How Do Medicalization and Rescue Fantasy Prevent Healthy Dying?
Before antibiotics, cardiopulmonary resuscitation (CPR), and life-sustaining technologies, humans had little choice about the timing and manner of their deaths. Today, the medicalization of death has enabled patients to delay death, prolonging their living and dying. New technology, the influence of the media, and medical professionals themselves have together transformed dying from a natural part of the human experience into a medical crisis from which a patient must be rescued, often through the aggressive extension of life or through its premature termination. In this paper, we examine problematic forms of rescue medicine and suggest the need to rethink medicalized dying within the context of medicine's orientation to health and wholeness.


Accelerated size-focusing light activated synthesis of atomically precise fluorescent Au22(Lys-Cys-Lys)16 clusters.
Atomically precise metal nanoclusters are promising candidates for various biomedical applications, including their use as photosensitizers in photodynamic therapy (PDT). However, typical synthetic routes of clusters often result in complex mixtures, where isolating and characterizing pure samples becomes challenging. In this work, a new Au22(Lys-Cys-Lys)16 cluster is synthesized using photochemistry, followed by a new type of light activated, accelerated size-focusing. Fluorescence excitation-emission matrix spectroscopy (EEM) and parallel factor (PARAFAC) analysis have been applied to track the formation of fluorescent species, and to assess optical purity of the final product. Furthermore, excited state reactivity of Au22(Lys-Cys-Lys)16 clusters is studied, and formation of type-I reactive oxygen species (ROS) from the excited state of the clusters is observed. The proposed size-focusing procedure in this work can be easily adapted to conventional cluster synthetic methods, such as borohydride reduction, to provide atomically precise clusters.


100 citation classics from the Journal of the American Medical Association.
The 100 most-cited JAMA articles were identified using the 1955 through 1983 Science Citation Index of the Institute for Scientific Information. The most-cited article received 705 citations, while the least-cited article received 158. The oldest was published in 1910 and the most recent in 1976. These articles describe important medical advances in areas such as asbestos exposure, smoking, and oral contraceptives. Most of the 285 JAMA authors are Americans and include Baruch S. Blumberg and Edward A. Doisy, both Nobel laureates. Thirteen of the articles were included in JAMA's original landmark series; the editorial committee used a combination of peer review and citation frequency to select 51 articles.


Responsiveness and minimal important changes for the Knee Injury and Osteoarthritis Outcome Score in subjects undergoing rehabilitation after total knee arthroplasty.
The aim of this study was to evaluate the responsiveness and minimal important changes for the Knee Injury and Osteoarthritis Outcome Score (KOOS) in subjects undergoing rehabilitation after total knee arthroplasty. At the beginning and end of a rehabilitation program, 148 patients completed the KOOS. A global perception of change scale was also completed at the end of the program and collapsed to produce a dichotomous outcome (improved vs. stable). Responsiveness was assessed on the KOOS subscales and calculated by distribution methods (effect size; standardized response mean). The minimal important changes of the KOOS subscales were assessed using anchor-based methods (receiver operating characteristic curves) to compute the best cutoff levels between the improved and stable subjects. The effect sizes ranged from 0.83 to 1.35, and the standardized response means ranged from 0.76 to 1.22. The receiver operating characteristic analyses revealed an area under the curve of 0.89, 0.88, 0.94, 0.93, and 0.85 for the Pain, Symptoms, Activities of Daily Living, Sport/Recreation, and Quality of Life subscales, respectively, showing discriminative capacities; the minimal important changes were 16.7 for Pain (sensitivity: 83%; specificity: 82%), 10.7 for Symptoms (80%; 80%), 18.4 for Activities of Daily Living (82%; 82%), 12.5 for Sport/Recreation (96%; 78%), and 15.6 for Quality of Life (88%; 67%). The KOOS was sensitive in detecting clinical changes. The authors recommend taking the minimal important changes provided into account when assessing patient improvement or planning studies in this clinical context.


Efficacy Analysis of Neoadjuvant versus Adjuvant Cisplatin-Paclitaxel Regimens for Initial Treatment of FIGO Stages IB3 and IIA2 Cervical Cancer.
BACKGROUND Large cancer lesions are often challenging to treat with surgical intervention alone. Neoadjuvant chemotherapy is frequently used for FIGO stage IB3 and IIA2 cervical cancers to optimize the outcomes of radical surgeries. This study aimed to compare the effectiveness of neoadjuvant chemotherapy, followed by adjuvant chemotherapy and radiotherapy, if necessary, with the traditional approach of adjuvant chemotherapy and radiotherapy after radical hysterectomy in treatment-naïve patients with cervical cancer of specified stages. MATERIAL AND METHODS A total of 245 female patients were administered either 70 to 85 mg/m² cisplatin and 165 to 175 mg/m² paclitaxel every 21 days (2 cycles) prior to radical hysterectomy, followed by adjuvant chemotherapy and radiotherapy if needed (neoadjuvant therapy, NT cohort, n=105), or received adjuvant chemotherapy and radiotherapy after radical hysterectomy adjuvant therapy, AT cohort, n=140). RESULTS In the NT cohort, 76% of patients responded to neoadjuvant chemotherapy, while 24% did not. Adverse operative, intraoperative, and postoperative outcomes were significantly more common among the non-responders (P<0.05). After 5 years, 91% of responders and 72% of non-responders survived without recurrence (P=0.0372), and 3% of responders and 28% of non-responders had died (P=0.0005). CONCLUSIONS The resistance to neoadjuvant chemotherapy is a poor prognostic factor. Neoadjuvant chemotherapy followed by radical hysterectomy and adjuvant chemotherapy/radiotherapy appears to be advantageous for cervical cancer patients who respond well to neoadjuvant chemotherapy.


Efficacy and quality of antibacterial generic products approved for human use: a systematic review.
Concerns have recently emerged about the efficacy and the quality of antibacterial generic products approved for use in humans. We searched Medline and Embase for original research articles on antibacterial generic products published in English or French before July 2013. We selected 37 original research articles: 15 on β-lactams, 10 on glycopeptides, and 12 on other antibacterial agents. The majority of articles (73.0%) were published during 2008-2012. Study designs included analytical chemistry (n = 9), in vitro susceptibility studies (n = 14), animal experiments (n = 6, including 5 using the neutropenic mouse thigh infection model), and clinical studies in humans (n = 15). Of the 37 studies, 14 (37.8%) suggested that some generic products may be inferior to the innovator in terms of purity (n = 2), in vitro activity (n = 3), in vivo efficacy in experimental models (n = 4), clinical efficacy (n = 2), taste (n = 2), or compliance and acceptability in children (n = 1). The majority of in vitro studies (78.6%) found no significant difference between generic products and the innovator. Most (5/6) in vivo studies suggesting a difference between generic products and the innovator were performed in an animal model that is not validated for the evaluation of the efficacy of antibacterial agents. The level of evidence was constantly low in clinical studies. Published data on antibacterial generic products are limited and heterogeneous, thus precluding any attempt to generalize the study results. This systematic review suggests that additional evidence would be needed before considering a revision of the marketing authorization process for antibacterial generic products.


Changes in COPD demographics and costs over 20 years.
Chronic obstructive pulmonary disease (COPD) is now the third leading cause of death in the US and responsible for significant healthcare resource use. The purpose of this study was to examine the changes in COPD costs over 20 years and assess total direct cost trends over the last 10. A cross-sectional study of a population-based survey (2007 Medical Expenditure Panel Survey compared to the 1987 National Medical Expenditures Panel Survey) of respondents aged 40 and older with COPD (ICD-9-CM codes 491.xx, 492.xx, or 496.xx) was assessed for demographic and healthcare services use characteristics and compared to reported statistics from 1987. Ten-year trends in total direct medical costs from 1997-2007 are presented. In 2007, there were 416 survey respondents with COPD compared to 228 in 1987. In 1987, women were only 39% of the COPD sample, while in 2007 they made up 58% of the sample. Mean cost per COPD patient was $16,135 (2007 dollars) in 2007, which was up from $11,807 (2007 dollars) in 1987 or a 37% increase. The proportional cost of emergency department visits (183%) and prescription drugs (170%) from 1987-2007 was high compared to other healthcare services. However, the mean cost of a hospitalization was the highest actual increase ($2289). Ten-year trends show a similar gradual increase. The prevalence of COPD among females as well as the mean cost per COPD patient has risen sharply over the last 20 years. Cost-shifting from acute services to preventive services may allow US payers and healthcare providers to improve care and better manage costs for patients with COPD. More attention on prevention, diagnosis, and management needs to be directed to women at risk of COPD.


Robust DNase activity of the ooplasm can act as a gametic transfection barrier in rainbow trout.
In this study, we evaluated DNase activity of rainbow trout oocyte using an in vitro and in vivo study. First, synthetic single strand and natural double strand DNA from Eukaryotic and prokaryotic sources as well as naked DNA were in vitro incubated with the oocyte cytoplasm. Results showed that the DNase activity of rainbow trout oocyte is strong enough to degrade any type of DNA at the onset of the incubation. Then, we evaluated if similar to the mammalian species, dead spermatozoa from rainbow trout can protect exogenous DNA from oocyte DNases. A series of dead spermatozoa was incubated with pDB2, carrying EGFP transgene, for 30 min followed by the ooplasm treatment for an additional 30 min. Not only did oocyte DNases completely degrade the exogenous DNA, but also it degraded the compact genome of spermatozoa. In conclusion, in vitro results clearly showed that strong DNase activity of ooplasm could degrade any types of foreign DNAs including oligonucleotides and intensively compact sperm genome. The strong DNase activity of rainbow trout ooplasm could be a stumbling block for genetic modification using plasmids in salmonids.


