Predicting hospital admission for older emergency department patients: Insights from machine learning.
Emergency departments (ED) are a portal of entry into the hospital and are uniquely positioned to influence the health care trajectories of older adults seeking medical attention. Older adults present to the ED with distinct needs and complex medical histories, which can make disposition planning more challenging. Machine learning (ML) approaches have been previously used to inform decision-making surrounding ED disposition in the general population. However, little is known about the performance and utility of ML methods in predicting hospital admission among older ED patients. We applied a series of ML algorithms to predict ED admission in older adults and discuss their clinical and policy implications. We analyzed the Canadian data from the interRAI multinational ED study, the largest prospective cohort study of older ED patients to date. The data included 2274 ED patients 75 years of age and older from eight ED sites across Canada between November 2009 and April 2012. Data were extracted from the interRAI ED Contact Assessment, with predictors including a series of geriatric syndromes, functional assessments, and baseline care needs. We applied a total of five ML algorithms. Models were trained, assessed, and analyzed using 10-fold cross-validation. The performance of predictive models was measured using the area under the receiver operating characteristic curve (AUC). We also report the accuracy, sensitivity, and specificity of each model to supplement performance interpretation. Gradient boosted trees was the most accurate model to predict older ED patients who would require hospitalization (AUC = 0.80). The five most informative features include home intravenous therapy, time of ED presentation, a requirement for formal support services, independence in walking, and the presence of an unstable medical condition. To the best of our knowledge, this is the first study to predict hospital admission in older ED patients using a series of geriatric syndromes and functional assessments. We were able to predict hospital admission in older ED patients with good accuracy using the items available in the interRAI ED Contact Assessment. This information can be used to inform decision-making about ED disposition and may expedite admission processes and proactive discharge planning.


Long [R3] insulin-like growth factor-I reduces growth, plasma growth hormone, IGF binding protein-3 and endogenous IGF-I concentrations in pigs.
Growth hormone (GH) improves growth performance in the pig. Analogues of insulin-like growth factor-I (IGF-I) that bind poorly to IGF binding proteins (IGFBP) stimulate growth in the rat but, in contrast, inhibit growth in the pig. This study was designed to determine the effect of IGF peptides alone or in combination with porcine GH (pGH) on growth characteristics and plasma hormone concentrations in finisher pigs. A four-day infusion of Long [R3] IGF-I (LR3IGF-I; 180 micrograms/kg/day) decreased the average daily gain, food intake, and plasma IGFBP-3, IGF-I and insulin concentrations. The mean plasma GH concentration was decreased by 23% and the area under the GH peaks was reduced by 60%. Co-administration of pGH (30 micrograms/kg/day) with LR3IGF-I had no interactive effect on growth performance, and plasma insulin, IGFBP-3 and IGF-I concentrations remained suppressed. The area under the GH peaks was not restored with this combination treatment although mean plasma GH concentrations were elevated in all animals receiving pGH. Infusion of IGF-I (180 micrograms/kg/day) decreased plasma insulin and mean GH concentrations but had no significant effect on IGFBP-3 concentrations. Average daily gain and feed intake were not changed by IGF-I treatment. A combination of IGF-I and pGH injection (30 micrograms/kg/day) increased plasma IGFBP-3 concentrations but plasma insulin levels remained suppressed. Plasma glucose levels were unaffected by any treatment. The study demonstrates that both IGF-I and LR3IGF-I suppress plasma GH concentrations in finisher pigs. This, in turn, may be responsible for the reduction in the plasma concentration of IGF-I, IGFBP-3 and insulin seen in LR3IGF-I-treated animals. The decrease in these parameters may contribute to the inhibitory effect of LR3IGF-I on growth performance in the pig.


Monitoring indirect presentation of alloantigens by utilizing the autologous processing machinery of dendritic cells in-vitro.
Judicious individualization of immunosuppression protocols requires the ability to monitor the recipients' specific immune response towards the allograft. While several indirect presentation studies have been reported, currently there are no consistently reliable means to assess the state of transplant acceptance. A potential explanation might be the lack of established kinetics for in-vitro indirect presentation assays. Dendritic cell (DCs) were used as self-specific "processing machinery" for the generation of allogeneic peptide repertoire tailored by the individual's capacity to process antigens via the indirect pathway. The kinetics of antigen processing and presentation of newly acquired antigens was then assessed to define the following: (1) Optimal time to introduce apoptotic-allogeneic cells to DCs; (2) optimal time for processing before induction of DC maturation; and (3) optimal time for stimulation of autologous T cells by the pulsed DCs. Altering kinetic parameters associated with time allotted for antigen processing; antigen presentation and DCs maturation, showed substantial variations in the level of T cell activation, as was documented by mixed lymphocyte reaction (MLR)-like proliferation assays. Further experiments using allogeneic cellular extracts showed similar variations in T cell stimulation by monitoring T cell precursor frequencies and interferon (IFN)-gamma secretion ELISPOT assays. Using the appropriate kinetic parameters, we have also shown difference in T-cell-subsets (CD4, CD8) precursor frequencies and cytokine secretion in response to different antigenic sources. The ability to construct an in-vitro, recipient-tailored, donor-specific, indirect presentation assay is dependent on essential kinetic parameters associated with antigen processing and presentation, as described in this report. Moreover, the use of this approach may circumvent the need for identifying specific immunogenic peptides for cancer-related or other vaccine-development studies.


Genome-wide DNA methylation analysis: no evidence for stable hemimethylation in the sheep muscle genome.
The importance of maintaining DNA methylation patterns and faithful transmission of these patterns during cell division to ensure appropriate gene expression has been known for many decades now. It has largely been assumed that the symmetrical nature of CpG motifs, the most common site for DNA methylation in mammals, together with the presence of maintenance methylases able to methylate newly synthesised DNA, ensures that there is concordance of methylation on both strands. However, although this assumption is compelling in theory, little experimental evidence exists that either supports or refutes this assumption. Here, we have undertaken a genome-wide single-nucleotide resolution analysis to determine the frequency with which hemimethylated CpG sites exist in sheep muscle tissue. Analysis of multiple independent samples provides strong evidence that stably maintained hemimethylation is a very rare occurrence, at least in this tissue. Given the rarity of stably maintained hemimethylation, next-generation sequencing data from both DNA strands may be carefully combined to increase the accuracy with which DNA methylation can be measured at single-nucleotide resolution.


A pilot study on the diagnostic accuracy of proadrenomedullin and proatrial natriuretic Peptide in lower respiratory tract infections.
Pneumonia is the leading cause of death among infectious diseases in developed countries. However, the severity of pneumonia requiring hospitalization often makes the initial diagnosis difficult because of an equivocal clinical picture or interpretation of the chest film. The objective of the present study was to assess the usefulness of the plasma levels of mid-regional proadrenomedullin (MR-proADM) and mid-regional proatrial natriuretic peptide (MR-proANP) in differentiating pneumonia from other lower respiratory tract infections (LRTIs). A retrospective study was conducted. The plasma levels of MR-proADM and MR-proANP were measured in 85 patients hospitalized for LRTIs, 56 of whom with diagnosis of pneumonia and 29 with other LRTIs. The patients with pneumonia had increased MR-proADM levels (median 1.46 nmol/L [IQR 25-75, 0.82-2.02 nmol/L]) compared with the patients with other LRTIs (median 0.88 nmol/mL [0.71-1.39 nmol/L]) (p= 0.04). However, the MR-proANP levels did not show differences between the groups. The optimal threshold of MR-proADM to predict pneumonia was 1.5 nmol/L, which yielded a sensitivity of 51.7% (95% CI, 38.0-65.3), a 79.3% specificity (95% CI, 60.3-92.0), and an odds ratio of 6.64 (95% CI, 1.32-32.85). The combination of this parameter with C-reactive protein in an "and" rule increased the specificity for detecting pneumonia significantly. MR-proADM levels (but not MR-proANP levels) are increased in patients with pneumonia although its discriminatory power is moderate.


Icotinib inhibits the proliferation of hepatocellular carcinoma cells in vitro and in vivo dependently on EGFR activation and PDL1 expression.
Hepatocellular carcinoma (HCC) accounts for one of the most prevalent tumor types in the world and still lacks an effective treatment regimen. The EGFR tyrosine-kinase inhibitor icotinib is capable of inhibiting proliferation of several kinds of cancer cells, but its anticancer effect in HCC is still not verified. In the current study, ten HCC cell lines were selected to test their original EGFR-activation status and PDL1 protein level, and in vitro antiproliferation assays were also conducted to analyze the IC50 and further investigate the correlation between IC50 and protein level of phosphorylated EGFR and PDL1. A in vivo nude mouse xenograft animal model was used as well to analyze its anticancer effect. Icotinib showed significant inhibitory effects only on HCC cell lines that had both higher p-EGFR and PDL1 protein level. This specific HCC cell line was subcutaneously injected to establish the in vivo xenograft tumor model, and icotinib reduced tumor weight remarkably and growth dose dependently. Molecular mechanism study revealed that icotinib inhibited the phosphorylation of EGFR and PDL1 expression in cancer cells and activated apoptosis. Knocking down PDL1 significantly reduced the inhibitory effect of icotinib on HCC, and knocking in PDL1 increased the sensitivity of icotinib in HCC. The current research suggests that icotinib has an inhibitory effect on a subgroup of HCC cells that have both higher p-EGFR and PDL1. This hints at the potential clinical usage of icotinib in HCC based on PDL1-biomarker examination.


Preclinical and clinical evaluation of elotuzumab, a SLAMF7-targeted humanized monoclonal antibody in development for multiple myeloma.
Although multiple myeloma has historically been treated with chemotherapy, prolonged survival has only been possible since the introduction of thalidomide, lenalidomide and bortezomib. However, multiple myeloma remains largely incurable, and new treatments are needed to improve long-term outcome. Elotuzumab is a humanized IgG1 monoclonal antibody that targets Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7) to activate NK cells, enabling selective killing of myeloma cells with minimal effects on normal tissue. The combination of elotuzumab with antimyeloma therapies that stimulate host immunity may be an attractive treatment option for patients with newly diagnosed or relapsed/refractory multiple myeloma. Here, we review the role of SLAMF7 in the pathogenesis of multiple myeloma and the preclinical and clinical development of elotuzumab.


