Psychological intervention for premenstrual syndrome: a meta-analysis of randomized controlled trials.
We conducted a systematic review and meta-analysis to determine the efficacy of psychological interventions for premenstrual syndrome. We systematically searched and selected studies that enrolled women with premenstrual syndrome in which investigators randomly assigned them to a psychological intervention or to a control intervention. Trials were included irrespective of their outcomes and, when possible, we conducted meta-analyses. Nine randomized trials, of which 5 tested cognitive behavioural therapy, contributed data to the meta-analyses. Low quality evidence (design and implementation weaknesses of the studies, possible reporting bias) suggests that cognitive behavioural therapy significantly reduces both anxiety (effect size [ES] = -0.58; 95% confidence interval [CI] = -1.15 to -0.01; number needed to treat [NNT] = 5), and depression (ES = -0.55; 95% CI = -1.05 to -0.05; NNT = 5), and also suggests a possible beneficial effect on behavioural changes (ES = -0.70; 95% CI = -1.29 to -0.10; NNT = 4) and interference of symptoms on daily living (ES = -0.78; 95% CI = -1.53 to -0.03; NNT = 4). Results provide much more limited support for monitoring as a form of therapy and suggest the ineffectiveness of education. Low quality evidence from randomized trials suggests that cognitive behavioural therapy may have important beneficial effects in managing symptoms associated with premenstrual syndrome.


The association of pediatric low- and high-density lipoprotein cholesterol dyslipidemia classifications and change in dyslipidemia status with carotid intima-media thickness in adulthood evidence from the cardiovascular risk in Young Finns study, the Bogalusa Heart study, and the CDAH (Childhood Determinants of Adult Health) study.
This study was designed to determine which of the National Cholesterol Education Program or National Health and Nutrition Examination Survey low- and high-density lipoprotein cholesterol classifications of dyslipidemia status in adolescents is most effective at predicting high common carotid artery intima-media thickness (IMT) in adulthood. Two classifications of pediatric dyslipidemia status have been proposed. No study has assessed which of these is most effective for predicting adolescents who will develop preclinical atherosclerosis in adulthood. Three population-based, prospective cohort studies collected lipoprotein measurements on 1,711 adolescents age 12 to 18 years who were remeasured as young adults age 29 to 39 years. Lipoproteins in adolescence were classified according to National Cholesterol Education Program and National Health and Nutrition Examination Survey cut points, and high IMT in adulthood was defined as those at or above the age-, sex-, race-, and cohort-specific 90th percentile of IMT. Independent of the classification employed, adolescents with dyslipidemia were at significantly increased risk of having high IMT in adulthood (relative risks from 1.6 to 2.5). Differences in predictive capacity between both classifications were minimal. Overweight or obese adolescents with dyslipidemia had increased carotid IMT (males: 0.11 mm; females: 0.08 mm) in adulthood compared with those who did not have both risk factors. Adolescent dyslipidemia status was more strongly associated with high IMT in adulthood than change in dyslipidemia status. Pediatric dyslipidemia classifications perform equally in the prediction of adolescents who are at increased risk of high IMT in young adulthood. Our data suggest that dyslipidemia screening could be limited to overweight or obese adolescents.


Reduction of propofol injection pain with a double lumen i.v. set.
To investigate if the use of a new double lumen i.v. set (DLIS) decreases the incidence of propofol injection pain compared with single lumen i.v. set (SLIS) administration. Prospective, randomized, double-blinded study. Operating rooms in a university hospital. 50 adult ASA physical status I and II patients of both genders undergoing general anesthesia for elective surgery. Patients were injected with propofol either through a DLIS or a SLIS. Three different pain indices were recorded to be present or absent: (1) verbal report of pain during propofol injection (2) grimacing during propofol injection, and (3) recall of injection pain in the recovery room. When the DLIS was used, the incidence of verbal pain, grimacing during propofol injection, and recall of pain during recovery were lowered significantly by 53%, 46%, and 52%, respectively (chi square analysis of contingency table with Yates correction, p < 0.05). The DLIS significantly reduced the incidence of propofol injection pain compared with SLIS. Further studies are indicated to evaluate the cost-effectiveness of this device.


Effect of Dentin Conditioning with EDTA and Diode Lasers on Expression of Odontoblast-like Cell Markers of Dental Pulp Stem Cells.
Regenerative endodontic procedures rely on the delivery of mesenchymal stem cells into the root canal and on the effect of local growth factors from the dentin and blood clot. The aim of this study was to assess the effect of dentin conditioning with ethylenediamine tetraacetic acid (EDTA) and diode lasers with different wavelengths (808 nm and 980 nm) on the expression of odontoblast-like cell markers. Forty dentin cylinders were divided into four groups according to the irrigation protocol: EDTA, EDTA + 808 nm diode laser, EDTA + 980 nm diode laser, and phosphate-buffered saline as the control group. Dental pulp stem cells were seeded into the previously conditioned cylinders and incubated for 14 days. The quantitative real-time polymerase chain reaction was used to evaluate the expression of dentin sialophosphoprotein (DSPP), dentin morphoprotein-1 (DMP-1), and transforming growth factor-beta 1 (TGF-β1). Data analysis was performed using the Kruskal-Wallis test. The activation of EDTA with 980 nm and 808 nm diode lasers resulted in lower DSPP and DMP-1 expression than that for EDTA alone (p < 0.05 and p < 0.01, respectively). The expression of TGF was similar among all groups. The highest level of expression of odontoblast-like differentiation markers was observed with EDTA alone. However, the use of an 808 nm diode laser during EDTA irrigation reduced the expression of odontoblastic differentiation markers.


Food allergy and non-allergic food hypersensitivity in children and adolescents.
Previous studies have shown a 10-fold discrepancy of self-reported food-induced symptoms and physician-diagnosed food hypersensitivity. Little information is available on the prevalence of food hypersensitivity in unselected paediatric populations. No data were available for German children. To study the perception of food-induced symptoms in the paediatric population, to investigate the allergens accused, to objectify patients' reports, and to identify subgroups at risk of having food-induced allergy (FA) or non-allergic food hypersensitivity (NAFH) reactions. This paper presents the data of the paediatric group (0-17 years) of a representative, randomly sampled, cross-sectional population-based survey studying 13 300 inhabitants of the German capital city Berlin regarding food-related symptoms. Instruments included mailed questionnaires, structured telephone interviews, physical examination, skin-prick tests, specific serum IgE and standardized, controlled and blinded oral food challenges. Two thousand three hundred and fifty-four individuals were contacted by mailed questionnaire, 739 (31.4%) responses could be fully evaluated. Four hundred and fifty-five (61.5%) participants reported symptoms related to food ingestion, 284 (38.4%) affirmed reproducible symptoms in the standardized telephone interview. One hundred and eighty-four (24.8%) individuals were fully examined. Reproducible symptoms to food were found in 31 (4.2%) children and adolescents: 26 (3.5%) showed symptoms of FA and five (0.7%) of NAFH. The oral allergy syndrome was most often observed. Foods most commonly identified by oral challenges were apple, hazelnut, soy, kiwi, carrot and wheat. The perception of food-related symptoms is common among children and adolescents from the general population. Self-reports could be confirmed in around one out of 10 individuals, still resulting in 4.2% of proven clinical symptoms. However, most reactions were mild and mainly because of pollen-associated FA, while NAFH reactions were less common. Severe IgE-mediated FA was observed in individuals with pre-existing atopic disease, who should be fully investigated for clinically relevant FA.


EVALUATION OF THYROID HORMONES AND AS INFLUENCED BY TREATMENT WITH DESLORELIN IN PALLAS' CATS (OTOCOLOBUS (FELIS) MANUL).
Thyroid hormones regulate a variety of physiologic functions including metabolism, growth, and reproductive cycling, and these other hormones can impact the thyroid function via the hypothalamic-pituitary axis. For instance, the gonadotropin-releasing hormone agonist, deslorelin, used in nondomestic carnivores for contraception and behavioral control, down-regulates reproductive hormones through this mechanism and so may impact thyroid function. Due to clinical concerns of hypothyroidism in a bachelor group of adult male Pallas' cats (Otocolobus (Felis) manul) which also had deslorelin implants, serum samples from treated captive (n = 8) individuals, untreated captive (n = 25), and free-ranging (n = 9) individuals were analyzed for thyroid hormone concentrations. Total and free thyroxine (TT4 and FT4), total and free tri-iodothyronine (TT3 and FT3), and thyroid stimulating hormone (TSH) were measured although, due to sample volume limitations, not every hormone could be analyzed for every sample. Of these hormones, only FT4 was found statistically different between the deslorelin-treated and untreated groups. As samples were unevenly distributed across season, true comparison between seasons could not be made. The values reported for the untreated captive and free-ranging group, while representing a small sample size, can serve as a baseline assessment when evaluating the thyroid status of captive Pallas' cats.


Chad Genetic Diversity Reveals an African History Marked by Multiple Holocene Eurasian Migrations.
Understanding human genetic diversity in Africa is important for interpreting the evolution of all humans, yet vast regions in Africa, such as Chad, remain genetically poorly investigated. Here, we use genotype data from 480 samples from Chad, the Near East, and southern Europe, as well as whole-genome sequencing from 19 of them, to show that many populations today derive their genomes from ancient African-Eurasian admixtures. We found evidence of early Eurasian backflow to Africa in people speaking the unclassified isolate Laal language in southern Chad and estimate from linkage-disequilibrium decay that this occurred 4,750-7,200 years ago. It brought to Africa a Y chromosome lineage (R1b-V88) whose closest relatives are widespread in present-day Eurasia; we estimate from sequence data that the Chad R1b-V88 Y chromosomes coalesced 5,700-7,300 years ago. This migration could thus have originated among Near Eastern farmers during the African Humid Period. We also found that the previously documented Eurasian backflow into Africa, which occurred ∼3,000 years ago and was thought to be mostly limited to East Africa, had a more westward impact affecting populations in northern Chad, such as the Toubou, who have 20%-30% Eurasian ancestry today. We observed a decline in heterozygosity in admixed Africans and found that the Eurasian admixture can bias inferences on their coalescent history and confound genetic signals from adaptation and archaic introgression.