Game On: Past Year Gambling, Gambling-Related Problems, and Fantasy Sports Gambling Among College Athletes and Non-athletes.
College students experience higher rates of gambling-related problems than most other population segments, including the general population. Although Division I (D1) athletes often have more at stake than the average student if and when they gamble (e.g., the potential to lose their athletic eligibility), relatively few studies have assessed the gambling behavior of this population and none have specifically assessed fantasy sports gambling. We conducted a study to examine gambling behavior (past-year gambling, gambling-related problems, and fantasy sport gambling) among a sample (N = 692) of college students at a private religiously affiliated university in the Southwest US. The sample for our study was unique in that approximately 30 % of the participants were D1 athletes. We compared the gambling behavior among three groups based on the athlete status: D1 athletes, club/intramural/recreational (CIR) athletes, and non-athletes (NAs). Compared to females in our sample, males observed higher rates of past year gambling, fantasy sports participation, fantasy sports gambling, and gambling-related problems. Among males, we found that CIR athletes observed the highest rates of past year gambling and fantasy sports participation and D1 athletes observed higher rates than NAs. We did not find differences in fantasy sport gambling and past year gambling-related problems based on athlete status in males or females.


Normal hematologic and biochemical values for prelaying greater sage grouse (Centrocercus urophasianus) and their influence on chick survival.
Declines in greater sage grouse (Centrocercus urophasianus) productivity and population numbers throughout their range demand a better understanding of how nutrition influences sage grouse populations. During March and April 1999-2001, blood samples were collected from 158 female (73 adult, 85 yearling), free-ranging, prelaying, greater sage grouse from an area in northwestern Nevada, USA, and southeastern Oregon, USA. These blood samples were evaluated to establish normal blood values for sage grouse and ascertain if certain blood parameters, as indices of nutrition, are useful for predicting if sage grouse hens would raise at least one chick to 1 August. Results of logistic regression indicated that three of six blood parameters analyzed--glucose, total plasma protein, and calcium: phosphorus ratio-affected the probability of a female sage grouse raising at least one chick to late summer. Ranking of the standardized estimates revealed that glucose and total plasma protein had the greatest impact on the likelihood of a female successfully raising chicks. Odds ratios indicated that a 1-unit increase in glucose (1 mg/dl) and plasma protein (0.1 g/dl) would result in a 4% and 113% positive increase, respectively, in the predicted odds of at least one chick surviving until 1 August. Odds ratios for calcium : phosphorus ratio revealed a 70% decline in the predicted odds of at least one chick surviving until 1 August if the level of this parameter increased one unit (e.g., 3:1 to 4:1). Based on these analyses, values of some blood parameters used as indices of nutrition, especially glucose, total plasma protein, and calcium : phosphorus ratio, can be successfully used to predict reproductive success of sage grouse. These parameters are not only indicative of the nutritional status of prelaying hens but may be associated with nutritional quality of the habitat and therefore have important management significance.


Testosterone transport in brain: primary role of plasma protein-bound hormone.
Physiologically based mathematical modeling is used to predict the steady-state concentration of intracellular free and bound testosterone in brain. On the basis of previous in vivo tracer kinetic studies of blood-to-brain and brain-to-blood transport of testosterone in the rat, values are assigned to various physiological parameters (hormone association and dissociation reactions with plasma and cytosolic binding proteins, capillary transit time, and membrane transport). The model does not adhere to the restrictions of the free hormone hypothesis and allows for the enhanced transport of hormone from the plasma protein-bound pool into the tissue extravascular space. This process is believed to occur via an endothelial inhibition of ligand binding to the plasma protein without the protein crossing the endothelial wall. The model predicts that the steady-state concentration of intracellular free hormone changes in parallel more closely to changes in the concentration of plasma protein-bound hormone as measured in vitro and not the free hormone as measured in vitro.


Medical and surgical treatment of chronic venous ulcers.
Venous ulcer of the lower extremity is a common vascular condition and is associated with decreased quality of life, reduced mobility, and social isolation. Treatment of chronic venous ulcer (CVU) includes compression therapy, debridement of the ulcer when necessary, and wound care. Collagen and antimicrobial dressings can improve the proportion of ulcers healed compared with compression alone. Acellular skin equivalents are not superior to compression, but cellular human skin equivalents can promote more rapid healing, particularly in patients with longstanding ulcers. Current vascular surgical practice is to eliminate documented reflux or obstruction in patients with CVU that have failed a 3-month period of compression dressing, debridement, and local wound care. We found that surgical treatment of the superficial venous system can decrease the time to healing of CVUs compared with compression therapy alone, but does not increase the proportion of ulcers healed.


The Communicative Modes Analysis System in Psychotherapy From Mixed Methods Framework: Introducing a New Observation System for Classifying Verbal and Non-verbal Communication.
Communication represents the core of psychotherapy. The dynamic interaction between verbal and non-verbal components during patient-therapist exchanges, indeed, promotes the co-construction of meanings bringing about change within a process of reciprocal influence of participants. Our paper aims to illustrate the building of a new observational instrument of the therapeutic discourse, the Communicative Modes Analysis System in Psychotherapy (CMASP), and its reliability study from Mixed Methods framework. The CMASP is a single classification system analyzing the communication features within therapeutic exchanges. Born to overcome the limits of traditional psychotherapy research which considers verbal and non-verbal dimensions of communication as in polar opposition, the CMASP building was based on the performative function derived from the Speech Act Theory. We used this function as a comprehensive theorization to interpret the communication components in psychotherapy as an integrated and interacting system. In fact, the instrument detects and classifies, at the overall and dimension level, the verbal and extra-linguistic components of psychotherapeutic communication implemented by the therapist and patients in the form of communicative modes. From the observational methodology framework, it was built an instrument able to record and analyze verbal, vocal and interruption behaviors by combining elements of qualitative and quantitative research approaches. The sample consisted of 30 psychotherapy audio recordings and verbatim transcripts of psychotherapy sessions (for a total of 8327 speaking turns). Four main dimensions were elaborated (Verbal Mode-Structural Form, Verbal Mode-Communicative Intent, Vocal Mode, and Interruption Mode) according to the agency role of communication components. The instrument is a field format combined with category systems. For each dimension, we built a category system that is exhaustive and mutually exclusive. From all dimensions, we have a total of 33 categories. Intra-and inter-judge reliability among four independent judges was computed on a total of 503 speaking turns coded through Cohen's κ and Krippendorff's canonical agreement coefficients (Cc), respectively. The CMASP showed high intra-and inter-judge agreement at the global, dimensional, and categorical level providing researchers and professionals with a single and flexible classification system, able to give multiple and concurrent information about the psychotherapy process.


The Perspectives of Adolescents and Young Adults on Adherence to Prophylaxis in Hemophilia: A Qualitative Study.
Adolescents and young adults (AYAs) with severe hemophilia use prophylaxis that requires a high level of adherence. The present study aimed to explore the underlying reason for adherence and non-adherence to prophylaxis in hemophilia from the perspective of AYAs. A qualitative study in Dutch AYAs with hemophilia (14-25 years) using prophylaxis was executed. Focus group interviews and individual interviews were recorded, transcribed, coded and analyzed using an iterative process. Member checking in three respondents was used to validate the potential model. A total of 21 interviews were performed. Parental support decreased when AYAs gained more treatment responsibilities, which resulted in a higher risk for non-adherence. AYAs were weighing their potential bleeding risk per activity based on the wish to do what they prefer while also wanting to simultaneously feel safe. When bleeding with low impact on their daily life occurred, or when bleeding remained absent, AYAs felt safe and the perceived need for prophylaxis decreased. The level of treatment responsibility per AYA and estimated risks per activity were the two main underlying reasons for (non-)adherence. We suggest using a conversation technique to discuss adherence, especially during bleeding assessment visits.


Application of the Pediatric Appropriate Use Criteria for Chest Pain.
To characterize the subgroup of outpatient pediatric patients presenting with chest pain and to determine the effectiveness of published pediatric appropriate use criteria (PAUC) to detect pathology. The Pediatric Appropriate Use of Echocardiography study evaluated the use and yield of transthoracic echocardiography (TTE) before and after PAUC release. Data were reviewed on patients ?18 years of age who underwent TTE for chest pain. Indications were classified as appropriate (A), may be appropriate (M), and rarely appropriate (R) based on PAUC ratings, and findings were normal, incidental, or abnormal. Chest pain was the primary indication in 772 of 4562 outpatient TTE studies (17%) (median age 14 years, IQR 10-16) ordered during the study period: 458 of 772 before (59%) and 314 of 772 after (41 %) the release of PAUC with no change in appropriateness. In A indications (n?=?654), 642 (98%) were normal, 5 (1%) had incidental findings, and 7 (1%) were abnormal. A and M detected 100% of all abnormal findings (A: n?=?7; M: n?=?6; R: n?=?0), with an association between ratings and findings (P?<.001). There was no association between R rating and any pathology. There was no change in ordering patterns with publication of the PAUC. Despite the high rate of TTEs ordered for indications rated A, most studies were normal. Studies that detected pathology were performed for indications rated A or M, but not R. This study supports PAUC as a useful tool in pediatric chest pain evaluation that may subsequently improve the use of TTE.


Associations between the use of critical care procedures and change in functional status at discharge.
Quality improvement initiatives in intensive care units (ICUs) have increased survival rates. Changes in functional status following ICU care have been studied, but results are inconclusive because of insufficient consideration of the combinations of critical care procedures used. Using the Japanese administrative database including the Barthel Index (BI) at admission and discharge, we measured the changes in functional status among the adult patients and determined whether longer ICU stay or use of various critical care procedures was associated with functional deterioration. Of the 12 502 528 patients admitted to 1206 hospitals over 5 consecutive years from 2006, we analyzed data from patients aged 15 years or older who survived ICU admission in 320 hospitals. Critical care procedures evaluated were ventilation, blood purification (hemodialysis, hemodiafiltration, or hemadsorption), and cardiac support devices (intra-aortic balloon pump or percutaneous cardiopulmonary support system). Functional outcomes were determined by the difference between BI at admission and at discharge and were divided into improvement, no change, or deterioration. We compared patient characteristics, principal diagnosis, comorbidities, timing of surgical procedure, complications, days in ICU, and use of critical care procedures among the 3 categories. Associations between critical care procedures and functional deterioration were identified using multivariate analysis. Of 234 209 patients with complete BI information, 7137 (3.1%) received blood purification, 27 100 (11.7%) received ventilation, 2888 (1.2%) received blood purification and ventilation, 5613 (2.4%) received a cardiac support device, 247 (0.1%) received a cardiac support device and blood purification, 10 444 (4.5%) received a cardiac support device and ventilation, and 1110 (0.5%) received a cardiac support device, ventilation, and blood purification. Longer use of blood purification or ventilation and a longer ICU stay were associated with functional deterioration. Intensivists should be aware of the effects of critical care procedures on functional deterioration and advance the appropriate use of functional support according to each patient's condition.