Professional satisfaction and client outcomes. A comparative organizational analysis.
In studies of the effectiveness of health care organizations, the job satisfaction level of professional staff is often viewed as an "outcome," since providing a climate that satisfies participants' needs is one aspect of organizational effectiveness. Staff satisfaction, however, has not been linked with outcomes associated with clients. In this article, the authors examine the relationship between the aggregate job satisfaction level of nursing staff in 77 family planning clinics and two client outcomes: the aggregate satisfaction level of teenage clients with contraceptive services obtained in the clinic, and the subsequent rate of client compliance with contraceptive prescriptions. Among the variables studied in testing an organizational-level model, it is found that the job satisfaction level of nursing staff is the strongest determinant of the aggregate satisfaction level of clients; client satisfaction level, in turn, predicts the rate of clients' subsequent contraceptive compliance. Staff satisfaction has a noteworthy indirect effect on compliance through client satisfaction. Compliance, however, appears to be more susceptible to variations in clinic structure than to variations in staff satisfaction levels. Implications of these findings for studies of effectiveness of health services and for management of health care organizations are discussed.


Response surface optimization, Ex vivo and In vivo investigation of nasal spanlastics for bioavailability enhancement and brain targeting of risperidone.
Transnasal brain drug targeting could ensure better drug delivery to the brain through the olfactory pathway. Risperidone bioavailability is 66% in extensive metabolizers and 82% in slow metabolizers. The aim of this study is to investigate the ability of the nanovesicular spanlastics to effectively deliver risperidone through the nasal route to the brain and increase its bioavailability. Spanlastics formulae, composed of span and polyvinyl alcohol, were designed based on central composite statistical design. The planned formulae were prepared using ethanol injection method. The prepared formulae were characterized by testing their particle size, polydispersity index, zeta potential and encapsulation efficiency. The optimized formula having the lowest particle size, polydispersity index, the highest zeta potential and encapsulation efficiency was subjected to further investigations including characterization of its rheological properties, elasticity, transmission electron microscopy, in vitro diffusion, ex vivo permeation, histopathology and in vivo biodistribution. The optimized formula was composed of 5mg/mL span and 30mg/mL polyvinyl alcohol. It showed significantly higher transnasal permeation and better distribution to the brain, when compared to the used control regarding the brain targeting efficiency and the drug transport percentage (2.16 and 1.43 folds increase, respectively). The study introduced a successful and promising formula to directly and effectively carry the drug from nose to brain.


Variations of retinal nerve fiber layer thickness and ganglion cell-inner plexiform layer thickness according to the torsion direction of optic disc.
To examine the relationship between the optic disc torsion and peripapillary retinal nerve fiber layer (RNFL) thickness through a comparison with the macular ganglion cell inner plexiform layer complex (GCIPL) thickness measured by Cirrus optical coherence tomography (OCT). Ninety-four eyes of 94 subjects with optic disc torsion and 114 eyes of 114 subjects without optic disc torsion were enrolled prospectively. The participants underwent fundus photography and OCT imaging in peripapillary RNFL mode and macular GCIPL mode. The participants were divided into groups according to the presence or absence of optic disc torsion. The eyes with optic disc torsion were further divided into supranasal torsion and inferotemporal torsion groups according to the direction of optic disc torsion. The mean RNFL and GCIPL thicknesses for the quadrants and subsectors were compared. The superior and inferior peak locations of the RNFL were also measured according to the torsion direction. The temporal RNFL thickness was significantly thicker in inferotemporal torsion, whereas the GCIPL thickness at all segments was unaffected. The inferotemporal optic torsion had more temporally positioned superior peak locations of the RNFL than the nontorsion and supranasal-torted optic disc. Thickening of the temporal RNFL with a temporal shift in the superior peak within the eyes with inferotemporal optic disc torsion can lead to interpretation errors. The ganglion cell analysis algorithm can assist in differentiating eyes with optic disc torsion.


Prescribing opioids for chronic noncancer pain in primary care: risk assessment.
The use of opioids for patients with chronic noncancer pain has increased dramatically, and with increasing use there is increasing concern about the potential for abuse and addiction during long-term treatment. Clinicians should avoid viewing formal or subjective risk assessment as a means of classifying patients into 2 distinct categories: compliant patients and substance abusers. The provider who perceives a patient as compliant may have a complacent attitude toward aberrant drug-related behavior, presuming that these signs reflect inadequately controlled pain, to be addressed by dose escalation. The provider who perceives a patient as a substance abuser may refuse to provide treatment for pain, leaving the patient to seek either illicit drugs or prescribed treatment from another provider. In fact, in seemingly compliant patients, any noncompliant use of opioids presents a safety risk regardless of the explanations offered. Even in known or suspected drug abusers, chronic pain warrants the use of adequate pharmacotherapy, although treatment in such cases may exclude drugs with high abuse potential. Thus, all aberrant drug-related behavior should be addressed within a treatment plan that combines adequate pain care with suitable interventions for the aberrant behavior, following current best practice strategies. This approach is consistent with the approach taken with other health conditions, such as diabetes or hypertension, for which it is understood that noncompliance with therapy presents a risk of harm.


CD20 antigen expression by lymphoma cells in lung allograft recipients is associated with higher remission rate and superior survival: a study on heart and lung transplant recipients.
Post-transplant lymphoproliferative disorders (PTLD) are one of the fatal complications of transplantation, and there is scarcity of data on the relevance of antigen expression by tumor cells in PTLD. In the current study, we aimed to investigate the potential effects of CD20 antigen expression by PTLD lesions developing in heart/lung transplant recipients. A comprehensive search was performed for reports indicating CD20 antigen tests in PTLD lesions developing in heart and/or lung transplant recipients. For data accumulation, we developed a standard questionnaire and data of patients presented in different published reports were entered into it. Finally, data from 26 previously published reports from different centers around the world were included in the analysis. CD20-positive PTLD lesions are significantly more likely to be of the B cell type (P = 0.006). PTLD in patients with a CD20-positive test represented relevantly shorter time from transplantation to PTLD, although it did not reach a significance level (P = 0.08). At the last follow-up, 53% patients were dead. Survival analysis showed no prognosis difference regarding CD20 test. When data were reanalyzed separately for heart and lung transplant recipients, lung recipients developing PTLD with a CD20-positive test were significantly more likely to represent remission episodes (P = 0.03), and also represented a significantly better outcome than CD20-negative PTLD patients (P = 0.04). CD20-positive PTLD lesions in heart/lung recipients are more likely of the B cell type and develop PTLD lesions earlier than their CD20-negative counterparts. Lung recipients developing CD20-positive PTLD lesions represented higher remission rates and better outcome. Further studies with prospective follow-up of patients are needed for confirming our findings.


Caveolae and scaffold detection from single molecule localization microscopy data using deep learning.
Caveolae are plasma membrane invaginations whose formation requires caveolin-1 (Cav1), the adaptor protein polymerase I, and the transcript release factor (PTRF or CAVIN1). Caveolae have an important role in cell functioning, signaling, and disease. In the absence of CAVIN1/PTRF, Cav1 forms non-caveolar membrane domains called scaffolds. In this work, we train machine learning models to automatically distinguish between caveolae and scaffolds from single molecule localization microscopy (SMLM) data. We apply machine learning algorithms to discriminate biological structures from SMLM data. Our work is the first that is leveraging machine learning approaches (including deep learning models) to automatically identifying biological structures from SMLM data. In particular, we develop and compare three binary classification methods to identify whether or not a given 3D cluster of Cav1 proteins is a caveolae. The first uses a random forest classifier applied to 28 hand-crafted/designed features, the second uses a convolutional neural net (CNN) applied to a projection of the point clouds onto three planes, and the third uses a PointNet model, a recent development that can directly take point clouds as its input. We validate our methods on a dataset of super-resolution microscopy images of PC3 prostate cancer cells labeled for Cav1. Specifically, we have images from two cell populations: 10 PC3 and 10 CAVIN1/PTRF-transfected PC3 cells (PC3-PTRF cells) that form caveolae. We obtained a balanced set of 1714 different cellular structures. Our results show that both the random forest on hand-designed features and the deep learning approach achieve high accuracy in distinguishing the intrinsic features of the caveolae and non-caveolae biological structures. More specifically, both random forest and deep CNN classifiers achieve classification accuracy reaching 94% on our test set, while the PointNet model only reached 83% accuracy. We also discuss the pros and cons of the different approaches.


Small intestinal submucosa as a small-diameter arterial graft in the dog.
Autogenous saphenous vein, human umbilical vein, modified bovine collagen, Dacron, and PTFE have been used as small-diameter arterial grafts with moderate success. We tested autogenous small intestine submucosa as a small-diameter arterial graft in both a carotid and femoral artery (mean ID 4.3 mm) of 18 dogs (total of 36 grafts). All dogs received aspirin and warfarin sodium for the first 8 weeks after surgery. Graft patency was evaluated by Doppler ultrasound techniques and angiography. Two grafts ruptured and 5 grafts occluded by 21 days after surgery. One graft became occluded at 14 weeks. Fifteen dogs were sacrificed at periodic intervals until 48 weeks after surgery. Patent grafts had no evidence of infection, propagating thrombus, or intimal hyperplasia. Graft aneurysmal dilation occurred in 4 grafts (11%). The grafts were composed of a dense organized collagenous connective tissue with no evidence of endothelial cell growth on the smooth luminal surface. Three dogs are alive at 76 to 82 weeks after surgery. Overall, graft patency was 75%. Graft patency after cessation of anticoagulation therapy was 92.3% (12 of 13 grafts). We conclude that autogenous small intestinal submucosa can be used as a small-diameter arterial graft in the dog and is worthy of further investigation.


Hand preference and local asymmetry in cerebral cortex, basal ganglia, and cerebellar white matter.
Hand preference is a striking example of functional lateralization, with 90% of the population preferentially using their right hand. However, the search for brain structural correlates of this lateralization has produced inconsistent results. While large-scale neuroimaging studies using automated methods have largely failed to find local anatomical asymmetries associated with hand preference, other studies identifying specific motor regions have been able to find local morphological and functional differences. The present study looked at brain asymmetries in the brain's motor system using established cortical landmarks to identify the somatomotor hand region and extracted regional volumes of subcortical and cerebellar regions. Our results showed a strong left-right asymmetry in the cortical hand region, with weaker asymmetries appearing in the striatum and cerebellar white matter. Such asymmetries were much more pronounced in right-handers, whereas much weaker or absent lateralizing effects were observed in left-handed subjects. This study demonstrates the importance of local landmarks in studying individual anatomical differences. More generally, establishing structural correlates of hand preference is important, as this could further establish the origins of cerebral lateralization.