Mutation of the Drosophila vesicular GABA transporter disrupts visual figure detection.
The role of gamma amino butyric acid (GABA) release and inhibitory neurotransmission in regulating most behaviors remains unclear. The vesicular GABA transporter (VGAT) is required for the storage of GABA in synaptic vesicles and provides a potentially useful probe for inhibitory circuits. However, specific pharmacologic agents for VGAT are not available, and VGAT knockout mice are embryonically lethal, thus precluding behavioral studies. We have identified the Drosophila ortholog of the vesicular GABA transporter gene (which we refer to as dVGAT), immunocytologically mapped dVGAT protein expression in the larva and adult and characterized a dVGAT(minos) mutant allele. dVGAT is embryonically lethal and we do not detect residual dVGAT expression, suggesting that it is either a strong hypomorph or a null. To investigate the function of VGAT and GABA signaling in adult visual flight behavior, we have selectively rescued the dVGAT mutant during development. We show that reduced GABA release does not compromise the active optomotor control of wide-field pattern motion. Conversely, reduced dVGAT expression disrupts normal object tracking and figure-ground discrimination. These results demonstrate that visual behaviors are segregated by the level of GABA signaling in flies, and more generally establish dVGAT as a model to study the contribution of GABA release to other complex behaviors.


Asking for a commitment: violations during the 2007 match and the effect on applicant rank lists.
Applicants to residency face a number of difficult questions during the interview process, one of which is when a program asks for a commitment to rank the program highly. The regulations governing the National Resident Matching Program (NRMP) match explicitly forbid any residency programs asking for a commitment. We conducted a cross-sectional survey of applicants from U.S. medical schools to five specialties during the 2006-2007 interview season using the Electronic Residency Application Service of the Association of American Medical Colleges. Applicants were asked to recall being asked to provide any sort of commitment (verbal or otherwise) to rank a program highly. Surveys were sent after rank lists were submitted, but before match day. We analyzed data using descriptive statistics and logistic regression. There were 7,028 unique responses out of 11,983 surveys sent for a response rate of 58.6%. Of those who identified their specialty (emergency medicine, internal medicine, obstetrics and gynecology [OBGYN], general surgery and orthopedics), there were 6,303 unique responders. Overall 19.6% (1380/7028) of all respondents were asked to commit to a program. Orthopedics had the highest overall prevalence at 28.9% (372/474), followed by OBGYN (23.7%; 180/759), general surgery (21.7%; 190/876), internal medicine (18.3%; 601/3278), and finally, emergency medicine (15.4%; 141/916). Of those responding, 38.4% stated such questions made them less likely to rank the program. Applicants to residencies are being asked questions expressly forbidden by the NRMP. Among the five specialties surveyed, orthopedics and OBGYN had the highest incidence of this violation. Asking for a commitment makes applicants less likely to rank a program highly.


Inducible protective processes in animal systems. X. Influence of nicotinamide in methyl methanesulfonate-adapted mouse bone marrow cells.
The adaptive response is an error-free DNA repair mechanism induced by low levels of physical or chemical agents. Cells pre-exposed to such agents are resistant to genetic damage induced by subsequent treatment at a high dose. There are many reports on such adaptive responses. Recently we have shown the existence of adaptive responses in vivo in the grasshopper Poecilocerus pictus and the mouse and in vitro in human lymphocytes. Different enzymes are implicated in this DNA repair pathway. In an attempt to understand the molecular mechanism of the methyl methanesulfonate (MMS)-induced adaptive response, the present investigations have been undertaken employing nicotinamide, an inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP). Pre-, inter- and post-treatments with nicotinamide of MMS-treated mouse bone marrow cells were carried out. The results revealed that there is a significant reduction in the frequency of chromosomal aberrations compared with combined treatment, suggesting an enhancement of the adaptive response by nicotinamide. Further, the results of NAD+ assay in the inter-treatment experiment showed that there is no depletion of NAD+. Thus, it can be stated that PARP is not involved in the MMS-induced adaptive response in mouse bone marrow cells.


Intermittent CSF drainage and rapid EVD weaning approach after subarachnoid hemorrhage: association with fewer VP shunts and shorter length of stay.
There is variability and uncertainty about the optimal approach to the management and discontinuation of an external ventricular drain (EVD) after subarachnoid hemorrhage (SAH). Evidence from single-center randomized trials suggests that intermittent CSF drainage and rapid EVD weans are safe and associated with shorter ICU length of stay (LOS) and fewer EVD complications. However, a recent survey revealed that most neurocritical care units across the United States employ continuous CSF drainage with a gradual wean strategy. Therefore, the authors sought to determine the optimal EVD management approach at their institution. The authors reviewed records of 200 patients admitted to their institution from 2010 to 2016 with aneurysmal SAH requiring an EVD. In 2014, the neurocritical care unit of the authors' institution revised the internal EVD management guidelines from a continuous CSF drainage with gradual wean approach (continuous/gradual) to an intermittent CSF drainage with rapid EVD wean approach (intermittent/rapid). The authors performed a retrospective multivariable analysis to compare outcomes before and after the guideline change. The authors observed a significant reduction in ventriculoperitoneal (VP) shunt rates after changing to an intermittent CSF drainage with rapid EVD wean approach (13% intermittent/rapid vs 35% continuous/gradual, OR 0.21, p = 0.001). There was no increase in delayed VP shunt placement at 3 months (9.3% vs 8.6%, univariate p = 0.41). The intermittent/rapid EVD approach was also associated with a shorter mean EVD duration (10.2 vs 15.6 days, p < 0.001), shorter ICU LOS (14.2 vs 16.9 days, p = 0.001), shorter hospital LOS (18.2 vs 23.7 days, p < 0.0001), and lower incidence of a nonfunctioning EVD (15% vs 30%, OR 0.29, p = 0.006). The authors found no significant differences in the rates of symptomatic vasospasm (24.6% vs 20.2%, p = 0.52) or ventriculostomy-associated infections (1.3% vs 8.8%, OR 0.30, p = 0.315) between the 2 groups. An intermittent CSF drainage with rapid EVD wean approach is associated with fewer VP shunt placements, fewer complications, and shorter LOS compared to a continuous CSF drainage with gradual EVD wean approach. There is a critical need for prospective multicenter studies to determine if the authors' experience is generalizable to other centers.


Grief, Stress, Trauma, and Support During the Organ Donation Process.
The organ donation process is complex and stressful for the family of the potential donor and members of the multidisciplinary team who may experience grief, ethical dilemmas, vicarious trauma, or compassion fatigue. Several studies each explore the role of a specific healthcare group and the impact of inhospital processes on group members. We conducted a systematic literature search to identify such studies and a qualitative synthesis to consolidate findings and highlight features of the interaction and relationships between role players. Our results suggest that, while healthcare professionals have different roles, attitudes, and views, the experience of stressors and interdisciplinary tension is common. Nevertheless, staff are united by the goal of caring for the patient and family. We therefore propose that, while focusing on bereavement care and other aspects of the family's experience, staff can find other shared goals and develop understanding, trust, empathy, and respect for each other's positions, thereby improving functioning in the complex adaptive system that forms at this time. Education and training can equip staff to facilitate anticipatory mourning, family-led activities, and a meaningful parting from their relative, assisting families with their grief and increasing staff members' efficacy, confidence, and interdisciplinary teamwork. Knowledge of systems thinking and opportunities to share ideas and experiences will enable staff to appreciate each other's roles, while supportive mentors, self-care strategies, and meaningful feedback between role players will foster healthy adjustment and shared learning. A focus on psychosocial outcomes such as family satisfaction with the process, collaboration within the multidisciplinary team, and reduction in the role stress of healthcare professionals will contribute to family well-being as well as personal and professional growth for staff.


Access and Health System Impact of an Early Intervention Treatment Program for Emerging Adults with Mood and Anxiety Disorders.
Early intervention programs are effective for improving outcomes in first-episode psychosis; however, less is known about their effectiveness for mood and anxiety disorders. We sought to evaluate the impact of an early intervention program for emerging adults with mood and anxiety disorders in the larger health system context, relative to standard care. Using health administrative data, we constructed a retrospective cohort of cases of mood and anxiety disorders among emerging adults aged 16 to 25 years in the catchment of the First Episode Mood and Anxiety Program (FEMAP) in London, Ontario, between 2009 and 2014. This cohort was linked to primary data from FEMAP to identify service users. We used proportional hazards models to compare indicators of service use between FEMAP users and a propensity score-matched group of nonusers receiving care elsewhere in the health system. FEMAP users (n = 490) had more rapid access to a psychiatrist relative to nonusers (hazard ratio [HR], 2.82; 95% confidence interval, 2.45 to 3.26; median time, 16 vs. 71 days). In the year following admission, FEMAP users also had lower rates of emergency department use for mental health reasons (HR, 0.73; 95% CI, 0.53 to 0.99). We did not observe differences in psychiatric hospitalization rates. An early intervention model of care for mood and anxiety disorders is associated with better access to psychiatric care and lower use of the emergency department. Our findings suggest that early intervention services for mood and anxiety disorders may be beneficial from a health systems perspective, and further research on the effectiveness of this model of care is warranted.


Revision of the genus Phloeoditica Schedl - with description of two new genera and two new species in Phloeosinini (Coleoptera, Curculionidae, Scolytinae).
The genus Phloeoditica Schedl currently includes four species from Southeast Asia. These species vary substantially in important morphological characters and indicate the existence of multiple genera for these species. A revision based on morphological and in part molecular data resulted in the transfer of Phloeoditica setosa to Pseudoxylechinus the erection of a new genus Asiophilus for Phloeoditica phloeosinoides and a new species Asiophilus macropunctatus from Vietnam. Another new genus with affinities to Phloeoditica is described based on the new species Microditica uniseriata from Thailand. The new genera are included in a revised key to the tribe Phloeosinini.


Performance of two-stage discrete fiber Raman amplifiers with and without all-optical gain clamping.
Using numerical simulations, we analyze the properties of two-stage discrete fiber Raman amplifiers without and with all-optical gain clamping. In both cases a two-stage amplifier can be designed to have the same gain characteristics as a single-stage amplifier with improved noise performance by use of either the same total length of gain fiber (but with increased pump power) or total pump power (but with increased total length of gain fiber).


