothelial cells, and thus creatine supplementation may protect the developing CNS of hyperammonemic patients.


A putative vulnerability locus to multiple sclerosis maps to 5p14-p12 in a region syntenic to the murine locus Eae2.
Multiple sclerosis (MS) is a chronic inflammatory disorder characterized by multifocal damage of myelin in the central nervous system (CNS). The prevalence of this putative autoimmune disease is 0.1% in individuals of northern European origin. Family, adoption and twin studies implicate genetic factors in the aetiology. MS is widely speculated to be a multifactorial disorder with a complex mode of inheritance. Despite many studies of candidate genes, only an association with HLA-DR2-DQ6 has been generally detected, and the number of susceptibility genes remains unknown. The chronic variant of experimental allergic encephalomyelitis (EAE), a T-cell mediated autoimmune disease in rodents, represents a relevant animal model for MS given the chronic relapsing disease course and inflammatory changes of CNS observed in these demyelinating disorders. Susceptibility to EAE is also influenced by the major histocompatibility complex (MHC). Human syntenic regions to murine loci predisposing to EAE were tested as candidate regions for genetic susceptibility of MS. Three chromosomal regions (1p22-q23, 5p14-p12 and Xq13.2-q22) were screened in 21 Finnish multiplex MS families most originating from a high risk region in western Finland. Several markers yielded positive lod scores on 5p14-p12, syntenic to the murine locus Eae2. Our data provide evidence for a predisposing locus for MS on 5p14-p12.


Guidewire-assisted cannulation of the common bile duct for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis.
Cannulation techniques have been recognized to be important in causing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). However, considerable controversy exists about the usefulness of the guidewire-assisted cannulation technique for the prevention of PEP. To systematically review evidence from randomised controlled trials (RCTs) assessing the effectiveness and safety of the guidewire-assisted cannulation technique compared to the conventional contrast-assisted cannulation technique for the prevention of PEP. We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE, and CINAHL databases and major conference proceedings, up to February 2012, using the Cochrane Upper Gastrointestinal and Pancreatic Diseases model with no language restrictions. RCTs comparing the guidewire-assisted cannulation technique versus the contrast-assisted cannulation technique in patients undergoing ERCP. Two review authors conducted study selection, data extraction and methodological quality assessment independently. Using intention-to-treat analysis with random-effects models, we combined dichotomous data to obtain risk ratios (RR) with 95% confidence intervals (CI). We assessed heterogeneity using the Chi² test (P < 0.15) and I² statistic (> 25%). To explore sources of heterogeneity, we conducted a priori subgroup analyses according to trial design, publication type, risk of bias, use of precut sphincterotomy, inadvertent guidewire insertion or contrast injection of the pancreatic duct (PD), use of a PD stent, cannulation device, and trainee involvement in cannulation. To assess the robustness of our results we carried out sensitivity analyses using different summary statistics (RR versus odds ratio (OR)) and meta-analytic models (fixed-effect versus random-effects), and per protocol analysis. Twelve RCTs comprising 3450 participants were included. There was statistical heterogeneity among trials for the outcome of PEP (P = 0.04, I² = 45%). The guidewire-assisted cannulation technique significantly reduced PEP compared to the contrast-assisted cannulation technique (RR 0.51, 95% CI 0.32 to 0.82). In addition, the guidewire-assisted cannulation technique was associated with greater primary cannulation success (RR 1.07, 95% CI 1.00 to 1.15), less precut sphincterotomy (RR 0.75, 95% CI 0.60 to 0.95), and no increase in other ERCP-related complications. Subgroup analyses indicated that this significant risk reduction in PEP with the guidewire-assisted cannulation technique existed only in 'non-crossover' trials (RR 0.22, 95% CI 0.12 to 0.42). The results were robust in sensitivity analyses. Compared with the contrast-assisted cannulation technique, the guidewire-assisted cannulation technique increases the primary cannulation rate and reduces the risk of PEP, and it appears to be the most appropriate first-line cannulation technique.


