Complications and Mortality Among Correctly Triaged and Undertriaged Severely Injured Older Adults With Traumatic Brain Injuries.
Determining differences in clinical outcomes of older adults treated at trauma centers (TCs) and nontrauma centers (NTCs) is imperative considering their persistent undertriage and the projected costs of fixing the problem. This study compared the incidence and predictors of complications and mortality among brain-injured older adults treated at TCs and NTCs. This secondary analysis of New York inpatient data included patients aged 55+ years, primary brain injury diagnosis, and acute care hospital admission. Interfacility transfers and nontraumatic brain injuries were excluded. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes identified complications and mortality. Injury severity was determined by mapping ICD-9-CM diagnoses to Abbreviated Injury Scale 2005 Revision 2008 dictionary scores. A subgroup analysis of 1,594 patients with New Injury Severity Scores greater than 15 was performed to examine complications and mortality. This study included 7,138 patients who met inclusion criteria. Predictors of subgroup complications included chronic renal failure, odds ratio (OR) = 2.251 (confidence interval [CI] = 1.470-3.447), p < .001; major operating room procedure, OR = 2.349 (CI = 1.679-3.285), p < .001; number of diagnoses, OR = 1.201 (CI = 1.158-1.245), p < .001; and number of procedures, OR = 1.119 (CI = 1.077-1.162), p £ .001. Mortality predictors included age, OR = 1.031 (CI = 1.017-1.045), p < .001; preexisting coagulopathy, OR = 1.753 (C = 1.130-2.719), p = .012; number of procedures, OR = 1.122 (CI = 1.081-1.166), p < .001; acute renal failure, OR = 3.114 (CI = 1.672-5.797), p < .001; systemic inflammatory response syndrome, OR = 4.058 (CI = 1.463-11.258), p = .007; adult respiratory distress syndrome, OR = 3.179 (CI = 1.673-6.041), p < .001; and subarachnoid bleed, OR = 2.667 (CI = 1.415-5.029), p = .002. Nearly 23% of the severely/critically injured patients experienced 1 or more complications. Incidence of complications was low and comparable for TCs and NTCs. The proportion of deaths was slightly higher at TCs but not significant. The most prevalent complications carry a high mortality risk.


Feeding practices and nutritional status of HIV-exposed and HIV-unexposed infants in the Western Cape.
Optimal infant- and young child-feeding practices are crucial for nutritional status, growth, development, health and, ultimately, survival. Human breast milk is optimal nutrition for all infants. Complementary food introduced at the correct age is part of optimal feeding practices. In South Africa, widespread access to antiretrovirals and a programme to prevent mother-to-child transmission of HIV have reduced HIV infection in infants and increased the number of HIV-exposed uninfected (HEU) infants. However, little is known about the feeding practices and nutritional status of HEU and HIV-unexposed (HU) infants. To assess the feeding practices and nutritional status of HIV-exposed and HIV-unexposed (HU) infants in the Western Cape. Prospective substudy on feeding practices nested in a pilot study investigating the innate immune abnormalities in HEU infants compared to HU infants. The main study commenced at week 2 of life with the nutrition component added from 6 months. Information on children's dietary intake was obtained at each visit from the caregiver, mainly the mother. Head circumference, weight and length were recorded at each visit. Data were obtained from 6-, 12- and 18-month visits. World Health Organization feeding practice indicators and nutrition indicators were utilised. Tygerberg Academic Hospital, Western Cape. Mothers were recruited from the postnatal wards. Forty-seven mother-infant pairs, 25 HEU and 22 HU infants, participated in this nutritional substudy. Eight (17%) infants, one HU and seven HEU, were lost to follow-up over the next 12 months. The HEU children were mainly Xhosa (76%) and HU were mainly mixed race (77%). The participants were from poor socio-economic backgrounds. In both groups, adherence to breastfeeding recommendations was low with suboptimal dietary diversity. We noted a high rate of sugar- and salt-containing snacks given from a young age. The HU group had poorer anthropometric and nutritional indicators not explained by nutritional factors alone. However, alcohol and tobacco use was much higher amongst the HU mothers. Adherence to breastfeeding recommendations was low. Ethnicity and cultural milieu may have influenced feeding choices and growth. Further research is needed to understand possible reasons for the poorer nutritional and anthropometric indicators in the HU group.


[Treatment of autosomal dominant polycystic kidney disease (ADPKD) - Tolvaptan].
The European Medicines Agency approved tolvaptan to slow cyst growth and renal failure progression in adults with ADPKD, glomerular filtration 60 mL/min x 1.73 m2 and rapidly progressive disease. In a multicenter 3-year study, conducted on 1,445 patients with non-genotyped ADPKD, ages 18-50 years, predicted creatinine clearance 60 mL/min and kidney total volume 750 mL, tolvaptan slowed kidney failure progression (-23%-46% for different objectives) and reduced kidney volume increase and pain without effects on hypertension and albuminuria.Tolvaptan induced reversible idiosyncratic hepatopathy in 4% of patients (1% in placebo). Tolvaptan antagonizes ADH effects, reduces cyclic-AMP generation in distal nephron, and induces water diuresis. It has high protein-binding and 8-hour half-life. Dosage is 60-120 mg/day in two different doses (for instance 45/15 or 60/30 mg). Treatment starts using lower dose and continues with cautious up-titolation. Data are insufficient for severe hepatopathy or nephropathy. There is no antidote against overdose. Dialysis should not remove tolvaptan. Aquaretic effects require high fluid intake to prevent dehydration. Treatment should be reduced or suspended in case of inadequate fluid intake or dehydration. Weight, natremia and plasma osmolality can inform on dehydration risks. Efficacy is not yet investigated on end-stage renal disease, non-renal ADPKD-related disorders, and mortality.


Association between glycemia and mortality in diabetic individuals on renal replacement therapy in the U.K.
In the U.K., one-third of patients receiving treatment with dialysis have diabetes. Guidelines from organizations representing patients with renal disease or diabetes advocate tight glycemic control in patients with end-stage renal disease, despite glucose-lowering trials having excluded these patients. Using national U.K. Renal Registry data, we tested whether glycemia as measured by hemoglobin (Hb) A(1c) (HbA(1c)) level is associated with death in adults with diabetes starting hemodialysis or peritoneal dialysis between 1997 and 2006, and observed for at least 6 months. Of 7,814 patients, we excluded those who had died within 6 months; had received transplants; were lost/recovered; or lacked measures of HbA1c, ethnicity, or Hb. Categorizing HbA1c measured in the first 6 months of starting dialysis as <6.5% (<48 mmol/mol), 6.5-7.4% (48-57 mmol/mol) (reference value), 7.5-8.4% (58-68 mmol/mol), and ≥8.5% (≥69 mmol/mol), we adjusted in proportional hazards models for age, sex, ethnicity, deprivation, year, dialysis type, and Hb, and tested for interactions. Of 3,157 patients observed for a median time of 2.7 years, 1,688 died. For patients ≥60 years of age, we found no association between HbA1c and death; among younger patients, relative to those with HbA(1c) values 6.5-7.4%, the hazard ratio for HbA(1c) level 7.5-8.4% was 1.2 (95% CI 0.9-1.5), and for HbA(1c) level >8.5% was 1.5 (1.2-1.9). The projected difference in median survival time between younger patients with a reference HbA1c value versus >8.5% was 1 year. In the absence of trials, and confounding notwithstanding, these observational data support improved glycemic control in younger patients prior to and during dialysis.


Longitudinal phenotype development in a minipig model of neurofibromatosis type 1.
Neurofibromatosis type 1 (NF1) is a rare, autosomal dominant disease with variable clinical presentations. Large animal models are useful to help dissect molecular mechanisms, determine relevant biomarkers, and develop effective therapeutics. Here, we studied a NF1 minipig model (NF1+/ex42del) for the first 12 months of life to evaluate phenotype development, track disease progression, and provide a comparison to human subjects. Through systematic evaluation, we have shown that compared to littermate controls, the NF1 model develops phenotypic characteristics of human NF1: [1] café-au-lait macules, [2] axillary/inguinal freckling, [3] shortened stature, [4] tibial bone curvature, and [5] neurofibroma. At 4 months, full body computed tomography imaging detected significantly smaller long bones in NF1+/ex42del minipigs compared to controls, indicative of shorter stature. We found quantitative evidence of tibial bowing in a subpopulation of NF1 minipigs. By 8 months, an NF1+/ex42del boar developed a large diffuse shoulder neurofibroma, visualized on magnetic resonance imaging, which subsequently grew in size and depth as the animal aged up to 20 months. The NF1+/ex42del minipig model progressively demonstrates signature attributes that parallel clinical manifestations seen in humans and provides a viable tool for future translational NF1 research.


Susceptibility of human T-lymphotropic virus type I infected cell line MT-2 to hepatitis C virus infection.
To obtain a hepatitis C virus (HCV) proliferation system, we examined the susceptibility of various cultured cell lines to HCV infection. We found that a human T-lymphotropic virus type I infected cell line MT-2 was fairly sensitive to HCV infection. Using the polymerase chain reaction, intracellular positive-stranded HCV RNA was detected until at least 15 days postinoculation (p.i.). Intracellular negative-stranded HCV RNA was also detected at 10 days p.i., although not at 7 days p.i., suggesting that HCV is replicating in MT-2 cells 10 days p.i. Sequence analysis of hypervariable region 1 (HVR1) revealed that HVR1 sequences from cells 10 days p.i. had become homogeneous, although HVR1 sequences from the inoculum showed the typical quasi-species. We also found a lack of anti-HVR1 antibody against the HVR1 species which became homogeneous at 10 days p.i., although we easily detected antibody against the other HVR1 species obtained from the inoculum. These findings suggest that MT-2 cells are susceptible to HCV infection and are capable of supporting HCV replication.