APPetite: Validation of a smartphone app-based tool for the remote measure of free-living subjective appetite.
This study determined the validity, reproducibility and usability of a smartphone app - APPetite - for the measure of free-living, subjective appetite. Validity was assessed compared with the criterion tool of pen-and-paper visual analogue scale (VAS) (n=22). Appetite was recorded using APPetite and VAS, one immediately after the other, upon waking and every hour thereafter for twelve hours. This was repeated the next day with the order of tool reversed. Agreement between tools was assessed using Bland-Altman analysis. Reproducibility and usability were assessed in a separate experiment (n=22) of two trials (APPetite vs. VAS), separated by seven days. Appetite was recorded in duplicate upon waking and every hour for twelve hours using APPetite or VAS. Agreement between duplicate measures was assessed using Bland-Altman analysis and coefficient of variation (CV) was compared between tools. Usability was assessed by comparing compliance and by qualitative evaluation. APPetite demonstrated good criterion validity with trivial bias of 1.65 units/mm·hr-1 between APPetite- and VAS-derived AUC appetite scores. Limits of agreement were within a maximum allowed difference of 10%. However, proportional bias was observed. APPetite demonstrated high reproducibility, with minimal bias (-0.578 units·hr-1) and no difference in CV between APPetite and VAS (1.29±1.42% vs 1.54±2.36%, p = 0.64). Compliance was high with APPetite (92.7±8.0%) and VAS (91.6±20.4%, p = 0.81). Ninety percent of participants preferred APPetite, citing greater accessibility, simplified process and easier/quicker use. While proportional bias precludes using APPetite and VAS interchangeably, APPetite appears a valid, reproducible and highly usable tool for measuring free-living appetite in young-to-middle-aged adults.


Therapeutic suggestions with critically ill in palliative care.
Suggestions can be used without formal hypnosis, especially with critically ill patients, due to their spontaneous trance state. In this paper we outline data on the effectiveness of therapeutic suggestions. We interpret the possible mechanism of therapeutic suggestions in the context of stress cognition. Basic principles of formulating suggestions are discussed and some recommended versions of non-pharmacological pain control are provided. Case vignettes are given of how suggestions are used with critically ill ICU patients.


The Impact of Accessible Cervical Cancer Screening in Peru-The Día del Mercado Project.
The purpose of this study was to determine the potential impact of accessible secondary cervical cancer prevention efforts in indigenous Peruvian women living in the rural Andes Mountain region of Peru. Peruvian women presenting for a Pap test or visiting a local marketplace, clinic, or public facility were asked to complete a questionnaire that assessed their response to the rural Pap screening program. We identified the following: 1) barriers to care, 2) patient knowledge of cervical cancer and Pap tests, and 3) perceptions of and reactions to the market clinic model. Chi-square or Fisher exact tests, t tests and 1-way ANOVA were used to examine differences between locations. Of 4,560 women enrolled, those examined in tents indicated it was easier to get a Pap test (98.7%, P = 0.001) compared with women seen in buildings (96.8%) or CerviCusco (98.0%), and they felt it was more important to have a Pap test close to their home more often (99.3%) than those seen at CerviCusco (97.8%) or buildings (98.8%). Women examined in tents felt the market was a good place to have a Pap test more often (67.0%, P < 0.001) than women who went to buildings (46.0%) or CerviCusco (29.2%). Many poor indigenous women living in isolated regions are unable to travel to distant health-care facilities. Using a novel mobile clinic model, the "Dia del Mercado Project" successfully reduced barriers to cervical cancer screening by using local marketplaces.


Sulfonylurea Receptor-1: A Novel Biomarker for Cerebral Edema in Severe Traumatic Brain Injury.
Cerebral edema is a key poor prognosticator in traumatic brain injury. There are no biomarkers identifying patients at-risk, or guiding mechanistically-precise therapies. Sulfonylurea receptor-1-transient receptor potential cation channel M4 is upregulated only after brain injury, causing edema in animal studies. We hypothesized that sulfonylurea receptor-1 is measurable in human cerebrospinal fluid after severe traumatic brain injury and is an informative biomarker of edema and outcome. A total of 119 cerebrospinal fluid samples were collected from 28 severe traumatic brain injury patients. Samples were retrieved at 12, 24, 48, 72 hours and before external ventricular drain removal. Fifteen control samples were obtained from patients with normal pressure hydrocephalus. Sulfonylurea receptor- 1 was quantified by enzyme-linked immunosorbent assay. Outcomes included CT edema, intracranial pressure measurements, therapies targeting edema, and 3-month Glasgow Outcome Scale score. Sulfonylurea receptor-1 was present in all severe traumatic brain injury patients (mean = 3.54 ± 3.39 ng/mL, peak = 7.13 ± 6.09 ng/mL) but undetectable in all controls (p < 0.001). Mean and peak sulfonylurea receptor-1 was higher in patients with CT edema (4.96 ± 1.13 ng/mL vs 2.10 ± 0.34 ng/mL; p = 0.023). There was a temporal delay between peak sulfonylurea receptor-1 and peak intracranial pressure in 91.7% of patients with intracranial hypertension. There was no association between mean/peak sulfonylurea receptor-1 and mean/peak intracranial pressure, proportion of intracranial pressure greater than 20 mm Hg, use of edema-directed therapies, decompressive craniotomy, or 3-month Glasgow Outcome Scale. However, decreasing sulfonylurea receptor-1 trajectories between 48 and 72 hours were significantly associated with improved cerebral edema and clinical outcome. Area under the multivariate model receiver operating characteristic curve was 0.881. This is the first report quantifying human cerebrospinal fluid sulfonylurea receptor-1. Sulfonylurea receptor-1 was detected in severe traumatic brain injury, absent in controls, correlated with CT-edema and preceded peak intracranial pressure. Sulfonylurea receptor-1 trajectories between 48 and 72 hours were associated with outcome. Because a therapy inhibiting sulfonylurea receptor-1 is available, assessing cerebrospinal fluid sulfonylurea receptor-1 in larger studies is warranted to evaluate our exploratory findings regarding its diagnostic, and monitoring utility, as well as its potential to guide targeted therapies in traumatic brain injury and other diseases involving cerebral edema.


Update on the Medical Treatment of Primary Open-Angle Glaucoma.
Glaucoma comprises a group of progressive, neurodegenerative disorders characterized by retinal ganglion cell death and nerve fiber layer atrophy. Several randomized controlled trials have consistently demonstrated the efficacy of intraocular pressure lowering to slow or halt the measurable progression of the disease. Medical therapy, in places where it is easily accessible, is often the primary method to lower intraocular pressure. We review the medical options currently available and possible future options currently in development. The 5 contemporary classes of topical agents in use include prostaglandin analogs, beta blockers, carbonic anhydrase inhibitors, alpha agonists, and cholinergics. In addition, several fixed combination agents are commercially available. Agents from each of these classes have unique mechanisms of action, adverse effects, and other characteristics that impact how they are used in clinical practice. Despite the plethora of medical options available, there are limitations to topical ophthalmic therapy such as the high rate of noncompliance and local and systemic adverse effects. Alternate and sustained drug delivery models, such as injectable agents and punctal plug delivery systems, may in the future alleviate some such concerns and lead to increased efficacy of treatment while minimizing adverse effects.


Renal tumors presentation: changing trends over two decades.
We have analyzed the changing trends in surgical treatment of renal tumors over the last 2 decades with regard to age incidence, presentation, incidental detection, and histopathology. Records of renal tumors were analyzed from January 1, 1988 to December 31, 2007. Data were split into 4 parts based on a 5-year time period, 1 for each cohort of patients: cohort 1 (1988-1992)-103 patients, cohort 2 (1993-1997)-161 patients, cohort 3 (1998-2002)-243 patients, and cohort 4 (2003-2007)-304 patients. A comparative study was performed with regard to age incidence, presentation, incidentallomas, histopathology, and management with statistical analysis. Out of 811 renal tumors, 17.63% cases were benign and 82.37% were malignant. In the first cohort, 34.95% cases were detected in the seventh decade as compared with cohort 4 in which these were detected in the sixth (34.86%) and fifth decades (21.38%). Incidentallomas increased from 11 (10.67%) in cohort 1 to 84 (27.63%) in cohort 4 (P = 0.001). The cases of surgically treated tumors increased in number from 103 to 304 in cohort 4. Among the presenting features, incidence of weight loss, flank pain, and lump decreased while other clinical syndromes were constant. Only open radical nephrectomy was performed in the first 2 consecutive timeperiods. Laparoscopic radical nephrectomy was increasingly used in cohort 4 as compared with cohort 3 (121 vs 32, respectively). Similarly, open nephron sparing surgery (NSS) was increasingly used in cohort 4 as compared with cohort 3. Among the histopathologies, clear cell carcinoma was most common (73.35 %), but Fuhrman grading showed a trend toward more cases detected with grade 1 and 2 in cohort 4; 23.73% and 61.86%, respectively, as compared with 15.85% and 45.12% in cohort 1 (P = 0.001); more T1 tumors were detected (63.42% in cohort 4 as compared with 41.46% in cohort 1). A majority of renal tumors presented as symptomatic tumors. Recently, tumors are being detected at an early stage and grade; in the younger patients, with an increasing trend of laparoscopic and open NSS.


Sp1 and Smad transcription factors co-operate to mediate TGF-beta-dependent activation of amyloid-beta precursor protein gene transcription.
Abnormal deposition of Abeta (amyloid-beta peptide) is one of the hallmarks of AD (Alzheimer's disease). This peptide results from the processing and cleavage of its precursor protein, APP (amyloid-beta precursor protein). We have demonstrated previously that TGF-beta (transforming growth factor-beta), which is overexpressed in AD patients, is capable of enhancing the synthesis of APP by astrocytes by a transcriptional mechanism leading to the accumulation of Abeta. In the present study, we aimed at further characterization of the molecular mechanisms sustaining this TGF-beta-dependent transcriptional activity. We report the following findings: first, TGF-beta is capable of inducing the transcriptional activity of a reporter gene construct corresponding to the +54/+74 region of the APP promoter, named APP(TRE) (APP TGF-beta-responsive element); secondly, although this effect is mediated by a transduction pathway involving Smad3 (signalling mother against decapentaplegic peptide 3) and Smad4, Smad2 or other Smads failed to induce the activity of APP(TRE). We also observed that the APP(TRE) sequence not only responds to the Smad3 transcription factor, but also the Sp1 (signal protein 1) transcription factor co-operates with Smads to potentiate the TGF-beta-dependent activation of APP. TGF-beta signalling induces the formation of nuclear complexes composed of Sp1, Smad3 and Smad4. Overall, the present study gives new insights for a better understanding of the fine molecular mechanisms occurring at the transcriptional level and regulating TGF-beta-dependent transcription. In the context of AD, our results provide additional evidence for a key role for TGF-beta in the regulation of Abeta production.