Applied genetic evaluations for production and functional traits in dairy cattle.
The objective of this study was to review the current status of genetic evaluation systems for production and functional traits as practiced in different Interbull member countries and to discuss that status in relation to research results and potential improvements. Thirty-one countries provided information. Substantial variation was evident for number of traits considered per country, trait definition, genetic evaluation procedure within trait, effects included, and how these were treated in genetic evaluation models. All countries lacked genetic evaluations for one or more economically important traits. Improvement in the genetic evaluation models, especially for many functional traits, could be achieved by closing the gaps between research and practice. More detailed and up to date information about national genetic evaluation systems for traits in different countries is available at www.interbull.org. Female fertility and workability traits were considered in many countries and could be next in line for international genetic evaluations.


The role of MRSA in healthcare-associated pneumonia.
An important continued trend in healthcare-associated infection, including healthcare-associated pneumonia (HCAP), is the rise of methicillin-resistant Staphylococcus aureus (MRSA). The emergence of community-acquired strains of MRSA has complicated the management further. We review likely risk factors for MRSA HCAP, which include prior antibiotic therapy, nasal colonization, poor infection control practices, and antecedent viral infection. The multiple mechanisms of antibiotic resistance are also described, and virulence factors that may affect antibiotic choices are discussed. The limitations of vancomycin and evidence for superior outcomes with linezolid are reviewed. Alternatives for community-acquired strains and future options are mentioned.


Posterior subcapsular prostate cancer: identification with mpMRI and MRI/TRUS fusion-guided biopsy.
The posterior subcapsular region of the prostate is often undersampled by transrectal ultrasound (TRUS)-guided biopsy. The close proximity of these lesions to the posterior capsular wall of the prostate makes them difficult to localize while increasing the need for early detection because of their increased risk for extracapsular extension. We retrospectively evaluated the multiparametric MRI (mpMRI) features of subcapsular prostate cancers to make radiologists more aware of this condition. Between January 2010 and July 2014, all patients referred for 3T mpMRI and subsequent MR-US Fusion-guided biopsy (FgBx) and systematic 12-core sextant biopsy (SBx) under an IRB approved protocol, were reviewed, and imaging confirmed subcapsular prostate cancers were identified. Subcapsular lesions were defined as thin lesions that were just inside the prostate capsule. Matching patient demographics and clinical findings including age, PSA, PSA density, whole prostate volume, history of prostate cancer, Gleason score, and clinical management were tabulated. Of 992 eligible patients, 33 patients had subcapsular lesions in the prostate detected by mpMRI. Mean age, PSA, and prostate volume in this group were 63 years (range: 52-76 years), 8.4 ng/mL (range: 1.22-65.20), and 53 mL (range: 12-125 mL), respectively. The combination biopsy (SBx + FgBx) confirmed prostate cancer in 24 of 33 patients (72.7%) and in 9 patients the biopsy was negative. Of the 24 cancers, 19 were confirmed on both FgBx and conventional biopsy; however, 5 cancers were only detected on FgBx. In 4 of the 19 patients in which both biopsy methods were positive, the FgBx yielded a higher Gleason score. Subcapsular lesions on mpMRI are relatively infrequent but are usually malignant. Although the majority are confirmed on conventional 12-core biopsies, about 20% of these lesions require FgBx for diagnosis, and FgBx more accurately grades the lesions in another 20%. Thus, FgBx is of considerable benefit in confirming the diagnosis of subcapsular prostate cancer despite their proximity to the prostatic capsule.


Hypertension subtype and risk of cardiovascular disease in Chinese adults.
We examined the relationship between hypertension subtype and cardiovascular disease incidence and mortality in Chinese adults. We conducted a prospective cohort study in a nationally representative sample of 169 871 Chinese men and women aged >or=40 years. Data on systolic (SBP) and diastolic blood pressure (DBP) and other variables were obtained at a baseline examination in 1991 with the use of standard protocols. Follow-up evaluation was conducted in 1999-2000, with a response rate of 93.4%. Hypertension subtypes were defined as combined systolic and diastolic hypertension (SBP >or=140 and DBP >or=90 mm Hg), isolated systolic hypertension (SBP >or=140 and DBP <90 mm Hg), isolated diastolic hypertension (SBP <140 and DBP >or=90 mm Hg), and 2 categories of treated hypertension (SBP <140 and DBP <90 mm Hg or SBP >or=140 and/or DBP >or=90 mm Hg). After participants with missing BP values were excluded, 169 577 adults were included in the analyses. Compared with normotensives, relative risks (95% CIs) of cardiovascular disease incidence and mortality were 2.73 (2.60 to 2.86) and 2.53 (2.39 to 2.68) for combined systolic and diastolic hypertension, 1.78 (1.69 to 1.87) and 1.68 (1.58 to 1.78) for isolated systolic hypertension, 1.59 (1.43 to 1.76) and 1.45 (1.27 to 1.65) for isolated diastolic hypertension, 2.01 (1.64 to 2.48) and 1.61 (1.28 to 2.03) for treated hypertension with SBP <140 and DBP <90 mm Hg, and 3.37 (3.07 to 3.69) and 2.88 (2.60 to 3.19) for treated hypertension with SBP >or=140 and/or DBP >or=90 mm Hg, respectively, after adjustment for important covariables. Our results indicate that all hypertension subtypes are associated with significantly increased risk of cardiovascular disease in Chinese adults. Primary prevention of hypertension should be a public health priority in the Chinese population.


Molecular Genetic Understanding of Photoperiodic Regulation of Flowering Time in Arabidopsis and Soybean.
The developmental switch from a vegetative phase to reproduction (flowering) is essential for reproduction success in flowering plants, and the timing of the floral transition is regulated by various environmental factors, among which seasonal day-length changes play a critical role to induce flowering at a season favorable for seed production. The photoperiod pathways are well known to regulate flowering time in diverse plants. Here, we summarize recent progresses on molecular mechanisms underlying the photoperiod control of flowering in the long-day plant Arabidopsis as well as the short-day plant soybean; furthermore, the conservation and diversification of photoperiodic regulation of flowering in these two species are discussed.


Herpes zoster with skin lesions and meningitis caused by 2 different genotypes of the Oka varicella-zoster virus vaccine.
A previously healthy boy who had received varicella vaccine developed herpes zoster with meningitis. The vaccine strain recovered from scabs of 3 skin lesions had the wild-type allele at position 108111, a vaccine marker never previously associated with vaccine-associated adverse events. The vaccine strain from cerebrospinal fluid also contained mutations never previously observed at vaccine-associated single nucleotide polymorphisms that would alter amino acid sequences in ORF54 and ORF59. The presence of distinct strains in skin lesions and cerebrospinal fluid indicate that >1 variant strain may reactivate to cause herpes zoster.


The role of dynamic, dyadic parent-child processes in parental socialization of emotion.
We investigated what a dyadic framework added to Eisenberg, Cumberland, and Spinrad's (1998) parental emotion socialization model based on the argument that the dynamic organization of emotion in the dyad is more than the sum of its parts and thus makes a unique contribution to emotion socialization. Preschoolers (N = 235) completed challenging problem-solving tasks with mothers and fathers, during which parental emotion-related socialization behaviors (ERSBs), child negative emotional arousal, and dyadic positive emotion data were collected. We examined whether dyadic synchrony of positive emotion at age 3 was a mechanism by which age 3 parental ERSBs impacted children's age 5 aggressive behavior in school, accounting for child gender, child negative emotional arousal, and aggressive behavior in preschool. ERSBs were significantly positively related to dyadic positive synchrony with both mothers and fathers at age 3. Longitudinal models supported an indirect effect, not a moderating effect, of dyadic synchrony: both mothers' and fathers' ERSBs contributed to children's less aggressive behavior at age 5 through the effects of higher dyadic positive synchrony. Findings suggest dynamic, dyadic emotional processes should be considered as a mechanism of emotion socialization and that parent-child positive emotional synchrony is supportive of early childhood emotional development. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


No evidence for a role of modified live virus vaccines in the emergence of canine parvovirus.
In this study the early evolution and potential origins of canine parvovirus (CPV) were examined. We cloned and sequenced the VP2 capsid protein genes of three German CPV strains isolated in 1979-1980, as well as two feline panleukopenia virus (FPV) vaccine viruses that were previously shown to have some restriction enzyme cleavage sites in common with CPV. Other partial VP2 gene sequences were obtained by amplifying CPV DNA from paraffin-embedded tissues of dogs which were early parvovirus disease cases in Germany in 1978-1979. Sequences were analysed with respect to their evolutionary relationships to other CPV and FPV isolates. Those analyses did not support the hypothesis that CPV emerged as a variant of an FPV vaccine virus. Neither did they reveal ancestral sequences among the very early CPV isolates examined. Other possible sources for the origin of CPV are examined, including the involvement of viruses from wild carnivores.


Manipulating the Self-Assembly of Phenyleneethynylenes under Vibrational Strong Coupling.
The chemical and physical properties of molecules and materials are known to be modified significantly under vibrational strong coupling (VSC). To gain insight into the effects of VSC on π-π interactions involved in molecular self-assembly, themselves sensitive to vacuum electromagnetic field fluctuations, the aggregation of two structural isomers (linear and V-shaped) of phenyleneethynylene under cooperative coupling was investigated. By coupling the aromatic C═C stretching band, the assembly of one of the molecules results in the formation of spheres as opposed to flakes under normal conditions. As a consequence, the electronic absorption and emission spectra of the self-assembled structures are also modified significantly. The VSC-induced changes depend not only on the type of vibration that is coupled but also on the symmetry of the phenyleneethynylene isomer. These results confirm that VSC can be used to drive molecular assemblies to new structural minima and thereby provide a new tool for supramolecular chemistry.