Free radical scavenging and apoptotic effects of Cordyceps sinensis fractionated by supercritical carbon dioxide.
Supercritical carbon dioxide (SC-CO2) was used as the elution solvent for fractioning ethanolic extract (E) of Cordyceps sinensis (CS), a traditional Chinese herbal remedy, into R, F1, F2, and F3 fractions. This extractive fractionation method is amenable to large scale and is nontoxic. These four fractions were characterized in terms of total polysaccharides and cordycepin concentrations, scavenging ability of free radicals, and anti-tumor activities. Experimental results demonstrated that fractionation altered the distributions of total polysaccharides and cordycepin in fractions. Fraction R was the most active fraction to scavenge free radicals and inhibit the proliferation of carcinoma cells, followed by the fraction F1 and the extract E. The effect of scavenging on 1,1-diphenyl-2-picryl hydrazyl (DPPH) of CS extract and fractions at 2 mg/ml was R (93%), F1 (75%), E (66%), F2 (47%), and F3 (27%). The IC50 (50% cell growth inhibitory concentration) of tumor cell proliferation and colony formation on human colorectal (HT-29 and HCT 116) and hepatocellular (Hep 3B and Hep G2) carcinoma cells by fraction R were around 2 microg/ml. Conversely, R did not affect the growth of normal dividing human peripheral blood mononuclear cells (PBMC) by exhibiting a large value of IC50 over 200 microg/ml. Accumulation of tumor cells at sub-G1 phase and the fragmentation of DNA, typical features of programmed cell death, were observed in a time and dose dependent manner. Scavenging of free radicals and anti-cancer activity (value of IC50) correlated closely with the quantities of polysaccharides (Spearman's rho=0.901 and -0.870, respectively). Taken together, our findings suggest that fraction R, obtained by SC-CO2 fluid extractive fractionation, showed strong scavenging ability and selectively inhibited the growth of colorectal and hepatocellular cancer cells by the process of apoptosis.


Natural killer cell responses to dendritic cells infected by the ANRS HIV-1 vaccine candidate, MVAHIV.
Innate mechanisms are critical for the development of the host immune responses to antigen. Particularly, early interaction between natural killer (NK) cells and dendritic cells (DC) greatly impacts the establishment of both innate and adaptive immune responses. In this study, using an autologous in vitro co-culture system we analyzed the NK cell response against MVAHIV-infected DC as well as the subsequent ability of these MVAHIV-primed NK cells to control HIV-1 infection in autologous DC. We found that NK cells responded early to MVAHIV- or MVAWT-infected DC in terms of degranulation and cytokine production. After a 4-day priming of NK cells by MVAHIV- or MVAWT-infected DC we observed an enhanced proliferation and modulation in the NK cell receptor repertoire expression. Interestingly, we found that MVAHIV-primed NK cells had a significant higher ability to control HIV-1 infection in autologous DC compared to MVAWT-primed NK cells; and this enhanced anti-HIV-1 activity appeared to be HIV-specific as MVAHIV-primed NK cells did not have a better ability to control other viral infections or respond against tumoral cells. Furthermore, we observed that NK cell receptors NKG2D and NKp46 modulate the priming of NK cells. This data provides evidence that in vitro NK cells can be primed by viral vector-infected DC, in the context of a NK/DC culture, to specifically target viral infected cells.


HLA patterns in pernicious anaemia.
The pattern of HLA antigens was studied in 127 patients with Addisonian pernicious anaemia. The pattern in the whole group of patients differed significantly from that in 586 controls. But different subgroups of the patients had different HLA antigens. Among 27 patients with anaemia associated with endocrine disease there was an increased frequency of HLA-B8, B18, and BW15. The remaining 100 patients, who did not have endocrine disease, showed increased frequencies of HLA-B7 and B12. The positive association with HLA-B12 among this subgroup was confined to 62 patients with severly impaired vitamin B12 absorption, including 13 patients with vitamin B12 neuromyelopathy, who had the highest frequencies of HLA-B7 and B12. The significant heterogeneity in HLA patterns in different clinical subgroups of these patients indicates genetic heterogeneity in pernicious anaemia and explains previous discrepancies in the associations between HLA antigens and pernicious anaemia.


Anal Adenocarcinoma Can Masquerade as Chronic Anal Fistula in Asians.
Perianal adenocarcinoma arising from a chronic anorectal fistula is a rare condition for which the natural history and optimal management are not well established. For that reason, we conducted a retrospective analysis of 5 consecutive patients with a perianal adenocarcinoma arising from a chronic anorectal fistula managed at our institution from January 2014 to December 2015. The patients were identified from a prospectively collected colorectal cancer database that included all patients managed for colorectal cancer at our institution. The median age at diagnosis was 64 years (range, 55-72 years). Magnetic resonance imaging (MRI) was the initial investigation for all patients and showed a hyperintense T2-weighted image. One patient underwent an abdominoperineal resection following neoadjuvant chemoradiotherapy and remained disease free during the 12-month follow-up. Three patients received neoadjuvant therapy with intent for surgery, but did not undergo surgery due to either worsening health or metastatic spread. One patient declined intervention. The median overall survival was 10.5 months (range, 2-19 months). A high index of suspicion is required to make a clinical diagnosis of an anal adenocarcinoma arising from a chronic fistula. Histologic diagnosis must be achieved to confirm the diagnosis. Multimodal therapy with neoadjuvant chemoradiotherapy followed by abdominoperineal resection is the treatment of choice.