Gastric perforation presenting as bilateral scrotal pneumatoceles.
Although processus vaginalis is patent in the majority of newborn infants, the expression of an intraabdominal pathology such as gastrointestinal perforation or bleeding in the scrotum is very rare. In a large percentage of neonates with the gastrointestinal perforation, pneumoperitoneum is absent. In any case, it may not be detected in early radiographs. We report a newborn baby who presented with bilateral scrotal pneumatoceles as a first sign of pneumoperitoneum due to gastric perforation. Plain x-ray of the abdomen was normal except for pneumoscrotum, but contrast study revealed gastric perforation.


Bovine Colostrum in the Treatment of Acute Diarrhea in Children: A Double-Blinded Randomized Controlled Trial.
To evaluate the effect of bovine colostrum (BC) on the treatment of children with acute diarrhea attending the outpatient clinic. This double-blind randomized controlled trial was conducted on 160 children with diarrhea; 80 cases were randomly treated with BC group and 80 cases randomly received placebo (placebo group). All cases were investigated for bacterial causes of diarrhea (Salmonella spp, Shigella spp, diarrheagenic E. coli (DEC), Campylobacter spp., and Vibrio cholerae) as well as for Rotavirus antigen in stool. After 48 h, the BC group had a significantly lower frequency of vomiting, diarrhea and Vesikari scoring compared with the placebo group (p = 0.000, p = 0.000, p = 0.000, respectively), whether it was due to Rotavirus or E. coli infection. BC is effective in the treatment of acute diarrhea and can be considered as adjuvant therapy in both viral and bacterial diarrhea to prevent diarrhea-related complications.


Topography-guided conductive keratoplasty: treatment for advanced keratoconus.
To evaluate the use of topography-guided conductive keratoplasty in eyes with keratoconus. Interventional case series. We examined 21 eyes in 21 patients with advanced keratoconus. Topography-guided conductive keratoplasty was performed with intraoperative monitoring of corneal astigmatism using a surgical keratometer. Uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), corneal topography, manifest refraction, intraocular pressure (IOP), corneal endothelial cell counts, complications, and eventual outcomes were evaluated. UCVA (logarithm of the minimal angle of resolution [logMAR]), which was 1.65 ± 0.49 preoperatively, improved to 1.04 ± 0.64 at 1 week (P < .001) and 1.12 ± 0.61 at 1 month after surgery (P < .001). BSCVA, which was 1.02 ± 0.56 preoperatively, improved to 0.76 ± 0.65 at 1 week (P = .026) and 0.76 ± 0.60 at 1 month after surgery (P = .003). Manifest refraction, which was -15.13 ± 6.66 diopters (D) before surgery, declined to -9.97 ± 6.71 D at 1 month after surgery (P = .002). Although corneal topography reverted to the preoperative pattern and UCVA and BSCVA also regressed toward preoperative values, 12 of 21 eyes were better able to tolerate and conduct normal daily activities using contact lenses. Five subjects have undergone or are considering corneal transplantation after unsatisfactory postoperative results. No serious perioperative complication was observed. Topography-guided conductive keratoplasty may be effective in reshaping corneal configuration in eyes with keratoconus, without serious complications, and possibly contributed to avoiding or delaying corneal transplantation.


Body mass index and risk of prostate cancer in U.S. health professionals.
The relationship between body mass index (BMI) and prostate cancer risk may be complex because obesity is associated with various hormonal factors and because the influence of BMI may differ according to whether the cancers are hereditary or sporadic. We used data from the Health Professionals Follow-Up Study, in which 2896 incident cases of prostate cancer were reported from February 1, 1986, through January 31, 2000, to determine prospectively whether BMI was associated with the risk of hereditary (men <60 years of age or with a positive family history of prostate cancer) and sporadic (men > or =60 years of age and without such a family history) prostate cancer. The risk of prostate cancer in men with a higher BMI (> or =30 kg/m2) was lower than that in men with a lower BMI (23-24.9 kg/m2) but only if they were younger (<60 years old) (relative risk = 0.52, 95% confidence interval = 0.33 to 0.83; P(trend)<.001) or had a family history of prostate cancer (relative risk = 0.74, 95% confidence interval = 0.45 to 1.19; P(trend) =.01). However, for groups with more sporadic cancers, BMI had a weak, non-statistically significant positive association with prostate cancer. We observed statistically significant interactions between BMI and age (P(interaction)<.001, two-sided Wald test) and between BMI and family history of prostate cancer (P(interaction) =.006, two-sided Wald test). Patterns for BMI and waist circumference were similar. Because obesity is associated with lower circulating concentrations of testosterone, our results suggest the hypothesis that androgens may play a more direct role for early-onset or hereditary prostate cancers than for sporadic prostate cancers.


Nocturnal distribution of Louisiana riceland mosquito adults.
Nocturnal riceland mosquito populations in southern Louisiana were monitored using nonbaited CDC miniature light traps. A mixed population of Anopheles quadrimaculatus, An. crucians, Psorophora columbiae and Culex salinarius adults was collected in a livestock occupied barn. Highly variable numbers of all 4 species were trapped in areas away from the barns. Species density at any given trap location was not related to trap location, type of habitat surrounding the trap or brush density near the trap. Captures of anophelines were not affected by moonlight, whereas trap collections of culicines were lower on moonlit nights. Mean numbers of anophelines captured at night in traps exhibited a linear function of trap distance from the barn, with higher catches at locations farther from the barn. No such function was observed for culicines.


Nitropyrenes: isolation, identificaton, and reduction of mutagenic impurities in carbon black and toners.
Extracts of selected xerographic toners and copies were found to be mutagenic in the Salmonella assay. The activity was independent of the xerographic hardware and process and was traced to nitropyrenes present as impurities in the carbon black, the toner colorant. Manufacturing process changes resulted in a substantial reduction of the nitropyrene content of the carbon black and thus in the mutagenicity of the corresponding toners. Nitropyrenes are potent frameshift mutagens, and possible mechanisms for their biological action are discussed.


An economic framework for transitioning to capacity building.
Global Health Organizations (GHOs) often focus on resource provisioning strategies to assist communities in need, especially when disaster strikes. While such strategies are commendable, how should GHOs approach the challenge of developing sustainable strategic objectives after critical needs have been addressed? Leveraging the context of GHOs partnering with communities in need of support after disaster strikes, we propose an economic framework for use in strategic assessment and transition planning. We focus on a strategic process by which GHOs can systematically assess and manage the temporal shift from resource provisioning to capacity building strategies. The proposed framework is applied to pragmatic field experiences undertaken by the American Red Cross in the aftermath of the 2007 Peru earthquake. We specifically develop and propose: (1) An economic strategy assessment framework for GHOs seeking to provide support to communities characterised by high risk variances, incentive complexities and contingencies, and, (2) A practical strategic transition model for GHOs that emphasises proactively moving towards capacity building programme objectives through an emphasis on co-creation of value with community partners.


Information displays for automated surveillance algorithms of in-hospital patient deterioration: a scoping review.
Surveillance algorithms that predict patient decompensation are increasingly integrated with clinical workflows to help identify patients at risk of in-hospital deterioration. This scoping review aimed to identify the design features of the information displays, the types of algorithm that drive the display, and the effect of these displays on process and patient outcomes. The scoping review followed Arksey and O'Malley's framework. Five databases were searched with dates between January 1, 2009 and January 26, 2022. Inclusion criteria were: participants-clinicians in inpatient settings; concepts-intervention as deterioration information displays that leveraged automated AI algorithms; comparison as usual care or alternative displays; outcomes as clinical, workflow process, and usability outcomes; and context as simulated or real-world in-hospital settings in any country. Screening, full-text review, and data extraction were reviewed independently by 2 researchers in each step. Display categories were identified inductively through consensus. Of 14 575 articles, 64 were included in the review, describing 61 unique displays. Forty-one displays were designed for specific deteriorations (eg, sepsis), 24 provided simple alerts (ie, text-based prompts without relevant patient data), 48 leveraged well-accepted score-based algorithms, and 47 included nurses as the target users. Only 1 out of the 10 randomized controlled trials reported a significant effect on the primary outcome. Despite significant advancements in surveillance algorithms, most information displays continue to leverage well-understood, well-accepted score-based algorithms. Users' trust, algorithmic transparency, and workflow integration are significant hurdles to adopting new algorithms into effective decision support tools.


Ellagic acid, a natural polyphenolic compound, induces apoptosis and potentiates retinoic acid-induced differentiation of human leukemia HL-60 cells.
All-trans retinoic acid (ATRA) is a standard drug used for differentiation therapy in acute promyelocytic leukemia. To potentiate this therapy, we examined the effect of ellagic acid (EA), a natural polyphenolic compound with antiproliferative and antioxidant properties, on the growth and differentiation of HL-60 acute myeloid leukemia cells. EA was found to induce apoptosis, which was blocked by pan-caspase inhibitor, Z-VAD-FMK. EA activated the caspase-3 pathway and enhanced the expressions of myeloid differentiation markers (CD11b, MRP-14 protein, granulocytic morphology) induced by ATRA treatment. These results indicate that EA is a potent apoptosis inducer and also effectively potentiates ATRA-induced myeloid differentiation of HL-60 cells.


Population pharmacokinetics of cyclosporine in transplant recipients.
A number of classical pharmacokinetic studies have been conducted in transplant patients. However, they suffer from some limitations, for example, (1) the study design was limited to intense blood sampling in small groups of patients during a certain posttransplant period, (2) patient factors were evaluated one at a time to identify their association with the pharmacokinetic parameters, and (3) mean pharmacokinetic parameters often cannot be precisely estimated due to large intraindividual variability. Population pharmacokinetics provides a potential means of addressing these limitations and is a powerful tool to evaluate the magnitude and consistency of drug exposure. Population pharmacokinetic studies of cyclosporine focused solely on developing limited sampling strategies and Bayesian estimators to estimate drug exposure, have been summarized before, and are, therefore, not a subject of this review. The major focus of this review is to describe factors (demographic factors, hepatic and gastrointestinal functions, drug-drug interactions, genetic polymorphisms of drug metabolizing enzymes and transporters) that have been identified to contribute to the large portion of observed variability in the pharmacokinetics of cyclosporine in transplant patients. This review summarizes and interprets the conclusions as well as the nonlinear mixed-effects modeling methodologies used in such studies. A highly diversified collection of structural models, variability models, and covariate submodels have been evaluated and validated using internal or external validation methods. This review also highlights areas where additional research is warranted to improve the models since a portion of model variability still remains unexplained.