Impact of aspirin on the transcriptome of Streptococcus pneumoniae D39.
Aspirin or acetylsalicylic acid (ASA) is a medicine used to treat pain, fever, and inflammation. Here, we for the very first time reported the genome-wide transcriptional profiling of aspirin-regulated genes in Streptococcus pneumoniae in the presence of 5 mM aspirin in chemically-defined medium (CDM) using microarray analysis. Our results showed that expression of several genes was differentially expressed in the presence of aspirin. These genes were further grouped into COG (Clusters of Orthologous Groups) functional categories based on the putative functions of the corresponding proteins. Most of affected genes belong to COG category E (Amino acid transport and metabolism), G (Carbohydrate transport and metabolism), J (Translation, ribosomal structure and biogenesis), and I (Lipid transport and metabolism). Transcriptional profiling data of aspirin-regulated genes was deposited to Gene Expression Omnibus (GEO) database under accession number GSE94514.


Area of exposure and treatment challenges of malaria in Eritrean migrants: a GeoSentinel analysis.
Recent reports highlight malaria as a frequent diagnosis in migrants who originate from Eritrea. A descriptive analysis of GeoSentinel cases of malaria in Eritrean migrants was done together with a literature review to elucidate key attributes of malaria in this group with a focus on possible areas of acquisition of malaria and treatment challenges. A total of 146 cases were identified from the GeoSentinel database from 1999 through September 2017, with a marked increase in 2014 and 2015. All patients originated from Eritrea and the main reporting GeoSentinel sites were in Norway, Switzerland, Sweden, Israel and Germany. The majority of patients (young adult males) were diagnosed with malaria following arrival in the host country. All patients had a possible exposure in Eritrea, but may have been exposed in documented transit countries including Ethiopia, Sudan and possibly Libya in detention centres. Most infections were due to Plasmodium vivax (84.2%), followed by Plasmodium falciparum (8.2%). Two patients were pregnant, and both had P. vivax malaria. Some 31% of the migrants reported having had malaria while in transit. The median time to onset of malaria symptoms post arrival in the host country was 39 days. Some 66% of patients were hospitalized and nine patients had severe malaria (according to WHO criteria), including five due to P. vivax. The 146 cases of mainly late onset, sometimes severe, P. vivax malaria in Eritrean migrants described in this multi-site, global analysis reflect the findings of single-centre analyses identified in the literature search. Host countries receiving asylum-seekers from Eritrea need to be prepared for large surges in vivax and, to a lesser extent, falciparum malaria, and need to be aware and prepared for glucose-6-phosphate dehydrogenase deficiency testing and primaquine treatment, which is difficult to procure and mainly unlicensed in Europe. There is an urgent need to explore the molecular epidemiology of P. vivax in Eritrean asylum-seekers, to investigate the area of acquisition of P. vivax along common transit routes and to determine whether there has been re-introduction of malaria in areas, such as Libya, where malaria is considered eliminated, but where capable vectors and Plasmodium co-circulate.


Traumatic rupture of the thoracic aorta.
Fifteen patients with blunt traumatic rupture of the aorta, secondary to automobile accidents, that occurred less than seven days prior to admission were treated between 1967 and 1976. The diagnosis was suspected on the basis of roentgenographic evidence of upper mediastinal widening. Aortography demonstrated a localized deformity and dilation of the aorta isthmus just distal to the subclavian artery in all but one patient whose lesion occurred in the mid-descending thoracic aorta. The salvage of one of five patients with free rupture by the prompt institution of total cardiopulmonary bypass has prompted us to begin each operation with the capability of using either left heart bypass or cardiopulmonary bypass. An associated rupture of the right atrium of one patient was successfully controlled. Nine of 12 patients survived the operation, eight were discharged from the hospital, and six were alive and well as least one year later.


Persantine Aspirin Trial in cerebral ischemia. The American-Canadian Co-operative Study Group.
The Persantine Aspirin Trial is a double-blind multi-centered cooperative study focusing primarily on the question of whether the administration of the combination of aspirin and dipyridamole (Persantine) will result in a greater reduction of cerebral or retinal infarction or death than the administration of aspirin alone. Fifteen centers in the United States and Canada are participating. More than 750 individuals with a history of recent carotid territory transient ischemic attacks (TIAs) have been admitted over the past four years and randomly allocated to either aspirin (325 mg) plus placebo four times daily or aspirin (325 mg) plus Persantine (75 mg) four times daily. It is anticipated that the study will continue through 1983. Analysis and publication of results are planned for 1984.


Renin inhibition improves cardiac function and remodeling after myocardial infarction independent of blood pressure.
Pharmacological renin inhibition with aliskiren is an effective antihypertensive drug treatment, but it is currently unknown whether aliskiren is able to attenuate cardiac failure independent of its blood pressure-lowering effects. We investigated the effect of aliskiren on cardiac remodeling, apoptosis, and left ventricular (LV) function after experimental myocardial infarction (MI). C57J/bl6 mice were subjected to coronary artery ligation and were treated for 10 days with vehicle or aliskiren (50 mg/kg per day via an SC osmopump), whereas sham-operated animals served as controls. This dose of aliskiren, which did not affect systemic blood pressure, improved systolic and diastolic LV function, as measured by the assessment of pressure-volume loops after MI. Furthermore, after MI LV dilatation, cardiac hypertrophy and lung weights were decreased in mice treated with aliskiren compared with placebo-treated mice after MI. This was associated with a normalization of the mitogen-activated protein kinase P38 and extracellular signal-regulated kinases 1/2, AKT, and the apoptotic markers bax and bcl-2 (all measured by Western blots), as well as the number of TUNEL-positive cells in histology. LV dilatation, as well as the associated upregulation of gene expression (mRNA abundance) and activity (by zymography) of the cardiac metalloproteinase 9 in the placebo group after MI, was also attenuated in the aliskiren-treated group. Aliskiren improved LV dysfunction after MI in a dose that did not affect blood pressure. This was associated with the amelioration of cardiac remodelling, hypertrophy, and apoptosis.


Prothrombin complex concentrate versus fresh-frozen plasma for reversal of coagulopathy of trauma: is there a difference?
The development of coagulopathy of trauma is multifactorial associated with hypoperfusion and consumption of coagulation factors. Previous studies have compared the role of factor replacement versus FPP for reversal of trauma coagulopathy. The purpose of our study was to determine the time to correction of coagulopathy and blood product requirement in patients who received PCC+FFP compared with patients who received FFP alone. We performed a retrospective analysis of a prospectively maintained database of all coagulopathic (INR ≥ 1.5) trauma patients presenting to our level I trauma center during a 2-years period (2011-2012). Patients were stratified into two groups: patients who received PCC+FFP and patients who received FFP alone. Patients in the two groups were matched in a 1:3 (PCC+FFP:FFP) ratio using propensity score matching for demographics, injury severity, vital parameters, and initial INR. The two groups were then compared for: correction of INR, time to correction of INR, thromboembolic complications, mortality, and cost of therapy. A total of 252 were included in the analysis [PCC+FFP:63; FFP:189]. The mean age was 44 ± 20 years; 70 % were male, with a median ISS score of 27 [16-38]. PCC use was associated with an accelerated correction of INR (394 vs. 1,050 min; p 0.001), reduction in requirement of pack red blood cell (6.6 vs. 10 units; p 0.001) and FFP (2.8 vs. 3.9 units; p 0.01), and decline in mortality (23 vs. 28%; p 0.04). PCC+FFP use was associated with a higher cost of therapy ($1,470 ± 845 vs. 1,171 ± 949; p 0.01) but lower overall cost of transfusion ($7,110 ± 1,068 vs. 9,571 ± 1,524; p 0.01) compared with FFP therapy alone. PCC in conjunction with FFP rapidly corrects INR in a matched cohort of trauma patients not on warfarin therapy compared with FFP therapy alone. The use of PCC as an adjunct to FFP therapy is associated with reduction of blood product requirement and also lowers overall cost.


Practical considerations in epilepsy neurostimulation.
Neuromodulation is a key therapeutic tool for clinicians managing patients with drug-resistant epilepsy. Multiple devices are available with long-term follow-up and real-world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide the selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS-ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death in epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7 to 10 years of follow-up for all modalities, albeit in uncontrolled follow-up or retrospective studies. A significant number of patients experience seizure-free intervals of 6 months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with comorbidities such as severe mood or sleep disorders, may influence the choice of modality. Programming has evolved-DBS is typically initiated at lower current/voltage than used in the pivotal trial, whereas target charge density is lower with RNS, however generalizable optimal parameters are yet to be defined. Noninvasive brain stimulation is an emerging stimulation modality, although it is currently not used widely. In summary, clinical practice has evolved from those established in pivotal trials. Guidance is now available for clinicians who wish to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences.


Prospective evaluation for upper gastrointestinal tract acute graft-versus-host disease after hematopoietic stem cell transplantation.
The incidence and clinical significance of upper gastrointestinal tract acute graft-versus-host disease (upper GI GVHD) were prospectively evaluated in 44 Japanese patients who underwent allogeneic (n = 26) or autologous (n = 18) stem cell transplantation. Endoscopic examination was routinely performed between days 20 and 50 post-transplant and when symptoms of upper GI and/or acute GVHD of other organs were present. The results were compared with the historical records of 49 allograft and 20 autograft recipients. The diagnosis of upper GI GVHD was confirmed by histologic findings of GVHD and persistent upper GI tract symptoms. The incidence of upper GI GVHD was 46% in the prospective allograft group, higher than in the retrospective group. Upper GI GVHD was not diagnosed in any autograft patients. Twelve of 19 patients with upper GI GVHD had skin GVHD, and two of the 12 had concurrent lower GI GVHD. Upper GI GVHD was successfully treated with steroids and did not progress to symptomatic lower GI GVHD. In addition, upper GI GVHD completely resolved without specific alteration in immunosuppressant therapy in six patients. No risk factors for upper GI GVHD could be identified. The presence of upper GI GVHD did not significantly affect early death rate, incidence of chronic GVHD, and overall survival. In conclusion, by the prospective evaluation of the upper GI tract by endoscopy we could accurately diagnose upper GI GVHD in half our allogeneic recipients. However, upper GI GVHD was successfully controlled with or without additional steroids in all cases and had little impact on transplant outcome.