Comparison of vascular smooth muscle cell apoptosis and fibrous cap morphology in symptomatic and asymptomatic carotid artery disease.
The biological cascades that lead to carotid plaque disruptions and symptoms are largely unknown. Certain cellular events within the plaque might be responsible for destabilizing the plaque, though the popular belief is that the plaque size is directly related to symptoms. The aim of our study was to assess the morphology of the fibrous cap and apoptosis in the plaque and compare these two pathological features in symptomatic and asymptomatic carotid artery disease. Our work was carried out in plaques obtained following carotid endarterectomy performed for symptomatic disease (including hemispheric transient ischemic attacks, amaurosis fugax, or stroke) or asymptomatic high-grade severe stenosis. Scion images of Gomori's stained sections were used to measure fibrous cap thickness and area. TUNEL assay was performed to assess the extent of apoptosis. The results indicated that the area of the fibrous cap did not significantly correlate with the presence of symptoms. There was a higher percentage of apoptotic nuclei and the thinner fibrous cap in symptomatic plaques than in asymptomatic plaques. This finding suggests that these factors might be involved in destabilizing plaque, causing rupture and leading to symptomatic carotid disease.


Optical spectrum analysis of large space bandwidth signals.
Coherent optical spectrum analyzers are available for determining the frequency content of many analog signals written simultaneously on film. The space bandwidth product of each signal must not exceed one thousand for a typical 35 mm system. By sacrificing the multichannel capability of such a computer, single signals with space bandwidth products greater than one million (10(6)) can be analyzed. Two optical systems are described. The first analyzes long signals but maintains the frequency resolution of the multichannel system (one part in one thousand). The second system yields frequency resolution of at least one part in one million. Near real-time, continuous spectrum analysis of analog signals is within the current state of the art. A breadboard system is being built.


Severe hypercalcemia and hypernatremia in a patient treated with canagliflozin.
Drugs that inhibit the sodium-glucose co-transporter-2 (SGLT2) are an exciting novel, insulin-independent treatment for diabetes that block glucose reabsorption from the proximal tubules of the kidney, leading to increased glucose excretion and lower blood glucose levels. Inhibition of SGLT2 activity also reduces sodium reabsorption, which together with glycosuria produces a mild diuretic effect with the potential for dehydration and hyperkalemia. We report on a 60-year-old man with uncontrolled type 2 diabetes treated with insulin, glimepiride, metformin and canagliflozin, who was admitted with altered mental status after a syncopal episode. He had a 1-week history of ingestion of Tums for heartburn followed by poor appetite and lethargy. Laboratory work-up showed acute kidney injury, diabetic ketoacidosis (DKA), and parathyroid hormone-independent severe hypercalcemia of 17.4 mg/dl. DKA resolved with insulin treatment, and saline hydration led to improvement in hypercalcemia and renal function over 48 h, but was accompanied by a rapid increase in the serum sodium concentration from 129 to 162 mmol/l despite changing fluids to 0.45% saline. Urine studies were consistent with osmotic diuresis. Hypernatremia was slowly corrected with hypotonic fluids, with improvement in his mental status over the next 2 days. This is the first report of hypercalcemia associated with the use of a SLGT2 inhibitor. Although the exact mechanism is unknown, canagliflozin may predispose to hypercalcemia in patients ingesting excessive calcium because of dehydration from osmotic diuresis, with reduced calcium excretion and possible increased intestinal calcium absorption. Saline therapy and osmotic diuresis may lead to hypernatremia from electrolyte-free water loss. Canagliflozin, an SGLT2 inhibitor, may cause hypercalcemia in susceptible patients.Although the exact mechanisms are unknown, dehydration from osmotic diuresis and increased intestinal calcium absorption play a role.Close monitoring of serum calcium levels is recommended in patients treated with SGLT2 inhibitors who are elderly, have established hypercalcemia, or take oral calcium supplements.Saline therapy and osmotic diuresis may lead to hypernatremia from electrolyte-free water loss in susceptible patients.


Brain Tissue Oxygen Levels as a Perspective Therapeutic Target in Traumatic Brain Injury. Retrospective Cohort Study.
Management of traumatic brain injury (TBI) requires a multidisciplinary approach and represents a significant challenge for both neurosurgeons and intensivists. The role of brain tissue oxygenation (PbtO2) monitoring and its impact on posttraumatic outcomes remains a controversial topic. Our study aimed to evaluate the impact of PbtO2 monitoring on mortality, 30 days and 6 months neurological outcomes in patients with severe TBI compared with those resulting from standard intracranial pressure (ICP) monitoring. In this retrospective cohort study, we analysed the outcomes of 77 patients with severe TBI who met the inclusion criteria. These patients were divided into two groups, including 37 patients who were managed with ICP and PbtO2 monitoring protocols and 40 patients who were managed using ICP protocols alone. There were no significant differences in demographic data between the two groups. We found no statistically significant differences in mortality or Glasgow Outcome Scale (GOS) scores one month after TBI. However, our results revealed that GOS scores at 6 months had improved significantly among patients managed with PbtO2; this finding was particularly notable for Glasgow Outcome Scale (GOS) scores of 4-5. Close monitoring and management of reductions in PbtO2, particularly by increasing the fraction of inspired oxygen, was associated with higher partial pressures of oxygen in this group. Monitoring of PbtO2 may facilitate the appropriate evaluation and treatment of low PbtO2 and represents a promising tool for the management of patients with severe TBI. Additional studies will be needed to confirm these findings.