An embolus in the right atrium caught in the Chiari network and resistant to thrombolysis.
This case report describes a patient with thromboemboli trapped in the Chiari network within the right side of the heart and resistant to thrombolysis. The right atrial masses were completely removed under cardiopulmonary bypass. Histological evaluation confirmed a mixed thromboemboli, with thrombus structures showing signs of organisation and surrounded by a fibrous capsule. The plasma level of the plasminogen activator inhibitor type-1 (PAI-1) was 50% higher than the normal upper limit. In this presented case, the Chiari network displayed a protective function but the expansion and organisation of the thromboembolus found there made it resistant to lytic treatment. Another important factor that could have influenced the resistance to thrombolysis was the high level of PAI-1.


Plasmon mediated coherent population oscillations in molecular aggregates.
The strong coherent coupling of quantum emitters to vacuum fluctuations of the light field offers opportunities for manipulating the optical and transport properties of nanomaterials, with potential applications ranging from ultrasensitive all-optical switching to creating polariton condensates. Often, ubiquitous decoherence processes at ambient conditions limit these couplings to such short time scales that the quantum dynamics of the interacting system remains elusive. Prominent examples are strongly coupled exciton-plasmon systems, which, so far, have mostly been investigated by linear optical spectroscopy. Here, we use ultrafast two-dimensional electronic spectroscopy to probe the quantum dynamics of J-aggregate excitons collectively coupled to the spatially structured plasmonic fields of a gold nanoslit array. We observe rich coherent Rabi oscillation dynamics reflecting a plasmon-driven coherent exciton population transfer over mesoscopic distances at room temperature. This opens up new opportunities to manipulate the coherent transport of matter excitations by coupling to vacuum fields.


Pulmonary artery intimal sarcoma misdiagnosed as pulmonary embolism: A case report.
Intimal sarcoma of the pulmonary artery is rare, but false diagnosis of this sarcoma as pulmonary embolism is not infrequent. The present study reports a case of pulmonary artery intimal sarcoma misdiagnosed as pulmonary artery embolism in a 37-year-old female patient. The patient was admitted to the cardiac intensive care unit of Guangdong General Hospital (Guangzhou, China) with the complaint of progressive exertional dyspnea over the past two years. Multi-slice spiral computed tomography, transthoracic echocardiography, right-heart catheterization and cardiac magnetic resonance imaging revealed mimicking severe pulmonary embolism in the pulmonary trunk and right pulmonary artery, with symptoms including chest pain, cough and breathing difficulties. In addition, positron emission tomography-computed tomography results did not identify increased 18F-fluorodeoxyglucose uptake and failed to distinguish whether the mass was a thrombus or a malignancy. The patient was diagnosed with pulmonary embolism and a subcutaneous injection of 5,000 AxaIU enoxaparin sodium (100 AXAIU/kg) was administered every 12 h, but no improvement was achieved after 5 days of treatment. Finally, pulmonary endarterectomy was performed to relieve the worsening clinical symptoms. The clinicopathological diagnosis was pulmonary artery intimal sarcoma with poor clinical outcome. For this type of tumor with fatal prognosis, early and correct diagnosis may lead to appropriate intervention and prolong survival.


Mechanism of association between BMI and dysfunction of the gastro-oesophageal barrier in patients with normal endoscopy.
The association between body mass index (BMI) and gastro-oesophageal pressure gradient (GOPG) is incompletely understood. We examined the association between BMI and gastro-oesophageal (GO) barrier function and the effect of mechanically increasing intra-abdominal pressure on GO physiology. (A) 103 dyspeptic patients with normal endoscopy underwent 24 h pH-metry and upper gastrointestinal manometry. Relationships between BMI and acid reflux, intragastric pressure (IGP), GOPG and lower oesophageal sphincter (LOS) pressure were calculated using bivariate correlations. (B) In 18 healthy volunteers, the effects of increasing IGP by abdominal belt on GO manometry were studied. (A) There was a linear correlation between BMI and oesophageal acid exposure in erect (R=0.35, p<0.001) and supine (R=0.40, p<0.001) positions. BMI was strongly associated with IGP (inspiration: R=0.66, p<0.001; expiration: R=0.78, p<0.001) and inspiratory GOPG (R=0.50, p<0.001). There were a positive correlation between BMI and inspiratory LOS pressure relative to atmospheric pressure (R=0.29, p=0.016) and a negative correlation with LOS pressure relative to IGP on expiration (R=-0.25, p=0.018). Logistic regression models using all significant manometric variables and relevant interactions revealed marked decline in the magnitude and significance of relationship between BMI and oesophageal acid exposure in supine (from OR 1.12 (95% CI 1.03 to 1.22), p=0.009, to 1.00 (0.86 to 1.17), p=0.999) and upright positions (from 1.11 (1.02 to 1.20), p=0.020, to 1.03 (0.89 to 1.18), p=0.717). (B) Application of the constricting abdominal belt produced similar manometric changes to those associated with increased BMI. However, the belt did not reproduce the reduced LOS pressure relative to IGP. The association between reflux and BMI may be largely explained by effects of increased intra-abdominal pressure. However, the reduced LOS pressure associated with BMI may be mediated by another mechanism or effects of chronic rather than acute elevation of intra-abdominal pressure.


Mouse APOBEC1 cytidine deaminase can induce somatic mutations in chromosomal DNA.
APOBEC1 (A1) enzymes are cytidine deaminases involved in RNA editing. In addition to this activity, a few A1 enzymes have been shown to be active on single stranded DNA. As two human ssDNA cytidine deaminases APOBEC3A (A3A), APOBEC3B (A3B) and related enzymes across the spectrum of placental mammals have been shown to introduce somatic mutations into nuclear DNA of cancer genomes, we explored the mutagenic threat of A1 cytidine deaminases to chromosomal DNA. Molecular cloning and expression of various A1 enzymes reveal that the cow, pig, dog, rabbit and mouse A1 have an intracellular ssDNA substrate specificity. However, among all the enzymes studied, mouse A1 appears to be singular, being able to introduce somatic mutations into nuclear DNA with a clear 5'TpC editing context, and to deaminate 5-methylcytidine substituted DNA which are characteristic features of the cancer related mammalian A3A and A3B enzymes. However, mouse A1 activity fails to elicit formation of double stranded DNA breaks, suggesting that mouse A1 possess an attenuated nuclear DNA mutator phenotype reminiscent of human A3B. At an experimental level mouse APOBEC1 is remarkable among 12 mammalian A1 enzymes in that it represents a source of somatic mutations in mouse genome, potentially fueling oncogenesis. While the order Rodentia is bereft of A3A and A3B like enzymes it seems that APOBEC1 may well substitute for it, albeit remaining much less active. This modifies the paradigm that APOBEC3 and AID enzymes are the sole endogenous mutator enzymes giving rise to off-target editing of mammalian genomes.


TNFalpha suppresses human colonic circular smooth muscle cell contractility by SP1- and NF-kappaB-mediated induction of ICAM-1.
Intercellular adhesion molecule 1 (ICAM-1) receptors are expressed at low levels on human colonic circular smooth muscle cells (HCCSMCs) and their expression is increased in patients with Crohn's disease. We investigated the roles of transcription factors Sp1 and nuclear factor kappa B (NF-kappaB) in the regulation of ICAM-1 expression on HCCSMCs and examined whether ICAM-1 expression mediates the suppression of contractility in response to TNFalpha. Experiments were performed on primary cultures of HCCSMCs and fresh human colonic circular muscle strips. TNFalpha treatment of HCCSMCs induced rapid and prolonged accumulation of ICAM-1 messenger RNA (mRNA) and protein. NF-kappaB inhibition before, but not after, 1 hour of TNFalpha-stimulation blocked the expression of ICAM-1. TNFalpha significantly enhanced Sp1/DNA binding. Sp1 bound to the 3' flanking region of a variant kappaB site in the -192/-172 region of ICAM-1 promoter. Mutation of this region abolished the response to TNFalpha. The treatment of HCCSMCs with Sp1 antisense oligonucleotides (ODNs) blocked the expression of ICAM-1, but sense ODNs had no effect. Protein kinase C zeta (PKCzeta) inhibition before or 3 hours after stimulation with TNFalpha also blocked the expression of ICAM-1. TNFalpha treatment of circular muscle strips pretreated with ICAM-1 sense ODNs or control medium significantly reduced their response to acetylcholine, whereas pretreatment with antisense ODNs blocked this effect. The expression of ICAM-1 on HCCSMCs in response to TNFalpha is regulated by transcription factors Sp1 and NF-kappaB binding independently to the -192/-172 region of the ICAM-1 promoter. The expression of ICAM-1 plays a critical role in the suppression of cell contractility in response to TNFalpha.


Precision data-driven modeling of cortical dynamics reveals idiosyncratic mechanisms underlying canonical oscillations.
Task-free brain activity affords unique insight into the functional structure of brain network dynamics and is a strong marker of individual differences. In this work, we present an algorithmic optimization framework that makes it possible to directly invert and parameterize brain-wide dynamical-systems models involving hundreds of interacting brain areas, from single-subject time-series recordings. This technique provides a powerful neurocomputational tool for interrogating mechanisms underlying individual brain dynamics ("precision brain models") and making quantitative predictions. We extensively validate the models' performance in forecasting future brain activity and predicting individual variability in key M/EEG markers. Lastly, we demonstrate the power of our technique in resolving individual differences in the generation of alpha and beta-frequency oscillations. We characterize subjects based upon model attractor topology and a dynamical-systems mechanism by which these topologies generate individual variation in the expression of alpha vs. beta rhythms. We trace these phenomena back to global variation in excitation-inhibition balance, highlighting the explanatory power of our framework in generating mechanistic insights.


hnRNA and its attachment to a nuclear protein matrix.
In this study, DNA-depleted nuclear protein matrices are isolated from HeLa S3 cells. These nuclear matrices consist of peripheral laminae, residual nucleoli, and internal fibrillar structures. High molecular weight, heterogeneous nuclear RNA (hnRNA) is quantitatively associated with these structures and can be released intact only by affecting the integrity of the matrices. It is, therefore, concluded that hnRNA is part of a highly organized nuclear structure. By irradiation of intact cells or isolated nuclear matrices with ultraviolet light, proteins tightly associated with hnRNA can be induced to cross-link with the RNA. Performing the cross-linking in vivo is an extra guarantee that only hnRNA-protein (hnRNP) complexes existing in the intact cell are covalently linked. Such hnRNP complexes were isolated and purified under conditions that completely dissociate nonspecific RNA-protein complexes. By comparison of the hnRNP found in nuclear matrices and the published data on the composition of hnRNP particles, it was found that the so-called hnRNP "packaging" proteins (32,000-38,000 mol wt) were not efficiently cross-linked to hnRNA by UV irradiation. They were, however, present in the matrix preparations, bound to hnRNA, because they were released from nuclear matrices after ribonuclease treatment of these structures. On the other hand, two major hnRNPs (41,500 and 43,000 mol wt) were efficiently cross-linked to hnRNA. These proteins were not released by ribonuclease treatment, which suggests that they are involved in the binding of hnRNA to the nuclear matrix.