Functional dissection of the NuA4 histone acetyltransferase reveals its role as a genetic hub and that Eaf1 is essential for complex integrity.
The Saccharomyces cerevisiae NuA4 histone acetyltransferase complex catalyzes the acetylation of histone H4 and the histone variant Htz1 to regulate key cellular events, including transcription, DNA repair, and faithful chromosome segregation. To further investigate the cellular processes impacted by NuA4, we exploited the nonessential subunits of the complex to build an extensive NuA4 genetic-interaction network map. The map reveals that NuA4 is a genetic hub whose function buffers a diverse range of cellular processes, many not previously linked to the complex, including Golgi complex-to-vacuole vesicle-mediated transport. Further, we probe the role that nonessential subunits play in NuA4 complex integrity. We find that most nonessential subunits have little impact on NuA4 complex integrity and display between 12 and 42 genetic interactions. In contrast, the deletion of EAF1 causes the collapse of the NuA4 complex and displays 148 genetic interactions. Our study indicates that Eaf1 plays a crucial function in NuA4 complex integrity. Further, we determine that Eaf5 and Eaf7 form a subcomplex, which reflects their similar genetic interaction profiles and phenotypes. Our integrative study demonstrates that genetic interaction maps are valuable in dissecting complex structure and provides insight into why the human NuA4 complex, Tip60, has been associated with a diverse range of pathologies.


The importance of bushmeat in the livelihoods of West African cash-crop farmers living in a faunally-depleted landscape.
Bushmeat is an important resource in the livelihoods of many rural communities in sub-Saharan Africa and may be a crucial safety-net for the most vulnerable households, especially during times of economic hardship. However, little is known about the impacts of wildlife depletion on these functions. This study quantifies the role of bushmeat in diversified rural household economies in a wildlife depleted forest-farm landscape in Ghana, assessing its importance overall, as well as differentiated by the relative vulnerability of households. Using repeat socioeconomic questionnaires (N=787) among 63 households over a one-year period, the following hypotheses were tested: (a) vulnerable households harvest more bushmeat; (b) bushmeat contributes a greater proportion of household production in vulnerable households; (c) bushmeat is more important for cash income than consumption in vulnerable households; and (d) bushmeat sales are more important for vulnerable households. The bushmeat harvest value averaged less than US$1.0 per day for 89% of households and comprised less than 7% of household production value. Household wealth and gender of the household head had little effect on the importance of bushmeat. However, bushmeat harvest and sales were highest during the agricultural lean season. Overall, most harvested bushmeat (64%) was consumed, enabling households to spend 30% less on meat/fish purchases. These findings suggest that, despite heavily depleted wildlife and diversified livelihoods, bushmeat continues to have an important role in rural livelihoods by acting as a safety net for income smoothing and reducing household expenditure during times of economic hardship.


East African cheetahs: evidence for two population bottlenecks?
A combined population genetic and reproductive analysis was undertaken to compare free-ranging cheetahs from east Africa (Acinonyx jubatus raineyi) with the genetically impoverished and reproductively impaired south African subspecies (Acinonyx jubatus jubatus). Like that of their south African counterparts, the quality of semen specimens from east African cheetahs was poor, with a low concentration of spermatozoa (25.3 X 10(6) per ejaculate) and a high incidence of morphological abnormalities (79%). From an electrophoretic survey of the products of 49 genetic loci in A. jubatus raineyi, two allozyme polymorphisms were detected; one of these, for a nonspecific esterase, shows an allele that is rare (less than 1% incidence) in south African specimens. Estimates of polymorphism (2-4%) and average heterozygosity (0.0004-0.014) affirm the cheetah as the least genetically variable felid species. The genetic distance between south and east African cheetahs was low (0.004), suggesting that the development of genetic uniformity preceded the recent geographic isolation of the subspecies. We propose that at least two population bottlenecks followed by inbreeding produced the modern cheetah species. The first and most extreme was ancient, possibly late Pleistocene (circa 10,000 years ago); the second was more recent (within the last century) and led to the south African populations.


Predicting Barrett's Esophagus in Families: An Esophagus Translational Research Network (BETRNet) Model Fitting Clinical Data to a Familial Paradigm.
Barrett's esophagus is often asymptomatic and only a small portion of Barrett's esophagus patients are currently diagnosed and under surveillance. Therefore, it is important to develop risk prediction models to identify high-risk individuals with Barrett's esophagus. Familial aggregation of Barrett's esophagus and esophageal adenocarcinoma, and the increased risk of esophageal adenocarcinoma for individuals with a family history, raise the necessity of including genetic factors in the prediction model. Methods to determine risk prediction models using both risk covariates and ascertained family data are not well developed. We developed a Barrett's Esophagus Translational Research Network (BETRNet) risk prediction model from 787 singly ascertained Barrett's esophagus pedigrees and 92 multiplex Barrett's esophagus pedigrees, fitting a multivariate logistic model that incorporates family history and clinical risk factors. The eight risk factors, age, sex, education level, parental status, smoking, heartburn frequency, regurgitation frequency, and use of acid suppressant, were included in the model. The prediction accuracy was evaluated on the training dataset and an independent validation dataset of 643 multiplex Barrett's esophagus pedigrees. Our results indicate family information helps to predict Barrett's esophagus risk, and predicting in families improves both prediction calibration and discrimination accuracy. Our model can predict Barrett's esophagus risk for anyone with family members known to have, or not have, had Barrett's esophagus. It can predict risk for unrelated individuals without knowing any relatives' information. Our prediction model will shed light on effectively identifying high-risk individuals for Barrett's esophagus screening and surveillance, consequently allowing intervention at an early stage, and reducing mortality from esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev; 25(5); 727-35. ©2016 AACR.


Oral health behaviour of Iranian mothers and their 9-year-old children.
The present study examined associations between the oral health behaviour (OHB) of Iranian mothers and the OHB and oral health status of their children. In 2005, two self-administered questionnaires provided data on the OHB of a random sample of 9-year-old children (n = 459) and their mothers in Tehran, Iran. Brushing frequency, use of fluoridated toothpaste and number of sugary snacks between meals served as oral self-care (OSC) assessment criteria for both. A clinical examination was performed for children at school. DMFT/dmft values, the restoration index (RI) and the unmet treatment needs index (UTN) facilitated an assessment of children's dental status and treatment. Chi-square test, bivariate correlation, and binary logistic regression model were employed in these analyses. Mother's OSC correlated with child's OSC (r = 0.18; p < 0.01). The reported children's brushing frequency correlated with mothers' brushing frequency (r = 0.2; p < 0.01). High maternal OSC levels were associated with lower dental treatment (DT) values in children (p < 0.01). Children's RI was positively and UTN negatively associated with mothers' OSC (p < 0.01). In the model, mothers' OSC (OR = 2.1) and female gender (OR = 2.1) were associated with children's OSC, while mothers' OSC was strongly associated with DT (OR = 11.0) and RI (OR = 34.0) in children. Higher OSC levels of the surveyed mothers were reflected positively in the oral health status and behaviour of their offspring. The potential of mothers to play a significant role in the oral health of their children should be kept in mind when developing oral health promotion programmes.


The study of etiological and demographic characteristics of neonatal mortality and morbidity - a consecutive case series study from Pakistan.
To determine the etiology, management, bacteriological spectrum and outcome of neonatal patients admitted in Civil Hospital Karachi (CHK) and to examine the factors associated with it. This hospital based descriptive study of 1463 patients from both sexes who were admitted to Paediatric department, CHK from 1st January 2008 till 31st December 2010 with an established cause according to modified Wigglesworth classification and fulfilling other inclusion criteria were included in the study. Data regarding their demographic profile and potential risk factors was collected on a well structured proforma. Cases were followed until discharge or expiry. Data was analyzed using descriptive statistics. The male to female ratio in our study was 1.12:1. Seven hundred and thirty-four patients were delivered at home (50.2%) and 1010 were less than 7 days old (69%). Out of the total cohort of expired subjects, 89 participants (74.8%) were < 7 days of life. Mortality was more in neonates born at home in rural areas to illiterate mother; 74 patients (62.2%). Most of the deaths; 57 were in neonates suffering from specific infections (47.9%) followed by 38 deaths in immaturity group (31.9%) and 19 related to asphyxial conditions (15.9%). The most common isolates were Staphylococcus aureus (28.7%) followed by Klebsiella (24.8%) and Pseudomonas aeruginosa (16.6 ). One hundred and nineteen (8.13%) of the neonates died in our study group. These results suggest that neonates with illiterate mothers with high parity and below average socioeconomic level were more susceptible to mortality in the early neonatal period. Most of the cases of mortality were due to specific infections.


Comparison of granisetron alone and granisetron plus dexamethasone in the prophylaxis of cytotoxic-induced emesis.
Two hundred and seventy-eight adult chemonaive patients, receiving moderately emetogenic chemotherapy were randomly allocated to receive either intravenous (i.v.) granisetron 3 mg plus i.v. dexamethasone 8 mg or i.v. granisetron 3 mg plus i.v. placebo dexamethasone prior to chemotherapy. Eight-two per cent of all patients recruited were female, and 91% of all patients consumed less than 10 units of alcohol per week, suggesting a study population with an increased risk of nausea and vomiting. In the first 24 h 85% of patients who received granisetron plus dexamethasone were complete responders compared with 75.9% of the patients receiving granisetron alone (P = 0.053). There were statistically significant improvements in complete response over 7 days (P = 0.029) and in the numbers of patients receiving rescue antiemetic (P = 0.0004). Toxicity was minimal with no significant differences between treatment groups. These results confirm the antiemetic activity of granisetron and show that it has an additive effect in combination with dexamethasone.