All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity.
The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread despite the global efforts taken to control it. The 3C-like protease (3CLpro), the major protease of SARS-CoV-2, is one of the most interesting targets for antiviral drug development because it is highly conserved among SARS-CoVs and plays an important role in viral replication. Herein, we developed high throughput screening for SARS-CoV-2 3CLpro inhibitor based on AlphaScreen. We screened 91 natural product compounds and found that all-trans retinoic acid (ATRA), an FDA-approved drug, inhibited 3CLpro activity. The 3CLpro inhibitory effect of ATRA was confirmed in vitro by both immunoblotting and AlphaScreen with a 50% inhibition concentration (IC50) of 24.7 ± 1.65 µM. ATRA inhibited the replication of SARS-CoV-2 in VeroE6/TMPRSS2 and Calu-3 cells, with IC50 = 2.69 ± 0.09 µM in the former and 0.82 ± 0.01 µM in the latter. Further, we showed the anti-SARS-CoV-2 effect of ATRA on the currently circulating variants of concern (VOC); alpha, beta, gamma, and delta. These results suggest that ATRA may be considered as a potential therapeutic agent against SARS-CoV-2.


Follow-up for women after treatment for cervical cancer.
What is the most appropriate follow-up strategy for patients with cervical cancer who are clinically disease-free after receiving primary treatment? For women with cervical cancer who have been treated with curative intent, follow-up includes identification of complications related to treatment and intervention in the event of recurrent disease. Most women who recur with cervical cancer are not curable; however, early identification of recurrence can alter disease management or treatment-planning options, and for those with a central pelvic recurrence and no evidence of distant disease, there is a potential for cure with additional therapy. Follow-up protocols in this population are variable, using a number of tests at a variety of intervals with questionable outcomes. Outcomes of interest included recurrence, survival, and quality of life. The Gynecology Cancer Disease Site Group (DSG) conducted a systematic review of the literature and a narrative review of emerging clinical issues to inform the most appropriate follow-up strategy for patients with cervical cancer. The evidence was insufficient to specify a clinically useful recommended follow-up schedule, and therefore, the expert consensus opinion of the Gynecology Cancer DSG was used to develop recommendations on patient surveillance. The resulting recommendations were reviewed and approved by the Gynecology Cancer DSG and by the Program in Evidence-Based Care Report Approval Panel. An external review by Ontario practitioners completed the final phase of the review process. Feedback from all parties was incorporated to create the final practice guideline. The systematic review of the literature identified seventeen retrospective studies. The Gynecology Cancer DSG used a consensus process to develop recommendations based on the available evidence from the systematic review, the narrative review, and the collective clinical experience and judgment of the DSG members. The recommendations in this practice guideline are based on the expert consensus opinion of the Gynecology Cancer DSG, informed by evidence from retrospective studies. These are some general features of an appropriate follow-up strategy: 1. At a minimum, follow-up visits with a complete physical examination, including a pelvic-rectal exam and a patient history, should be conducted by a physician experienced in the surveillance of cancer patients. 2. There is little evidence to suggest that vaginal vault cytology adds significantly to the clinical exam in detecting early disease recurrence. 3. Routine use of various other radiologic or biologic follow-up investigations in asymptomatic patients is not advocated, because the role of those investigations has yet to be evaluated in a definitive manner. 4. A reasonable follow-up schedule involves follow-up visits every 3-4 months in the first 2 years and every 6-12 months in years 3-5. Patients should return to annual population-based general physical and pelvic examinations after 5 years of recurrence-free follow-up.


Spirituality and religion in older adults with dementia: a systematic review.
Religious and spiritual issues are clearly important to the older adult population and may play a positive role in maintaining health and recovering from illness. This study systematically reviewed the literature examining the effects of religion and spirituality on health outcomes such as cognitive functioning, coping strategies, and quality of life in people with dementia. First, 51 articles with defined keywords were collected from online databases. Then, using inclusion and exclusion criteria, 11 articles were selected. These were classified according to methodological quality before being analyzed one by one. The findings highlight the benefits of spirituality and religion on health outcomes. Three articles showed that in participants who used their spirituality or religion more, through their faith, their practices and in maintaining social interactions, their cognitive disorders tended to reduce or stabilize. In the other eight articles, use of spirituality or faith in daily life enabled people to develop coping strategies to help accept their disease, maintain their relationships, maintain hope, and find meaning in their lives, thereby improving their quality of life. Spirituality and religion appear to slow cognitive decline, and help people use coping strategies to deal their disease and have a better quality of life. This literature review allows us to take stock of research over the last decade on spirituality/religion and health outcomes. The benefits observed should be considered with caution and included in rigorous experimental research in the future.


Protective effects of honokiol against oxidized LDL-induced cytotoxicity and adhesion molecule expression in endothelial cells.
Honokiol, a compound extracted from Chinese medicinal herb Magnolia officinalis, has several biological effects. However, its protective effects against endothelial injury remain unclarified. In this study, we examined whether honokiol prevented oxidized low-density lipoprotein (oxLDL)-induced vascular endothelial dysfunction. Incubation of oxLDL with honokiol (2.5-20 microM) inhibited copper-induced oxidative modification as demonstrated by diene formation, thiobarbituric acid reactive substances (TBARS) assay and electrophoretic mobility assay. Expression of adhesion molecules (ICAM, VCAM and E-selectin) and endothelial NO synthase (eNOS) affected by oxLDL was investigated by flow cytometry and Western blot. We also measured the production of reactive oxygen species (ROS) using the fluorescent probe 2',7'-dichlorofluorescein acetoxymethyl ester (DCF-AM). Furthermore, several apoptotic phenomena including increased cytosolic calcium, alteration of mitochondrial membrane potential, cytochrome c release and activation of caspase-3 were also investigated. Apoptotic cell death was characterized by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) stain. The results showed that honokiol prevented the copper-induced oxidative modification of LDL. Honokiol also ameliorated the oxLDL-diminished eNOS protein expression and reduced the oxLDL-induced adhesion molecules and the adherence of THP-1 cells to HUVECs. Furthermore, honokiol attenuated the oxLDL-induced cytotoxicity, apoptotic features, ROS generation, intracellular calcium accumulation and the subsequent mitochondrial membrane potential collapse, cytochrome c release and activation of caspase-3. Our results suggest that honokiol may have clinical implications in the prevention of atherosclerotic vascular disease.


Health Professionals' Views on Key Enabling Factors and Barriers of National Multidisciplinary Team Meetings in Cancer Care: A Qualitative Study.
Multidisciplinary team meetings (MDTMs) are an integral component of cancer care. Increasingly, virtual MDTMs are used to grant high-quality treatment recommendations across health-care regions, which expands and develops the local MDTM team to a regional or national expert network. We investigated health professionals' experiences from national, virtual MDTMs for rare cancer with a focus on key enabling factors and barriers. Health professionals who participate in seven national, virtual MDTMs in Swedish health-care responded to a questionnaire exploring key enabling factors, barriers and opportunities for MDTM development. Conventional content analysis was used to identify thematic categories based on free-text responses. Participants´ perspectives could be assigned into three categories ie, a national arena with potential for comprehensive knowledge and collaboration, prerequisites for decision-making and organization and responsibilities. These categories consisted of nine sub-categories that referred to, eg, collective competence, resources, clinical research, case discussion, meeting climate, patient-related information, MDTMs potential, referral and technical insufficiencies. National, virtual MDTMs represent a new multidisciplinary collaborative arena that introduces benefits as well as challenges. Consideration of key enabling factors and barriers may ease implementation and further optimize MDTMs in cancer care.


Intraprotein electron transfer in inducible nitric oxide synthase holoenzyme.
Intraprotein electron transfer (IET) from flavin mononucleotide (FMN) to heme is essential in NO synthesis by NO synthase (NOS). Our previous laser flash photolysis studies provided a direct determination of the kinetics of the FMN-heme IET in a truncated two-domain construct (oxyFMN) of murine inducible NOS (iNOS), in which only the oxygenase and FMN domains along with the calmodulin (CaM) binding site are present (Feng et al. J. Am. Chem. Soc. 128, 3808-3811, 2006). Here we report the kinetics of the IET in a human iNOS oxyFMN construct, a human iNOS holoenzyme, and a murine iNOS holoenzyme, using CO photolysis in comparative studies on partially reduced NOS and a NOS oxygenase construct that lacks the FMN domain. The IET rate constants for the human and murine iNOS holoenzymes are 34 +/- 5 and 35 +/- 3 s(-1), respectively, thereby providing a direct measurement of this IET between the catalytically significant redox couples of FMN and heme in the iNOS holoenzyme. These values are approximately an order of magnitude smaller than that in the corresponding iNOS oxyFMN construct, suggesting that in the holoenzyme the rate-limiting step in the IET is the conversion of the shielded electron-accepting (input) state to a new electron-donating (output) state. The fact that there is no rapid IET component in the kinetic traces obtained with the iNOS holoenzyme implies that the enzyme remains mainly in the input state. The IET rate constant value for the iNOS holoenzyme is similar to that obtained for a CaM-bound neuronal NOS holoenzyme, suggesting that CaM activation effectively removes the inhibitory effect of the unique autoregulatory insert in neuronal NOS.


[NOTES and other minimally invasive surgical techniques (hybrid NOTES, NOTUS, SPS, SILS), and their effect on surgical approaches].
A new surgical technique--called Natural Orifice Translumenal Endoscopic Surgery (NOTES)--evolved in 2004. Although numerous problems arose regarding this method--and most of them are unresolved yet--several new articles about the human application have been published. In order to find solutions of a certain extent, new techniques have been developed (hybrid NOTES, NOTUS, SPS, SLIS, etc). Although these could not eliminate difficulties completely, they do provide some solutions in many cases. It is very important for the surgeon of modern days to be familiar with these techniques and analyze them in a critically. Application of these methods requires a review of principles of surgery and flexible endoscopy. Although in many cases these are considered axioms, there data exist in literature of different management principles, as well. It is fundamental that critically review of the basic questions of NOTES (which natural orifice is the best, how to close the viscerotomy, how to avoid infection, who should carry out the NOTES surgery) is carried out in relation of the complications of the original 'gold standard' methods (e.g. frequency of infection or hernia after laparoscopy). Based on human data there is minimal postoperative pain after the NOTES procedure, and patients in general will leave the hospital on the same day. Is such a short postoperative stay enough and can we entirely dismiss drainage after cholecystectomy? Results of the human procedures are adequate to draw further conclusions regarding the new technique. Retrospective analysis of problems occurring during the evolution of laparoscopy can make it possible to avoid mistakes that can be made in the development of NOTES.


