New Model for Estimating Glomerular Filtration Rate in Patients With Cancer.
Purpose The glomerular filtration rate (GFR) is essential for carboplatin chemotherapy dosing; however, the best method to estimate GFR in patients with cancer is unknown. We identify the most accurate and least biased method. Methods We obtained data on age, sex, height, weight, serum creatinine concentrations, and results for GFR from chromium-51 (51Cr) EDTA excretion measurements (51Cr-EDTA GFR) from white patients ≥ 18 years of age with histologically confirmed cancer diagnoses at the Cambridge University Hospital NHS Trust, United Kingdom. We developed a new multivariable linear model for GFR using statistical regression analysis. 51Cr-EDTA GFR was compared with the estimated GFR (eGFR) from seven published models and our new model, using the statistics root-mean-squared-error (RMSE) and median residual and on an internal and external validation data set. We performed a comparison of carboplatin dosing accuracy on the basis of an absolute percentage error > 20%. Results Between August 2006 and January 2013, data from 2,471 patients were obtained. The new model improved the eGFR accuracy (RMSE, 15.00 mL/min; 95% CI, 14.12 to 16.00 mL/min) compared with all published models. Body surface area (BSA)-adjusted chronic kidney disease epidemiology (CKD-EPI) was the most accurate published model for eGFR (RMSE, 16.30 mL/min; 95% CI, 15.34 to 17.38 mL/min) for the internal validation set. Importantly, the new model reduced the fraction of patients with a carboplatin dose absolute percentage error > 20% to 14.17% in contrast to 18.62% for the BSA-adjusted CKD-EPI and 25.51% for the Cockcroft-Gault formula. The results were externally validated. Conclusion In a large data set from patients with cancer, BSA-adjusted CKD-EPI is the most accurate published model to predict GFR. The new model improves this estimation and may present a new standard of care.


Perceptions of the Targets and Sources of COVID-19 Threat are Structured by Group Memberships and Responses are Influenced by Identification with Humankind.
The purpose of this study was to investigate which social groups are perceived as a threat target and which are perceived as a threat source during the COVID-19 outbreak. In a German sample (N = 1454) we examined perceptions of social groups ranging from those that are psychologically close and smaller (family, friends, neighbors) to those that are more distal and larger (people living in Germany, humankind). We hypothesized that psychologically closer groups would be perceived as less affected by COVID-19 as well as less threatening than more psychologically distal groups. Based on social identity theorizing, we also hypothesized that stronger identification with humankind would change these patterns. Furthermore, we explored how these threat perceptions relate to adherence to COVID-19 health guidelines. In line with our hypotheses, latent random-slope modelling revealed that psychologically distal and larger groups were perceived as more affected by COVID-19 and as more threatening than psychologically closer and smaller groups. Including identification with humankind as a predictor into the threat target model resulted in a steeper increase in threat target perception patterns, whereas identification with humankind did not predict differences in threat source perceptions. Additionally, an increase in threat source perceptions across social groups was associated with more adherence to health guidelines, whereas an increase in threat target perceptions was not. We fully replicated these findings in a subgroup from the original sample (N = 989) four weeks later. We argue that societal recovery from this and other crises will be supported by an inclusive approach informed by a sense of our common identity as human beings.


Adsorption of glucose, cellobiose, and cellotetraose onto cellulose model surfaces.
Reliable simulation of molecular adsorption onto cellulose surfaces is essential for the design of new cellulose nanocomposite materials. However, the applicability of classical force field methods to such systems remains relatively unexplored. In this study, we present the adsorption of glucose, cellobiose, and cellotetraose on model surfaces of crystalline cellulose Iα and Iβ. The adsorption of the two large carbohydrates was simulated with the GLYCAM06 force field. To validate this approach, quantum theoretical calculations for the adsorption of glucose were performed: Equilibrium geometries were studied with density functional theory (DFT) and dispersion-corrected DFT, whereas the adsorption energies were calculated with two standard density functional approximations and five dispersion-containing DFT approaches. We find that GLYCAM06 gives a good account of geometries and, in most cases, accurate adsorption energies when compared to dispersion-corrected DFT energies. Adsorption onto the (100) surface of cellulose Iα is, in general, stronger than onto the (100) surface of cellulose Iβ. Contrary to intuition, the adsorption energy is not directly correlated with the number of hydrogen bonds; rather, it is dominated by dispersion interactions. Especially for bigger adsorbates, a neglect of these interactions leads to a dramatic underestimation of adsorption energies.