Comparative mapping in the Fagaceae and beyond with EST-SSRs.
Genetic markers and linkage mapping are basic prerequisites for comparative genetic analyses, QTL detection and map-based cloning. A large number of mapping populations have been developed for oak, but few gene-based markers are available for constructing integrated genetic linkage maps and comparing gene order and QTL location across related species. We developed a set of 573 expressed sequence tag-derived simple sequence repeats (EST-SSRs) and located 397 markers (EST-SSRs and genomic SSRs) on the 12 oak chromosomes (2n = 2x = 24) on the basis of Mendelian segregation patterns in 5 full-sib mapping pedigrees of two species: Quercus robur (pedunculate oak) and Quercus petraea (sessile oak). Consensus maps for the two species were constructed and aligned. They showed a high degree of macrosynteny between these two sympatric European oaks. We assessed the transferability of EST-SSRs to other Fagaceae genera and a subset of these markers was mapped in Castanea sativa, the European chestnut. Reasonably high levels of macrosynteny were observed between oak and chestnut. We also obtained diversity statistics for a subset of EST-SSRs, to support further population genetic analyses with gene-based markers. Finally, based on the orthologous relationships between the oak, Arabidopsis, grape, poplar, Medicago, and soybean genomes and the paralogous relationships between the 12 oak chromosomes, we propose an evolutionary scenario of the 12 oak chromosomes from the eudicot ancestral karyotype. This study provides map locations for a large set of EST-SSRs in two oak species of recognized biological importance in natural ecosystems. This first step toward the construction of a gene-based linkage map will facilitate the assignment of future genome scaffolds to pseudo-chromosomes. This study also provides an indication of the potential utility of new gene-based markers for population genetics and comparative mapping within and beyond the Fagaceae.


Nucleic acid functionalized graphene for biosensing.
There is immense demand for complex nanoarchitectures based on graphene nanostructures in the fields of biosensing or nanoelectronics. DNA molecules represent the most versatile and programmable recognition element and can provide a unique massive parallel assembly strategy with graphene nanomaterials. Here we demonstrate a facile strategy for covalent linking of single stranded DNA (ssDNA) to graphene using carbodiimide chemistry and apply it to genosensing. Since graphenes can be prepared by different methods and can contain various oxygen containing groups, we thoroughly investigated the utility of four different chemically modified graphenes for functionalization by ssDNA. The materials were characterized in detail and the different DNA functionalized graphene platforms were then employed for the detection of DNA hybridization and DNA polymorphism by using impedimetric methods. We believe that our findings are very important for the development of novel devices that can be used as alternatives to classical techniques for sensitive and fast DNA analysis. In addition, covalent functionalization of graphene with ssDNA is expected to have broad implications, from biosensing to nanoelectronics and directed, DNA programmable, self-assembly.


Synergistic Effect and Antibiofilm Activity of a Skin and Wound Cleanser.
Biofilm in chronic wounds impedes the wound healing process. Each biofilm has differing characteristics requiring a multifaceted approach for removal while maintaining a surrounding environment conducive to wound healing. In this study, 3 of the components in a wound cleanser are tested to determine synergy in eradicating biofilms of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa in vitro. The 3 components assessed for synergy were ethylenediamine tetraacetic acid sodium salts (EDTA), vicinal diols (VD; ethylhexylglycerin and octane-1,2-diol), and polyhexamethylene biguanide (PHMB). Each component was assessed individually and in combination while dissolved in a base solution. The Calgary assay method was used for biofilm growth and treatment. Kull Equation analysis for synergy was conducted using viable count results. Synergy is defined as the interaction of components to produce a combined effect greater than the sum of their separate effects. The base solution containing all 3 components (EDTA, VD, and PHMB) reduced biofilm viability by more than 5 logs, demonstrating statistically significant synergy. The 3 components tested individually in the base solution resulted in the following: EDTA did not reduce bacteria viability; VD reduced viability by about 1 log; and PHMB reduced P aeruginosa viability by about 2.5 logs and MRSA viability by about 4 logs. Of importance, the MRSA biofilm failed to regrow in the recovery plates after combined treatment, indicating complete elimination of the biofilm bacteria. The experimental and calculated results indicate the 3 components (VD, EDTA, and PHMB) when used together act synergistically to eradicate MRSA and P aeruginosa biofilms in vitro.


Effect of the new zinc compound beta-alanyl-L-histidinato zinc on bone metabolism in elderly rats.
The effect of a new zinc compound beta-alanyl-L-histidinato zinc (AHZ) on bone metabolism was investigated in aged rats (30 weeks old). AHZ (1.0, 2.5 and 7.5 mg/100 g body weight) was orally administered to rats 3 times at 24-hour intervals, and the rats were bled 24 h after the last administration. The administration of AHZ (7.5 mg/100 g) did not cause an appreciable alteration of calcium and inorganic phosphorus concentrations in the serum, and zinc, calcium and deoxyribonucleic acid contents in the femoral diaphysis were significantly increased by the administration of AHZ (7.5 mg/100 g). The bone alkaline phosphatase activity was significantly increased by doses of 1.0-7.5 mg AHZ/100 g. These results suggest that AHZ has a stimulatory effect on bone formation and calcification in aged rats.


Amentoflavone Ameliorates Streptococcus suis-Induced Infection In Vitro and In Vivo.
Streptococcus suis, an important zoonotic pathogen, has caused considerable economic losses in the swine industry and severe public health issues worldwide. The development of a novel effective strategy for the prevention and therapy of S. suis is urgently needed. Here, amentoflavone, a natural biflavonoid compound isolated from Chinese herbs that has negligible anti-S. suis activity, was identified as a potent antagonist of suilysin (SLY)-mediated hemolysis without interfering with the expression of SLY. Amentoflavone effectively inhibited SLY oligomerization, which is critical for its pore-forming activity. The treatment with amentoflavone reduced S. suis-induced cytotoxicity in macrophages (J774 cells). Furthermore, S. suis-infected mice that received amentoflavone exhibited lower mortality and bacterial burden. Additionally, amentoflavone significantly decreased the production of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and IL-6 in an S. suis-infected cell model. Analyses of signaling pathways demonstrated that amentoflavone reduced S. suis-induced inflammation in S. suis serotype 2 (SS2)-infected cells by regulating the p38, Jun N-terminal protein kinase 1 and 2 (JNK1/2), and NF-κB pathways. The antivirulence and anti-inflammatory properties of amentoflavone against S. suis infection provide the possibility for future pharmaceutical application of amentoflavone in the treatment of S. suis infection.IMPORTANCE The widespread use of antibiotics in therapy and in the prevention of Streptococcus suis infection in the swine industry raises concerns for the emergence of a resistant strain. The use of antivirulence agents has potential benefits, mainly because of the reduced selective pressure for the development of bacterial resistance. In this study, we found that amentoflavone is an effective agent against S. suis serotype 2 (SS2) infection both in vitro and in vivo Our results demonstrated that amentoflavone is a promising anti-infective therapeutic for S. suis infections, due to its antivirulence and anti-inflammatory effects without antibacterial activity, with fewer side effects than conventional antibacterial agents.


Mid-aortic syndrome: long-term outcome of 36 children.
The clinical characteristics and outcomes of children with mid-aortic syndrome (MAS) and the effectiveness of different therapeutic approaches in reducing hypertension are still debated. We conducted a single-centre retrospective review of the records of children with MAS over 30 years. Children with angiographic evidence of a narrowed abdominal aorta were included. Therapeutic approaches included medical management, percutaneous transluminal angioplasty and/or surgical intervention. Thirty-six children had presented at a median age of 2.7 years (10 days-10 years). Thirteen (36%) patients had associated syndromes, and 44% had been diagnosed with cerebrovascular disease. All patients had involvement of multiple arteries. The mortality rate was 8% after a median follow-up period of 4.5 (range 1.1-19.7) years. Among the children who survived, 90% had obtained a reduction in their blood pressure (BP). Of the patients, 76% had had a normal estimated glomerular filtration rate (eGFR) at the last follow-up examination. Seventeen percent (six of 36) had renal dysfunction at presentation. Although MAS is a severe and widespread disease, in most cases it can be effectively treated with a combination of medical, angioplasty and surgical interventions.


A novel patatin-like gene stimulated by drought stress encodes a galactolipid acyl hydrolase.
A cDNA (Vupat1) encoding a predicted 43 kDa protein was isolated from drought-stressed cowpea (Vigna unguiculata) leaves. It has homology with patatin, a potato tuber storage protein with lipolytic acyl hydrolase activity. The recombinant protein VUPAT1 expressed in the baculovirus system displays preferentially galactolipid acyl hydrolase activity. Phospholipids are very slowly hydrolyzed and apparently triacylglycerols are not deacylated. Vupat1 promoter contains putative drought-inducible sequences. Northern blots showed that gene expression is stimulated by drought stress and is more pronounced in a drought-sensitive cultivar than in a drought-tolerant one. An involvement in drought-induced galactolipid degradation is proposed for VUPAT1.


Current use and future potential of (physiologically based) pharmacokinetic modelling of radiopharmaceuticals: a review.
Rationale: Physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PK) modelling approaches are widely accepted in non-radiopharmaceutical drug development and research, while there is no major role for these approaches in radiopharmaceutical development yet. In this review, a literature search was performed to specify different research purposes and questions that have previously been answered using both PBPK and population PK modelling for radiopharmaceuticals. Methods: The literature search was performed using the databases PubMed and Embase. Wide search terms included radiopharmaceutical, tracer, radioactivity, physiologically based pharmacokinetic model, PBPK, population pharmacokinetic model and nonlinear mixed-effects model. Results: Eight articles and twenty articles were included for this review based on this literature search for population PK modelling and PBPK modelling, respectively. Included population PK analyses showed to have an added value to develop predictive models for a population and to describe individual variability sources. Main purposes of PBPK models appeared related to optimizing treatment (planning), or more specifically: to find the optimal combination of peptide amount and radioactivity, to optimize treatment planning by reducing the number of measurements, to individualize treatment, to get insights in differences between pre-therapeutic and therapeutic scans or to understand inter-patient differences. Other main research subjects were regarding radiopharmaceutical comparisons, selecting ligands based on their peptide characteristics and gaining a better understanding of drug-drug interactions. Conclusions: The use of PK modelling approaches in radiopharmaceutical research remains scarce, but can be expanded to obtain a better understanding of PK and whole-body distribution of radiopharmaceuticals in general. PK modelling of radiopharmaceuticals has great potential for the nearby future and could contribute to the evolving research of radiopharmaceuticals.