Comparison of four variable selection methods to determine the important variables in predicting the prognosis of traumatic brain injury patients by support vector machine.
Large amounts of information have called for increased computational complexity. Data dimension reduction is therefore critical to preliminary analysis. In this research, four variable selection (VS) methods are compared to obtain the important variables in predicting the prognosis of traumatic brain injury (TBI) patients. In a retrospective follow-up study, 741 TBI patients who were hospitalized for at least 2 days and had a Glasgow Coma Scale score of at least one were followed. Their clinical data recorded during intensive care unit (ICU) admission and eight-category extended GOS conditions 6 months after discharge were utilized here. Two filter- and two wrapper-based VS methods were applied for comparison. A support vector machine (SVM) classifier was then used, and the sensitivity, specificity, accuracy, and the area under the receiver characteristic curve (AUC) values were calculated. Theoretically, the variables selected by sequential forward selection (SFS) method would better predict the prognosis (AUC = 0.737, 95% confidence interval [0.701, 0.772], specificity = 89.2%, sensitivity = 58.9% and accuracy = 79.1%) than the others. Genetic algorithm (GA), minimum redundancy maximum relevance (MRMR), and mutual information method were in the next orders, respectively. The use of an SVM classifier on optimal subsets given by GA and SFS reveals that wrapper-based methods perform better than filter-based methods in our data set, although all selected subsets, except for the MRMR, were clinically accepted. In addition, for prognosis prediction of TBI patients, a small subset of clinical records during ICU admission is enough to achieve an accepted accuracy.


Model-based dose calculations for COMS eye plaque brachytherapy using an anatomically realistic eye phantom.
To investigate the effects of the composition and geometry of ocular media and tissues surrounding the eye on dose distributions for COMS eye plaque brachytherapy with(125)I, (103)Pd, or (131)Cs seeds, and to investigate doses to ocular structures. An anatomically and compositionally realistic voxelized eye model with a medial tumor is developed based on a literature review. Mass energy absorption and attenuation coefficients for ocular media are calculated. Radiation transport and dose deposition are simulated using the EGSnrc Monte Carlo user-code BrachyDose for a fully loaded COMS eye plaque within a water phantom and our full eye model for the three radionuclides. A TG-43 simulation with the same seed configuration in a water phantom neglecting the plaque and interseed effects is also performed. The impact on dose distributions of varying tumor position, as well as tumor and surrounding tissue media is investigated. Each simulation and radionuclide is compared using isodose contours, dose volume histograms for the lens and tumor, maximum, minimum, and average doses to structures of interest, and doses to voxels of interest within the eye. Mass energy absorption and attenuation coefficients of the ocular media differ from those of water by as much as 12% within the 20-30 keV photon energy range. For all radionuclides studied, average doses to the tumor and lens regions in the full eye model differ from those for the plaque in water by 8%-10% and 13%-14%, respectively; the average doses to the tumor and lens regions differ between the full eye model and the TG-43 simulation by 2%-17% and 29%-34%, respectively. Replacing the surrounding tissues in the eye model with water increases the maximum and average doses to the lens by 2% and 3%, respectively. Substituting the tumor medium in the eye model for water, soft tissue, or an alternate melanoma composition affects tumor dose compared to the default eye model simulation by up to 16%. In the full eye model simulations, the average dose to the lens is larger by 7%-9% than the dose to the center of the lens, and the maximum dose to the optic nerve is 17%-22% higher than the dose to the optic disk for all radionuclides. In general, when normalized to the same prescription dose at the tumor apex, doses delivered to all structures of interest in the full eye model are lowest for(103)Pd and highest for (131)Cs, except for the tumor where the average dose is highest for (103)Pd and lowest for (131)Cs. The eye is not radiologically water-equivalent, as doses from simulations of the plaque in the full eye model differ considerably from doses for the plaque in a water phantom and from simulated TG-43 calculated doses. This demonstrates the importance of model-based dose calculations for eye plaque brachytherapy, for which accurate elemental compositions of ocular media are necessary.