Recurrent urinary tract infections in females.
Uncomplicated Urinary tract infections are common in adult women across the entire age spectrum, with mean annual incidence of 15% and 10% in those aged 15-39 and 40-79 years, respectively. Urinary tract infection (UTI), with its diverse clinical syndromes and affected host groups, remains one of the most common but widejly misunderstood and challenging infectious diseases encountered in clinical practice. Recurrent urinary tract infections (UTIs) present a significant problem for women and a challenge for the doctors who care for them. The diagnosis of uncomplicated UTI can be achieved best by a thorough assessment of patient symptoms with or without the addition of a urine dipstick test. Treatment should be based on the most recent guidelines, taking into account resistance patterns in the local community. The patient who suffers from recurrent UTIs can be treated safely and effectively with continuous antibiotic prophylaxis, post-coital therapy, or self-initiated treatment. This review article covers the latest trends in the management of recurrent UTI among women. Further research is needed regarding rapid diagnosis of UTI, accurate presumptive identification of patients with resistant pathogens, and development of new antimicrobials for drug-resistant UTI.


Complex N-glycans or core 1-derived O-glycans are not required for the expression of stage-specific antigens SSEA-1, SSEA-3, SSEA-4, or Le(Y) in the preimplantation mouse embryo.
The glycan epitopes termed stage-specific embryonic antigens (SSEA) occur on glycoproteins and glycolipids in mammals. However, it is not known whether these epitopes are attached to N- or O-glycans on glycoproteins and/or on glycolipids in the developing mouse embryo. In this paper the expression of the antigens SSEA-1, SSEA-3, SSEA-4 and Le(Y) was examined on ovulated eggs, early embryos and blastocysts lacking either complex and hybrid N-glycans or core-1 derived O-glycans. In all cases, antigen expression determined by fluorescence microscopy of bound monoclonal antibodies to embryos at the stage of development of maximal expression was similar in mutant and control embryos. Thus, none of these developmental antigens are expressed solely on either complex N- or core 1-derived O-glycans attached to glycoproteins in the preimplantation mouse embryo. Furthermore, neither of these classes of glycan is essential for the expression of SSEA-1, SSEA-3, SSEA-4 or Le(Y) on mouse embryos.


Longitudinal analysis of emotional problems in children with congenital heart defects: a follow-up from age 6 to 36 months.
To investigate whether children with varying severity of congenital heart defects (CHDs) have a higher risk of internalizing or externalizing emotional problems at 36 months of age. In addition, to analyze whether a history of emotional problems at 6 or 18 months of age increases the risk of emotional problems at 36 months in children with CHDs. Prospective data from the Norwegian Mother and Child Cohort Study, conducted by the Norwegian Institute of Public Health, was linked with a nationwide CHD registry, and 175 children with CHDs were identified in a cohort of 44,104 children aged 36 months. Maternal reports on child characteristics were assessed by questionnaires at child age 6, 18, and 36 months. Children with CHDs did not have elevated scores on internalizing or externalizing problems at 36 months of age compared with controls. Not even the children with CHDs with a history of emotional problems at age 6 or 18 months showed an increased risk. The absence of risk of emotional problems at 36 months of age in children with CHDs could be a consequence of the completion of the most extensive medical treatment.


The FaceBase Consortium: a comprehensive program to facilitate craniofacial research.
The FaceBase Consortium consists of ten interlinked research and technology projects whose goal is to generate craniofacial research data and technology for use by the research community through a central data management and integrated bioinformatics hub. Funded by the National Institute of Dental and Craniofacial Research (NIDCR) and currently focused on studying the development of the middle region of the face, the Consortium will produce comprehensive datasets of global gene expression patterns, regulatory elements and sequencing; will generate anatomical and molecular atlases; will provide human normative facial data and other phenotypes; conduct follow up studies of a completed genome-wide association study; generate independent data on the genetics of craniofacial development, build repositories of animal models and of human samples and data for community access and analysis; and will develop software tools and animal models for analyzing and functionally testing and integrating these data. The FaceBase website (http://www.facebase.org) will serve as a web home for these efforts, providing interactive tools for exploring these datasets, together with discussion forums and other services to support and foster collaboration within the craniofacial research community.


Pools of cadmium in Chlamydomonas reinhardtii revealed by chemical imaging and XAS spectroscopy.
The green micro-alga Chlamydomonas reinhardtii is commonly used as a model to investigate metallic stress in photosynthetic organisms. The aim of this study was to explore processes implemented by three C. reinhardtii strains to cope with cadmium (Cd), and particularly to evidence Cd sequestration in the cell. For that, we used a combination of subcellular fractionation and chemical imaging (micro X-ray fluorescence (μXRF) and transmission electron microscopy (TEM/X-EDS)) to identify subcellular compartments of Cd accumulation, and X-ray absorption spectroscopy (XAS) to determine chemical Cd speciation. C. reinhardtii wild type strain 11/32b (wt), a newly design strain (pcs1) expressing a modified phytochelatin synthase in the chloroplast and a cell wall less strain CC400 (cw15) were exposed to 70 μM Cd. At this Cd concentration, cell vitality was not affected, however, the strains showed various strategies to cope with Cd stress. In wt, most of Cd was diffused in the whole cell, and complexed by thiol ligands, while the other part was associated with phosphate in vacuolar Ca polyphosphate granules. Thiol ligands increased with exposure time, confirming their important role in Cd stress. In pcs1, Cd was also present as vacuolar Ca polyphosphate granules, and diffused in the cell as Cd-thiol complexes. In addition, while it should be regarded with caution, a minor proportion of Cd complexed by carboxyl groups, was potentially provided by starch produced around the pyrenoid and in the chloroplast. Results suggested that pcs1 uses thiol compounds such as PC to a lesser extent for Cd sequestration than wt. In cw15, an excretion of Cd, Ca polyphosphate granules has to be considered. Finally, Cd was detected in the pyrenoid of all strains.


Claudin-4 SPECT Imaging Allows Detection of Aplastic Lesions in a Mouse Model of Breast Cancer.
The expression of claudin-4, a protein involved in tight junction complexes, is widely dysregulated in epithelial malignancies. Claudin-4 is overexpressed in several premalignant precursor lesions, including those of cancers of the breast, pancreas, and prostate, and is associated with poor survival. A noncytotoxic C-terminal fragment of Clostridium perfringens enterotoxin (cCPE) is a natural ligand for claudin-4. Here, we demonstrate whole-body quantitative SPECT imaging of preneoplastic breast cancer tissue using (111)In-labeled cCPE. cCPE.GST or GST (GST is glutathione S-transferase) was conjugated to the metal ion chelator benzyl-diethylenetriaminepentaacetic acid to allow (111)In radiolabeling. The affinity of radiolabeled cCPE.GST for claudin-4 was confirmed using claudin-4-expressing MDA-MB-468 and SQ20b cells, compared with claudin-4-negative HT1080 cells. In vivo SPECT imaging was performed using athymic mice bearing MDA-MB-468 or HT1080 xenografts and using genetically modified BALB/neuT mice, which spontaneously develop claudin-4-expressing breast cancer lesions. The uptake of (111)In-cCPE.GST in claudin-4-positive MDA-MB-468 xenograft tumors in athymic mice was significantly higher than in (111)In-GST or claudin-4-negative HT1080 tumors (6.72 ± 0.18 vs. 3.88 ± 1.00 vs. 2.36 ± 1.25 percentage injected dose per gram [%ID/g]; P < 0.0001). No other significant differences were observed in any of the examined organs. BALB/neuT mice, expressing rat neuT under mmtv promotor control, spontaneously developed tumorous lesions within their mammary fat pads over the course of 130 d. Overt mammary tumors were claudin-4-positive, and (111)In-cCPE.GST uptake was 3.2 ± 0.70 %ID/g, significantly higher than (111)In-GST (1.00 ± 0.60 %ID/g; P < 0.05). Mammary fat pads in mice aged 80 d bore claudin-4-positive aplastic lesions and accumulated (111)In-cCPE.GST (3.17 ± 0.51 %ID/g) but not (111)In-GST (0.99 ± 0.39 %ID/g; P < 0.001). Taken together, (111)In-cCPE.GST targets claudin-4 expression in frank tumors and preneoplastic tissue, and cCPE imaging may be used as an early detection tool for breast, prostate, and pancreatic cancer.


Chlamydia pneumoniae (TWAR).
Chlamydia pneumoniae (TWAR) is a recently recognized third species of the genus Chlamydia that causes acute respiratory disease. It is distinct from the other two chlamydial species that infect humans, C. trachomatis and C. psittaci, in elementary body morphology and shares less than 10% of the DNA homology with those species. The organism has a global distribution, with infection most common among children between the ages of 5 and 14 years. In children, TWAR infection is usually mild or asymptomatic, but it may be more severe in adults. Pneumonia and bronchitis are the most common clinical manifestations of infection, and TWAR is responsible for approximately 10% of cases of pneumonia and 5% of cases of bronchitis in the United States. The microimmunofluorescence serologic assay is specific for TWAR and can distinguish between recent and past infections. The organism can be isolated in cell culture; however, PCR techniques have recently facilitated its detection in tissues and clinical specimens.


Developing a national patient safety education framework for Australia.
In 2004, The Australian Council for Safety and Quality in Health Care recognised that the lack of a comprehensive framework describing competencies for patient safety was a barrier to achieving a competent and safe health workforce. This article describes the building of a national patient safety education framework that describes the competencies for healthcare workers. Develop an educational framework that was patient centred and identified the knowledge, skills and behaviours required by healthcare workers irrespective of their profession, position or location. The content of the framework was developed using a four-staged approach: literature review, development of learning areas and topics, classification into learning domains and, lastly, converting into a performance-sbased format. An extensive consultation and validation process was also undertaken. A national patient safety education framework was endorsed by The Australian Council for Safety and Quality in Health Care in 2005. The framework is already being used to develop curricula and train the trainer programmes in patient safety. The framework, which draws its educational approach from adult learning principles, was extensively researched and built on the experience of healthcare workers. The next challenge is to test different strategies for implementing the framework.