Anthroposophic therapy for asthma: A two-year prospective cohort study in routine outpatient settings.
Anthroposophic treatment for asthma includes special artistic and physical therapies and special medications. We studied consecutive outpatients starting anthroposophic treatment for asthma under routine conditions in Germany. Main outcomes were average asthma severity (0-10, primary outcome); symptoms (1-4); and asthma-related quality of life at 12-month follow-up (Asthma Quality of Life Questionnaire [AQLQ] overall score, 1-7, for adults; KINDL Questionnaire for Measuring Health-Related Quality of Life in Children and Adolescents, asthma module, 0-100, for children) at 12-month follow-up. Ninety patients (54 adults, 36 children) were included. Anthroposophic treatment modalities used were medications (88% of patients, n = 79/90); eurythmy therapy (22%); art therapy (10%); and rhythmical massage therapy (1%). Median number of eurythmy/art/massage sessions was 12 (interquartile range 10-20), median therapy duration was 120 days (84-184). From baseline to 12-month follow-up, all outcomes improved significantly (P < 0.001 for all comparisons). Average improvements were: average asthma severity 2.61 points (95% confidence interval CI: 1.90-3.32); cough 0.93 (95% CI: 0.60-1.25); dyspnea 0.92 (95% CI: 0.56-1.28); exertion-induced symptoms 0.95 (95% CI: 0.64-1.25); frequency of asthma attacks 0.78 (95% CI: 0.41-1.14); awakening from asthma 0.90 (95% CI: 0.58-1.21); AQLQ overall score 1.44 (95% CI: 0.97-1.92); and KINDL asthma module 14.74 (95% CI: 9.70-19.78). All improvements were maintained until last follow-up after 24 months. Patients with asthma under anthroposophic treatment had long-term improvements of symptoms and quality of life.


GenK-catalyzed C-6' methylation in the biosynthesis of gentamicin: isolation and characterization of a cobalamin-dependent radical SAM enzyme.
The existence of cobalamin (Cbl)-dependent enzymes that are members of the radical S-adenosyl-l-methionine (SAM) superfamily was previously predicted on the basis of bioinformatic analysis. A number of these are Cbl-dependent methyltransferases, but the details surrounding their reaction mechanisms have remained unclear. In this report we demonstrate the in vitro activity of GenK, a Cbl-dependent radical SAM enzyme that methylates an unactivated sp(3) carbon during the biosynthesis of gentamicin, an aminoglycoside antibiotic. Experiments to investigate the stoichiometry of the GenK reaction revealed that 1 equiv each of 5'-deoxyadenosine and S-adenosyl-homocysteine are produced for each methylation reaction catalyzed by GenK. Furthermore, isotope-labeling experiments demonstrate that the S-methyl group from SAM is transferred to Cbl and the aminoglycoside product during the course of the reaction. On the basis of these results, one mechanistic possibility for the GenK reaction can be ruled out, and further questions regarding the mechanisms of Cbl-dependent radical SAM methyltransferases, in general, are discussed.


Influences of micronutrient and omega-3 fatty acid supplementation on cognition, learning, and behavior: methodological considerations and implications for children and adolescents in developed societies.
The purpose of this review is to outline the current evidence regarding the effects of micronutrient and omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation on the cognition, learning, and behavior of children and adolescents living in developed societies. Existing evidence suggests that children and adolescents in developed countries may perform better on tests of nonverbal intelligence and on behavioral measures after receiving vitamin and mineral supplements with or without n-3 PUFA supplementation compared with those receiving placebo, regardless of age and supplementation formula. The strongest effects were observed in trials that lasted over 3 months and in subgroups of children with low socioeconomic status, symptoms of attention deficit hyperactivity disorder, and/or learning disabilities. Future studies should focus on children and adolescents who have a low socioeconomic status or are likely to be suffering nutritional deficiencies to determine the impact of vitamin and mineral supplements with or without n-3 PUFA supplementation on their cognitive and behavioral functioning. These studies should ideally include blood sample analyses to help determine if nutritional status influences the response to supplementation and whether changes in blood status account for effects on cognition and behavior.


Long-term wine consumption is related to cardiovascular mortality and life expectancy independently of moderate alcohol intake: the Zutphen Study.
Light to moderate alcohol intake lowers the risk of cardiovascular mortality, but whether this protective effect can be attributed to a specific type of beverage remains unclear. Moreover, little is known about the effects of long-term alcohol intake on life expectancy. The impact of long-term alcohol intake and types of alcoholic beverages consumed on cardiovascular mortality and life expectancy at age 50 was investigated in the Zutphen Study, a cohort of 1373 men born between 1900 and 1920 and examined repeatedly between 1960 and 2000. Hazard ratios (HRs) for total alcohol intake and alcohol from wine, beer and spirits were obtained from time-dependent Cox regression models. Life expectancy at age 50 was calculated from areas under survival curves. Long-term light alcohol intake, that is < or =20 g per day, compared with no alcohol, was strongly and inversely associated with cerebrovascular (HR 0.43, 95% CI 0.26 to 0.70), total cardiovascular (HR 0.70, 95% CI 0.55 to 0.89) and all-cause mortality (HR 0.75, 95% CI 0.63 to 0.91). Independent of total alcohol intake, long-term wine consumption of, on average, less than half a glass per day was strongly and inversely associated with coronary heart disease (HR 0.61, 95% CI 0.41 to 0.89), total cardiovascular (HR 0.68, 95% CI 0.53 to 0.86) and all-cause mortality (HR 0.73, 95% CI 0.62 to 0.87). These results could not be explained by differences in socioeconomic status. Life expectancy was about 5 years longer in men who consumed wine compared with those who did not use alcoholic beverages. Long-term light alcohol intake lowered cardiovascular and all-cause mortality risk and increased life expectancy. Light wine consumption was associated with 5 years longer life expectancy; however, more studies are needed to verify this result.


The influence of age on reproductive performance of the predatory ladybird beetle, Propylea dissecta.
The influence of age on reproductive performance of an aphidophagous ladybird beetle, Propylea dissecta was examined using male and female beetles of varying ages (1-30 days) after a single mating stimulus. All the intermediate (10 to 20 days old) and old (30 days old) age females mated with all intermediate and old age males, while only a fraction (0.29%) of younger females, 1 to 5 days old, mated with males of similar or older age. The willingness to mate was male age dependent. It increased sigmoidally with increase in adult age. Adult males were more willing to mate with females irrespective of age. Mating duration was longest amongst older adults (30 day-old males and 20 day-old females). Male age did not contribute to shaping the fecundity of the female ladybird. Fecundity was female age dependent and it increased with age up to 20 days and thereafter decreased. 20 day-old females were most fecund producing 867 eggs after a single mating. Progeny production was male age dependent and eggs sired by 20-30 day-old males had significantly higher viability than those sired by younger males. Prolonged mating increased fecundity and egg viability. The results reveal that males of intermediate age were better mates. This information may improve our understanding of the effect of aging on reproduction in ladybirds and may help mass-multiplication of the ladybird beetles using adults of optimal age.


Peeling dynamics of fluid membranes bridged by molecular bonds: moving or breaking.
Biological adhesion is a critical mechanical function of complex organisms. At the scale of cell-cell contacts, adhesion is remarkably tunable to enable both cohesion and malleability during development, homeostasis and disease. It is physically supported by transient and laterally mobile molecular bonds embedded in fluid membranes. Thus, unlike specific adhesion at solid-solid or solid-fluid interfaces, peeling at fluid-fluid interfaces can proceed by breaking bonds, by moving bonds or by a combination of both. How the additional degree of freedom provided by bond mobility changes the mechanics of peeling is not understood. To address this, we develop a theoretical model coupling diffusion, reactions and mechanics. Mobility and reaction rates determine distinct peeling regimes. In a diffusion-dominated Stefan-like regime, bond motion establishes self-stabilizing dynamics that increase the effective fracture energy. In a reaction-dominated regime, peeling proceeds by travelling fronts where marginal diffusion and unbinding control peeling speed. In a mixed reaction-diffusion regime, strengthening by bond motion competes with weakening by bond breaking in a force-dependent manner, defining the strength of the adhesion patch. In turn, patch strength depends on molecular properties such as bond stiffness, force sensitivity or crowding. We thus establish the physical rules enabling tunable cohesion in cellular tissues and in engineered biomimetic systems.


The Influence of Parents and Friends on Adolescent Substance Use: A Multidimensional Approach.
The current study examined longitudinal associations between friend's substance use, friendship quality, parent-adolescent relationship quality and subsequent substance use. Participants were 166 adolescents, their parents and their close same-sex friends. Measures of relationship characteristics in the 10(th) grade were used to predict concurrent substance use and changes in substance use over a one-year period. The most consistent predictor of the use of different substances and changes in substance use over time was the friend's substance using behavior. Negative interactions with a friend were related only to tobacco use, and friendship support neither contributed to nor protected against substance use. Mother-adolescent relationship support was associated with lower levels of concurrent substance use, as well as lower levels of hard drug use over time. Findings highlight the need to examine parents and peers simultaneously and the importance of parental relationships and peer behavior on adolescent substance use. Limitations and future directions are discussed.


Next-generation visitation models using social media to estimate recreation on public lands.
Outdoor and nature-based recreation provides countless social benefits, yet public land managers often lack information on the spatial and temporal extent of recreation activities. Social media is a promising source of data to fill information gaps because the amount of recreational use is positively correlated with social media activity. However, despite the implication that these correlations could be employed to accurately estimate visitation, there are no known transferable models parameterized for use with multiple social media data sources. This study tackles these issues by examining the relative value of multiple sources of social media in models that estimate visitation at unmonitored sites and times across multiple destinations. Using a novel dataset of over 30,000 social media posts and 286,000 observed visits from two regions in the United States, we compare multiple competing statistical models for estimating visitation. We find social media data substantially improve visitor estimates at unmonitored sites, even when a model is parameterized with data from another region. Visitation estimates are further improved when models are parameterized with on-site counts. These findings indicate that while social media do not fully substitute for on-site data, they are a powerful component of recreation research and visitor management.