Pain control at the end of life.
Pain control at the end of life is almost always achievable regardless of the cause. Most of the principles for managing pain at the end of life are derived from cancer practice. However, this knowledge can be extended to patients with pain from other illnesses at the end of life. Pain assessment is the most important step toward achieving optimal analgesia. It determines the appropriate analgesic therapy; drug dose and route of administration; drug dosing intervals; titration of drug doses; control and prevention of analgesic side effects; and application of adjuvant, loco-regional (nonsystemic), and invasive treatments. A comprehensive approach that integrates patient preferences and management of psychosocial and spiritual/existential components of the patient's pain and suffering with physical components will improve analgesia, reduce the burden of the illness and its treatment, and improve the patient's quality of life.


Water-Assisted Programmable Assembly of Flexible and Self-Standing Janus Membranes.
Janus membranes with asymmetric wettability have been considered cutting-edge for energy/environmental-sustainable applications like water/fog harvester, breathable skin, and smart sensor; however, technical challenges in fabrication and accurate regulation of asymmetric wettability limit their development. Herein, by using water-assisted hydrogen-bonded (H-bonded) assembly of small molecules at water/oil interface, a facile strategy is proposed for one-step fabrication of membranes with well-regulable asymmetric wettability. Asymmetric orderly patterns, beneficial for mass transport based on abundant high-permeability sites and large surface area, are constructed on opposite membrane surfaces. Upon tuning water-assisted H-bonding via H-sites/configuration design and temperature/pH modulation, double-hydrophobic, double-hydrophilic, and hydrophobic-hydrophilic membranes are facilely fabricated. The Janus membranes show smart vapor-responsive curling and unidirectional water transport with promising flux of 1158±25 L m-2 h-1 under natural gravity and 31500±670 L·(m-2 h-1 bar-1 ) at negative pressure. This bottom-up approach offers a feasible-to-scalable avenue to precise-manipulation of Janus membranes for advanced applications, providing an effective pathway for developing tailor-made self-assembled nanomaterials.


[N-tris-(beta-D-galactopyranosyloxymethyl)glycine methylamide as an antigenic determinant of neoglycoproteins].
A chemical synthesis of N-tris (beta-D-galactopyranosyloxymethyl) glycine methylamide (trisgalactosylglycine) has been carried out. Trisgalactosylglicine derivatives of bovine serum albumin, ovalbumin and amyloglucosidase from Aspergillus have been obtained. The binding of trisgalactosylglycine residues to bovine serum albumin and ovalbumin was performed by the carbodiimide method; amyloglucosidase galactosylation was performed by using the reductive amination method. The latter technique seems to be the most mild one because it does not interfere with the peptide structure of the protein being analyzed. The antiserum specifically raised against the trisgalactosylglycine derivative of bovine serum albumin as well as the monospecific antibodies isolated from it can interact with both the antigen and the trisgalactosylglycine derivatives of ovalbumin and amyloglucosidase. Native proteins are not precipitated with this antiserum. This suggests that the trigalactosylglycine residues (bovine serum albumin, ovalbumin, amyloglucosidase) covalently bound to various proteins act as immunologic determinants regardless of the mode of their binding.


The Decrease of Leaf Dark Respiration during Water Stress Is Related to Leaf Non-Structural Carbohydrate Pool in Vitis vinifera L.
Dark respiration (Rd) is a fundamental plant process used to gain biomass and maintain plant physiological activity. It accounts for the metabolization of a large share of the carbon fixed by photosynthesis. However, Rd during conditions of severe plant water stress is still poorly understood. The decrease in leaf transpiration increases temperature, one of the most important drivers of leaf Rd. On the other hand, water stress decreases the pool of leaf carbohydrates, which are the most important substrate for respiration. The aim of the present work was to determine the impact of water shortage on leaf Rd in grapevine and understand the driving factors in modulating leaf Rd response under plant water stress conditions. Water stressed vines had lower Rd as the water shortage severity increased. Rd was correlated with leaf temperature in well-watered vines. Instead, in water stressed vines, Rd correlated with leaf soluble sugars. The decrease of leaf Rd in water stressed vines was due to the decrease of leaf non-structural carbohydrate that, under water stress conditions, exerted a limiting effect on Rd.


Factors influencing pre-hospital care time intervals in Iran: a qualitative study.
Pre-hospital time management provides better access to victims of road traffic crashes (RTCs) and can help minimize preventable deaths, injuries and disabilities. While most studies have been focused on measuring various time intervals in the pre-hospital phase, to our best knowledge there is no study exploring the barriers and facilitators that affects these various intervals qualitatively. The present study aimed to explore factors affecting various time intervals relating to road traffic incidents in the pre-hospital phase and provides suggestions for improvements in Iran. The study was conducted during 2013-2014 at both the national and local level in Iran. Overall, 18 face-to-face interviews with emergency medical services (EMS) personnel were used for data collection. Qualitative content analysis was employed to analyze the data. The most important barriers in relation to pre-hospital intervals were related to the manner of cooperation by members of the public with the EMS and their involvement at the crash scene, as well as to pre-hospital system factors, including the number and location of EMS facilities, type and number of ambulances and manpower. These factors usually affect how rapidly the EMS can arrive at the scene of the crash and how quickly victims can be transferred to hospital. These two categories have six main themes: notification interval; activation interval; response interval; on-scene interval; transport interval; and delivery interval. Despite more focus on physical resources, cooperation from members of the public needs to be taken in account in order to achieve better pre-hospital management of the various intervals, possibly through the use of public education campaigns.


Abdomino-thoracic transmission during acs: facts and figures.
Elevated intra-abdominal pressure (IAP) exerts effects not only on intra-abdominal organs, but also on organs distant to the abdominal compartment. Abdomino-thoracic interaction during intra-abdominal hypertension (IAH) or abdominal compartment syndrome (ACS) interferes with pulmonary, cardiovascular and cerebral function. In accordance with recent guidelines, IAH is defined as IAP above 12 mmHg and ACS as IAP more than 20 mmHg with one or more new organ failures. In this review we will first discuss the effects of elevated IAP on pulmonary dynamics and the relevance for interpreting airway pressures and adjusting ventilator settings. We will then discuss the interaction between abdomino-thoracic pressure transmission and global haemodynamics, the knowledge of which is necessary for correct assessment of cardiac preload and to optimize fluid therapy in the setting of IAH/ACS. A discussion on the relationship between increased IAP, increased intracranial pressure (ICP) and decreased cerebral perfusion pressure (CPP) will follow. Finally, we will review ventilator-induced thoracic pressure swings and their transmission to the abdominal compartment.


Glutamate, substance P, and calcitonin gene-related peptide cooperate in inflammation-induced heat hyperalgesia.
The transient receptor potential cation channel subfamily V member 1 (TRPV1) is known as a thermosensor and integrator of inflammation-induced hyperalgesia. TRPV1 is expressed in a subpopulation of primary afferent neurons that express several different neurotransmitters. The role of the TRPV1 channel in the development of hyperalgesia is established, but the role of the neurotransmitter glutamate, used partially by the same neuronal population and thus probably mediating the response, is still under investigation. We have used a Trpv1-Cre mouse line in which we either ablated Trpv1-Cre expressing neurons or induced vesicular glutamate transporter 2 (Vglut2) deficiency in Trpv1-Cre expressing neurons and investigated specific states of hyperalgesia after persistent inflammation. Furthermore, by pharmacologic inhibition of substance P (SP) or calcitonin gene-related peptide (CGRP) signaling in Vglut2-deficient mice, we also evaluated the contribution of SP or CGRP to inflammation-induced hyperalgesia, with or without the presence of vesicular glutamate transporter 2 (VGLUT2)-mediated glutamatergic transmission in Trpv1-Cre neurons. This examination, together with c-Fos analyses, showed that VGLUT2-mediated glutamatergic transmission in Trpv1-Cre afferents together with SP or CGRP is essential for the development of the heat hyperalgesia associated with persistent inflammation. Additionally, SP-, CGRP-, and VGLUT2-mediated transmission together were found to play a role in the development of mechanical hyperalgesia after persistent inflammation.


Sound waves effectively assist tobramycin in elimination of Pseudomonas aeruginosa biofilms in vitro.
Microbial biofilms are highly refractory to antimicrobials. The aim of this study was to investigate the use of low-frequency vibration therapy (20-20 kHz) on antibiotic-mediated Pseudomonas aeruginosa biofilm eradication. In screening studies, low-frequency vibrations were applied on model biofilm compositions to identify conditions in which surface standing waves were observed. Alginate surface tension and viscosity were also measured. The effect of vibration on P. aeruginosa biofilms was studied using a standard biofilm assay. Subminimal inhibitory concentrations (sub-MIC) of tobramycin (5 μg/ml) were added to biofilms 3 h prior, during, and immediately after vibration and quantitatively assessed by (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) reduction assay (XTT) and, qualitatively, by confocal laser scanning microscopy (CLSM). The standing waves occurred at frequencies <1,000 Hz. Biofilms vibrated without sub-MIC tobramycin showed a significantly reduced metabolism compared to untreated controls (p < 0.05). Biofilms treated with tobramycin and vibrated simultaneously (450, 530, 610, and 650 Hz), or vibrated (450 and 650 Hz) then treated with tobramycin subsequently, or vibrated (610 Hz, 650 Hz) after 3 h of tobramycin treatment showed significantly lower metabolism compared to P. aeruginosa biofilm treated with tobramycin alone (p < 0.05). CLSM imaging further confirmed these findings. Low frequency vibrations assisted tobramycin in killing P. aeruginosa biofilms at sub-MIC. Thus, sound waves together with antibiotics are a promising approach in eliminating pathogenic biofilms.