Muscle Synergies in Response to Biofeedback-Driven Gait Adaptations in Children With Cerebral Palsy.
Children with cerebral palsy (CP) often show impaired selective motor control (SMC) that induces limitations in motor function. Children with CP can improve aspects of pathological gait in an immediate response to visual biofeedback. It is not known, however, how these gait adaptations are achieved at the neural level, nor do we know the extent of SMC plasticity in CP. Investigate the underlying SMC and changes that may occur when gait is adapted with biofeedback. Twenty-three ambulatory children with CP and related (hereditary) forms of spastic paresis (Aged: 10.4 ± 3.1, 6-16 years, M: 16/F: 9) were challenged with real-time biofeedback to improve step length, knee extension, and ankle power while walking on an instrumented treadmill in a virtual reality environment. The electromyograms of eight superficial muscles of the leg were analyzed and synergies were further decomposed using non-negative matrix factorization (NNMF) using 1 to 5 synergies, to quantify SMC. Total variance accounted for (tVAF) was used as a measure of synergy complexity. An imposed four synergy solution was investigated further to compare similarity in weightings and timing patterns of matched paired synergies between baseline and biofeedback trials. Despite changes in walking pattern, changes in synergies were limited. The number of synergies required to explain at least 90% of muscle activation increased significantly, however, the change in measures of tVAF1 from baseline (0.75 ± 0.08) were less than ±2% between trials. In addition, within-subject similarity of synergies to baseline walking was high (>0.8) across all biofeedback trials. These results suggest that while gait may be adapted in an immediate response, SMC as quantified by synergy analysis is perhaps more rigidly impaired in CP. Subtle changes in synergies were identified; however, it is questionable if these are clinically meaningful at the level of an individual. Adaptations may be limited in the short term, and further investigation is essential to establish if long term training using biofeedback leads to adapted SMC.


Pump-controlled flexible generation between dissipative soliton and noise-like pulses from a mode-locked Er-doped fiber laser.
We experimentally investigate the alternative generation of dissipative solitons (DSs) or noise-like pulses (NLPs) from a passively mode-locked Er-doped all-fiber laser with a 45° tilted fiber grating (45° TFG). The 45° TFG serves as an in-fiber polarizer for mode locking in the all-fiber laser cavity. Under the fixed orientations of the polarization controllers, flexible generation between DSs and NLPs can be precisely controlled by adjusting the pump power only. To the best of our knowledge, the total cavity length 4.92 m of our fiber laser is the shortest one among all NLP fiber lasers. We obtain the DS with 3 dB bandwidth of 20.4 nm centered at 1577 nm and the NLP with 3 dB bandwidth of 25.2 nm centered at 1574 nm. The fundamental repetition rate of the mode-locked pulses is 42.3 MHz. This DS-NLP switchable Er-doped fiber laser can be regarded as a multifunctional optical source for diverse practical and potential applications.


Characterization of aminoaciduria and hypoaminoacidemia in dogs with hepatocutaneous syndrome.
OBJECTIVE To characterize aminoaciduria and plasma amino acid concentrations in dogs with hepatocutaneous syndrome (HCS). ANIMALS 20 client-owned dogs of various breeds and ages. PROCEDURES HCS was definitively diagnosed on the basis of liver biopsy specimens (n = 12), gross and histologic appearance of skin lesions (4), and examination of skin and liver biopsy specimens (2) and presumptively diagnosed on the basis of cutaneous lesions with compatible clinicopathologic and hepatic ultrasonographic (honeycomb or Swiss cheese pattern) findings (2). Amino acid concentrations in heparinized plasma and urine (samples obtained within 8 hours of each other) were measured by use of ion exchange chromatography. Urine creatinine concentration was used to normalize urine amino acid concentrations. Plasma amino acid values were compared relative to mean reference values; urine-corrected amino acid values were compared relative to maximal reference values. RESULTS All dogs had generalized hypoaminoacidemia, with numerous amino acid concentrations < 50% of mean reference values. The most consistent and severe abnormalities involved glutamine, proline, cysteine, and hydroxyproline, and all dogs had marked lysinuria. Urine amino acids exceeding maximum reference values (value > 1.0) included lysine, 1-methylhistidine, and proline. CONCLUSIONS AND CLINICAL RELEVANCE Hypoaminoacidemia in dogs with HCS prominently involved amino acids associated with the urea cycle and synthesis of glutathione and collagen. Marked lysinuria and prolinuria implicated dysfunction of specific amino acid transporters and wasting of amino acids essential for collagen synthesis. These findings may provide a means for tailoring nutritional support and for facilitating HCS diagnosis.


Office Workers' Risk of Metabolic Syndrome-Related Indicators: A 10-Year Cohort Study.
The purpose of the study is to assess the relationship between the prevalence of metabolic syndrome-related risk factors and work tenure among office workers. A 10-year cohort analysis was conducted using employees' health examinations given to new employees within 1 or 2 years of joining the firm and every 5 years thereafter. Age-adjusted odds ratios (95% confidence interval [CI], p < .05) were calculated based on a contrast test with general estimating equations. Specifically, the age-adjusted odds ratios and CIs of those with 20 ± 1 years of work, compared with those with 1 to 2 years of work, were as follows: triglycerides (≥150 mg/dl) 3.01 (2.11, 4.28), waist circumference (male ≥90 cm) 2.70 (1.63, 4.45), and fasting glucose (≥100 mg/dl) 2.67 (1.78, 4.01). The findings of the relationship between metabolic syndrome risk and work tenure as well as the baseline health data of new employees provide a foundation for developing a workplace health management system.


Autosomal recessive retinitis pigmentosa E150K opsin mice exhibit photoreceptor disorganization.
The pathophysiology of the E150K mutation in the rod opsin gene associated with autosomal recessive retinitis pigmentosa (arRP) has yet to be determined. We generated knock-in mice carrying a single nucleotide change in exon 2 of the rod opsin gene resulting in the E150K mutation. This novel mouse model displayed severe retinal degeneration affecting rhodopsin's stabilization of rod outer segments (ROS). Homozygous E150K (KK) mice exhibited early-onset retinal degeneration, with disorganized ROS structures, autofluorescent deposits in the subretinal space, and aberrant photoreceptor phagocytosis. Heterozygous (EK) mice displayed a delayed-onset milder retinal degeneration. Further, mutant receptors were mislocalized to the inner segments and perinuclear region. Though KK mouse rods displayed markedly decreased phototransduction, biochemical studies of the mutant rhodopsin revealed only minimally affected chromophore binding and G protein activation. Ablation of the chromophore by crossing KK mice with mice lacking the critical visual cycle protein LRAT slowed retinal degeneration, whereas blocking phototransduction by crossing KK mice with GNAT1-deficient mice slightly accelerated this process. This study highlights the importance of proper higher-order organization of rhodopsin in the native tissue and provides information about the signaling properties of this mutant rhodopsin. Additionally, these results suggest that patients heterozygous for the E150K mutation should be periodically reevaluated for delayed-onset retinal degeneration.


Estimating alcohol-related premature mortality in San Francisco: use of population-attributable fractions from the global burden of disease study.
In recent years, national and global mortality data have been characterized in terms of well-established risk factors. In this regard, alcohol consumption has been called the third leading "actual cause of death" (modifiable behavioral risk factor) in the United States, after tobacco use and the combination of poor diet and physical inactivity. Globally and in various regions of the world, alcohol use has been established as a leading contributor to the overall burden of disease and as a major determinant of health disparities, but, to our knowledge, no one has characterized alcohol-related harm in such broad terms at the local level. We asked how alcohol-related premature mortality in San Francisco, measured in years of life lost (YLLs), compares with other well-known causes of premature mortality, such as ischemic heart disease or HIV/AIDS. We applied sex- and cause-specific population-attributable fractions (PAFs) of years of life lost (YLLs) from the Global Burden of Disease Study to 17 comparable outcomes among San Francisco males and females during 2004-2007. We did this in three ways: Method 1 assumed that all San Franciscans drink like populations in developed economies. These estimates were limited to alcohol-related harm. Method 2 modified these estimates by including several beneficial effects. Method 3 assumed that Latino and Asian San Franciscans drink alcohol like populations in the global regions related to their ethnicity. By any of these three methods, alcohol-related premature mortality accounts for roughly a tenth of all YLLs among males. Alcohol-related YLLs among males are comparable to YLLs for leading causes such as ischemic heart disease and HIV/AIDS, in some instances exceeding them. Latino and black males bear a disproportionate burden of harm. Among females, for whom estimates differed more by method and were smaller than those for males, alcohol-related YLLs are comparable to leading causes which rank somewhere between fifth and fourteenth. Alcohol consumption is a major contributor to premature mortality in San Francisco, especially among males. Interventions to avert alcohol-related harm in San Francisco should be taken at the population level and deserve the same attention that is given to other major risk factors, such as smoking or obesity.


Anatomical connectivity influences both intra- and inter-brain synchronizations.
Recent development in diffusion spectrum brain imaging combined to functional simulation has the potential to further our understanding of how structure and dynamics are intertwined in the human brain. At the intra-individual scale, neurocomputational models have already started to uncover how the human connectome constrains the coordination of brain activity across distributed brain regions. In parallel, at the inter-individual scale, nascent social neuroscience provides a new dynamical vista of the coupling between two embodied cognitive agents. Using EEG hyperscanning to record simultaneously the brain activities of subjects during their ongoing interaction, we have previously demonstrated that behavioral synchrony correlates with the emergence of inter-brain synchronization. However, the functional meaning of such synchronization remains to be specified. Here, we use a biophysical model to quantify to what extent inter-brain synchronizations are related to the anatomical and functional similarity of the two brains in interaction. Pairs of interacting brains were numerically simulated and compared to real data. Results show a potential dynamical property of the human connectome to facilitate inter-individual synchronizations and thus may partly account for our propensity to generate dynamical couplings with others.