Decoding upper limb residual muscle activity in severe chronic stroke.
Stroke is a leading cause of long-term motor disability. Stroke patients with severe hand weakness do not profit from rehabilitative treatments. Recently, brain-controlled robotics and sequential functional electrical stimulation allowed some improvement. However, for such therapies to succeed, it is required to decode patients' intentions for different arm movements. Here, we evaluated whether residual muscle activity could be used to predict movements from paralyzed joints in severely impaired chronic stroke patients. Muscle activity was recorded with surface-electromyography (EMG) in 41 patients, with severe hand weakness (Fugl-Meyer Assessment [FMA] hand subscores of 2.93 ± 2.7), in order to decode their intention to perform six different motions of the affected arm, required for voluntary muscle activity and to control neuroprostheses. Decoding of paretic and nonparetic muscle activity was performed using a feed-forward neural network classifier. The contribution of each muscle to the intended movement was determined. Decoding of up to six arm movements was accurate (>65%) in more than 97% of nonparetic and 46% of paretic muscles. These results demonstrate that some level of neuronal innervation to the paretic muscle remains preserved and can be used to implement neurorehabilitative treatments in 46% of patients with severe paralysis and extensive cortical and/or subcortical lesions. Such decoding may allow these patients for the first time after stroke to control different motions of arm prostheses through muscle-triggered rehabilitative treatments.


Predicting amplitude death with machine learning.
In nonlinear dynamics, a parameter drift can lead to a sudden and complete cessation of the oscillations of the state variables-the phenomenon of amplitude death. The underlying bifurcation is one at which the system settles into a steady state from chaotic or regular oscillations. As the normal functioning of many physical, biological, and physiological systems hinges on oscillations, amplitude death is undesired. To predict amplitude death in advance of its occurrence based solely on oscillatory time series collected while the system still functions normally is a challenge problem. We exploit machine learning to meet this challenge. In particular, we develop the scheme of "parameter-aware" reservoir computing, where training is conducted for a small number of bifurcation parameter values in the oscillatory regime to enable prediction upon a parameter drift into the regime of amplitude death. We demonstrate successful prediction of amplitude death for three prototypical dynamical systems in which the transition to death is preceded by either chaotic or regular oscillations. Because of the completely data-driven nature of the prediction framework, potential applications to real-world systems can be anticipated.


Looking at appearance of urine before performing a renal biopsy in nephrotic syndrome.
Chyluria results from an abnormal connection between lymphatic bed and urinary tract, causing lymph leakage into the urine. The clinical picture often begins with the appearance of cloudy, milky urines accompanied by monolateral flank pain, malnutrition, weight loss and weakness. We report a case of chyluria that occurred in a young woman who was referred to our unit for nephrotic-range proteinuria. Before performing a renal biopsy, we found that urine analysis demonstrated a massive lipiduria. Therefore, we collected urine samples from each kidney with a selective ureteral catheterization, demonstrating a monolateral source of lipids and proteins. We suspended the renal biopsy and performed a lymphography that showed an inherited lymphangioma on the left lumbar lymphatic bed. Sclerosing solution instillation, renal pedicle lymphatic disconnection or laser therapy are invasive therapeutical options that may cause severe adverse effects. Instead of these procedures, a conservative therapy based on a low-fat diet supplemented with medium-chain triglycerides was chosen. This dietetic schedule was followed by complete resolution of proteinuria and lipiduria. The patient progressively gained body weight and improved quality of life. No relapses were observed after 3 years of follow-up. This case emphasizes the possible role of a noninvasive therapeutical option for patients with chyluria.


Vestibular dysfunction in Turner syndrome: a case report.
Turner syndrome is a well-known cause of sensorineural hearing loss, and the lack of estrogen has been implicated in cochlear dysfunction. It has never been associated with vestibular dysfunction. We report a case of a patient with Turner syndrome who was found to have bilateral vestibular dysfunction based on video-oculography (VOG) testing. A single patient with a history of Turner syndrome who was found to have significant bilateral vestibular dysfunction. After noticing a deficit in the vestibulo-ocular reflexes on qualitative horizontal head impulse examination, the patient underwent VOG testing. VOG testing quantatively measures angular vestibulo-ocular reflex (AVOR) gain in the horizontal semicircular canal plane. AVOR gain represents the eye movement response to a head movement; in normal individuals the eye movement is fully compensatory and gain values are close to unity. VOG results showed AVOR gains of 0.29 and 0.36 on the right and left sides, respectively. We have presented a case of a woman with Turner syndrome with asymptomatic vestibular dysfunction demonstrated with VOG testing. Although there is a documented relationship between Turner syndrome and sensorineural hearing loss, there are no previous studies or case reports linking Turner syndrome and vestibular dysfunction. Additional research and added vigilance in monitoring Turner syndrome patients may be warranted.


A novel highly potent inhibitor of TMPRSS2-like proteases blocks SARS-CoV-2 variants of concern and is broadly protective against infection and mortality in mice.
The COVID-19 pandemic caused by the SARS-CoV-2 virus remains a global public health crisis. Although widespread vaccination campaigns are underway, their efficacy is reduced against emerging variants of concern (VOCs) 1,2 . Development of host-directed therapeutics and prophylactics could limit such resistance and offer urgently needed protection against VOCs 3,4 . Attractive pharmacological targets to impede viral entry include type-II transmembrane serine proteases (TTSPs), such as TMPRSS2, whose essential role in the virus lifecycle is responsible for the cleavage and priming of the viral spike protein 5-7 . Here, we identify and characterize a small-molecule compound, N-0385, as the most potent inhibitor of TMPRSS2 reported to date. N-0385 exhibited low nanomolar potency and a selectivity index of >10 6 at inhibiting SARS-CoV-2 infection in human lung cells and in donor-derived colonoids 8 . Importantly, N-0385 acted as a broad-spectrum coronavirus inhibitor of two SARS-CoV-2 VOCs, B.1.1.7 and B.1.351. Strikingly, single daily intranasal administration of N-0385 early in infection significantly improved weight loss and clinical outcomes, and yielded 100% survival in the severe K18-human ACE2 transgenic mouse model of SARS-CoV-2 disease. This demonstrates that TTSP-mediated proteolytic maturation of spike is critical for SARS-CoV-2 infection in vivo and suggests that N-0385 provides a novel effective early treatment option against COVID-19 and emerging SARS-CoV-2 VOCs.


Influence of androgen deprivation therapy on serum urate levels in patients with prostate cancer: A retrospective observational study.
Although estrogenic modulation of serum urate levels is well-known, the androgenic effect on urate homeostasis remains controversial. We investigated the effect of androgen deprivation therapy (ADT) on serum urate levels. We retrospectively enrolled a total of 489 prostate cancer patients with available serum urate levels at baseline and 3 and 6 months after ADT (n = 150) or prostate surgery (n = 339). We extracted the demographic, clinical, and laboratory data from a data warehouse and compared the changes in urate levels between the two treatment groups and between the different ADT regimens (with versus without luteinizing hormone-releasing hormone (LHRH) agonists) using generalized estimating equation (GEE). The baseline urate levels and the proportion of hyperuricemic subjects were comparable between the two groups. After 6 months, the urate levels were significantly decreased (by -0.66 mg/dL, 95% confidence interval (CI) [-0.81 to -0.51]) in the ADT group, whereas they did not significantly change in the surgery group in the univariate GEE analysis. The ADT group (4.7% from 18.0% at baseline) had a significantly lower proportion of hyperuricemic patients than surgery group (16.5% from 15.9% at baseline) at 6-month (p < 0.001). Regardless of whether LHRH agonists were used, the serial urate levels were lowered by the ADT. Temporal changes in the urate levels were significantly associated with the treatment group, baseline hyperuricemia, and poor functional or advanced cancer status. The ADT-related serum urate level reduction also remained significant in the multivariate GEE analysis (regression coefficient = -0.43 [-0.67 to -0.19] after 3 months and -0.37 [-0.64 to -0.10] after 6 months). Moreover, propensity-score-matched analyses yielded the same results. Our results showed that longitudinal serum urate levels were significantly reduced in men receiving ADT. This finding suggests that androgen could have an independent role in urate homeostasis.


Properties of vascular ADP-ase.
The properties of vascular ADP-ase were investigated in microsomal preparations of rabbit aortic cell homogenates. The enzyme was found to have a Km of 9 microM. Its activity was not affected by substrates for other purine nucleoside phosphatases nor by substrates for non-specific phosphatases. However, ATP and beta-gamma-methylene ATP inhibited the enzyme. None of sodium fluoride, ouabain, neuraminidase affected ADP-ase activity whereas oligomycin potentiated the activity. The enzyme had an SH requirement and a divalent cation requirement.