Cytoview: development of a cell modelling framework.
The biological cell, a natural self-contained unit of prime biological importance, is an enormously complex machine that can be understood at many levels. A higher-level perspective of the entire cell requires integration of various features into coherent, biologically meaningful descriptions. There are some efforts to model cells based on their genome, proteome or metabolome descriptions. However, there are no established methods as yet to describe cell morphologies, capture similarities and differences between different cells or between healthy and disease states. Here we report a framework to model various aspects of a cell and integrate knowledge encoded at different levels of abstraction, with cell morphologies at one end to atomic structures at the other. The different issues that have been addressed are ontologies, feature description and model building. The framework describes dotted representations and tree data structures to integrate diverse pieces of data and parametric models enabling size, shape and location descriptions. The framework serves as a first step in integrating different levels of data available for a biological cell and has the potential to lead to development of computational models in our pursuit to model cell structure and function, from which several applications can flow out.


Synthesis of peptide-protein conjugates using N-succinimidyl carbamate chemistry.
Peptide-protein conjugates are useful tools in different fields of research as, for instance, the development of vaccines and drugs or for studying biological mechanisms, to cite only few applications. N-Succinimidyl carbamate (NSC) chemistry has been scarcely used in this area. We show that unprotected peptides, featuring one lysine residue within their sequences, can be converted in good yield into NSC derivatives by reaction with disuccinimidylcarbonate (DSC). No hydrolysis of the NSC group was observed during RP-HPLC purification, lyophilization, or storage. NSC peptides reacted efficiently within minutes with lysozyme used as model protein. To illustrate usefulness of the method consisting of the synthesis of a peptide-protein conjugate of biological interest, a NSC peptide derived from a peptide substrate for tyrosylprotein sulfotransferase (TS) was synthesized and ligated to receptor-binding nontoxic B-subunit of Shiga toxin (STxB). Immunofluorescence studies showed the intracellular delivery of the TS-STxB conjugate and its ability to circulate to the Golgi as the native STxB protein. Moreover, we demonstrate that the TS label could be sulfated by tyrosylprotein sulfotransferases present in the Golgi. Thus, NSC chemistry permitted rapid synthesis of a peptide-protein conjugate worthwhile for studying the transport of proteins from the plasma membrane to the Golgi. The second part of this article describes a more general method for synthesizing peptide-protein conjugates without any limitation of the peptide sequence. The conjugates were assembled by combining NSC chemistry and alpha-oxo semicarbazone ligation. To this end, a glyoxylyl NSC peptide was synthesized and reacted with lysozyme. The glyoxylyl groups on the protein were then reacted with a semicarbazide peptide to produce the target peptide-protein conjugate. Both reactions, namely, urea bond formation and alpha-oxo semicarbazone ligation, were carried at pH 8.0 using a one-pot procedure.


Structural and mechanistic basis of zinc regulation across the E. coli Zur regulon.
Commensal microbes, whether they are beneficial or pathogenic, are sensitive to host processes that starve or swamp the prokaryote with large fluctuations in local zinc concentration. To understand how microorganisms coordinate a dynamic response to changes in zinc availability at the molecular level, we evaluated the molecular mechanism of the zinc-sensing zinc uptake regulator (Zur) protein at each of the known Zur-regulated genes in Escherichia coli. We solved the structure of zinc-loaded Zur bound to the P(znuABC) promoter and show that this metalloregulatory protein represses gene expression by a highly cooperative binding of two adjacent dimers to essentially encircle the core element of each of the Zur-regulated promoters. Cooperativity in these protein-DNA interactions requires a pair of asymmetric salt bridges between Arg52 and Asp49' that connect otherwise independent dimers. Analysis of the protein-DNA interface led to the discovery of a new member of the Zur-regulon: pliG. We demonstrate this gene is directly regulated by Zur in a zinc responsive manner. The pliG promoter forms stable complexes with either one or two Zur dimers with significantly less protein-DNA cooperativity than observed at other Zur regulon promoters. Comparison of the in vitro Zur-DNA binding affinity at each of four Zur-regulon promoters reveals ca. 10,000-fold variation Zur-DNA binding constants. The degree of Zur repression observed in vivo by comparison of transcript copy number in wild-type and Δzur strains parallels this trend spanning a 100-fold difference. We conclude that the number of ferric uptake regulator (Fur)-family dimers that bind within any given promoter varies significantly and that the thermodynamic profile of the Zur-DNA interactions directly correlates with the physiological response at different promoters.