Residential Mobility and Geospatial Disparities in Colon Cancer Survival.
Identifying geospatial cancer survival disparities is critical to focus interventions and prioritize efforts with limited resources. Incorporating residential mobility into spatial models may result in different geographic patterns of survival compared with the standard approach using a single location based on the patient's residence at the time of diagnosis. Data on 3,949 regional-stage colon cancer cases diagnosed from 2006 to 2011 and followed until December 31, 2016, were obtained from the New Jersey State Cancer Registry. Geographic disparity based on the spatial variance and effect sizes from a Bayesian spatial model using residence at diagnosis was compared with a time-varying spatial model using residential histories [adjusted for sex, gender, substage, race/ethnicity, and census tract (CT) poverty]. Geographic estimates of risk of colon cancer death were mapped. Most patients (65%) remained at the same residence, 22% changed CT, and 12% moved out of state. The time-varying model produced a wider range of adjusted risk of colon cancer death (0.85-1.20 vs. 0.94-1.11) and resulted in greater geographic disparity statewide after adjustment (25.5% vs. 14.2%) compared with the model with only the residence at diagnosis. Including residential mobility may allow for more precise estimates of spatial risk of death. Results based on the traditional approach using only residence at diagnosis were not substantially different for regional stage colon cancer in New Jersey. Including residential histories opens up new avenues of inquiry to better understand the complex relationships between people and places, and the effect of residential mobility on cancer outcomes.See related commentary by Williams, p. 2107.


A Clinical Trial to Introduce Voluntary Medical Male Circumcision for HIV Prevention in Areas of High Prevalence in the Dominican Republic.
Voluntary Medical Male Circumcision (VMMC) is an effective strategy to reduce the risk of HIV infection. Studies conducted in the Dominican Republic (DR) suggest that acceptability of VMMC among men may be as high as 67%. The goal of this clinical trial was to assess the acceptability, uptake and safety for VMMC services in two areas of high HIV prevalence in the country. This was a single-arm, non-randomized, pragmatic clinical trial. Study personnel received background information about the risks and benefits of VMMC and practical training on the surgical technique. A native speaking research assistant administered a questionnaire of demographics, sexual practices and knowledge about VMMC. One week after the surgery, participants returned for wound inspection and to answer questions about their post-surgical experience. 539 men consented for the study. Fifty seven were excluded from participation for medical or anatomical reasons and 28 decided not to have the procedure after providing consent. A total of 454 men were circumcised using the Forceps Guided Method Under Local Anesthesia. The rate of adverse events (AE) was 4.4% (20% moderate, 80% mild). There were no serious AEs and all complications resolved promptly with treatment. Eighty eight percent of clients reported being "very satisfied" and 12% were "somewhat satisfied" with the outcome at the one-week postoperative visit. Recruitment and uptake were satisfactory. Client satisfaction with VMMC was high and the rate of AEs was low. Roll out of VMMC in targeted areas of the DR is feasible and should be considered. ClinicalTrials.gov NCT02337179.


Control of information in working memory: Encoding and removal of distractors in the complex-span paradigm.
The article reports four experiments with complex-span tasks in which encoding of memory items alternates with processing of distractors. The experiments test two assumptions of a computational model of complex span, SOB-CS: (1) distractor processing impairs memory because distractors are encoded into working memory, thereby interfering with memoranda; and (2) free time following distractors is used to remove them from working memory by unbinding their representations from list context. Experiment 1 shows that distractors are erroneously chosen for recall more often than not-presented stimuli, demonstrating that distractors are encoded into memory. Distractor intrusions declined with longer free time, as predicted by distractor removal. Experiment 2 shows these effects even when distractors precede the memory list, ruling out an account based on selective rehearsal of memoranda during free time. Experiments 3 and 4 test the notion that distractors decay over time. Both experiments show that, contrary to the notion of distractor decay, the chance of a distractor intruding at test does not decline with increasing time since encoding of that distractor. Experiment 4 provides additional evidence against the prediction from distractor decay that distractor intrusions decline over an unfilled retention interval. Taken together, the results support SOB-CS and rule out alternative explanations. Data and simulation code are available on Open Science Framework: osf.io/3ewh7.


Prognostic impact of acute myeloid leukemia classification. Importance of detection of recurring cytogenetic abnormalities and multilineage dysplasia on survival.
To evaluate the prognostic impact of acute myeloid leukemia (AML) classifications, specimens from 300 patients with 20% or more bone marrow myeloblast cells were studied. Specimens were classified according to the French-American-British Cooperative Group (FAB), the World Health Organization (WHO), the Realistic Pathologic Classification, and a cytogenetic risk group scheme. Cases with fewer than 30% blast cells did not have a 5-year survival significantly different from cases with 30% or more blast cells, and survival was similar for the low blast cell count group and cases with multilineage dysplasia and 30% or more blasts. Categories of AML with recurrent cytogenetic abnormalities of t(15;17), t(8;21), inv(16)/t(16;16), and 11q23 showed significant differences in 5-year survival. No significant difference was identified between AMLs arising from myelodysplasia and de novo AMLs with multilineage dysplasia, but all cases with multilineage dysplasia had a worse survival than all other AMLs and other AMLs without favorable cytogenetics. FAB types M0, M3, and M4Eo showed differences in survival compared with all other FAB types, with M0 showing a significant association with high-risk cytogenetics and 11q23 abnormalities. Other FAB groups and WHO AML, not otherwise categorized subgroups did not show survival differences. These findings suggest that the detection of recurring cytogenetic abnormalities and multilineage dysplasia are the most significant features of current AML classification.


BiGG: a Biochemical Genetic and Genomic knowledgebase of large scale metabolic reconstructions.
Genome-scale metabolic reconstructions under the Constraint Based Reconstruction and Analysis (COBRA) framework are valuable tools for analyzing the metabolic capabilities of organisms and interpreting experimental data. As the number of such reconstructions and analysis methods increases, there is a greater need for data uniformity and ease of distribution and use. We describe BiGG, a knowledgebase of Biochemically, Genetically and Genomically structured genome-scale metabolic network reconstructions. BiGG integrates several published genome-scale metabolic networks into one resource with standard nomenclature which allows components to be compared across different organisms. BiGG can be used to browse model content, visualize metabolic pathway maps, and export SBML files of the models for further analysis by external software packages. Users may follow links from BiGG to several external databases to obtain additional information on genes, proteins, reactions, metabolites and citations of interest. BiGG addresses a need in the systems biology community to have access to high quality curated metabolic models and reconstructions. It is freely available for academic use at http://bigg.ucsd.edu.


Understanding HIV risks among adolescent girls and young women in informal settlements of Nairobi, Kenya: Lessons for DREAMS.
High incidence of HIV infection among adolescent girls and young women (AGYW) has been attributed to the numerous and often layered vulnerabilities that they encounter including violence against women, unfavourable power relations that are worsened by age-disparate sexual relations, and limited access to sexual and reproductive health information and services. For AGYW living in urban informal settlements (slums), these vulnerabilities are compounded by pervasive poverty, fragmented social networks, and limited access to social services including health and education. In this paper, we assess sexual risk behaviours and their correlates among AGYW in two slum settlements in Nairobi, Kenya, prior to the implementation of interventions under the Determined Resilient Empowered AIDS-free Mentored and Safe (DREAMS) Partnership. We drew on secondary data from the Transition to Adulthood study, the most recent representative study on adolescent sexual behaviour in the two settlements. The study was nested within the Nairobi Urban Health and Demographic Surveillance System (NUHDSS). Data were collected in 2009 from 1,390 AGYW aged 12-23 years. We estimated the proportions of AGYW reporting ever tested for HIV, condom use, multiple sexual partners and age-disparate sex by socio-demographic characteristics. "High risk" sexual behaviour was defined as a composite of these four variables and age at first sex. Multivariable regression analyses were performed to identify factors associated with risk behaviours. Fifty-one percent of AGYW reported that they had ever tested for HIV and received results of their last test, with the proportion rising steeply by age (from 15% to 84% among those <15 years and 20-23 years, respectively). Of 578 AGYW who were sexually active in the 12 months preceding the survey, 26% reported using a condom at last sex, 4% had more than one sexual partner, and 26% had sex with men who were at least 5 years older or younger. All girls aged below 15 years who had sex (n = 9) had not used condoms at last sex. The likelihood of engaging in "high risk" sexual risk behaviour was higher among older AGYW (19-23 years), those in marital unions, of Luo ethnicity, out of school, living alone or with a friend (versus parents), living with spouse (versus parents), and those whose friends engaged in risky/anti-social behaviours. In contrast, Muslim faith, co-residence with both parents, and belonging to an organised social group were associated with lower odds of risky sexual behaviours. Our study findings suggest that multifaceted approaches addressing the educational and social mediators of AGYW's vulnerability and that also reach the people with whom AGYW live and interact, are needed to reduce the rapid onset of sexual risk during the adolescent years. There is a particular need to reach the youngest adolescent girls in poor urban settings, among whom condom use and awareness of HIV status is rare.


Chronic exposure to non-eruptive volcanic activity as cause of bronchiolar histomorphological alteration and inflammation in mice.
It is estimated that 10% of the worldwide population lives in the vicinity of an active volcano. However, volcanogenic air pollution studies are still outnumbered when compared with anthropogenic air pollution studies, representing an unknown risk to human populations inhabiting volcanic areas worldwide. This study was carried out in the Azorean archipelago of Portugal, in areas with active non-eruptive volcanism. The hydrothermal emissions within the volcanic complex of Furnas (São Miguel Island) are responsible for the emission of nearly 1000 tons of CO2 per day, along with H2S, the radioactive gas - radon, among others. Besides the gaseous emissions, metals (e.g., Hg, Cd, Al, Ni) and particulate matter are also released into the environment. We test the hypothesis that chronic exposure to volcanogenic air pollution alters the histomorphology of the bronchioles and terminal bronchioles, using the house mouse, Mus musculus, as bioindicator species. Mus musculus were live-captured at three different locations: two villages with active volcanism and a village without any type of volcanic activity (reference site). The histomorphology of the bronchioles (diameter, epithelium thickness, smooth muscle layer thickness, submucosa thickness and the histological evaluation of the peribronchiolar inflammation) and of the terminal bronchioles (epithelium thickness and classification) were evaluated. Mice chronically exposed to volcanogenic air pollution presented bronchioles with increased epithelial thickness, increased smooth muscle layer, increased submucosa thickness and increased peribronchiolar inflammation. Similarly, terminal bronchioles presented structural alterations consistent with bronchodysplasia. For the first time we demonstrate that chronic exposure to non-eruptive volcanically active environments causes inflammation and histomorphological alterations in mice lower airways consistent with asthma and chronic bronchitis. These results reveal that chronic exposure to non-eruptive volcanic activity represents a risk factor that can affect the health of the respiratory system of humans inhabiting hydrothermal areas.