Identification of PSD-95 in the Postsynaptic Density Using MiniSOG and EM Tomography.
Combining tomography with electron microscopy (EM) produces images at definition sufficient to visualize individual protein molecules or molecular complexes in intact neurons. When freeze-substituted hippocampal cultures in plastic sections are imaged by EM tomography, detailed structures emerging from 3D reconstructions reveal putative glutamate receptors and membrane-associated filaments containing scaffolding proteins such as postsynaptic density (PSD)-95 family proteins based on their size, shape, and known distributions. In limited instances, structures can be identified with enhanced immuno-Nanogold labeling after light fixation and subsequent freeze-substitution. Molecular identification of structure can be corroborated in their absence after acute protein knockdown or gene knockout. However, additional labeling methods linking EM level structure to molecules in tomograms are needed. A recent development for labeling structures for TEM employs expression of endogenous proteins carrying a green fluorescent tag, miniSOG, to photoconvert diaminobenzidine (DAB) into osmiophilic polymers. This approach requires initial mild chemical fixation but many of structural features in neurons can still be discerned in EM tomograms. The photoreaction product, which appears as electron-dense, fine precipitates decorating protein structures in neurons, may diffuse to fill cytoplasm of spines, thus obscuring specific localization of proteins tagged with miniSOG. Here we develop an approach to minimize molecular diffusion of the DAB photoreaction product in neurons, which allows miniSOG tagged molecule/complexes to be identified in tomograms. The examples reveal electron-dense clusters of reaction product labeling membrane-associated vertical filaments, corresponding to the site of miniSOG fused at the C-terminal end of PSD-95-miniSOG, allowing identification of PSD-95 vertical filaments at the PSD. This approach, which results in considerable improvement in the precision of labeling PSD-95 in tomograms without complications due to the presence of antibody complexes in immunogold labeling, may be applicable for identifying other synaptic proteins in intact neurons.


[Investigation of the accurate measurement of the basic imaging properties for the digital radiographic system based on flat panel detector].
PURPOSE/AIM OF THE EXHIBIT: The purpose of this exhibit is: 1. To explain "resampling", an image data processing, performed by the digital radiographic system based on flat panel detector (FPD). 2. To show the influence of "resampling" on the basic imaging properties. 3. To present accurate measurement methods of the basic imaging properties of the FPD system. 1. The relationship between the matrix sizes of the output image and the image data acquired on FPD that automatically changes depending on a selected image size (FOV). 2. The explanation of the image data processing of "resampling". 3. The evaluation results of the basic imaging properties of the FPD system using two types of DICOM image to which "resampling" was performed: characteristic curves, presampled MTFs, noise power spectra, detective quantum efficiencies. CONCLUSION/SUMMARY: The major points of the exhibit are as follows: 1. The influence of "resampling" should not be disregarded in the evaluation of the basic imaging properties of the flat panel detector system. 2. It is necessary for the basic imaging properties to be measured by using DICOM image to which no "resampling" is performed.


Modification of experimental gentamicin nephrotoxicity by selective parathyroidectomy.
Dietary calcium loading reduces gentamicin nephrotoxicity in rats. Since parathyroid hormone increases renal brush border membrane anionic phospholipids, the putative gentamicin receptors, the effects of selective parathyroidectomy on gentamicin nephrotoxicity were examined. Male Fisher 344 rats underwent parathyroidectomy or sham surgery. All animals were fed a diet containing 0.5% calcium for 2 wk prior to gentamicin, 20 mg/kg twice daily for 6 and 10 days. Other parathyroidectomized rats were fed a 4% calcium diet for 2 wk and treated similarly with gentamicin On day 6, serum creatinine (mg/100 ml) was 2.0 +/- 0.9 in the sham-operated animals, 1.7 +/- 1.6 in the parathyroidectomized animals on the 0.5% diet, and 0.8 +/- 0.1 in the parathyroidectomized animals on the 4% diet. By 10 days, the sham-operated animals had creatinine values of 6.3 +/- 1.6 (mg/100 ml) compared with 1.7 +/- .9 in the parathyroidectomized animals on the same diet and 0.8 +/- 0.2 in the 4% diet animals. More severe tubular necrosis was present in the sham-operated compared with the parathyroidectomized animals. High calcium diet in the parathyroidectomized animals produced structural and functional protection from gentamicin nephrotoxicity. Human parathyroid hormone (1-34) 20 IU twice daily given subcutaneously to a separate group of parathyroidectomized rats, eliminated the protective effect of parathyroidectomy on renal structure and function. Parathyroidectomy modifies experimental gentamicin nephrotoxicity. The additional protective effect of dietary calcium loading may be independent of parathyroid ablation.


Assessment of catastrophic risk using Bayesian network constructed from domain knowledge and spatial data.
Prediction of natural disasters and their consequences is difficult due to the uncertainties and complexity of multiple related factors. This article explores the use of domain knowledge and spatial data to construct a Bayesian network (BN) that facilitates the integration of multiple factors and quantification of uncertainties within a consistent system for assessment of catastrophic risk. A BN is chosen due to its advantages such as merging multiple source data and domain knowledge in a consistent system, learning from the data set, inference with missing data, and support of decision making. A key advantage of our methodology is the combination of domain knowledge and learning from the data to construct a robust network. To improve the assessment, we employ spatial data analysis and data mining to extend the training data set, select risk factors, and fine-tune the network. Another major advantage of our methodology is the integration of an optimal discretizer, informative feature selector, learners, search strategies for local topologies, and Bayesian model averaging. These techniques all contribute to a robust prediction of risk probability of natural disasters. In the flood disaster's study, our methodology achieved a better probability of detection of high risk, a better precision, and a better ROC area compared with other methods, using both cross-validation and prediction of catastrophic risk based on historic data. Our results suggest that BN is a good alternative for risk assessment and as a decision tool in the management of catastrophic risk.


Impact of proton pump inhibitors on clinical outcomes in patients treated with a 6- or 24-month dual-antiplatelet therapy duration: Insights from the PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY trial.
Proton pump inhibitors (PPIs) are frequently prescribed in combination with clopidogrel, but conflicting data exist as to whether PPIs diminish the efficacy of clopidogrel. We assessed the association between PPI use and clinical outcomes for patients treated with percutaneous coronary intervention (PCI) and dual-antiplatelet therapy (DAPT) with clopidogrel plus aspirin. In the PRODIGY trial, 1,970 patients were randomized to 6- or 24-month DAPT at 30 days from index procedure. Among them, 738 patients (37.5%) received PPI (mainly lansoprazole; 90.1%) at the time of randomization. Proton pump inhibitor users were older, were most likely to be woman, had a lower creatinine clearance, presented more frequently with acute coronary syndrome, and had a higher CRUSADE bleeding score. After adjustment, the primary efficacy end point (composite of all-cause death, myocardial infarction, and cerebrovascular accident) was similar between no PPI and PPI users (9.2% vs 11.5%, adjusted hazard ratio [HR] 1.051, 95% CI 0.788-1.400, P = .736). Bleeding rates did not differ between the 2 groups (Bleeding Academic Research Consortium type 2, 3, or 5: adjusted HR 0.996, 95% CI 0.672-1.474, P = .980). Net clinical adverse events were also similar in no PPI and PPI patients (12.9% vs 14.9%, adjusted HR 0.99, 95% CI 0.772-1.268, P = .93). Results remained consistent at sensitivity analysis when focusing on the 548 patients who remained on PPI for the whole study duration. The current findings suggest that the concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel is not associated with adverse clinical outcome.


Raising the pressure: Hemodynamic effects of splanchnic nerve stimulation.
A number of cardiovascular and neurological diseases are characterized by a dysregulation of intravascular volume distribution. The veins and arteries of the visceral organs form the so-called splanchnic vascular compartment and are the largest reservoir for intravascular blood. The blood localized in the splanchnic compartment can be mobilized in and out of the compartment via passive compression or active neurohormonal recruitment. We studied the hemodynamic effects of splanchnic nerve stimulation during five cases of irreversible electroporation (IRE) in patients with pancreatic cancer. In IRE, repeated bursts of high-voltage electrical fields are applied to visceral beds for >1 min, which induces rapid increase in blood pressure, heart rate, and cardiac output. We present the first analysis into the hemodynamic changes with splanchnic nerve stimulation and explore potential mechanisms of the hyperdynamic state. Our analysis presents the first human report of splanchnic nerve stimulation to induce hypertension and volume redistribution, introducing the splanchnic nerves as a key component of cardiovascular regulation.NEW & NOTEWORTHY Our case series provides the first detailed description of human hemodynamic effects with splanchnic nerve stimulation. Splanchnic nerve stimulation results in profound hemodynamic alteration with rapid onset of hypertension and blood mobilization.


Clean and Confident: Impact of Sterile Instrument Processing Workshops on Knowledge and Confidence in Five Low- and Middle-Income Countries.
Background: Proper sterilization of surgical instruments is essential for safe surgery, yet re-processing methods in low-resource settings can fall short of standards. Training of Trainers (TOT) workshops in Ethiopia and El Salvador instructed participants in sterile processing concepts and prepared participants to teach others. This study examines participants' knowledge and confidence post-TOT workshop, and moreover discusses subsequent non-TOT workshops and observed sterile processing practices. Methods: Five TOT workshops were conducted between 2018 and 2020 in Ethiopia and Central America. Participant trainers then led nine non-TOT workshops in El Salvador, Guatemala, Honduras, and Nicaragua. Interactive sessions covered instrument cleaning, packaging, disinfection, sterilization, and transportation. Participants completed pre- and post-tests, demonstrated skill competencies, and shared feedback. Peri-operative sterile processing metrics were also observed in Ethiopian hospitals pre- and post-workshops. Results: Ninety-five trainees participated in TOT workshops, whereas 169 participated in non-TOT workshops. Knowledge on a 10-point scale increased substantially after all training sessions (+2.3 ± 2.8, +2.9 ± 1.7, and 2.7 ± 2.5 after Ethiopian, Central American, and non-TOT workshops, respectively; all p < 0.05). Scores on tests of sterile processing theory also increased (Ethiopian TOT, +68% ± 92%; Central American TOT, +26% ± 20%; p < 0.01). Most respondents felt "very confident" about teaching (Ethiopian TOT, 72%; Central American TOT, 83%; non-TOT, 70%), whereas fewer participants felt "very confident" enacting change (Ethiopian TOT, 36%; Central American TOT, 58%; non-TOT, 38%). Reasons included resource scarcity and inadequate support. Nonetheless, observed instrument compliance improved after Ethiopian TOT workshops (odds ratio [OR], 1.47; 95% confidence interval [CI], 1.21-1.78; p < 0.01). Conclusions: Sterile processing workshops can improve knowledge, confidence, and sterility compliance in selected low- and middle-income countries. Training of Trainers models empower participants to adapt programs locally, enhancing sterile processing knowledge in different communities. However, national guidelines, physical and administrative resources, and long-term follow-up must improve to ensure effective sterile processing.