The effect of deuteration on the keto-enol equilibrium and photostability of the sunscreen agent avobenzone.
The remarkable properties of deuterium have led to many exciting and favourable results in enhancing material properties, for applications in the physical, medical, and biological sciences. Deuterated isotopologues of avobenzone, a sunscreen active ingredient, were synthesised to examine for any changes to the equilibrium between the diketone and enol isomers, as well as their UV photostability and photoprotective properties. Prior to UV irradiation, deuteration of the diketone methylene/enol moiety (i.e. avobenzone-d2) led to an increase in the % diketone compared to non-deuterated, determined by 1H NMR experiments in CDCl3 and C6D12. This can be rationalised from two angles; mechanistically by a deuterium kinetic isotope effect for the CH vs. CD abstraction step during tautomerisation from the diketone to the enol, and a weaker chelating hydrogen bond for the enol when deuterated allowing increased equilibration to the diketone. Avobenzone-d2 was further examined by solid state 13C NMR. The higher % diketone for avobenzone-d2 was postulated to favour increased photodegradation by a non-reversible pathway. This was investigated by UV irradiation of the avobenzone isotopologues in C6D12, both in real time in situ within the NMR by fibre optic cable as well as ex situ using sunlight. An increase in the relative amount of photoproducts for avobenzone-d2 compared to non-deuterated was observed by 1H NMR upon UV irradiation ex situ. Overall, the study demonstrates that deuteration can be applied to alter complex equilibria, and has potential to be manifested as changes to the properties and behaviour of materials.


Metabolism of dITP in HeLa cell extracts, incorporation into DNA by isolated nuclei and release of hypoxanthine from DNA by a hypoxanthine-DNA glycosylase activity.
dITP may be generated from dATP by a slow, nonenzymatic hydrolysis. While [3H]dITP was degraded rapidly to [3H]deoxyinosine by HeLa cell nuclear extracts, no net degradation of [3H]dITP was observed in the presence of physiological concentrations of ATP, apparently because the extract contained deoxynucleoside diphosphate kinase activity that regenerated [3H]dITP from [3H]dIDP. Isolated HeLa cell nuclei, as well as partially purified DNA polymerase alpha, incorporated [3H]dITP into DNA at 50-60% of the rate of [3H]dGTP incorporation. No rapid release of the incorporated radioactivity was observed. The molecular weight of nascent DNA containing dIMP residues, however, decreased slightly after prolonged incubation in the presence of EDTA, suggesting that a repair process is initiated in dIMP-containing chromatin. Furthermore, release of free [3H]hypoxanthine from [3H]dIMP-containing DNA was detected after incubation with nuclear extracts in the presence of EDTA, suggesting the presence of hypoxanthine-DNA glycosylase activity in HeLa cell nuclei.


The Genetic Paradox of Invasions revisited: the potential role of inbreeding × environment interactions in invasion success.
Invasive species that successfully establish, persist, and expand within an area of introduction, in spite of demographic bottlenecks that reduce their genetic diversity, represent a paradox. Bottlenecks should inhibit population growth and invasive expansion, as a decrease in genetic diversity should result in inbreeding depression, increased fixation of deleterious mutations by genetic drift (drift load), and reduced evolutionary potential to respond to novel selection pressures. Here, we focus on the problems of inbreeding depression and drift load in introduced populations as key components of the Genetic Paradox of Invasions (GPI). We briefly review published explanations for the GPI, which are based on various mechanisms (invasion history events, reproductive traits, genetic characteristics) that mediate the avoidance of inbreeding depression and drift load. We find that there is still a substantial lack of explanation and empirical evidence for explaining the GPI for strongly bottlenecked invasions, or for during critical invasion phases (e.g. initial colonization, leading edges of range expansion) where strong genetic depletion, inbreeding depression and drift load occurs. Accordingly, we suggest that discussion of the GPI should be revived to find additional mechanisms applicable to explaining invasion success for such species and invasion phases. Based on a synthesis of the literature on the population genetics of invaders and the ecology of invaded habitats, we propose that inbreeding × environment (I × E) interactions are one such mechanism that may have strong explanatory power to address the GPI. Specifically, we suggest that a temporary or permanent release from stress in invaded habitats may alleviate the negative effects of genetic depletion on fitness via I × E interactions, and present published empirical evidence supporting this hypothesis. We additionally discuss that I × E interactions can result in rapid evolutionary changes, and may even contribute to adaptation of invaders in the absence of high genetic variation. With a view to encouraging further empirical research, we propose an experimental approach to investigate the occurrence of I × E interactions in ongoing invasions. Revived research on the GPI should provide new fundamental insights into eco-evolutionary invasion biology, and more generally into the evolutionary consequences of the interactions between inbreeding and environment.


Dual-Acting Cholinesterase-Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo.
We have designed and synthesized a series of 14 hybrid molecules out of the cholinesterase (ChE) inhibitor tacrine and a benzimidazole-based human cannabinoid receptor subtype 2 (hCB2R) agonist and investigated them in vitro and in vivo. The compounds are potent ChE inhibitors, and for the most promising hybrids, the mechanism of human acetylcholinesterase (hAChE) inhibition as well as their ability to interfere with AChE-induced aggregation of β-amyloid (Aβ), and Aβ self-aggregation was assessed. All hybrids were evaluated for affinity and selectivity for hCB1R and hCB2R. To ensure that the hybrids retained their agonist character, the expression of cAMP-regulated genes was quantified, and potency and efficacy were determined. Additionally, the effects of the hybrids on microglia activation and neuroprotection on HT-22 cells were investigated. The most promising in vitro hybrids showed pronounced neuroprotection in an Alzheimer's mouse model at low dosage (0.1 mg/kg, i.p.), lacking hepatotoxicity even at high dose (3 mg/kg, i.p.).


Androgens increase survival of adult-born neurons in the dentate gyrus by an androgen receptor-dependent mechanism in male rats.
Gonadal steroids are potent regulators of adult neurogenesis. We previously reported that androgens, such as testosterone (T) and dihydrotestosterone (DHT), but not estradiol, increased the survival of new neurons in the dentate gyrus of the male rat. These results suggest androgens regulate hippocampal neurogenesis via the androgen receptor (AR). To test this supposition, we examined the role of ARs in hippocampal neurogenesis using 2 different approaches. In experiment 1, we examined neurogenesis in male rats insensitive to androgens due to a naturally occurring mutation in the gene encoding the AR (termed testicular feminization mutation) compared with wild-type males. In experiment 2, we injected the AR antagonist, flutamide, into castrated male rats and compared neurogenesis levels in the dentate gyrus of DHT and oil-treated controls. In experiment 1, chronic T increased hippocampal neurogenesis in wild-type males but not in androgen-insensitive testicular feminization mutation males. In experiment 2, DHT increased hippocampal neurogenesis via cell survival, an effect that was blocked by concurrent treatment with flutamide. DHT, however, did not affect cell proliferation. Interestingly, cells expressing doublecortin, a marker of immature neurons, did not colabel with ARs in the dentate gyrus, but ARs were robustly expressed in other regions of the hippocampus. Together these studies provide complementary evidence that androgens regulate adult neurogenesis in the hippocampus via the AR but at a site other than the dentate gyrus. Understanding where in the brain androgens act to increase the survival of new neurons in the adult brain may have implications for neurodegenerative disorders.


DNA Privacy: Analyzing Malicious DNA Sequences Using Deep Neural Networks.
Recent advances in next-generation sequencing technologies have led to the successful insertion of video information into DNA using synthesized oligonucleotides. Several attempts have been made to embed larger data into living organisms. This process of embedding messages is called steganography and it is used for hiding and watermarking data to protect intellectual property. In contrast, steganalysis is a group of algorithms that serves to detect hidden information from covert media. Various methods have been developed to detect messages embedded in conventional covert channels. However, conventional steganalysis algorithms are mostly limited to common covert media. Most common detection approaches, such as frequency analysis-based methods, often overlook important signals when directly applied to DNA steganography and are easily bypassed by recently developed steganography techniques. To address the limitations of conventional approaches, a sequence-learning-based malicious DNA sequence analysis method based on neural networks has been proposed. The proposed method learns intrinsic distributions and identifies distribution variations using a classification score to predict whether a sequence is to be a coding or non-coding sequence. Based on our experiments and results, we have developed a framework to safeguard security against DNA steganography.


PreMosa: extracting 2D surfaces from 3D microscopy mosaics.
A significant focus of biological research is to understand the development, organization and function of tissues. A particularly productive area of study is on single layer epithelial tissues in which the adherence junctions of cells form a 2D manifold that is fluorescently labeled. Given the size of the tissue, a microscope must collect a mosaic of overlapping 3D stacks encompassing the stained surface. Downstream interpretation is greatly simplified by preprocessing such a dataset as follows: (i) extracting and mapping the stained manifold in each stack into a single 2D projection plane, (ii) correcting uneven illumination artifacts, (iii) stitching the mosaic planes into a single, large 2D image and (iv) adjusting the contrast. We have developed PreMosa, an efficient, fully automatic pipeline to perform the four preprocessing tasks above resulting in a single 2D image of the stained manifold across which contrast is optimized and illumination is even. Notable features are as follows. First, the 2D projection step employs a specially developed algorithm that actually finds the manifold in the stack based on maximizing contrast, intensity and smoothness. Second, the projection step comes first, implying all subsequent tasks are more rapidly solved in 2D. And last, the mosaic melding employs an algorithm that globally adjusts contrasts amongst the 2D tiles so as to produce a seamless, high-contrast image. We conclude with an evaluation using ground-truth datasets and present results on datasets from Drosophila melanogaster wings and Schmidtae mediterranea ciliary components. PreMosa is available under https://cblasse.github.io/premosa. email@example.com or firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


Multiple factors confer specific Cdc42 and Rac protein activation by dedicator of cytokinesis (DOCK) nucleotide exchange factors.
DOCK (dedicator of cytokinesis) guanine nucleotide exchange factors (GEFs) activate the Rho-family GTPases Rac and Cdc42 to control cell migration, morphogenesis, and phagocytosis. The DOCK A and B subfamilies activate Rac, whereas the DOCK D subfamily activates Cdc42. Nucleotide exchange is catalyzed by a conserved DHR2 domain (DOCK(DHR2)). Although the molecular basis for DOCK(DHR2)-mediated GTPase activation has been elucidated through structures of a DOCK9(DHR2)-Cdc42 complex, the factors determining recognition of specific GTPases are unknown. To understand the molecular basis for DOCK-GTPase specificity, we have determined the crystal structure of DOCK2(DHR2) in complex with Rac1. DOCK2(DHR2) and DOCK9(DHR2) exhibit similar tertiary structures and homodimer interfaces and share a conserved GTPase-activating mechanism. Multiple structural differences between DOCK2(DHR2) and DOCK9(DHR2) account for their selectivity toward Rac1 and Cdc42. Key determinants of selectivity of Cdc42 and Rac for their cognate DOCK(DHR2) are a Phe or Trp residue within β3 (residue 56) and the ability of DOCK proteins to exploit differences in the GEF-induced conformational changes of switch 1 dependent on a divergent residue at position 27. DOCK proteins, therefore, differ from DH-PH GEFs that select their cognate GTPases through recognition of structural differences within the β2/β3 strands.