Patient management after noninvasive cardiac imaging results from SPARC (Study of myocardial perfusion and coronary anatomy imaging roles in coronary artery disease).
This study examined short-term cardiac catheterization rates and medication changes after cardiac imaging. Noninvasive cardiac imaging is widely used in coronary artery disease, but its effects on subsequent patient management are unclear. We assessed the 90-day post-test rates of catheterization and medication changes in a prospective registry of 1,703 patients without a documented history of coronary artery disease and an intermediate to high likelihood of coronary artery disease undergoing cardiac single-photon emission computed tomography, positron emission tomography, or 64-slice coronary computed tomography angiography. Baseline medication use was relatively infrequent. At 90 days, 9.6% of patients underwent catheterization. The rates of catheterization and medication changes increased in proportion to test abnormality findings. Among patients with the most severe test result findings, 38% to 61% were not referred to catheterization, 20% to 30% were not receiving aspirin, 35% to 44% were not receiving a beta-blocker, and 20% to 25% were not receiving a lipid-lowering agent at 90 days after the index test. Risk-adjusted analyses revealed that compared with stress single-photon emission computed tomography or positron emission tomography, changes in aspirin and lipid-lowering agent use was greater after computed tomography angiography, as was the 90-day catheterization referral rate in the setting of normal/nonobstructive and mildly abnormal test results. Overall, noninvasive testing had only a modest impact on clinical management of patients referred for clinical testing. Although post-imaging use of cardiac catheterization and medical therapy increased in proportion to the degree of abnormality findings, the frequency of catheterization and medication change suggests possible undertreatment of higher risk patients. Patients were more likely to undergo cardiac catheterization after computed tomography angiography than after single-photon emission computed tomography or positron emission tomography after normal/nonobstructive and mildly abnormal study findings. (Study of Perfusion and Anatomy's Role in Coronary Artery [CAD] [SPARC]; NCT00321399).


Germline landscape of BRCAs by 7-site collaborations as a BRCA consortium in Turkey.
BRCA1/2 mutations play a significant role in cancer pathogenesis and predisposition particularly in breast, ovarian and prostate cancers. Thus, germline analysis of BRCA1 and BRCA2 is essential for clinical management strategies aiming at the identification of recurrent and novel mutations that could be used as a first screening approach. We analyzed germline variants of BRCA1/2 genes for 2168 individuals who had cancer diagnosis or high risk assessment due to BRCAs related cancers, referred to 10 health care centers distributed across 7 regions covering the Turkish landscape. Overall, 68 and 157 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-two novel variants were reported from both genes while BRCA2 showed higher mutational heterogeneity. We herein report the collective data as BRCA Turkish consortium that confirm the molecular heterogeneity in BRCAs among Turkish population, and also as the first study presenting the both geographical, demographical and gene based landscape of all recurrent and novel mutations which some might be a founder effect in comparison to global databases. This wider perspective leads to the most accurate variant interpretations which pave the way for the more precise and efficient management affecting the clinical and molecular aspects.


Diagnostic accuracy of clinical prediction rules to exclude acute coronary syndrome in the emergency department setting: a systematic review.
We sought to determine the diagnostic accuracy of clinical prediction rules to exclude acute coronary syndrome (ACS) in the emergency department (ED) setting. We searched MEDLINE, EMBASE, Web of Science and the Cochrane Database of Systematic Reviews. We contacted content experts to identify additional articles for review. Reference lists of included studies were hand searched. We selected articles for review based on the following criteria: 1) enrolled consecutive ED patients; 2) incorporated variables from the history or physical examination, electrocardiogram and cardiac biomarkers; 3) did not incorporate cardiac stress testing or coronary angiography into prediction rule; 4) based on original research; 5) prospectively derived or validated; 6) did not require use of a computer; and 7) reported sufficient data to construct a 2 x 2 contingency table. We assessed study quality and extracted data independently and in duplicate using a standardized data extraction form. Eight studies met inclusion criteria, encompassing 7937 patients. None of the studies verified the prediction rule with a reference standard on all or a random sample of patients. Six studies did not report blinding prediction rule assessors to reference standard results, and vice versa. Three prediction rules were prospectively validated. Sensitivities and specificities ranged from 94% to 100% and 13% to 57%, and positive and negative likelihood ratios from 1.1 to 2.2 and 0.01 to 0.17, respectively. Current prediction rules for ACS have substantial methodological limitations and have not been successfully implemented in the clinical setting. Future methodologically sound studies are needed to guide clinical practice.