L-Ascorbic acid potentiates nitric oxide synthesis in endothelial cells.
Ascorbic acid has been shown to enhance impaired endothelium-dependent vasodilation in patients with atherosclerosis by a mechanism that is thought to involve protection of nitric oxide (NO) from inactivation by free oxygen radicals. The present study in human endothelial cells from umbilical veins and coronary arteries investigates whether L-ascorbic acid additionally affects cellular NO synthesis. Endothelial cells were incubated for 24 h with 0.1-100 microM ascorbic acid and were subsequently stimulated for 15 min with ionomycin (2 microM) or thrombin (1 unit/ml) in the absence of extracellular ascorbate. Ascorbate pretreatment led to a 3-fold increase of the cellular production of NO measured as the formation of its co-product citrulline and as the accumulation of its effector molecule cGMP. The effect was saturated at 100 microM and followed a similar kinetics as seen for the uptake of ascorbate into the cells. The investigation of the precursor molecule L-gulonolactone and of different ascorbic acid derivatives suggests that the enediol structure of ascorbate is essential for its effect on NO synthesis. Ascorbic acid did not induce the expression of the NO synthase (NOS) protein nor enhance the uptake of the NOS substrate L-arginine into endothelial cells. The ascorbic acid effect was minimal when the citrulline formation was measured in cell lysates from ascorbate-pretreated cells in the presence of known cofactors for NOS activity. However, when the cofactor tetrahydrobiopterin was omitted from the assay, a similar potentiating effect of ascorbate pretreatment as seen in intact cells was demonstrated, suggesting that ascorbic acid may either enhance the availability of tetrahydrobiopterin or increase its affinity for the endothelial NOS. Our data suggest that intracellular ascorbic acid enhances NO synthesis in endothelial cells and that this may explain, in part, the beneficial vascular effects of ascorbic acid.


Structural and mechanical properties of glassy water in nanoscale confinement.
We investigate the structure and mechanical properties of glassy water confined between silica-based surfaces with continuously tunable hydrophobicity and hydrophilicity by computing and analyzing minimum energy, mechanically stable configurations (inherent structures). The structured silica substrate imposes long-range order on the first layer of water molecules under hydrophobic confinement at high density (p > or = 1.0 g cm(-3)). This proximal layer is also structured in hydrophilic confinement at very low density (p approximately 0.4 g cm(-3)). The ordering of water next to the hydrophobic surface greatly enhances the mechanical strength of thin films (0.8 nm). This leads to a substantial stress anisotropy; the transverse strength of the film exceeds the normal strength by 500 MPa. The large transverse strength results in a minimum in the equation of state of the energy landscape that does not correspond to a mechanical instability, but represents disruption of the ordered layer of water next to the wall. In addition, we find that the mode of mechanical failure is dependent on the type of confinement. Under large lateral strain, water confined by hydrophilic surfaces preferentially forms voids in the middle of the film and fails cohesively. In contrast, water under hydrophobic confinement tends to form voids near the walls and fails by loss of adhesion.