Effects Of State Insurance Mandates On Health Care Use And Spending For Autism Spectrum Disorder.
Forty-six states and the District of Columbia have enacted insurance mandates that require commercial insurers to cover treatment for children with autism spectrum disorder (ASD). This study examined whether implementing autism mandates altered service use or spending among commercially insured children with ASD. We compared children age twenty-one or younger who were eligible for mandates to children not subject to mandates using 2008-12 claims data from three national insurers. Increases in service use and spending attributable to state mandates were detected for all outcomes. Mandates were associated with a 3.4-percentage-point increase in monthly use and a $77 increase in monthly spending on ASD-specific services. Effects were larger for younger children and increased with the number of years since mandate implementation. These increases suggest that state mandates are an effective tool for broadening access to autism treatment under commercial insurance.


Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document.
Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD. A Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75% agreement and no disagreement. For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m(2)) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped. The recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations.


Norepinephrine and isoproterenol increase the phosphorylation of synapsin I and synapsin II in dentate slices of young but not aged Fisher 344 rats.
A number of recent reports have suggested that norepinephrine (NE) produces a form of synaptic enhancement that resembles long-term potentiation (LTP). LTP, thought to be an electrophysiological correlate of memory, in part involves an augmentation of transmitter release. Although the effects of NE have not been unequivocally linked to LTP, it is clear that NE can produce increased transmitter release in the dentate gyrus of the hippocampus. The purpose of this study was to determine whether NE was capable of enhancing the phosphorylation of synapsin I and synapsin II, two homologous phosphoproteins thought to be involved in modulation of neurotransmitter release. NE (10 microM) and isoproterenol (250 nM) produced an increase in the phosphorylation of synapsin I and synapsin II in dentate slices from young rats. Phosphorylation site analysis of synapsin I, performed by limited proteolysis, indicated that NE and isoproterenol increased the phosphorylation of synapsin I at sites modified by Ca2+/calmodulin-dependent protein kinase II as well as cAMP-dependent protein kinase. These data demonstrate that NE stimulates the phosphorylation of synapsin I at its Ca2+/calmodulin-dependent protein kinase II site, which is a site that has been shown to regulate the effect of synapsin I on neurotransmitter release. We have also examined the effects of NE and isoproterenol on synapsin phosphorylation in dentate slices prepared from aged animals. Such animals have previously been shown to exhibit deficits in NE sensitivity as well as significant impairment in their ability to exhibit LTP. Neither NE nor isoproterenol stimulated synapsin phosphorylation in slices prepared from aged animals. Interestingly, the basal level of phosphorylation of the synapsin proteins was higher in slices prepared from aged animals. This higher basal level of phosphorylation may underlie the failure of aged animals to exhibit NE-stimulated increases in phosphorylation of the synapsin proteins. We hypothesize that the beta-adrenergic agonist-stimulated phosphorylation of synapsin I and synapsin II in young rats plays a role in the increase in transmitter release produced by NE in the dentate. Thus, the failure of the aged rats to show such phosphorylation may underlie, in part, their failure to exhibit normal responsiveness to NE. Moreover, these deficits in synapsin phosphorylation may also play some role in the deficits in plasticity seen in aged rats.


Studies on the separation of hydronium ion using surfactant-modified reversed-phase stationary phases and eluents containing an acidified electrolyte.
A further investigation of a chromatographic system allowing determination of hydrogen ions is reported. For this purpose an octadecylsilica column dynamically modified with sodium dodecylsulfate (SDS) or lithium dodecylsulfate (LDS) was used as stationary phase and a slightly acidified electrolyte (usually KCl)-SDS solution was used as the eluent. The concentration of SDS, KCl and the acidity of the eluent affected the structure of aggregates formed by the molecules of dodecylsulfate at the surface of the stationary phase. These aggregates of dodecylsulfate were found to be responsible for the appearance of a chromatographic peak attributed to the presence of H3O+ ions in a sample. Other cations in the sample could be separated in the same manner, permitting the simultaneous separation of monovalent cations from H3O+. The detection limit for H3O+ ions was 2.25 x 10(-6) M using an eluent comprising 0.3 mM LDS, 50.0 mM KCl and 0.10 mM H2SO4. The proposed method is shown to be applicable for the determination of free H3O+ ions in aqueous solutions of strong acids.


3D Bioprinted Scaffolds Containing Viable Macrophages and Antibiotics Promote Clearance of Staphylococcus aureus Craniotomy-Associated Biofilm Infection.
Craniotomy involves the removal of a skull fragment to access the brain, such as during tumor or epilepsy surgery, which is immediately replaced intraoperatively. The infection incidence after craniotomy ranges from 0.8 to 3%, with approximately half caused by Staphylococcus aureus ( S. aureus). To mitigate infectious complications following craniotomy, we engineered a three-dimensional (3D) bioprinted bone scaffold to harness the potent antibacterial activity of macrophages (MΦs) together with antibiotics using a mouse S. aureus craniotomy-associated biofilm model that establishes a persistent infection on the bone flap, subcutaneous galea, and brain. The 3D scaffold contained rifampin and daptomycin printed in a composite slurry, with viable MΦs incorporated into a hydrogel-based bioink, which was assessed for both the treatment and prevention of craniotomy-associated infections in the mouse model. For the treatment paradigm, the bone flap was removed at day 7 post infection after a mature biofilm had formed and was replaced with a 3D printed antibiotic scaffold, with or without MΦ incorporation. Bacterial burdens in the galea and brain were reduced by at least 100-fold at early time points, which was potentiated by bioprinting viable MΦs into the 3D antibiotic scaffold. We also examined a prevention paradigm, where the scaffolds were placed at the time of surgery and challenged with S. aureus one day later at the surgical site. Interestingly, unlike the treatment paradigm, the incorporation of viable MΦs into the 3D antibiotic scaffold did not enhance bacterial clearance compared to that of antibiotic alone. With further refinement, our 3D bioprinted scaffold represents a potential treatment modality, as it delivers therapeutic antibiotic levels more rapidly than systemic administration, based on its proximity to the infection site. In addition, the incorporation of viable MΦs into the 3D scaffold is an important advance, which demonstrated an improved therapeutic benefit for the treatment of established biofilms that represent the most clinically challenging scenario.


Computational archaeology of the Pristionchus pacificus genome reveals evidence of horizontal gene transfers from insects.
The recent sequencing of nematode genomes has laid the basis for comparative genomics approaches to study the impact of horizontal gene transfer (HGT) on the adaptation to new environments and the evolution of parasitism. In the beetle associated nematode Pristionchus pacificus HGT events were found to involve cellulase genes of microbial origin and Diapausin genes that are known from beetles, but not from other nematodes. The insect-to-nematode horizontal transfer is of special interest given that P. pacificus shows a tight association with insects. In this study we utilized the observation that horizontally transferred genes often exhibit codon usage patterns more similar to that of the donor than that of the acceptor genome. We introduced GC-normalized relative codon frequencies as a measure to detect characteristic features of P. pacificus orphan genes that show no homology to other nematode genes. We found that atypical codon usage is particularly prevalent in P. pacificus orphans. By comparing codon usage profiles of 71 species, we detected the most significant enrichment in insect-like codon usage profiles. In cross-species comparisons, we identified 509 HGT candidates that show a significantly higher similarity to insect-like profiles than genes with nematode homologs. The most abundant gene family among these genes are non-LTR retrotransposons. Speculating that retrotransposons might have served as carriers of foreign genetic material, we found a significant local clustering tendency of orphan genes in the vicinity of retrotransposons. Our study combined codon usage bias, phylogenetic analysis, and genomic colocalization into a general picture of the computational archaeology of the P. pacificus genome and suggests that a substantial fraction of the gene repertoire is of insect origin. We propose that the Pristionchus-beetle association has facilitated HGT and discuss potential vectors of these events.


A sequential treatment regimen with melatonin and all-trans retinoic acid induces apoptosis in MCF-7 tumour cells.
Neoplastic events are marked by uncontrolled cell proliferation. One major focus of cancer research has been to identify treatments that reduce or inhibit cell growth. Over the years, various compounds, both naturally occurring and chemically synthesized, have been used to inhibit neoplastic cell proliferation. Two such oncostatic agents, melatonin and retinoic acid, have been shown to suppress the growth of hormone-responsive breast cancer. Currently, separate clinical protocols exist for the administration of retinoids and melatonin as adjuvant therapies for cancer. Using the oestrogen receptor (ER)-positive MCF-7 human breast tumour cell line, our laboratory has studied the effects of a sequential treatment regimen of melatonin followed by all-trans retinoic acid (atRA) on breast tumour cell proliferation in vitro. Incubation of hormonally responsive MCF-7 and T47D cells with melatonin (10(-9) M) followed 24 h later by atRA (10(-9) M) resulted in the complete cessation of cell growth as well as a reduction in the number of cells to below the initial plating density. This cytocidal effect is in contrast to the growth-suppressive effects seen with either hormone alone. This regimen of melatonin followed by atRA induced cytocidal effects on MCF-7 cells by activating pathways leading to apoptosis (programmed cell death) as evidenced by decreased ER and Bcl-2 and increased Bax and transforming growth factor beta 1 (TGF-beta1) expression. Apoptosis was reflected morphologically by an increase in the number of lysosomal bodies and perinuclear chromatin condensation, cytoplasmic blebbing and the presence of apoptotic bodies. The apoptotic effect of this sequential treatment with melatonin and atRA appears to be both cell and regimen specific as (a) ER-negative MDA-MB-231 and BT-20 breast tumour cells were unaffected, and (b) the simultaneous administration of melatonin and atRA was not associated with apoptosis in any of the breast cancer cell lines studied. Taken together, the results suggest that use of an appropriate regimen of melatonin and atRA should be considered for preclinical and clinical evaluation against ER-positive human breast cancer.