Differential effects of Rifampin and Ketoconazole on the blood and liver concentration of atorvastatin in wild-type and Cyp3a and Oatp1a/b knockout mice.
Atorvastatin is eliminated by CYP3A4 which follows carrier-mediated uptake into hepatocytes by OATP1B1, OATP1B3, and OATP2B1. Multiple clinical studies demonstrated that OATP inhibition by rifampin had a greater impact on atorvastatin systemic concentration than itraconazole-mediated CYP3A4 inhibition. If it is assumed that the blood and hepatocyte compartments are differentiated by the concentration gradient that is established by OATPs, and if the rate of uptake into the hepatocyte is rate-determining to the elimination of atorvastatin from the body, then it is hypothesized that blood concentrations may not necessarily reflect liver concentrations. In wild-type mice, rifampin had a greater effect on systemic exposure of atorvastatin than ketoconazole, as the blood area under the blood concentration-time curve increased 7- and 2-fold, respectively. In contrast, liver concentrations were affected more by ketoconazole than by rifampin, as liver levels increased 21- and 4-fold, respectively. Similarly, in Cyp3a knockout animals, 39-fold increases in liver concentrations were observed despite insignificant changes in the blood area under the blood concentration-time curve. Interestingly, blood and liver levels in Oatp1a/b knockout animals were similar to wild types, suggesting that Oatp1a/b knockout may be necessary but not sufficient to completely describe atorvastatin uptake in mice. Data presented in this work indicate that there is a substantial drug interaction when blocking atorvastatin metabolism, but the effects of this interaction are predominantly manifested in the liver and may not be captured when monitoring changes in the systemic circulation. Consequently, there may be a disconnect when trying to relate blood exposure to instances of hepatotoxicity because a pharmacokinetic-toxicity relationship may not be obvious from blood concentrations.


Transition of Techniques to Treat Choledochal Cysts in Children.
Traditionally open resection with hepaticojejunostomy (HJ) reconstruction has been the surgical treatment for cases of choledochal cyst. Our center has recently transitioned from open to laparoscopic and HJ to hepaticoduodenostomy (HD) as our preferred method of excision and biliary reconstruction. Our initial experience is presented here. A single-center retrospective chart review was performed from 2005 to 2014. All patients undergoing surgical treatment for choledochal disease were considered. During the study period 18 patients had surgical treatment for choledochal cyst disease. The average age of all patients was 4.7 years (range, 2 months-15.5 years). Eleven of these patients had laparoscopic excision and reconstruction. Of these 11 patients, 7 had an HD anastomosis. Comparing the laparoscopic with the open group and the HD with the HJ group, there was no significant difference in operative time, estimated blood loss, time to regular diet, length of stay, or complication rate. Mean follow-up of 3.1 years revealed no documented cases of bile reflux or cholangitis. A recent adaptation in technique may improve ease of HD anastomosis. In this method, two strands of temporary monofilament suture cut to 8-10 cm each are tied extracorporeally. This knot is then placed on the outside of the medial corner. The anastomosis is then completed in a running fashion with the two strands and then secured intracorporeally at the lateral corner. Laparoscopic choledochal cyst resection with both HJ and HD reconstruction appears safe and has equivalent outcomes to open procedures in our series.


Chronic kidney disease as a coronary artery disease risk equivalent.
Chronic kidney disease (CKD) is associated with accelerated cardiovascular disease (CVD) risk and a higher CVD event rate. Substantial data from prospective cohort studies support the concept that dialysis patients as well as those with advanced stage (stages 3-5) CKD are associated with an increased risk for all-cause and cardiovascular mortality. The risk for coronary artery disease (CAD) increases exponentially with declining kidney function, i.e., stage 3 or higher CKD. Indeed, CVD accounts for more than 50 % of deaths in patients with CKD. CKD patients are more likely to die of CVD than to progress to end stage kidney disease. This increase in CV risk is commonly attributed to co-existence of numerous traditional and nontraditional risk factors for the development of CVD that frequently accompany reduced kidney function. Therefore, CKD itself is now considered an independent CVD risk factor and a coronary artery disease (CAD) equivalent for all-cause mortality. All patients at risk for CAD should be evaluated for kidney disease. Treatments used for management of established CAD might have similar benefits for patients with concomitant CKD.


HFSP: high speed homology-driven function annotation of proteins.
The rapid drop in sequencing costs has produced many more (predicted) protein sequences than can feasibly be functionally annotated with wet-lab experiments. Thus, many computational methods have been developed for this purpose. Most of these methods employ homology-based inference, approximated via sequence alignments, to transfer functional annotations between proteins. The increase in the number of available sequences, however, has drastically increased the search space, thus significantly slowing down alignment methods. Here we describe homology-derived functional similarity of proteins (HFSP), a novel computational method that uses results of a high-speed alignment algorithm, MMseqs2, to infer functional similarity of proteins on the basis of their alignment length and sequence identity. We show that our method is accurate (85% precision) and fast (more than 40-fold speed increase over state-of-the-art). HFSP can help correct at least a 16% error in legacy curations, even for a resource of as high quality as Swiss-Prot. These findings suggest HFSP as an ideal resource for large-scale functional annotation efforts. Supplementary data are available at Bioinformatics online.