Tooth survival following non-surgical root canal treatment: a systematic review of the literature.
To investigate (i) the effect of study characteristics on reported tooth survival after root canal treatment (RCTx) and (ii) the effect of clinical factors on the proportion of root filled teeth surviving after RCTx. Longitudinal human clinical studies investigating tooth survival after RCTx which were published up to the end of 2007 were identified electronically (MEDLINE and Cochrane database 1966-2007 December, week 4). In addition, four journals (Dental Traumatology, International Endodontic Journal, Journal of Endodontics, Oral Surgery Oral Medicine Oral Pathology Oral Radiology & Endodontics), bibliographies of all relevant articles and review articles were hand searched. Two reviewers (Y-LN, KG) assessed and selected the studies based on specified inclusion criteria and extracted the data onto a pre-designed proforma, independently. The criteria were as follows: (i) clinical study on RCTx; (ii) stratified analysis of primary and secondary RCTx available; (iii) sample size given and larger than 10; (iv) at least 6-month postoperative review; (v) success based on survival of tooth; and (vi) proportion of teeth surviving after treatment given or could be calculated from the raw data. Three strands of evidence or analyses were used to triangulate a consensus view. The reported findings from individual studies, including those excluded for quantitative analysis, were utilized for the intuitive synthesis, which constituted the first strand of evidence. Secondly, the pooled weighted proportion of teeth surviving and thirdly the combined effects of potential prognostic factors were estimated using the fixed and random effects meta-analyses on studies fulfilling all the inclusion criteria. Of the 31 articles identified, 14 studies published between 1993 and 2007 were included. The majority of studies were retrospective (n = 10) and only four prospective. The pooled percentages of reported tooth survival over 2-3, 4-5 and 8-10 years following RCTx were 86% (95% CI: 75%, 98%), 93% (95% CI: 92%, 94%) and 87% (95% CI: 82%, 92%), respectively. Substantial differences in study characteristics were found to hinder effective direct comparison of findings. Evidence for the effect of prognostic factors on tooth survival was weak. Based on the data available for meta-analyses, four conditions were found to significantly improve tooth survival. In descending order of influence, the conditions increasing observed proportion of survival were as follows: (i) a crown restoration after RCTx; (ii) tooth having both mesial and distal proximal contacts; (iii) tooth not functioning as an abutment for removable or fixed prosthesis; and (iv) tooth type or specifically non-molar teeth. Statistical heterogeneity was substantial in some cases but its source could not be investigated because of insufficient available information. The pooled proportion of teeth surviving over 2-10 years following RCTx ranged between 86% and 93%. Four factors (listed above) were identified as significant prognostic factors with concurrence between all three strands of evidence.


Differences in the motor response to apomorphine between untreated and fluctuating patients with Parkinson's disease.
Behavioral hyposensitivity to repeated apomorphine administration has been observed in fluctuating parkinsonian patients. To investigate whether a similar phenomenon occurs in patients never treated with levodopa, we studied the response to apomorphine in 20 de novo patients with Parkinson's disease. Six patients showed no or minimal improvement after apomorphine injections (maximal dose 3.5 mg). Fourteen patients responded and were then given up to four repeated subcutaneous injections of apomorphine [minimal effective dose (MED)]. The responses of de novo patients were compared with responses in 10 patients with motor fluctuations previously studied by the same protocol. There was no significant difference in latency and duration of motor responses after repeated apomorphine injections in de novo patients. MED was similar in de novo and fluctuating patients, but duration of improvement induced by each apomorphine bolus was longer in the de novo group. These results indicate that response duration to apomorphine is longer in previously untreated patients and that behavioral tolerance associated with pulsatile dopaminergic stimulation by apomorphine occurs mainly in patients with more advanced disease under chronic levodopa therapy.


Does the Brain Detect 3G Mobile Phone Radiation Peaks? An Explorative In-Depth Analysis of an Experimental Study.
This study aimed to investigate whether third generation mobile phone radiation peaks result in event related potentials. Thirty-one healthy females participated. In this single-blind, cross-over design, a 15 minute mobile phone exposure was compared to two 15 minute sham phone conditions, one preceding and one following the exposure condition. Each participant was measured on two separate days, where mobile phone placement was varied between the ear and heart. EEG activity and radiofrequency radiation were recorded jointly. Epochs of 1200 ms, starting 200 ms before and lasting until 1000 ms after the onset of a radiation peak, were extracted from the exposure condition. Control epochs were randomly selected from the two sham phone conditions. The main a-priori hypothesis to be tested concerned an increase of the area in the 240-500 ms post-stimulus interval, in the exposure session with ear-placement. Using multilevel regression analyses the placement*exposure interaction effect was significant for the frontal and central cortical regions, indicating that only in the mobile phone exposure with ear-placement an enlarged cortical reactivity was found. Post-hoc analyses based on visual inspection of the ERPs showed a second significantly increased area between 500-1000 ms post-stimulus for almost every EEG location measured. It was concluded that, when a dialing mobile phone is placed on the ear, its radiation, although unconsciously, is electrically detected by the brain. The question of whether or not this cortical reactivity results in a negative health outcome has to be answered in future longitudinal experiments.