Characterization of the tpr gene product and isolation of a specific protease-deficient mutant of Porphyromonas gingivalis W83.
The previously described protease gene (tpr) of Porphyromonas gingivalis W83 was shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the recombinant protein and in vitro translation to encode a 50-kDa protein whose active form migrates with an apparent molecular mass of 90 kDa. The 50-kDa protein was expressed at high levels by using a T7 RNA polymerase/promoter system. The NH2-terminal sequence of the protein was identical to the amino acid sequence deduced from the DNA sequence of the protease gene. Affinity-purified antibody to the 90-kDa recombinant protease reacted with an 80-kDa P. gingivalis protein. A specific protease (Tpr)-deficient isogenic mutant of P. gingivalis was generated by homologous recombination between P. gingivalis chromosomal DNA and a suicide plasmid carrying the cloned gene disrupted by insertion of an erythromycin resistance gene. Gelatin substrate zymography showed that cell extracts of the mutant lacked a protease band that migrated with an apparent molecular mass of 80 kDa. Western immunoblots of the cell extracts indicated the loss of an antigen with a similar mass.


Analysis of the Cariogenic Potential of Various Almond Milk Beverages using a Streptococcus mutans Biofilm Model in vitro.
To evaluate the cariogenic properties of almond milk beverages, 6 almond milks, along with soy and whole bovine milk, were analyzed for their abilities to support Streptococcus mutans biofilm formation and acid production, and their capacity to buffer changes in pH. Biofilm formation by S. mutans was analyzed using an in vitro 96-well plate model and measured by crystal violet staining. Acid production by S. mutans was evaluated by a colorimetric L-lactate assay and pH measurement of bacterial cultures. Buffering capacity was assessed by a pH titration assay. Soy milk supported the most biofilm growth, while the least was observed with unsweetened almond milk (both p < 0.001). Among almond milks, sucrose-sweetened milk led to the highest level of biofilm formation (p < 0.001), while the least was observed with unsweetened milk (p < 0.05). Sucrose-sweetened almond milk yielded the lowest pH (4.56 ± 0.66), followed by soy milk and bovine milk; the highest pH was with unsweetened almond milk (6.48 ± 0.5). When analyzed by pH titration, the unsweetened almond milk displayed the weakest buffering capacity while bovine milk showed the highest (p < 0.001). These results suggest that the almond milk beverages, except those that are sweetened with sucrose, possess limited cariogenic properties, while soy milk exhibits the most cariogenic potential. As milk alternatives become increasingly popular, dentists must counsel their patients that almond milks, especially sucrose-sweetened varieties, have cariogenic potential. For patients who are lactose-intolerant or suffer from milk allergy, almond milks may be a better alternative than soy-based products.


Modeling the segmentation clock as a network of coupled oscillations in the Notch, Wnt and FGF signaling pathways.
The formation of somites in the course of vertebrate segmentation is governed by an oscillator known as the segmentation clock, which is characterized by a period ranging from 30 min to a few hours depending on the organism. This oscillator permits the synchronized activation of segmentation genes in successive cohorts of cells in the presomitic mesoderm in response to a periodic signal emitted by the segmentation clock, thereby defining the future segments. Recent microarray experiments [Dequeant, M.L., Glynn, E., Gaudenz, K., Wahl, M., Chen, J., Mushegian, A., Pourquie, O., 2006. A complex oscillating network of signaling genes underlies the mouse segmentation clock. Science 314, 1595-1598] indicate that the Notch, Wnt and Fibroblast Growth Factor (FGF) signaling pathways are involved in the mechanism of the segmentation clock. By means of computational modeling, we investigate the conditions in which sustained oscillations occur in these three signaling pathways. First we show that negative feedback mediated by the Lunatic Fringe protein on intracellular Notch activation can give rise to periodic behavior in the Notch pathway. We then show that negative feedback exerted by Axin2 on the degradation of beta-catenin through formation of the Axin2 destruction complex can produce oscillations in the Wnt pathway. Likewise, negative feedback on FGF signaling mediated by the phosphatase product of the gene MKP3/Dusp6 can produce oscillatory gene expression in the FGF pathway. Coupling the Wnt, Notch and FGF oscillators through common intermediates can lead to synchronized oscillations in the three signaling pathways or to complex periodic behavior, depending on the relative periods of oscillations in the three pathways. The phase relationships between cycling genes in the three pathways depend on the nature of the coupling between the pathways and on their relative autonomous periods. The model provides a framework for analyzing the dynamics of the segmentation clock in terms of a network of oscillating modules involving the Wnt, Notch and FGF signaling pathways.


Complete mitochondrial genome suggests diapsid affinities of turtles.
Despite more than a century of debate, the evolutionary position of turtles (Testudines) relative to other amniotes (reptiles, birds, and mammals) remains uncertain. One of the major impediments to resolving this important evolutionary problem is the highly distinctive and enigmatic morphology of turtles that led to their traditional placement apart from diapsid reptiles as sole descendants of presumably primitive anapsid reptiles. To address this question, the complete (16,787-bp) mitochondrial genome sequence of the African side-necked turtle (Pelomedusa subrufa) was determined. This molecule contains several unusual features: a (TA)n microsatellite in the control region, the absence of an origin of replication for the light strand in the WANCY region of five tRNA genes, an unusually long noncoding region separating the ND5 and ND6 genes, an overlap between ATPase 6 and COIII genes, and the existence of extra nucleotides in ND3 and ND4L putative ORFs. Phylogenetic analyses of the complete mitochondrial genome sequences supported the placement of turtles as the sister group of an alligator and chicken (Archosauria) clade. This result clearly rejects the Haematothermia hypothesis (a sister-group relationship between mammals and birds), as well as rejecting the placement of turtles as the most basal living amniotes. Moreover, evidence from both complete mitochondrial rRNA genes supports a sister-group relationship of turtles to Archosauria to the exclusion of Lepidosauria (tuatara, snakes, and lizards). These results challenge the classic view of turtles as the only survivors of primary anapsid reptiles and imply that turtles might have secondarily lost their skull fenestration.


The Steady State Great Ape? Long Term Isotopic Records Reveal the Effects of Season, Social Rank and Reproductive Status on Bonobo Feeding Behavior.
Dietary ecology of extant great apes is known to respond to environmental conditions such as climate and food availability, but also to vary depending on social status and life history characteristics. Bonobos (Pan paniscus) live under comparatively steady ecological conditions in the evergreen rainforests of the Congo Basin. Bonobos are an ideal species for investigating influences of sociodemographic and physiological factors, such as female reproductive status, on diet. We investigate the long term dietary pattern in wild but fully habituated bonobos by stable isotope analysis in hair and integrating a variety of long-term sociodemographic information obtained through observations. We analyzed carbon and nitrogen stable isotopes in 432 hair sections obtained from 101 non-invasively collected hair samples. These samples represented the dietary behavior of 23 adult bonobos from 2008 through 2010. By including isotope and crude protein data from plants we could establish an isotope baseline and interpret the results of several general linear mixed models using the predictors climate, sex, social rank, reproductive state of females, adult age and age of infants. We found that low canopy foliage is a useful isotopic tracer for tropical rainforest settings, and consumption of terrestrial herbs best explains the temporal isotope patterns we found in carbon isotope values of bonobo hair. Only the diet of male bonobos was affected by social rank, with lower nitrogen isotope values in low-ranking young males. Female isotope values mainly differed between different stages of reproduction (cycling, pregnancy, lactation). These isotopic differences appear to be related to changes in dietary preference during pregnancy (high protein diet) and lactation (high energy diet), which allow to compensate for different nutritional needs during maternal investment.


International variation in clinical injury incidence: exploring the performance of indicators based on health care, anatomical and outcome criteria.
To analyse international variation in clinical injury incidence, and explore the performance of different injury indicators in cross-country comparisons. Hospital discharge data of seven European countries (Austria, Denmark, Ireland, Netherlands, Norway, England and Wales) were analysed. We tested existing and newly developed indicators based on (a) health care use, (b) anatomical criteria, or (c) expected health outcome: admissions excluding day-cases (a), hospital stay 4+ (a) and 7+ days (a), (serious) long-bone fractures (b), selected radiological verifiable fractures 'SRVFs' (b), and indicators based on international (Global Burden of Disease) and Dutch disability weights). Assessment criteria were reduction in incidence variation and length of stay in hospital, and the association between incidence and mortality rates. Indicators based on health care use led to increased variation in incidence rates. Long bone fractures and SRVFs, and both indicators based on injuries with moderate to high disability showed similar variation in clinical incidence compared to the crude rates, smaller variation in median length of stay in hospital and a good association with mortality rates. No perfect or near perfect indicators of clinical injury incidence exist. For international comparisons, indicators based on disability weights, SRVFs and long bone fractures may be sensible indicators to use, in the absence of a direct measure of anatomical severity.


Effects of replacing soybean meal with raw or extruded blends containing faba bean or lupin seeds on nitrogen metabolism and performance of dairy cows.
The objective was to test the effects of replacing soybean meal in dairy cow diets with either raw or extruded faba bean:linseed or lupin:linseed blends on intake, milk yield and composition, N partitioning, and ruminal and plasma parameters. Our main hypotheses were that N from extruded blends was less degradable in the rumen than N from raw seeds, and that a higher extrusion temperature favored ruminal protection of proteins and milk protein yield, and lowered urinary N excretion. Eight Holstein cows fitted with ruminal cannulas were used in two 4 × 4 Latin square design experiments conducted in parallel. In both experiments, cows were fed diets with a crude protein content of 14.6%, containing 60% of forage (dry matter basis). Treatments differed by the composition of the concentrates: control in both experiments was based on soybean meal, and experimental treatments were based on proteaginous:linseed (90:10%) blends consisting of faba bean blends (first experiment) or lupin blends (second experiment) presented either raw, extruded at 140°C, or extruded at 160°C. Intake, milk yield and composition, ruminal pH, volatile fatty acids and ammonia kinetics, digestibility, N partitioning, Maillard compounds in feed and feces, plasma AA, and 15N natural enrichment were measured. Data were analyzed using ANOVA according to the MIXED procedure of SAS (version 9.4, SAS Institute Inc., Cary, NC). Ammonia content in ruminal fluid did not significantly change when soybean meal was replaced by either raw or extruded faba bean, but tended to be higher with lupin. Milk yield was increased by 2.6 kg with faba bean blend extruded at 140°C compared with faba bean blend extruded at 160°C. Milk fat and milk protein concentrations were decreased by 3.1 and 2.3 g/kg, respectively, with lupin blends compared with soybean meal. Nitrogen partitioning between milk, feces, and urine did not change. Nitrogen apparent digestibility decreased by 3 g/100 g of N between faba bean blend extruded at low and at high temperatures. The content of Maillard compounds in feces was higher with blends extruded at 160°C than with raw or extruded at 140°C blends within both experiments. Total plasma AA tended to be higher with extruded blends than with raw in the faba bean experiment. Both extrusion temperatures appeared to protect dietary proteins from ruminal degradability, but proteins seemed to be overprotected at 160°C.