Follow up of surgically-assisted rapid maxillary expansion after 6.5 years: skeletal and dental effects.
Surgically-assisted rapid maxillary expansion (SARME) is a technique used to widen the maxilla, and we present the results of our long-term follow up (6.5 years). Seventeen patients who had been treated with SARME and prospectively followed were invited for long-term follow up using dental casts and posteroanterior cephalograms. The following measurements were made on the dental casts: transverse distances at canine, premolar, and molar level, length of the arch, and width and depth of the palate at premolar and molar level. The distance between the left and right nasal bases and the widening of the inferior maxilla were measured on the posteroanterior cephalograms. Boneborne and toothborne distractors were used in 8 and 9 patients, respectively. In the study of dental casts, there was a significant increase in transverse width in the canine (P<0.001), premolar (P<0.001) and molar (P=0,001) and these remained stable in the long term. The arch length did not increase significantly, but the palatal width increased significantly in the premolar (P<0.001) and molar (P=0.001) regions. No effect was seen in palatal depth. On the posteroanterior cephalograms the width of the inferior part of the maxilla was increased, but not significantly so. There were no significant changes at the nasal base. We conclude that SARME is a predictable technique to widen the maxilla in the long term.


Relationship between post-traumatic stress disorder and diabetes among 105,180 asylum seekers in the Netherlands.
Several reports have demonstrated a relationship between post-traumatic stress disorder (PTSD) and type 2 diabetes (T2DM) mainly in combat veterans. The relationship between PTSD and T2DM has not been evaluated among vulnerable migrant populations. The main objective of this study was therefore to assess the relationship between PTSD and T2DM among asylum seekers in the Netherlands. Analysis of a national electronic database of the Dutch Community Health Services for Asylum seekers aged≥18 years (N=105,180). Asylum seekers with PTSD had a higher prevalence of T2DM compared with those without PTSD. The age-adjusted prevalence ratios (APR) were 1.40 (95% CI, 1.12-1.76) in men and 1.22 (95% CI, 0.95-1.56) in women compared with individuals without PTSD, respectively. There was an interaction between PTSD and comorbid depression (P<0.05) in men and women, indicating that the effect of PTSD and comorbid depression on T2DM differed. When the analyses were stratified by depression status, among non-depressed group, individuals with PTSD had a higher prevalence of T2DM compared with those without PTSD [APR=1.47 (95% CI, 1.15-1.87) in men and APR=1.27 (95% CI, 0.97-1.66) in women]. Among the depressed individuals, however, there was no association between PTSD and T2DM [APR=0.87 (95% CI, 0.43-1.76) in men, and APR=1.00, (95% CI, 0.54-1.83) in women]. The findings suggest that history of PTSD is related to high levels of T2DM among asylum seekers independent of comorbid depression. Clinicians and policy makers need to take PTSD into account when assessing and treating diabetes among vulnerable migrant populations.


Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms.
Chromosomal abnormalities are frequent in myeloid malignancies, but in most cases of myelodysplasia (MDS) and myeloproliferative neoplasms (MPN), underlying pathogenic molecular lesions are unknown. We identified recurrent areas of somatic copy number-neutral loss of heterozygosity (LOH) and deletions of chromosome 4q24 in a large cohort of patients with myeloid malignancies including MDS and related mixed MDS/MPN syndromes using single nucleotide polymorphism arrays. We then investigated genes in the commonly affected area for mutations. When we sequenced TET2, we found homozygous and hemizygous mutations. Heterozygous and compound heterozygous mutations were found in patients with similar clinical phenotypes without LOH4q24. Clinical analysis showed most TET2 mutations were present in patients with MDS/MPN (58%), including CMML (6/17) or sAML (32%) evolved from MDS/MPN and typical MDS (10%), suggesting they may play a ubiquitous role in malignant evolution. TET2 mutations affected conserved domains and the N terminus. TET2 is widely expressed in hematopoietic cells but its function is unknown, and it lacks homology to other known genes. The frequency of mutations in this candidate myeloid regulatory gene suggests an important role in the pathogenesis of poor prognosis MDS/MPN and sAML and may act as a disease gene marker for these often cytogenetically normal disorders.


Combined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells.
The network of thymic stromal cells provides essential niches with unique molecular cues controlling T cell development and selection. Recent single-cell RNA sequencing studies have uncovered previously unappreciated transcriptional heterogeneity among thymic epithelial cells (TEC). However, there are only very few cell markers that allow a comparable phenotypic identification of TEC. Here, using massively parallel flow cytometry and machine learning, we deconvoluted known TEC phenotypes into novel subpopulations. Using CITEseq, these phenotypes were related to corresponding TEC subtypes defined by the cells' RNA profiles. This approach allowed the phenotypic identification of perinatal cTEC and their physical localisation within the cortical stromal scaffold. In addition, we demonstrate the dynamic change in the frequency of perinatal cTEC in response to developing thymocytes and reveal their exceptional efficiency in positive selection. Collectively, our study identifies markers that allow for an unprecedented dissection of the thymus stromal complexity, as well as physical isolation of TEC populations and assignment of specific functions to individual TEC subtypes.