Rising threats of hospital-borne multidrug resistant Stenotrophomonas maltophilia in the adolescent at Najran, Saudi Arabia.
The aim of this study was to investigate the clinical isolates of patients infected by Stenotrophomonas maltophilia (S. maltophilia) in the intensive care unit (ICU) at King Khalid Hospital, Kingdom of Saudi Arabia (KSA), and to identify the healthcare complications, antimicrobial resistance patterns, and risk factors associated with infection for this emerging pathogen. In this cross-sectional observational study, patients admitted in the ICU (n = 127) were analyzed, and 36 non-duplicating S. maltophilia strains were clinically isolated in King Khalid Hospital, KSA between September 2020 and April 2021. Antimicrobial susceptibility testing was performed using standard antibiotics (n = 13). In this study, 36 clinical isolates of S. maltophilia were identified as true infection pathogens. The main locations of S. maltophilia infection were in the respiratory tract (13, 36.1%) followed by surgical area (10, 27.7%) and wound infection (7, 19.4%). The significant risk factors included a medical history of respiratory infection, exposure to a bomb blast, and infected from an implant (p < 0.05). Among the 36 clinical isolates, 5 strains were positive for extended spectrum beta-lactamase (ESBL). The most active antimicrobials were vancomycin (69.4% sensitivity) and trimethoprim/sulfamethoxazole (80.5% sensitivity). Our study concludes that S. maltophilia is an emerging nosocomial pathogen in the ICU, indicating the possibility of direct or indirect transfer from one person to another. Specific identification and active antibiotic susceptibility testing of S. maltophilia are needed for the treatment management and prevention of spread of the S. maltophilia pathogen.


Comparison of physical work capacity and systolic time intervals with ventricular inhibited and atrial synchronous ventricular inhibited pacing.
Sixteen patients with a non-invasively programmable pacemaker (Medtronic 2409) were examined with the unit in ventricular inhibited (VVI) and atrial synchronous ventricular inhibited (VDT/I) mode, respectively. Maximal exercise capacity was determined by means of bicycle ergometry. Work load was increased in steps of 10 watts each minute. Atrial and ventricular rates, brachial artery pressure, and respiratory rate were studied at rest and during exercise while systolic time intervals were determined at rest. There was an important increase in maximal exercise capacity when changing from VVI to VDT/I pacing. The extent of improvement was the same for patients above and below the age of 65 years. At comparable work loads VDT/I pacing resulted in significantly lower atrial rates than VVI pacing. Systolic time intervals did not differ between VVI and VDT/I pacing apart from an increase in left ventricular ejection time index with VDT/I pacing. Systolic time intervals and maximal exercise capacity with VVI pacing did not correlate with the increase in exercise capacity induced by VDT/I pacing. Physical performance can be significantly improved by VDT/I pacing in both young and old patients. Exercise capacity on VVI pacing cannot predict the possible benefit of change to VDT/I pacing.


Long-term morphological and immunohistochemical observations on biopsy specimens of small intestine from children with gluten-sensitive enteropathy.
Jejunal biopsy specimens from nine Spanish children with gluten-sensitive enteropathy were studied with morphometric and immunohistochemical techniques in three stages of the diseases: the first biopsy was taken for diagnosis, when the child had a gluten-containing diet, the second after gluten withdrawal, and the third biopsy after gluten-provocation. The findings were compared with those in 10 healthy adults. The villous:crypt ratio and the length of the surface epithelium per stretched millimetre muscularis mucosae were decreased, whereas the number of interepithelial lymphocytes per millimetre surface epithelium was increased when the child had a gluten-containing diet. Although these parameters improved after withdrawal of gluten for at least seven months, they never reached the values of the healthy control group. With the indirect immunoperoxidase technique it was shown that the numbers of IgA-, IgG-, and IgM-containing cells, expressed per "mucosal tissue unit" of 4 micrometer thick and 1 mm wide, were significantly increased during the active phases of the disease. This increase was most striking for the IgM-containing cells. The most sensitive parameters for the histological diagnosis of gluten-sensitive enteropathy are the villous:crypt ratio or the length of the surface epithelium per millimetre muscularis mucosae, the number of interepithelial lymphocytes per millimetre surface epithelium, and the number of IgM-containing cells per millimetre muscularis mucosae.


Ultrafast Propulsion of Water Nanodroplets on Patterned Graphene.
The directed transport of liquids at the nanoscale is of great importance for nanotechnology applications ranging from water filtration to the cooling of electronics and precision medicine. Here we demonstrate such unidirectional, pumpless transport of water nanodroplets on graphene sheets patterned with hydrophilic/phobic areas inspired by natural systems. We find that spatially varying patterning of the graphene surfaces can lead to water transport at ultrafast velocities, far exceeding macroscale estimates. We perform extensive molecular dynamics simulations to show that such high transport velocities ( O(102 m/s)) are due to differences of the advancing and receding contact angles of the moving droplet. This contact angle hysteresis and the ensuing transport depend on the surface pattern and the droplet size. We present a scaling law for the driving capillary and resisting friction forces on the water droplet and use it to predict nanodroplet trajectories on a wedge-patterned graphene sheet. The present results demonstrate that graphene with spatially variable wettability is a potent material for fast and precise transport of nanodroplets with significant potential for directed nanoscale liquid transport and precision drug delivery.


Identification of two subpopulations of purified human blood B cells, CD27- CD23+ and CD27high CD80+, that strongly express cell surface Toll-like receptor 9 and secrete high levels of interleukin-6.
B-cell expression of certain Toll-like receptors (TLRs) is important in linking innate and adaptive immune responses in normal and pathological conditions. The expression of TLR9 plays a role in the recognition of conserved pathogen motifs in a manner that is dependent on B-cell localization, deduced from B-cell phenotype. The nature of TLR9 function is unclear. A first step in unravelling the function of this pattern recognition receptor is to discover the precise nature of the cell types that express TLR9. This study used three-colour flow cytometry to characterize the B lymphocytes from human peripheral blood mononuclear cells (PBMCs) that express TLR9 on the surface. We sorted TLR9-positive B and non-B cells from the PBMC population and detected TLR9 expression on naïve and memory B cells. Moreover, we identified two discrete subpopulations of B cells: CD19(+) CD27(-) CD23(+) cells and CD19(+) CD27(high) CD80(+) cells. These subpopulations expressed high levels of membrane TLR9 and exhibited a strong in vitro response to binding a relevant CpG motif by secreting high levels of interleukin-6 (compared to controls). Our finding that this pattern recognition receptor is expressed on a variety of cell subsets adds to the current understanding of the functional complexity of B-cell membrane TLR9.


Cytomegalovirus-specific cell-mediated immunity in lower-socioeconomic-class adolescent women with local cytomegalovirus infections.
The factors that regulate cytomegalovirus (CMV) excretion from the genitourinary tract are poorly understood. To assess the role of cell-mediated immunity in such excretion, a CMV-specific mononuclear blastogenesis assay was used to study a predominantly lower-socioeconomic-status population of 92 healthy nonpregnant adolescent women who also had CMV complement-fixing antibody titers and viral cultures of cervix, urine, saliva, and blood performed. Eighteen were studied more than once. No blood cultures were positive and no seroconversions were noted. There was no significant difference for frequency or degree of systemic CMV-specific blastogenesis between the 20 who were culture positive and the 41 who were seropositive but culture negative, although 40% of the culture-positive group and 27% of the seropositive, culture-negative group lacked CMV-specific blastogenesis. One of 31 seronegative subjects displayed CMV-specific blastogenesis. No systematic deficits were noted in any groups or individuals for E rosette number or mitogen response, though some isolated significant differences among groups for mitogen responses existed. Local CMV excretion in the study population was not related to systemic CMV-specific mononuclear blastogenesis.


The Regulation of Nucleic Acid Vaccine Responses by the Microbiome.
Nucleic acid vaccines, including both RNA and DNA platforms, are key technologies that have considerable promise in combating both infectious disease and cancer. However, little is known about the extrinsic factors that regulate nucleic acid vaccine responses and which may determine their effectiveness. The microbiome is recognized as a significant regulator of immune development and response, whose role in regulating some traditional vaccine platforms has recently been discovered. Using germ-free and specific pathogen-free mouse models in combination with different protein, DNA, and mRNA vaccine regimens, we demonstrate that the microbiome is a significant regulator of nucleic acid vaccine immunogenicity. Although the presence of the microbiome enhances CD8+ T cell responses to mRNA lipid nanoparticle immunization, the microbiome suppresses Ig and CD4+ T cell responses to DNA-prime, DNA-protein-boost immunization, indicating contrasting roles for the microbiome in the regulation of these different nucleic acid vaccine platforms. In the case of mRNA lipid nanoparticle vaccination, germ-free mice display reduced dendritic cell/macrophage activation that may underlie the deficient vaccine response. Our study identifies the microbiome as a relevant determinant of nucleic acid vaccine response with implications for continued therapeutic development and deployment of these vaccines.


The hyperkinetic child syndrome and brain monoamines: pharmacology and therapeutic implications.
Decreased catecholaminergic activity within the central nervous system has been associated with altered arousal, attention, learning, and kinetic function in animals and humans. The hyperkinetic child syndrome (HCS) involves dysfunction in all these spheres and may thus reflect diminished catecholamine activity, particularly as related to brain dopamine. Accordingly, the efficacy of catecholaminergic agents in treating the HCS is a predictable rather than a paradoxical effect of these agents. Sufficient evidence is now available to strongly implicate catecholamine hypoactivity in the pathopharmacology of the HCS.