Rep15 interacts with several Rab GTPases and has a distinct fold for a Rab effector.
In their GTP-bound (active) form, Rab proteins interact with effector proteins that control downstream signaling. One such Rab15 effector is Rep15, which is known to have a role in receptor recycling from the endocytic recycling compartment but otherwise remains poorly characterized. Here, we report the characterization of the Rep15:Rab15 interaction and identification of Rab3 paralogs and Rab34 as Rep15 interacting partners from a yeast two-hybrid assay. Biochemical validation of the interactions is presented and crystal structures of the Rep15:Rab3B and Rep15:Rab3C complexes provide additional mechanistic insight. We find that Rep15 adopts a globular structure that is distinct from other reported Rab15, Rab3 and Rab34 effectors. Structure-based mutagenesis experiments explain the Rep15:Rab interaction specificity. Rep15 depletion in U138MG glioblastoma cells impairs cell proliferation, cell migration and receptor recycling, underscoring the need for further clarification of the role of Rep15 in cancer.


"Burden of osteoporotic fractures in primary health care in Catalonia (Spain): a population-based study".
Knowledge on the epidemiology of non-hip fractures in Spain is limited and somewhat outdated. Using computerized primary care records from the SIDIAP database, we derived age and sex-specific fracture incidence rates for the region of Catalonia during the year 2009. The SIDIAP database contains quality-checked clinical information from computerized medical records of a representative sample of >5,800,000 patients (80% of the population of Catalonia). We conducted a retrospective cohort study including all patients aged ≥50 years, and followed them from January 1 to December 31, 2009. Major osteoporotic fractures registered in SIDIAP were ascertained using ICD-10 codes and validated by comparing data to hospital admission and patient-reported fractures records. Incidence rates and 95% confidence intervals were calculated. In total, 2,011,430 subjects were studied (54.6% women). Overall fracture rates were 10.91/1,000 person-years (py) [95%CI 10.89-10.92]: 15.18/1,000 py [15.15-15.21] in women and 5.78/1,000 py [5.76-5.79] in men. The most common fracture among women was wrist/forearm (3.86/1,000 py [3.74-3.98]), while among men it was clinical spine (1.25/1,000 py [1.18-1.33]). All fracture rates increased with age, but varying patterns were observed: while most of the fractures (hip, proximal humerus, clinical spine and pelvis) increased continuously with age, wrist and multiple rib fractures peaked at age 75-80 and then reached a plateau. Our study provides local estimates of age, sex and site-specific fracture burden in primary health care, which will be helpful for health-care planning and delivery. A proportion of fractures are not reported in primary care records, leading to underestimation of fracture incidence rates in these data.


Examining sex and gender disparities in total joint arthroplasty.
Total joint arthroplasty (TJA) is remarkably successful for treating osteoarthritis: most patients see substantial gains in function. However, there are considerable geographic, racial, and gender variations in the utilization of these procedures. The reasons for these differences are complex. We examined sex and gender disparities in TJA. Through Medline/PubMed searches, we identified 632 articles and from these selected 61 for our review. WHERE ARE WE NOW?: A number of factors might explain sex and gender disparities in TJA: underrepresentation in clinical trials, differences in willingness to undergo surgery, pain responses to underlying disease and treatment, patient-physician relationships, treatment preferences, provider-level factors such as physician-patient communication style, and system-level factors such as access to specialist care. Since women have a higher prevalence of arthritis and degenerative joint diseases and overall demand for these procedures will continue to grow, the need to understand why there is a gap in utilization based on gender is imperative. WHERE DO WE NEED TO GO?: Understanding what exactly is meant by "disparity" is essential because it is possible anatomic factors may have different impacts on utilization from cultural factors. Ideally, information about these factors should be integrated into the decision-making process so that patients and providers can make the most informed choice about whether or not to undergo the procedure. HOW DO WE GET THERE?: To better understand all of the potential reasons for how anatomic and cultural factors related to sex and gender might impact decision-making and overall utilization of TJA, more research focusing on these factors must be designed and carried out.


Top-down visual activity underlying VSTM and preparatory attention.
Attention and visual short-term memory (VSTM) are both associated with top-down activity in visual cortex. To-be-remembered visual input triggers persistent activity in visual cortex, and preparatory attention elicits visual activity in anticipation of an expected target stimulus. This brief review considers similarities, and differences, in top-down visual activity underlying VSTM maintenance and preparatory attention. The extant evidence suggests that top-down visual activity provides a common neural substrate for VSTM maintenance and preparatory attention, however the precise neural implementation depends on the specific task parameters. A similar neurobiological framework may also apply to other high-level visual phenomena, including visual imagery and awareness.


Enabling new mindsets and transformative skills for negotiating and activating climate action: Lessons from UNFCCC conferences of the parties.
Technological and policy solutions for transitioning to a fossil-free society exist, many countries could afford the transition, and rational arguments for rapid climate action abound. Yet effective action is still lacking. Dominant policy approaches have failed to generate action at anywhere near the rate, scale or depth needed to avoid potentially catastrophic futures. This is despite 30 years of climate negotiations under the United Nations Framework Convention on Climate Change (UNFCCC), and wide-ranging actions at national, transnational and sub-national levels. Practitioners and scholars are, thus, increasingly arguing that also the root causes of the problem must be addressed - the mindset (or paradigm) out of which the climate emergency has arisen. Against this background, we investigate decision-makers' views of the need for a different mindset and inner qualities that can support negotiating and activating climate action, along with factors that could enable such a mindset shift. Data were collected during participatory workshops run at the 25th UNFCCC Conference of the Parties (COP25) in 2019, and comprise surveys, as well as social media communication and semi-structured interviews with COP attendees. Our results underline vast agreement among participants regarding the need for a mindset shift that can support new ways of communication and collaboration, based on more relational modes of knowing, being and acting. They also suggest the emergence of such a mindset shift across sectors and contexts, but not yet at the collective and systems levels. Finally, they highlight the importance of transformative skills and the need for experimental, safe spaces. The latter are seen as a visible manifestation and enabler that can support agency for change through shared self-reflection, experience and practice. We present a transformative skills framework, and conclude with further research needs and policy recommendations.


Use of medication and in vivo exposure in volunteers for panic disorder research.
A survey of 794 subjects volunteering for studies of panic disorder with or without phobic avoidance revealed that fewer than 15% had received imipramine and fewer than 15% had undergone in vivo exposure, although the majority had engaged in some form of counseling and had used benzodiazepines. Subjects with spontaneous panic attacks reported more avoidance than subjects with situational attacks. One-half of the subjects were unemployed. The authors recommend wider use of the available effective treatments for panic disorder and phobic avoidance.


Cardiac findings at necropsy in patients with chronic kidney disease maintained on chronic hemodialysis.
Studies of multiple hearts at necropsy are lacking in patients who have been on chronic hemodialysis for chronic kidney disease (CKD). We studied at necropsy 120 patients who had been treated with hemodialysis for more than 1 year (mean, 5.25 ± 4.33 yr). Their ages ranged from 24 to 81 years (mean, 53 yr); 91 (76%) were men. Calcific deposits were present in the heart at necropsy in 74 (62%) patients: in the epicardial coronary arteries in all 74 (62%); in the mitral annular region in 52 (42%) patients, and in the aortic valve cusps in 42 (35%) patients. The frequency and quantity of the cardiac calcific deposits were significantly greater in the older compared with the younger patients, and in those with longer durations of hemodialysis compared with those with shorter durations. Despite the calcific deposits, which were sometimes huge, only 47 (39%) patients had 1 or more coronary arteries narrowed more than 75% in cross-sectional area by atherosclerotic plaques, apparently no patient had clinical evidence of mitral stenosis, and 9 patients had clinical evidence of aortic valve stenosis. Thus, we found that CKD treated with hemodialysis is a major producer of cardiac calcific deposits, some of which can be massive. Only a minority of the calcific deposits, however, appeared to lead to cardiac dysfunction or myocardial ischemia during life.


Dog breed affiliation with a forensically validated canine STR set.
We tested a panel of 13 highly polymorphic canine short tandem repeat (STR) markers for dog breed assignment using 392 dog samples from the 23 most popular breeds in Austria, Germany, and Switzerland. This STR panel had originally been selected for canine identification. The dog breeds sampled in this study featured a population frequency ≥1% and accounted for nearly 57% of the entire pedigree dog population in these three countries. Breed selection was based on a survey comprising records for nearly 1.9 million purebred dogs belonging to more than 500 different breeds. To derive breed membership from STR genotypes, a range of algorithms were used. These methods included discriminant analysis of principal components (DAPC), STRUCTURE, GeneClass2, and the adegenet package for R. STRUCTURE analyses suggested 21 distinct genetic clusters. Differentiation between most breeds was clearly discernable. Fourteen of 23 breeds (61%) exhibited maximum mean cluster membership proportions of more than 0.70 with a highest value of 0.90 found for Cavalier King Charles Spaniels. Dogs of only 6 breeds (26%) failed to consistently show only one major cluster. The DAPC method yielded the best assignment results in all 23 declared breeds with 97.5% assignment success. The frequency-based assignment test also provided a high success rate of 87%. These results indicate the potential viability of dog breed prediction using a well-established and sensitive set of 13 canine STR markers intended for forensic routine use.