Luminescent solar concentrators and the reabsorption problem.
The problem of reabsorption in luminescent solar concentrators (LSC) is discussed. A mathematical development is presented which enables the LSC gain to be calculated based on the optical properties of the materials and a random walk formalism. Two- and three-dimensional analyses are used. A detailed set of calculations for a common dye (rhodamine 6G) is used to examine the practicality of employing a single dye. The effects of diameter, thickness, and quantum yield on the LSC output are presented. The spectrum of the LSC output as a function of concentration is calculated. It is suggested that LSCs can be made more efficient with a system which utilizes radiationless electronic excited state transport and trapping as intermediate steps between absorption and reemission. Trap emission substantially avoids the reabsorption problem.


Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid.
Three large, randomized trials of patients with bone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events. These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy. Urinary measurements of N-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824 bisphosphonate-treated patients-1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210; non-small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). This exploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low (< 50 nmol/mmol creatinine), moderate (50 to 99 nmol/mmol creatinine), or high (> or = 100 nmol/mmol creatinine), and BAP as low (< 146 U/L) or high (> or = 146 U/L). The relative risks for negative clinical outcomes were estimated for each group using multiple-event and Cox regression models with time-varying covariates. Patients with high and moderate Ntx levels had 2-fold increases in their risk of skeletal complications and disease progression compared with patients with low Ntx levels (P < .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increased risk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels (P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinical outcomes. The bone resorption marker Ntx provides valuable prognostic information in patients with bone metastases receiving bisphosphonates.


WITHDRAWN: Surgical treatment for meniscal injuries of the knee in adults.
Injuries to the knee menisci are common and operations to treat them are among the most common procedures performed by orthopaedic surgeons. To evaluate the effects of common surgical interventions in the treatment of meniscal injuries of the knee. The four comparisons under test were: a) surgery versus conservative treatment, b) partial versus total meniscectomy, c) excision versus repair of meniscal tears, d) surgical access, in particular arthroscopic versus open. We searched the Cochrane Bone, Joint and Muscle Trauma Group specialised register (March 2001), MEDLINE (1966 -1998) and bibliographies of published papers. All randomised and quasi-randomised trials which involved the above four comparisons or which compared other surgical interventions for the treatment of meniscal injury. Trial inclusion was agreed by both reviewers who independently assessed trial quality, by use of a 12 item scale, and extracted data. Where possible and appropriate, data were presented graphically. Three trials, involving 260 patients, which addressed two (partial versus total meniscectomy; surgical access) comparisons were included.Partial meniscectomy may allow a slightly enhanced recovery rate as well as a potentially improved overall functional outcome including better knee stability in the long term. It is probably associated with a shorter operating time with no apparent difference in early complications or re-operation between partial and total meniscectomy. The long term advantage of partial meniscectomy indicated by the absence of symptoms (symptoms or further operation at six years or over: 14/98 versus 22/94; Peto odds ratio 0.55, 95% confidence interval 0.27 to 1.14) or radiographical outcome was not established.The results available from the only trial comparing arthroscopic with open meniscectomy were very limited in terms of patient numbers and length of follow-up. However it is likely that partial meniscectomy via arthroscopy is associated with shorter operating times and a quicker recovery. The lack of randomised trials means that no conclusions can be drawn on the issue of surgical versus non-surgical treatment of meniscal injuries, nor meniscal tear repair versus excision.In randomised trials so far reported, there is no evidence of difference in radiological or long term clinical outcomes between arthroscopic and open meniscal surgery, or between total and partial meniscectomy. Partial meniscectomy seems preferable to the total removal of the meniscus in terms of recovery and overall functional outcome in the short term.


Effectiveness of dry needling for the treatment of temporomandibular myofascial pain: a double-blind, randomized, placebo controlled study.
To test the hypothesis that dry needling is more effective than sham dry needling in relieving myofascial pain of the temporomandibular muscles. Fifty-two subjects with established myofascial trigger points were randomized into two groups; study group (N: 26) and placebo group (N: 26). Dry needling was applied using acupuncture needles. Sham dry needling was applied to the placebo group. Pain pressure threshold was measured with pressure algometry, pain intensity was rated using a 10-cm visual analog scale (VAS) and the unassisted jaw opening without pain measurement was performed. Evaluations were done by a physician blinded to the data. Of 52 patients assigned, 50 completed the study. Mean algometric values were significantly higher in the study group when compared to the placebo group (p values being less than 0.05). There were no differences between the two groups in terms of VAS and unassisted jaw-opening without pain values. Dry needling appears to be an effective treatment method in relieving the pain and tenderness of myofascial trigger points.