Mapping of capillary flow, cellular redox state, and resting membrane potential in hypoperfused rat myocardium.
The influence on myocyte viability of ischemia-induced changes in capillary perfusion was studied in the hearts of anesthetized rats subjected to partial occlusion of the left coronary artery for 45 min. Timed plasma labeling was applied to determine perfusion patterns. Changes in the fluorescence of preloaded potential-sensitive dyes [tetramethylrhodamine methyl ester (TMRM) and bis-oxonol], of trypan blue, and of endogeneous NADH were utilized in characterizing myocyte viability in histological sections of the heart. Within the hypoperfused zone, localized areas appeared vascularly nonlabeled for periods of at least 10 min. Within these areas a reduction in TMRM fluorescence occurred in 82. 5% of the tissue, signaling a reduced resting membrane potential. In the same areas 37.7% of the myocytes revealed an NADH fluorescence lower than that regularly found in anoxic tissues. This correlated with an especially low level of TMRM, with increased fluorescence bis-oxonol and with an accumulation of trypan blue. In conclusion, in localized hypoperfusion-induced zones lacking capillary flow, an inhomogeneous pattern of reductions in myocyte viability develops, which appears to be relevant in ischemia-induced arrhythmias.


Clinicopathological and genomic analysis of double-hit follicular lymphoma: comparison with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements.
Most high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are aggressive B-cell lymphomas. Occasional double-hit follicular lymphomas have been described but the clinicopathological features of these tumors are not well known. To clarify the characteristics of double-hit follicular lymphomas, we analyzed 10 cases of double-hit follicular lymphomas and 15 cases of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements for clinicopathological and genome-wide copy-number alterations and copy-neutral loss-of-heterozygosity profiles. For double-hit follicular lymphomas, the median age was 67.5 years (range: 48-82 years). The female/male ratio was 2.3. Eight patients presented with advanced clinical stage. The median follow-up time was 20 months (range: 1-132 months). At the end of the follow-up, 8 patients were alive, 2 patients were dead including 1 patient with diffuse large B-cell lymphoma transformation. Rearrangements of MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6 were seen in 8, 1, and 1 cases, respectively. The partner of MYC was IGH in 6 cases. There were no cases of histological grade 1, 4 cases of grade 2, 5 cases of grade 3a, and 1 case of grade 3b. Two cases of grade 3a exhibited immunoblast-like morphology. Immunohistochemistry demonstrated 9 cases with ≥50% MYC-positive cells. There was significant difference in MYC intensity (P=0.00004) and MIB-1 positivity (P=0.001) between double-hit follicular lymphomas and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements. The genome profile of double-hit follicular lymphomas was comparable with conventional follicular lymphomas (GSE67385, n=198) with characteristic gains of 2p25.3-p11.1, 7p22.3-q36.3, 12q11-q24.33, and loss of 18q21.32-q23 (P<0.05). In comparison with high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements, double-hit follicular lymphomas had fewer copy-number alterations and minimal common region of gain at 2p16.1 (70%), locus also significant against conventional follicular lymphomas (P=0.0001). In summary, double-hit follicular lymphomas tended to be high-grade histology, high MYC protein expression, high MYC/IGH fusion, and minimal common region of gain at 2p16.1. Double-hit follicular lymphomas seemed to be a different disease from high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements and have an indolent clinical behavior similar to follicular lymphomas without MYC rearrangement.


Use of medications and vitamin-mineral supplements by children and youths.
The National Health Interview Survey was administered in 1981 to a national probability sample of approximately 42,000 families. The questions on the Child Health Supplement of the survey were asked about one child in each family that had a child under age 18. The supplement included a series of questions about prescription and nonprescription medications and vitamin and mineral supplements. The respondents supplied information on 15,416 children under age 18. About two-thirds of the children had had some form of medication or vitamin-mineral supplement during any 2-week period in 1981. About one-third of the children were using medications that had been prescribed or recommended by a physician. About 17 percent of the children had been taking medication (excluding vitamin-mineral supplements) daily or nearly every day for the previous 3 months. Use of medications varied by age group. About one-fourth of the children 0-2 years were being given two or more physician-prescribed or -recommended medications or supplements. Use of medications was highest in the first quarter of the year.


Immunobiology of chronic lung allograft dysfunction: new insights from the bench and beyond.
The first successful human lung transplants were performed in the 1980s. Since that time lung transplantation has been a therapeutic modality for end-stage pulmonary diseases. However, chronic rejection, known as obliterative bronchiolitis (OB)/bronchiolitis obliterans syndrome (BOS), is the key reason why the 5-year survival is only 50%, which is significantly worse than most other solid organ transplants. Recent studies have provided exciting advances that are beginning to be translated into findings in humans. This review will highlight the current advances in understanding the mechanisms of OB/BOS in lung transplant recipients.


[The postoperative monitoring of intracranial pressure in patients in the acute period of aneurysmatic hemorrhage].
Changes in intracranial pressure (ICP) and cerebral circulation were evaluated from Doppler transcranial ultrasound (DTU) in 29 patients with spontaneous aneurysmal hemorrhage in acute rupture. There is a tendency for the pulse wave amplitude (PWA) of ICP to increase concurrently with higher ICP values (r = 0.768, p < 0.01), the tendency being smoother in patients with severe diffuse spasm (r = 0.573, p < 0.01). There was also a linear correlation between the ICP values and the pulse index of blood flow velocity (r = 0.783, p < 0.01). Evidence is given for the possibility of indirect assessment of ICP from DTU data and for that of indirect evaluation of cerebral perfusion from ICP monitoring data. In the latter case, the authors used a ICP PWA ratio. The findings suggest that the decrease in PWA/ICP values by less than 0.2 during intracranial hypertension and severe diffuse arterial spasm corresponds to the reduction in cerebral blood filling beyond the critical values.


Toward on-the-fly trajectory optimization for C-arm CBCT under strong kinematic constraints.
Cone beam computed tomography (CBCT) has become a vital tool in interventional radiology. Usually, a circular source-detector trajectory is used to acquire a three-dimensional (3D) image. Kinematic constraints due to the patient size or additional medical equipment often cause collisions with the imager while performing a full circular rotation. In a previous study, we developed a framework to design collision-free, patient-specific trajectories for the cases in which circular CBCT is not feasible. Our proposed trajectories included enough information to appropriately reconstruct a particular volume of interest (VOI), but the constraints had to be defined before the intervention. As most collisions are unpredictable, performing an on-the-fly trajectory optimization is desirable. In this study, we propose a search strategy that explores a set of trajectories that cover the whole collision-free area and subsequently performs a search locally in the areas with the highest image quality. Selecting the best trajectories is performed using simulations on a prior diagnostic CT volume which serves as a digital phantom for simulations. In our simulations, the Feature SIMilarity Index (FSIM) is used as the objective function to evaluate the imaging quality provided by different trajectories. We investigated the performance of our methods using three different anatomical targets inside the Alderson-Rando phantom. We used FSIM and Universal Quality Image (UQI) to evaluate the final reconstruction results. Our experiments showed that our proposed trajectories could achieve a comparable image quality in the VOI compared to the standard C-arm circular CBCT. We achieved a relative deviation less than 10% for both FSIM and UQI metrics between the reconstructed images from the optimized trajectories and the standard C-arm CBCT for all three targets. The whole trajectory optimization took approximately three to four minutes.


Factors associated with participation in resistance training: a systematic review.
Regular participation in resistance training (RT) is critical to health and recommended in most international physical activity guidelines. Few people, however, participate in RT. The purpose of this review was to assess the demographic, behavioural, intrapersonal, interpersonal and environmental factors associated with participating in RT. Eligible studies were from English peer-reviewed published articles that examined correlates or determinants of RT in adult samples. Searches were performed from August 2015 to April 2016 in six databases. We identified 51 independent data sets, from nine countries, primarily of moderate to high quality, and 23 factors related to participating in RT. Education, perceived health status, quality of life, affective judgements, self-efficacy, intention, self-regulation behaviours, subjective norm and programme leadership were associated with RT. Low education levels and poor health status were associated with low participation rates in RT. Intrapersonal factors including affective judgements, self-efficacy, and self-regulation behaviours, and interpersonal factors including subjective norms and programme leadership may be important for promoting RT behaviours.


Broadening the Scope: A Qualitative Study of Pathologists' Attitudes Toward Patient-Pathologist Interactions.
This study qualitatively explored and described pathologists' attitudes toward patient interaction. In a survey to pathologists, we asked, "How interested would you be in meeting with patients to discuss their pathology report and show them microscopic images of their tissue?" Then, we asked "Why," followed by a free-text box. We asked pathologists to assume that their time would be adequately compensated and that patients' treating clinicians had already told them their diagnosis. Physician age, gender, rank, and type of practice were also collected. We surveyed 197 pathologists, 86% of whom were either definitely interested or interested in meeting with patients. Interest level did not differ by age, gender, or rank but was higher in academic practices than in community practices. Thematic analysis showed that pathologists believed that meeting with patients could impact (1) patients, through cognitive and emotional pathways; (2) pathologists, through patient contact and job satisfaction; and (3) the field of pathology, through quality of care and a redefined image of the specialty. Pathologists' interest level in meeting with patients was high. Potential impacts on patients, pathologists, and the field of pathology were identified.


Deficiency in the amino aldehyde dehydrogenase encoded by GmAMADH2, the homologue of rice Os2AP, enhances 2-acetyl-1-pyrroline biosynthesis in soybeans (Glycine max L.).
2-Acetyl-1-pyrroline (2AP), the volatile compound that provides the 'popcorn-like' aroma in a large variety of cereal and food products, is widely found in nature. Deficiency in amino aldehyde dehydrogenase (AMADH) was previously shown to be the likely cause of 2AP biosynthesis in rice (Oryza sativa L.). In this study, the validity of this mechanism was investigated in soybeans (Glycine max L.). An assay of AMADH activity in soybeans revealed that the aromatic soybean, which contains 2AP, also lacked AMADH enzyme activity. Two genes, GmAMADH1 and GmAMADH2, which are homologous to the rice Os2AP gene that encodes AMADH, were characterized. The transcription level of GmAMADH2 was lower in aromatic varieties than in nonaromatic varieties, whereas the expression of GmAMADH1 did not differ. A double nucleotide (TT) deletion was found in exon 10 of GmAMADH2 in all aromatic varieties. This variation caused a frame-shift mutation and a premature stop codon. Suppression of GmAMADH2 by introduction of a GmAMADH2-RNAi construct into the calli of the two nonaromatic wild-type varieties inhibited the synthesis of AMADH and induced the biosynthesis of 2AP. These results suggest that deficiency in the GmAMADH2 product, AMADH, plays a similar role in soybean as in rice, which is to promote 2AP biosynthesis. This phenomenon might be a conserved mechanism among plant species.