CALIBRATION OF GAFCHROMIC EBT3 FILM FOR DOSIMETRY OF SCANNING PROTON PENCIL BEAM (PBS).
Gafchromic EBT3 films are applied in proton radiotherapy for 2D dose mapping because they demonstrate spatial resolution well below 1 mm. However, the film response must be corrected in order to reach the accuracy of dose measurements required for the clinical use. The in-house developed AnalyseGafchromic software allows to analyze and correct the measured response using triple channel dose calibration, statistical scan-to-scan fluctuations as well as experimentally determined dose and LET dependence. Finally, the optimized protocol for evaluation of response of Gafchromic EBT3 films was applied to determine 30 × 40 cm2 dose profiles of the scanning therapy unit at the Cyclotron Centre Bronowice, CCB in Krakow, Poland.


Effect of dietary restriction and subsequent re-alimentation on the transcriptional profile of bovine jejunal epithelium.
Compensatory growth (CG), an accelerated growth phenomenon which occurs following a period of dietary restriction is utilised worldwide in animal production systems as a management practise to lower feed costs. The objective of this study was to evaluate the contribution of jejunal epithelial to CG in cattle through transcriptional profiling following a period of dietary restriction as well as subsequent re-alimentation induced CG. Sixty Holstein Friesian bulls were separated into two groups; RES and ADLIB, with 30 animals in each. RES animals were offered a restricted diet for 125 days (Period 1) followed by ad libitum feeding for 55 days (Period 2). ADLIB animals had ad libitum access to feed across both periods 1 and 2. At the end of each period, 15 animals from each treatment group were slaughtered, jejunal epithelium collected and RNAseq analysis performed. Animals that were previously diet restricted underwent CG, gaining 1.8 times the rate of their non-restricted counterparts. Twenty-four genes were differentially expressed in RES compared to ADLIB animals at the end of Period 1, with only one gene, GSTA1, differentially expressed between the two groups at the end of Period 2. When analysed within treatment (RES, Period 2 v Period 1), 31 genes were differentially expressed between diet restricted and animals undergoing CG. Dietary restriction and subsequent re-alimentation were associated with altered expression of genes involved in digestion and metabolism as well as those involved in cellular division and growth. Compensatory growth was also associated with greater expression of genes involved in cellular protection and detoxification in jejunal epithelium. This study highlights some of the molecular mechanisms regulating the response to dietary restriction and subsequent re-alimentation induced CG in cattle; however the gene expression results suggest that most of the CG in jejunal epithelium had occurred by day 55 of re-alimentation.


Auger electron angular distributions from surfaces: direct comparison with isoenergetic photoelectrons.
Angular distribution patterns of Auger electrons and of photoelectrons from a Cu (001) surface were measured at the same electron kinetic energy. These measurements reveal that the low kinetic energy angular distributions for Cu Auger electrons and Cu 3p(3/2) photoelectrons differ substantially. This direct comparison between the photoelectron and Auger electron angular distributions demonstrates that, in some circumstances, the Auger process produces a complicated source wave whose nature must be explored before Auger angular distributions can be used for surface structure analysis.


Long-term exposure to fluoride in drinking water and sister chromatid exchange frequency in human blood lymphocytes.
The genetic toxicity of fluoride has been investigated extensively by various test systems. However, results obtained have been inconsistent. Fluoride has been reported to be non-genotoxic, genotoxic, and synergistic or antagonistic with certain mutagens. To date, there are no published human studies on the genotoxicity of fluoride. The purpose of this investigation was to determine genotoxic risks of long-term exposure to various concentrations of fluoride in drinking water in humans with normal or inadequate nutrition. Six groups of subjects with either normal or inadequate nutritional intakes were selected from areas of approximately 0.2, 1.0, or 4.8 ppm (10.5, 52.6, or 252.6 mumol/L) fluoride in water. The subjects had been continuous residents in the area for at least 35 years. Samples of drinking water, plasma, and urine were analyzed for fluoride content. Blood lymphocytes were examined to determine the frequency of sister chromatid exchange (SCE). Blood chemistry and electrolytes were also analyzed. The results showed that average daily fluoride intake as well as urine and plasma fluoride levels increased with increase in the fluoride content of the drinking water. The blood chemistry and electrolyte values were within the normal range for all populations, but several parameters were significantly different. While the numerical differences were small, the subjects with low fluoride in the water (0.11 and 0.23 ppm or 5.8 and 12.1 mumol/L) had significantly higher SCE frequencies than those with higher fluoride exposures.(ABSTRACT TRUNCATED AT 250 WORDS)


Visible-light sensitization of boron-doped nanocrystalline diamond through non-covalent surface modification.
A novel simple and versatile synthetic strategy is developed for the surface modification of boron-doped diamond. In a two-step procedure, polyethyleneimine is adsorbed on the hydrogenated diamond surface and subsequently modified with a model light-harvesting donor-π-bridge-acceptor molecule (coded P1). The sensitized diamond exhibits stable cathodic photocurrents under visible-light illumination in aqueous electrolyte solution with dimethylviologen serving as an electron mediator. In spite of the simplicity of the surface sensitization protocol, the photoelectrochemical performance is similar to or better than that of other sensitized diamond electrodes which were reported in previous studies (2008-2014).