Evaluating atmospheric CO2 inversions at multiple scales over a highly inventoried agricultural landscape.
An intensive regional research campaign was conducted by the North American Carbon Program (NACP) in 2007 to study the carbon cycle of the highly productive agricultural regions of the Midwestern United States. Forty-five different associated projects were conducted across five US agencies over the course of nearly a decade involving hundreds of researchers. One of the primary objectives of the intensive campaign was to investigate the ability of atmospheric inversion techniques to use highly calibrated CO2 mixing ratio data to estimate CO2 flux over the major croplands of the United States by comparing the results to an inventory of CO2 fluxes. Statistics from densely monitored crop production, consisting primarily of corn and soybeans, provided the backbone of a well studied bottom-up inventory flux estimate that was used to evaluate the atmospheric inversion results. Estimates were compared to the inventory from three different inversion systems, representing spatial scales varying from high resolution mesoscale (PSU), to continental (CSU) and global (CarbonTracker), coupled to different transport models and optimization techniques. The inversion-based mean CO2 -C sink estimates were generally slightly larger, 8-20% for PSU, 10-20% for CSU, and 21% for CarbonTracker, but statistically indistinguishable, from the inventory estimate of 135 TgC. While the comparisons show that the MCI region-wide C sink is robust across inversion system and spatial scale, only the continental and mesoscale inversions were able to reproduce the spatial patterns within the region. In general, the results demonstrate that inversions can recover CO2 fluxes at sub-regional scales with a relatively high density of CO2 observations and adequate information on atmospheric transport in the region.


Mechanical environment affects allograft incorporation.
In a bilateral canine tibial model, the mechanical, radiologic, and histologic characteristics of intercalary allografts stabilized with locked intramedullary nails were compared with those of allografts fixed with compression plates. Both methods of fixation achieved healing to host bone. Tibiae that were plated had more callus with statistically greater mean torsional rigidity and strength than those treated with nails (paired t-test, p </= 0.05). On average, tibiae which had been plated had much higher bending rigidity than those fixed with locked nails; however, the difference in means was not statistically significant. Histomorphometric analysis showed an overall greater total bone formation in those limbs treated with plates compared to nails (paired t-test, p </= 0.04). The mechanical environment created by the different fixation methods are thought to be responsible for the observed differences in healing pattern. The traditional concept of fixation for allografts to achieve maximum rigidity of the construct may not necessarily promote the most appropriate host healing response in all situations. A less rigid fixation method (plates) produced more callus resulting in superior torsional and bending properties. These data show that in this canine intercalary allograft model, limbs fixed with plates produced more external callus resulting in stronger, more rigid healing.


Inability to noninvasively diagnose gastric intestinal metaplasia in Hispanics or reverse the lesion with Helicobacter pylori eradication.
Helicobacter pylori infection has been linked with the development of gastric adenocarcinoma and its precursor lesion, intestinal metaplasia (IM). The presence of gastric IM is not associated with symptoms, which makes identification of individuals with this lesion difficult. It is not clear whether eradication of H. pylori infection leads to reversal of gastric IM or the potential decrease in the risk of cancer in these patients. The purpose of this pilot study was to define the prevalence of gastric IM in a population at high risk for gastric cancer (Southwestern Hispanics), examine the ability of noninvasive testing to identify individuals with the lesion, and determine whether eradication of H. pylori infection reverses gastric IM in this population. Subjects from the Tucson metropolitan area were recruited, and baseline data, including the presence of upper gastrointestinal (UGI) symptoms, urinary sodium, and serum pepsinogen levels, were obtained. Upper endoscopy was performed and six gastric biopsies from specific anatomic sites were obtained, followed by methylene blue staining with targeted biopsies from blue-stained mucosa. Biopsies were evaluated for the presence of H. pylori infection and gastric IM. A subset of patients with gastric IM were treated to eradicate H. pylori infection. Follow-up exams with methylene blue staining, including biopsies for histology and rapid urease testing, were performed for up to 48 months. There were 84 subjects with a mean age of 53.0 years; 24 (29%) had gastric IM and 65 (77%) had H. pylori. There was no significant association between gastric IM and age, gender, UGI symptoms, H. pylori, or urine sodium. There was an association identified between gastric IM and a decreased pepsinogen I:II ratio (p = 0.03). Of the 11 individuals with gastric IM treated for H. pylori infection, 9 had successful therapy and underwent at least 2 follow-up examinations. The mean length of follow-up was 3.3 years. Eight of the nine (89%) had gastric IM identified histologically at the final endoscopic exam. H. pylori infection and gastric IM are frequent findings in Southwestern Hispanics, a high-risk population for gastric cancer. Noninvasive testing is not clinically useful in distinguishing individuals within this group who harbor gastric IM. Although eradication of H. pylori infection may lead to a decrease in the amount of gastric IM in some individuals, the lesion may be detected in the majority of individuals after more than 3 years of follow-up. These data suggest that therapy for H. pylori may not eliminate the risk of gastric cancer once IM has developed.


Oral methotrexate in ulcerative colitis.
We performed an audit of methotrexate for ulcerative colitis, because efficacy is unclear. Aim : To investigate the role of methotrexate in the management of ulcerative colitis. Patients with ulcerative colitis treated with oral methotrexate at the inflammatory bowel disease clinics of Oxford and Wycombe General Hospital, UK, were evaluated. Efficacy was defined by remission (complete steroid withdrawal for >3 months) and response (good, partial or nil, proportionate reduction of steroids). There were 50 patients (42 ulcerative colitis alone; eight had rheumatoid arthritis associated with ulcerative colitis and were analysed separately). Indications for methotrexate in ulcerative colitis alone were azathioprine intolerance (31 of 42) and lack of benefit from azathioprine (11 of 42). The mean dose of methotrexate in ulcerative colitis alone was 19.9 mg/week for a median of 30 weeks (range: 7-395). Remission occurred in 42%. The response was good in 54% and partial in 18%. Side-effects occurred in 23%; 10% stopped treatment because of side-effects. Of those treated with methotrexate because of treatment failure with azathioprine, three of 11 achieved remission, but four came to colectomy within 90 days of starting methotrexate. The colitis remained in remission in seven of eight of those with RA treated with methotrexate and ulcerative colitis (mean dose 15.0 mg/week). Oral methotrexate (approximately 20 mg/week) is well-tolerated and moderately effective in steroid-dependent or steroid-refractory patients with ulcerative colitis.


Usual interstitial pneumonia-pattern fibrosis in surgical lung biopsies. Clinical, radiological and histopathological clues to aetiology.
Pulmonary fibrosis in surgical lung biopsies is said to have a 'usual interstitial pneumonia-pattern' (UIP-pattern) of disease when scarring of the parenchyma is present in a patchy, 'temporally heterogeneous' distribution. These biopsies are one of the more common non-neoplastic specimens surgical pathologists encounter and often pose a number of challenges. UIP is the expected histopathological pattern in patients with clinical idiopathic pulmonary fibrosis (IPF), but the UIP-pattern can be seen in other conditions on occasion. Most important among these are the rheumatic interstitial lung diseases (RILD) and chronic hypersensitivity pneumonitis (CHrHP). Because theses entities have different mechanisms of injury, approach to therapy, and expected clinical progression, it is imperative for the surgical pathologist to correctly classify them. Taken in isolation, the UIP-pattern seen in patients with IPF may appear to overlap with that of RILD and CHrHP, at least when using the broadest definition of this term (patchy fibrosis). However, important distinguishing features are nearly always present in our experience, and the addition of a multidisciplinary approach will often resolve the critical differences between these diseases. In this manuscript, we review the distinguishing clinical, radiologic and histopathological features of UIP of IPF, RILD and CHrHP, based, in part, on the existing literature, but also lessons learned from a busy lung biopsy consultation practice.


Possible blindsight in infants lacking one cerebral hemisphere.
Patients with damage to the striate cortex have a subjectively blind region of the visual field, but may still be able to detect and localize targets within this region. But the relative roles in this 'blindsight' of subcortical neural systems, and of pathways to extra-striate visual areas, have been uncertain. Here we report results on two infants in whom one cerebral hemisphere, including both striate and extra-striate visual cortex, needed surgical removal in their first year. Single conspicuous targets in the half-field contralateral to the lesion could elicit fixations, implying detection and orienting by a subcortical system. In contrast, binocular optokinetic nystagmus (OKN), for which a subcortical pathway has often been thought adequate, showed a marked asymmetry. In normal neonates, fixation shifts and OKN have both been taken to reflect subcortical control; our results are consistent with subcortical control for fixation but not for OKN.


Pathogen diversity and hidden regimes of apparent competition.
Competition through cross-reacting host immune responses, a form of apparent competition, is a major driver of pathogen evolution and diversity. Most models of pathogens have focused on intraspecific interactions to explain observed patterns. Two recent experiments suggested that Haemophilus influenzae, a common nasopharyngeal colonizer of humans, might alter the immune environment in a way that favors otherwise less fit serotypes of another common pathogen, pneumococcus. Using a computational model, we demonstrate that H. influenzae, if it consistently raises the fitness of the less fit serotypes, can strongly promote pneumococcal diversity. However, the effects of H. influenzae are so sensitive to the prevalence of H. influenzae that this species is unlikely to be the main driver of serotype coexistence. Interactions that significantly affect diversity could furthermore be extremely difficult to detect through co-occurrence analysis alone. These results suggest that small differences in strains' adaptations to different immunological regimes, which are shaped by coinfections with other pathogens, can have dramatic effects on strain dynamics and patterns of phenotypic variation. Studies of microbial communities might therefore benefit from the use of varied approaches to infer the presence of indirect interactions.