Effect of phenolphthalein on monkey intestinal water and electrolyte transport.
To assess Na-K-ATPase inhibiton and prostaglandin synthesis stimulation as the mechanism of the secretory (cathartic) action of phenolphthalein in the primate, we investigated water and electrolyte transport and Na-K-ATPase levels in monkey intestine. Both jejunum and colon were studied with in vivo perfusion and in vitro Ussing chamber techniques. Water, Na, and Cl absorption was inhibited or secretion was induced by phenolphthalein (10(-3) M) in the jejunum and colon when the drug was present in the mucosal bathing (perfusion) solution. Serosal addition of phenolphthalein (10(-4) or 10(-3) M) induced Na and anion absorption in the jejunum but not in the colon. Phenolphthalein inhibited Na-K-ATPase activity in the test tube, but assays of intestine previously perfused or bathed in the drug showed no inhibiton. Indomethacin, in doses sufficient to inhibit prostaglandin synthesis in the intestine, inhibited the secretion induced by phenolphthalein in the jejunum but not in the colon. These inconsistencies cast doubt on the role of Na-K-ATPase inhibition or the role of prostaglandin synthesis stimulation in the mechanism of action of phenolphthalein.


CD4⁺ follicular helper T cell infiltration predicts breast cancer survival.
CD4⁺ T cells are critical regulators of immune responses, but their functional role in human breast cancer is relatively unknown. The goal of this study was to produce an image of CD4⁺ T cells infiltrating breast tumors using limited ex vivo manipulation to better understand the in vivo differences associated with patient prognosis. We performed comprehensive molecular profiling of infiltrating CD4⁺ T cells isolated from untreated invasive primary tumors and found that the infiltrating T cell subpopulations included follicular helper T (Tfh) cells, which have not previously been found in solid tumors, as well as Th1, Th2, and Th17 effector memory cells and Tregs. T cell signaling pathway alterations included a mixture of activation and suppression characterized by restricted cytokine/chemokine production, which inversely paralleled lymphoid infiltration levels and could be reproduced in activated donor CD4⁺ T cells treated with primary tumor supernatant. A comparison of extensively versus minimally infiltrated tumors showed that CXCL13-producing CD4⁺ Tfh cells distinguish extensive immune infiltrates, principally located in tertiary lymphoid structure germinal centers. An 8-gene Tfh signature, signifying organized antitumor immunity, robustly predicted survival or preoperative response to chemotherapy. Our identification of CD4⁺ Tfh cells in breast cancer suggests that they are an important immune element whose presence in the tumor is a prognostic factor.


A 3-year study of addiction mutual-help group participation following intensive outpatient treatment.
Addiction-focused mutual-help group participation is associated with better substance use disorder (SUD) treatment outcomes. However, little has been documented regarding which types of mutual-help organizations patients attend, what levels of participation may be beneficial, and which patients, in particular, are more or less likely to participate. Furthermore, much of the evidence supporting the use of these organizations comes from studies examining participation and outcomes concurrently, raising doubts about cause-effect connections, and little is known about influences that may moderate the degree of any general benefit. Alcohol-dependent outpatients (N=227; 27% female; M age=42) enrolled in a randomized-controlled telephone case monitoring trial were assessed at treatment intake and at 1, 2, and 3 years postdischarge. Lagged-panel, hierarchical linear models tested whether mutual-help group participation in the first and second year following treatment predicted subsequent outcomes and whether these effects were moderated by gender, concurrent axis I diagnosis, religious preference, and prior mutual-help experience. Robust regression curve analysis was used to examine dose-response relationships between mutual-help and outcomes. Mutual-help participation was associated with both greater abstinence and fewer drinks per drinking day and this relationship was not found to be influenced by gender, Axis I diagnosis, religious preference, or prior mutual-help participation. Mutual-help participants attended predominantly Alcoholics Anonymous and tended to be Caucasian, be more educated, have prior mutual-help experience, and have more severe alcohol involvement. Dose-response curve analyses suggested that even small amounts of participation may be helpful in increasing abstinence, whereas higher doses may be needed to reduce relapse intensity. Use of mutual-help groups following intensive outpatient SUD treatment appears to be beneficial for many different types of patients and even modest levels of participation may be helpful. Future emphasis should be placed on ways to engage individuals with these cost-effective resources over time and to gather and disseminate evidence regarding additional mutual-help organizations.


3D segmentation of nasopharyngeal carcinoma from CT images using cascade deep learning.
In the paper, we propose a new deep learning-based method for segmenting nasopharyngeal carcinoma (NPC) in the nasopharynx from three orthogonal CT images. The proposed method introduces a cascade strategy composed of two-phase manners. In CT images, there are organs, called non-target organs, which NPC never invades. Therefore, the first phase is to detect and eliminate non-target organ regions from the CT images. In the second phase, NPC is extracted from the remained regions in the CT images. Convolutional neural networks (CNNs) are applied to detect non-target organs and NPCs. The proposed system determines the final NPC segmentation by integrating three results obtained from coronal, axial and sagittal images. Moreover, we construct two CNN-based NPC detection systems using one kind of overlapping patches with a fixed size and various overlapping patches with different sizes. From the experiments using CT images of 70 NPC patients, our proposed systems, especially the system using various patches, achieves the best performance for detecting NPC compared with conventional NPC detection methods.


Minimum 5-year results of degenerative spondylolisthesis treated with decompression and instrumented posterior fusion.
An analysis of consecutive cases of degenerative spondylolisthesis treated by one of two surgeons at a university hospital. To assess at a minimum 5-year follow-up the complication rate, reoperation rate, radiographic results, and patient satisfaction with surgical treatment of lumbar degenerative spondylolisthesis by means of segmental posterior instrumented fusion with decompression. No reports of minimum 5-year follow-up for surgical treatment of degenerative spondylolisthesis were found in the literature. The potential study population consisted of 49 consecutive patients who had undergone no prior surgery for degenerative spondylolisthesis (average age, 66.7 years; range, 52.2-78.7 years) with mean follow-up of 6.5 years (range, 5-10.75 years) who were treated with decompression, autogenous iliac crest bone grafting, intertransverse process fusion, and segmental (pedicle screw) instrumentation. Eight patients had died; the remaining 41 were included in the study sample. Thirty-six (88%) of the 41 patients returned an outcome questionnaire and had current radiographs. There was one case of instrument failure (one broken screw with late fusion), and one superficial infection. There were no neurologic deficits, no pseudarthroses, no recurrent stenosis at the fused segment, and no progression of deformity at the fused level. Five patients had symptomatic adjacent level transition syndromes. There were seven additional currently asymptomatic radiographic transition syndromes. Segmental sagittal Cobb angles were maintained at the fused level (17.7 +/- 8-18.8 +/- 7 degrees). Eighty-three percent reported satisfaction with the procedure, 86% thought their back and leg pain was still significantly better than before surgery, and 77% would have the procedure again if needed. Poor satisfaction (n = 4) was associated with more than four medical comorbidities (P < 0.03). A significant number (12 of 49, 24%) of patients had died or were ill more than 5 years after surgery. Radiographic transition syndromes were common. Major complications (2%), implant failures (2%), and symptomatic pseudarthroses (0%) were low.


The transcription factor ST18 regulates proapoptotic and proinflammatory gene expression in fibroblasts.
Suppression of tumorigenicity 18 (ST18) and the homologues neural zinc-finger protein-3 (NZF3) and myelin transcription factor 3 (Myt3) are transcription factors with unknown function. Previous studies have established that they repress transcription of a synthetic reporter construct consisting of the consensus sequence AAAGTTT linked to the thymidine kinase promoter. In addition, ST18 exhibits significantly reduced expression in breast cancer and breast cancer cell lines. We report here for the first time evidence that ST18 mediates tumor necrosis factor (TNF) -alpha induced mRNA levels of proapoptotic and proinflammatory genes in fibroblasts by mRNA profiling and silencing with ST18 small interfering RNA (siRNA). Gene set enrichment analysis and mRNA profiling support this conclusion by identifying several apoptotic and inflammatory pathways that are down-regulated by ST18 siRNA. In addition, ST18 siRNA reduces TNF-induced fibroblast apoptosis and caspase-3/7 activity. Fibroblasts that overexpress ST18 by transient transfection exhibit significantly increased apoptosis and increased expression of TNF-alpha, interleukin (IL) -1alpha, and IL-6. In addition, cotransfection of ST18 and a TNF-alpha or IL-1alpha reporter construct demonstrates that ST18 overexpression in fibroblasts significantly enhanced promoter activity of these genes. Taken together, these studies demonstrate that the transcription factor ST18/NZF3 regulates the mRNA levels of proapoptotic and proinflammatory genes in revealing a previously unrecognized function.


The source of MHC class I presented peptides and its implications.
The source of peptides that enter the major histocompatibility class I (MHCI) pathway has been intensively debated over the last two decades. The initial assumption that peptides are derived from degradation of full length proteins was challenged by a model in which alternative translation products are a source of peptides. This model has been tested and supported by scientific data. We now need new hypotheses on the physiological implications of different sources of peptides for the MHCI pathway. The aim of this overview is to give an up-to-date account of the source of antigenic peptide material for the MHCI pathway and to incorporate the more recent observations of alternative mRNA translation products into existing models of the direct and cross-presentation pathways.


TNFR1 signaling is associated with backbone conformational changes of receptor dimers consistent with overactivation in the R92Q TRAPS mutant.
The widely accepted model for tumor necrosis factor 1 (TNFR1) signaling is that ligand binding causes receptor trimerization, which triggers a reorganization of cytosolic domains and thus initiates intracellular signaling. This model of stoichiometrically driven receptor activation does not account for the occurrence of ligand independent signaling in overexpressed systems, nor does it explain the constitutive activity of the R92Q mutant associated with TRAPS. More recently, ligand binding has been shown to result in the formation of high molecular weight, oligomeric networks. Although the dimer, shown to be the preligand structure, is thought to remain present within ligand-receptor networks, it is unknown whether network formation or ligand-induced structural change to the dimer itself is the trigger for TNFR1 signaling. In the present study, we investigate the available crystal structures of TNFR1 to explore backbone dynamics and infer conformational transitions associated with ligand binding. Using normal-mode analysis, we characterize the dynamic coupling between the TNFR1 ligand binding and membrane proximal domains and suggest a mechanism for ligand-induced activation. Furthermore, our data are supported experimentally by FRET showing that the constitutively active R92Q mutant adopts an altered conformation compared to wild-type. Collectively, our results suggest that the signaling competent architecture is the receptor dimer and that ligand binding modifies domain mobilities intrinsic to the receptor structure, allowing it to sample a separate, active conformation mediated by network formation.