A systematic evaluation of prevalence and diagnostic accuracy of sacroiliac joint interventions.
The contributions of the sacroiliac joint to low back and lower extremity pain have been a subject of considerable debate and research. It is generally accepted that 10% to 25% of patients with persistent mechanical low back pain below L5 have pain secondary to sacroiliac joint pathology. However, no single historical, physical exam, or radiological feature can definitively establish a diagnosis of sacroiliac joint pain. Based on present knowledge, a proper diagnosis can only be made using controlled diagnostic blocks. The diagnosis and treatment of sacroiliac joint pain continue to be characterized by wide variability and a paucity of the literature. To evaluate the accuracy of diagnostic sacroiliac joint interventions. A systematic review of diagnostic sacroiliac joint interventions. Methodological quality assessment of included studies was performed using Quality Appraisal of Reliability Studies (QAREL). Only diagnostic accuracy studies meeting at least 50% of the designated inclusion criteria were utilized for analysis. Studies scoring less than 50% are presented descriptively and analyzed critically. The level of evidence was classified as good, fair, or poor based on the quality of evidence developed by the United States Preventive Services Task Force (USPSTF). Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 to December 2011, and manual searches of the bibliographies of known primary and review articles. In this evaluation we utilized controlled local anesthetic blocks using at least 50% pain relief as the reference standard. The evidence is good for the diagnosis of sacroiliac joint pain utilizing controlled comparative local anesthetic blocks. The prevalence of sacroiliac joint pain is estimated to range between 10% and 62% based on the setting; however, the majority of analyzed studies suggest a point prevalence of around 25%, with a false-positive rate for uncontrolled blocks of approximately 20%. The evidence for provocative testing to diagnose sacroiliac joint pain was fair. The evidence for the diagnostic accuracy of imaging is limited. The limitations of this systematic review include a paucity of literature, variations in technique, and variable criterion standards for the diagnosis of sacroiliac joint pain. Based on this systematic review, the evidence for the diagnostic accuracy of sacroiliac joint injections is good, the evidence for provocation maneuvers is fair, and evidence for imaging is limited.


Detection of subclinical infection in significant breast implant capsules.
The pathogenesis of fibrous capsular contracture after augmentation mammaplasty is still debated. One hypothesis implicates low-grade bacterial infections as a cause. The presence of a staphylococcal biofilm in a patient with recurrent capsular contracture was previously reported. A comparative, prospective, blinded, clinical study of implants and capsules removed from patients with or without significant capsular contracture was conducted to investigate the association of biofilm contamination, breast implants, and capsular contracture. Capsule and implant samples obtained during explantation were tested by routine microbiological culture, sensitive broth culture (after maceration and sonication), and scanning electron microscopy. Clinical parameters were correlated with microbiological findings. A total of 48 implant and/or capsule samples were obtained from 27 breasts during a 22-month period. Of the 27 breasts, 19 exhibited significant contracture (Baker grade III/IV). The mean duration of implantation was 9.2 years (range, 0.4 to 26.0 years). Routine swab cultures obtained at the time of explantation were negative for bacterial growth for all samples. The sensitive broth culture technique yielded 24 positive samples (50 percent, n = 48). An analysis of capsules demonstrated that 17 of 19 samples obtained from patients with significant contracture were positive, compared with only one of eight samples obtained from patients with minimal or no contracture (p = 0.0006). Fourteen of the 17 positive cultures from significantly contracted breasts yielded coagulase-negative staphylococci, mainly, species of the Staphylococcus epidermidis group. The presence of coagulase-negative staphylococci was also significantly associated with capsular contracture (p = 0.01). There was no significant difference in the frequency of culture positivity for saline versus silicone implants (p = 0.885). Scanning electron microscopy confirmed the presence of extensive biofilm on implants and within capsules.Biofilm, in particular, S. epidermidis biofilm, was detected for a significant proportion of patients with capsular contracture. This implicates biofilm disease in the pathogenesis of contracture, and strategies for its prevention should be explored.