Optimization and standardization of an enzyme-linked immunosorbent assay protocol for serodiagnosis of Actinobacillus pleuropneumoniae serotype 5.
An indirect enzyme-linked immunosorbent assay protocol has been optimized with special emphasis given to assay standardization and quality control. Technical aspects such as choice of a microplate, antigen immobilization, buffer composition, optimal screening dilution of sera, and kinetics of the enzymatic reaction were studied and evaluated in order to design a standard protocol offering maximal analytical sensitivity and specificity, as well as to obtain minimal within- and between-plate variability. Among the 27 plates tested, the Nunc 475-094 and 269-620 immunoplates were found to be the best in terms of high positive-to-negative ratio and low variability. No significant differences in antigen immobilization were found by using buffers of various compositions or pHs; however, the presence of magnesium ions (Mg2+; 0.02 M) resulted in a twofold increase in nonspecific background. An optimal screening dilution of sera was established at 1:200. A 1-h incubation period for test serum was found to be optimal. Maximum enzymatic activity for peroxidase was obtained by adjusting both substrate (H2O2) and hydrogen donor [2,2' -azinobis(3-ethylbenz-thiazoline sulfonic acid)] concentrations to 4 and 1 mM, respectively. To control between-plate variability, a timing protocol was adopted. Within-plate variability was also controlled by using a sample placement configuration pattern. Sliding scales were determined by repeated testing of a cross section of samples to set acceptance limits for both within- and between-plate variability. These limits were used in a quality control program to monitor assay performance. The results obtained suggest that this standardized protocol might be useful in the serodiagnosis of Actinobacillus pleuropneumoniae serotype 5.


Optimization of electroporation-enhanced intradermal delivery of DNA vaccine using a minimally invasive surface device.
In vivo electroporation (EP) is an efficient nonviral method for enhancing DNA vaccine delivery and immunogenicity in animals and humans. Intradermal delivery of DNA vaccines is an attractive strategy because of the immunocompetence of skin tissue. We have previously reported a minimally invasive surface intradermal EP (SEP) device for delivery of prophylactic DNA vaccines. Robust antibody responses were induced after vaccine delivery via surface EP in several tested animal models. Here we further investigated the optimal EP parameters for efficient delivery of DNA vaccines, with a specific emphasis on eliciting cellular immunity in addition to robust humoral responses. In a mouse model, using applied voltages of 10-100 V, transgene expression of green fluorescent protein and luciferase reporter genes increased significantly when voltages as low as 10 V were used as compared with DNA injection only. Tissue damage to skin was undetectable when voltages of 20 V and less were applied. However, inflammation and bruising became apparent at voltages above 40 V. Delivery of DNA vaccines encoding influenza virus H5 hemagglutinin (H5HA) and nucleoprotein (NP) of influenza H1N1 at applied voltages of 10-100 V elicited robust and sustained antibody responses. In addition, low-voltage (less than 20 V) EP elicited higher and more sustained cellular immune responses when compared with the higher voltage (above 20 V) EP groups after two immunizations. The data confirm that low-voltage EP, using the SEP device, is capable of efficient delivery of DNA vaccines into the skin, and establishes that these parameters are sufficient to elicit both robust and sustainable humoral as well as cellular immune responses without tissue damage. The SEP device, functioning within these parameters, may have important clinical applications for delivery of prophylactic DNA vaccines against diseases such as HIV infection, malaria, and tuberculosis that require both cellular and humoral immune responses for protection.


Nutritional assessment and its correlation with anthropometric measurements in hemodialysis patients.
One of the most important problems in patients on hemodialysis (HD) is chronic malnutrition. This study is aimed to assess the prevalence of malnutrition using a subjective global assessment (SGA) in HD patients referred to the Valie ASR Hospital, Arak, Iran. In this descriptive analysis study, 190 HD patients were selected with random sampling. SGA and anthropometric and biochemical measurements were assessed in all patients. Data were analyzed with the Chi-square and t-tests and Pearson correlation coefficient. P <0.05 was considered statistically significant. Of the 190 patients studied, 78 patients (41.1%) were male and 112 patients (58.9%) were female. Sixteen patients were detected to have adequate nutritional status (8.4%), 90 (47.4%) had mild malnutrition and 84 patients (44.2%) had moderate malnutrition. We found a significant negative correlation of SGA score with patient's weight (r = -0.147) and patient's body mass index (BMI) (r = -0.238). Also, it correlated significantly with duration of dialysis treatment (years) (r = 0.404). The SGA score showed a significant negative correlation with mid-arm circumference (MAC) (r = - 0.152). No significant correlation was found between SGA score and mid-arm muscle area. Our study showed that >50% of patients on maintenance HD had mild or moderate malnutrition. There was no case of severe malnutrition. Duration of dialysis treatment and some anthropometric indices (weight, BMI and MAC) also showed a significant correlation with SGA score, which are important to determine the nutritional status of HD patients.


Colorectal anastomotic stenosis. Results of a survey of the ASCRS membership.
Anastomotic stenosis is a poorly understood and underexamined complication of gastrointestinal surgery, reportedly most frequent in the coloproctostomy. In order to better define this problem, a questionnaire was sent to members of the American Society of Colon and Rectal Surgeons regarding patients with gastrointestinal anastomotic stenosis. A total of 123 patients with intestinal anastomotic stenosis were analyzed. Eighty-two anastomoses were stapled and 41 were handsewn. Nearly all stenoses occurred in the distal bowel (70 rectal, 23 sigmoid colon). Preoperative risk factors identified were obesity (28 patients) and abscess (12 patients). Incomplete "doughnuts" were noted in 12 patients. Postoperative anastomotic leaks (15 patients), pelvic infection (13 patients), and postoperative radiation (7 patients) were believed to be contributing factors. Dilatation, using a variety of techniques, was the sole treatment for 65 patients, however, intra-abdominal surgery was necessary in 34 patients. Large intestinal anastomotic stenosis probably occurs most commonly following coloproctostomy (both with handsewn and stapled anastomoses). Dilatation alone resulted in adequate treatment in most patients in the study. Major surgery was required to correct this problem in a significant number of patients (28 percent) in this series. The true incidence of anastomotic stenosis in colorectal surgery is unknown and warrants further study.


[Impact of dementia on length of stay and costs in acute care hospitals].
The treatment of patients with dementia in acute care hospitals is becoming increasingly more important. The aim of this study was to investigate and demonstrate aspects of the healthcare situation and resource consumption of dementia patients during their hospital stay in a ward for internal medicine. Secondary data from a ward of internal medicine were analyzed on a retrospective and case-related basis. For 100 patients a diagnosis of dementia by a general practitioner before hospitalization was identified. The control group was selected by age and sex from the other patients in the ward (n = 100). The costs were calculated on the basis of the German diagnosis-related groups (G-DRG) flat rate case classification. The relationship between dementia, deviation from the average length of stay and costs was investigated under the control of comorbidities using multivariate regression analysis. Patients with dementia had poorer health at admission with respect to functionality and orientation and a higher risk of falls and pressure ulcers. During hospitalization patients with dementia fell more frequently than patients without dementia (12 % versus 3 %, p = 0.029). Regarding the average length of stay, according to the G‑DRG catalogue patients with dementia stayed 1.4 days longer in hospital than patients without dementia and caused excess costs of 19 %. Patients with dementia are a highly vulnerable patient group with a higher consumption of resources than patients without dementia. The results demonstrate the care-related and economic consequences, which the increasing number of patients with dementia could have in the future.


Profiling a Spectrum of Mental Job Demands and their Linkages to Employee Outcomes.
Working life is becoming more mentally demanding and intense due to technological acceleration. The present study explored employees' experiences of different mental job demands (MJDs) and their outcomes (job burnout, job performance, and meaning of work). We focused on intra- and inter-individual variations and possible harmful combinations of MJDs, which we explored via latent profile analysis (LPA). To identify harmful combinations of MJDs, we also investigated how the profiles of MJDs related to the outcomes of interest. The study was based on a diverse sample of Finnish employees (n = 4,583). LPA showed that both intra-individual and inter-individual variation characterized MJDs as we identified five latent profiles of MJDs. The most harmful profile, which predicted the most negative outcomes (particularly job burnout), was characterized by employees' scoring high on all MJDs. A profile characterized by low learning demands and moderate level of other MJDs was also a harmful combination in terms of outcomes. In contrast, a profile characterized by moderate level of learning demands and low level of other MJDs did not relate to negative outcomes. Altogether, the findings suggest that different MJDs may co-occur implying risks to employee well-being and performance. However, MJDs simultaneously form a complex spectrum that may differ within and between individuals.


Whole-body vibration therapy for osteoporosis: state of the science.
Clinical guidelines for osteoporosis recommend dietary and pharmacologic interventions and weight-bearing exercise to prevent bone fractures. These interventions sometimes have low adherence and can cause adverse effects. A proposed alternative or adjunctive treatment is whole-body vibration therapy (WBV), in which energy produced by a forced oscillation is transferred to an individual from a mechanical vibration platform. Whole-body vibration platforms are not approved by the U.S. Food and Drug Administration for medical purposes. This review provides a broad overview of important issues related to WBV therapy for prevention and treatment of osteoporosis. Relying on key informants and a search of the gray and published literature from January 2000 to August 2011, the investigators found that the designs of WBV platforms and protocols for their use vary widely. The optimal target population for the therapy is not defined. Although WBV has some theoretical advantages, key informants have voiced several concerns, including uncertain safety and potential consumer confusion between low-intensity vibration platforms intended for osteoporosis therapy and high-intensity platforms intended for exercise. Finally, the scant literature did not establish whether WBV therapy leads to clinically important increases in bone mineral density or reduces risk for fracture.