Polyamines decrease Escherichia coli outer membrane permeability.
The permeability of the outer membranes of gram-negative bacteria to hydrophilic compounds is mostly due to the presence of porin channels. We tested the effects of four polyamines (putrescine, cadaverine, spermidine, and spermine) on two processes known to depend on intact porin function: fluxes of beta-lactam antibiotics in live cells and chemotaxis. In both cases, inhibition was observed. Measurements of the rate of permeation of cephaloridine and of chemotaxis in swarm plates and capillary assays were used to determine the concentration dependence of this modulation. The effective concentration ranges depended on the nature of the polyamine and varied from submillimolar for spermine to tens of millimolar for cadaverine. Both OmpC and OmpF porins were inhibited, although the effects on OmpC appeared to be milder. These results are in agreement with our observations that polyamines inhibit porin-mediated ion fluxes in electrophysiological experiments, and they suggest that a low-affinity polyamine binding site might exist in these porins. These results reveal the potential use of porins as targets for blocking agents and suggest that polyamines may act as endogenous modulators of outer membrane permeability.


The spatial level of analysis affects the patterns of forest ecosystem services supply and their relationships.
The implementation of the Ecosystem Services (ES) framework (including supply and demand) should be based on accurate spatial assessments to make it useful for land planning or environmental management. Despite the inherent dependence of ES assessments on the spatial resolution at which they are conducted, the studies analyzing these effects on ES supply and their relationships are still scarce. To study the influence of the spatial level of analysis on ES patterns and on the relationships among different ES, we selected seven indicators representing ES supply and three variables that describe forest cover and biodiversity for Catalonia (NE Iberian Peninsula). These indicators were estimated at three different scales: local, municipality and county. Our results showed differences in the ES patterns among the levels of analysis. The higher levels (municipality/county) removed part of the local heterogeneity of the patterns observed at the local scale, particularly for ES indicators characterized by a finely grained, scattered distribution. The relationships between ES indicators were generally similar at the three levels. However, some negative relationships (potential trade-offs) that were detected at the local level changed to positive (and significant) relationships at municipality and county. Spatial autocorrelation showed similarities between patterns at local and municipality levels, but differences with county level. We conclude that the use of high-resolution spatial data is preferable whenever available, in particular when identifying hotspots or trade-offs/synergies is of primary interest. When the main objective is describing broad patterns of ES, intermediate levels (e.g., municipality) are also adequate, as they conserve many of the properties of assessments conducted at finer scales, allowing the integration of data sources and, usually, being more directly relevant for policy-making. In conclusion, our results warn against the uncritical use of coarse (aggregated) spatial ES data and indicators in strategies for land use planning and forest conservation.


Memory's penumbra: episodic memory decisions induce lingering mnemonic biases.
How do we decide if the people we meet and the things we see are familiar or new? If something is new, we need to encode it as a memory distinct from already stored episodes, using a process known as pattern separation. If familiar, it can be used to reactivate a previously stored memory, by a process known as pattern completion. To orchestrate these conflicting processes, current models propose that the episodic memory system uses environmental cues to establish processing biases that favor either pattern separation during encoding or pattern completion during retrieval. To assess this theory, we measured how people's memory formation and decisions are influenced by their recent engagement in episodic encoding and retrieval. We found that the recent encoding of novel objects improved subsequent identification of subtle changes, a task thought to rely on pattern separation. Conversely, recent retrieval of old objects increased the subsequent integration of stored information into new memories, a process thought to rely on pattern completion. These experiments provide behavioral evidence that episodic encoding and retrieval evoke lingering biases that influence subsequent mnemonic processing.


Bioavailability of Beclometasone From Two HFA-BDP Formulations With a Spacer.
The drug delivery characteristics of each inhaler/spacer combination are unique. The spacer size as well as the presence of electrostatic charge greatly influence the inhaler dose emission and in vivo delivery. Using a previously developed urinary pharmacokinetic method, we have measured the relative lung and systemic bioavailability of beclometasone dipropionate (BDP) after inhalation from 2 hydrofluroalkane-beclometasone dipropionate (HFA-BDP) formulations when used with a spacer. 12 healthy volunteers received 8 randomized doses, separated by 7 d, of inhaled of BDP with either the Clenil pressurized metered-dose inhaler (pMDI; 250 μg) or the breath-actuated Qvar Easi-Breathe inhaler (100 μg), used alone or with a spacer. The urinary amounts of BDP excreted and retained in the spacer were assayed using a liquid chromatographic mass spectrometer. The spacer was assessed after washing with a detergent solution that was either rinsed or not rinsed with water. In addition, the aerodynamic characterization of each inhaler/spacer combination was assessed using the Andersen Cascade Impactor operated at 28 L/min using a 4-L inhalation volume. The amount of BDP deposited in the induction port, spacer, and various Anderson Cascade Impactor stages were determined. The in vivo 30-min urinary excretion and the in vitro fine particle dose results were only slightly affected by adding the spacer to the Clenil pMDI or the Qvar Easi-Breathe inhaler. However, the spacer significantly reduced drug particle impaction in the oropharynx and minimized deposition in the gastrointestinal tract. Therefore, using spacers with BDP inhalers is associated with a more favorable therapeutic ratio because it has little effect on lung dose, but it significantly reduced throat deposition. An improved lung deposition was achieved with non-rinsed spacers compared to spacers rinsed with water. The difference in the BDP particle size between formulations as well as spacer size greatly affected drug deposition in different regions of the respiratory tract.


Wait list status of pediatric dialysis patients in North America.
Kidney transplantation is the treatment of choice for the majority of pediatric patients with end-stage kidney disease. Previous studies demonstrating racial or gender disparities in access to the deceased donor transplant list could not evaluate the impact of medical concerns or patient preference on waitlist status. We undertook a retrospective cohort study using the NAPRTCS registry to begin to determine barriers to wait list registration for kidney transplantation among pediatric dialysis patients. Clinical and demographic factors were compared in listed vs. non-listed patients. Reasons cited for not listing patients were examined by clinical and demographic factors. At dialysis initiation, 88.7% of pediatric dialysis patients were not on the renal transplant wait list. Twelve months after dialysis initiation, 67.1% of pediatric dialysis patients were not on the wait list. The groups least likely to be on the wait list were infants (adjusted OR 0.23, 95% CI 0.16, 0.32) and girls (adjusted OR 0.78, 95% CI 0.67, 0.90) after adjusting for multiple confounders. The reason most often cited for not listing was medical reason for young infants and that the transplant workup was pending for girls. Further study is needed to identify barriers to wait list registration.


Transradial approach to subclavian artery stenting.
Subclavian artery angioplasty has been traditionally performed via the transfemoral approach. Transradial access is becoming increasingly used for coronary as well as for certain peripheral vascular beds. We describe our experience with transradial access for subclavian artery stenting. We performed a retrospective review of subclavian artery interventions from 2007 to 2009 at our institution. Demographics, clinical data, lesion and procedural characteristics were collected. Safety and efficacy endpoints were recorded, and follow-up was performed at 1 year post intervention. Descriptive statistics were used to analyze the data. Fourteen cases of subclavian artery stenting, including 5 total occlusions, were performed using transradial access. The procedural success was 93%, and there were no complications recorded. All patients remained symptom-free at 1-year follow up. Subclavian artery stenting can be safely performed via transradial access with success rates comparable to the transfemoral approach.


[Analysis of the first cluster of cases in a family of novel coronavirus pneumonia in Gansu Province].
The epidemiological history and clinical characteristics of 7 cases of COVID-19 and 1 case of close contact in the first family aggregation epidemic of COVID-19 in Gansu Province were analyzed. The first patient A developed on January 22, 2020, with a history of residence in Wuhan, and confirmed severe cases of NCP on January 24, 2020; patient B, on January 23, 2020, diagnosed on January 31, severe cases; patient C, asymptomatic, diagnosed on January 27; patient D, asymptomatic, diagnosed on January 27; patient E, on January 24, diagnosed on January 28; patient F, asymptomatic, diagnosed on January 31; Patient G was asymptomatic and was diagnosed on January 31. In close contact, H was asymptomatic, PCR test was negative and asymptomatic, and he was discharged early. Among the 7 patients, 1 case died of (B) aggravation, and the other patients' condition was effectively controlled after active treatment. Except for the discharged cases, 5 cases were positive for COVID-19 specific IgM antibody and 1 case was negative. In this clustering outbreak, 4 patients remained asymptomatic, but PCR and IgM antibodies were positive, indicating that asymptomatic patients may be the key point to control the epidemic. Specific IgM antibody screening for patients whose pharyngeal swab nucleic acid test is negative but with ground glass-like lung lesions is very important for early detection and early isolation.


Interacting with the biomolecular solvent accessible surface via a haptic feedback device.
From the 1950s computer based renderings of molecules have been produced to aid researchers in their understanding of biomolecular structure and function. A major consideration for any molecular graphics software is the ability to visualise the three dimensional structure of the molecule. Traditionally, this was accomplished via stereoscopic pairs of images and later realised with three dimensional display technologies. Using a haptic feedback device in combination with molecular graphics has the potential to enhance three dimensional visualisation. Although haptic feedback devices have been used to feel the interaction forces during molecular docking they have not been used explicitly as an aid to visualisation. A haptic rendering application for biomolecular visualisation has been developed that allows the user to gain three-dimensional awareness of the shape of a biomolecule. By using a water molecule as the probe, modelled as an oxygen atom having hard-sphere interactions with the biomolecule, the process of exploration has the further benefit of being able to determine regions on the molecular surface that are accessible to the solvent. This gives insight into how awkward it is for a water molecule to gain access to or escape from channels and cavities, indicating possible entropic bottlenecks. In the case of liver alcohol dehydrogenase bound to the inhibitor SAD, it was found that there is a channel just wide enough for a single water molecule to pass through. Placing the probe coincident with crystallographic water molecules suggests that they are sometimes located within small pockets that provide a sterically stable environment irrespective of hydrogen bonding considerations. By using the software, named HaptiMol ISAS (available from http://www.haptimol.co.uk), one can explore the accessible surface of biomolecules using a three-dimensional input device to gain insights into the shape and water accessibility of the biomolecular surface that cannot be so easily attained using conventional molecular graphics software.