Analgesic Effects of Hydromorphone versus Buprenorphine in Buprenorphine-maintained Individuals.
Managing acute pain in buprenorphine-maintained individuals in emergency or perioperative settings is a significant challenge. This study compared analgesic and abuse liability effects of adjunct hydromorphone and buprenorphine using quantitative sensory testing, a model of acute clinical pain, in persons maintained on 12 to 16 mg sublingual buprenorphine/naloxone. Participants (N = 13) were enrolled in a randomized within-subject, double-blind, placebo-controlled three-session experiment. Each session used a cumulative dosing design with four IV injections (4, 4, 8, and 16 mg of hydromorphone or 4, 4, 8, and 16 mg of buprenorphine); quantitative sensory testing and abuse liability assessments were measured at baseline and after each injection. The primary analgesia outcome was change from baseline cold pressor testing; secondary outcomes included thermal and pressure pain testing, as well as subjective drug effects and adverse events. A significant two-way interaction between study drug condition and dose was exhibited in cold pressor threshold (F10,110 = 2.14, P = 0.027) and tolerance (F10,110 = 2.69, P = 0.006). Compared to after placebo, participants displayed increased cold pressor threshold from baseline after cumulative doses of 32 mg of IV hydromorphone (means ± SD) (10 ± 14 s, P = 0.035) and 32 mg of buprenorphine (3 ± 5 s, P = 0.0.39) and in cold pressor tolerance after cumulative doses of 16 mg (18 ± 24 s, P = 0.018) and 32 mg (48 ± 73 s, P = 0.041) IV hydromorphone; cold pressor tolerance scores were not significant for 16 mg (1 ± 15 s, P = 0.619) or 32 mg (7 ± 16 s, P = 0.066) buprenorphine. Hydromorphone and buprenorphine compared with placebo showed greater ratings on subjective measures of high, any drug effects, good effects, and drug liking. Adverse events were more frequent during the hydromorphone compared with buprenorphine and placebo conditions for nausea, pruritus, sedation, and vomiting. In this acute clinical pain model, high doses of IV hydromorphone (16 to 32 mg) were most effective in achieving analgesia but also displayed higher abuse liability and more frequent adverse events. Cold pressor testing was the most consistent measure of opioid-related analgesia.


Japanese family with parkinsonism, depression, weight loss, and central hypoventilation.
The authors describe the clinical and pathologic characteristics of the Fukuoka 1 family, the first Japanese family recognized to have hereditary parkinsonism associated with depression, weight loss, and central alveolar hypoventilation. The pedigree contains 14 family members spanning four generations, with five affected individuals. All available medical records were collected for affected members, including autopsy results. The inheritance pattern was autosomal dominant. The average age at onset of symptoms was 41 years. All patients had parkinsonism characterized by rigidity, bradykinesia, and resting and postural tremor. Bradykinesia and depression developed in the proband at age 43 years. He responded to levodopa in the initial stage only. A year later, he had weight loss and central hypoventilation leading to respiratory failure. Symptoms developed in his cousin at age 38 years. The proband's father developed a resting tremor and depression at age 43 years. The tremor was initially responsive to levodopa therapy, but the disease was relentlessly progressive, leading to severe bradykinesia, rigidity, weight loss, and respiratory distress. He died of respiratory failure at age 49 years. Autopsy showed marked neuronal loss and gliosis in the substantia nigra and locus ceruleus. Lewy bodies, neurofibrillary tangles, senile plaques, and other abnormal structures were not seen in the cortical and subcortical regions. The Fukuoka 1 family shares many clinical and pathologic features with five previously reported kindreds from North America and Europe, suggesting that this syndrome has a worldwide distribution and can occur in different ethnic populations.


Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales.
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a prothrombotic state, but long-term effects of COVID-19 on incidence of vascular diseases are unclear. We studied vascular diseases after COVID-19 diagnosis in population-wide anonymized linked English and Welsh electronic health records from January 1 to December 7, 2020. We estimated adjusted hazard ratios comparing the incidence of arterial thromboses and venous thromboembolic events (VTEs) after diagnosis of COVID-19 with the incidence in people without a COVID-19 diagnosis. We conducted subgroup analyses by COVID-19 severity, demographic characteristics, and previous history. Among 48 million adults, 125 985 were hospitalized and 1 319 789 were not hospitalized within 28 days of COVID-19 diagnosis. In England, there were 260 279 first arterial thromboses and 59 421 first VTEs during 41.6 million person-years of follow-up. Adjusted hazard ratios for first arterial thrombosis after COVID-19 diagnosis compared with no COVID-19 diagnosis declined from 21.7 (95% CI, 21.0-22.4) in week 1 after COVID-19 diagnosis to 1.34 (95% CI, 1.21-1.48) during weeks 27 to 49. Adjusted hazard ratios for first VTE after COVID-19 diagnosis declined from 33.2 (95% CI, 31.3-35.2) in week 1 to 1.80 (95% CI, 1.50-2.17) during weeks 27 to 49. Adjusted hazard ratios were higher, for longer after diagnosis, after hospitalized versus nonhospitalized COVID-19, among Black or Asian versus White people, and among people without versus with a previous event. The estimated whole-population increases in risk of arterial thromboses and VTEs 49 weeks after COVID-19 diagnosis were 0.5% and 0.25%, respectively, corresponding to 7200 and 3500 additional events, respectively, after 1.4 million COVID-19 diagnoses. High relative incidence of vascular events soon after COVID-19 diagnosis declines more rapidly for arterial thromboses than VTEs. However, incidence remains elevated up to 49 weeks after COVID-19 diagnosis. These results support policies to prevent severe COVID-19 by means of COVID-19 vaccines, early review after discharge, risk factor control, and use of secondary preventive agents in high-risk patients.


Can false memories prime problem solutions?
Previous research has suggested that false memories can prime performance on related implicit and explicit memory tasks. The present research examined whether false memories can also be used to prime higher order cognitive processes, namely, insight-based problem solving. Participants were asked to solve a number of compound remote associate task (CRAT) problems, half of which had been primed by the presentation of Deese/Roediger-McDermott (DRM) lists whose critical lure was also the solution to the problem. The results showed that when the critical lure: (a) was falsely recalled, CRAT problems were solved more often and significantly faster than problems that were not primed by a DRM list and (b) was not falsely recalled, CRAT problem solution rates and times were no different than when there was no DRM priming. A second experiment demonstrated that these outcomes were not a simple artifact of the inclusion of a recall test prior to the problem solving task. The implications of these results are discussed with regard to the previous literature on priming and the adaptive function of false memories.


A survey of access to trial of labor in California hospitals in 2012.
In 2010, the NIH and ACOG recommended increasing women's access to trial of labor after cesarean (TOLAC). This study explored access to TOLAC in California, change in access since 2007 and 2010, and characteristics of TOLAC and non-TOLAC hospitals. Between November 2011 and June 2012, charge nurses at all civilian California birth hospitals were surveyed about hospitals' TOLAC availability and requirements for providers. VBAC rates were obtained from the California Office of Statewide Health Planning and Development (OSHPD). Distance between hospitals was calculated using OSHPD geocoding. All 243 birth hospitals that were contacted participated. In 2010, among the 56% TOLAC hospitals, the median VBAC rate among TOLAC hospitals was 10.8% (range 0-37.3%). The most cited reason for low VBAC rates was physician unwillingness to perform them, especially due to the requirement to be continually present during labor. TOLAC hospitals were more likely to be larger hospitals in urban communities with obstetrical residency training. However, there were six (11.3%) residency programs in non-TOLAC hospitals and 5 (13.5%) rural hospitals offering TOLAC. The majority of TOLAC hospitals had 24/7 anesthesia coverage and required the obstetrician to be continually present if a TOLAC patient was admitted; 17 (12.2%) allowed personnel to be 15-30 minutes away. TOLAC eligibility criteria included one prior cesarean (32.4%), spontaneous labor (52.5%), continuous fetal monitoring and intravenous access (99.3%), and epidural analgesia (19.4%). The mean distance from a non-TOLAC to a TOLAC hospital was 37 mi. with 25% of non-TOLAC hospitals more than 51 mi. from the closest TOLAC hospital. In 2012, 139 hospitals (57.2%) offered TOLAC, 16.6% fewer than in 2007. Since 2010, five hospitals started and four stopped offering TOLAC, a net gain of one hospital offering TOLAC with three more considering it. Only two hospitals cited change in ACOG guidelines as a reason for the change. Despite the 2010 NIH and ACOG recommendations encouraging greater access to TOLAC, 44% of California hospitals do not allow TOLAC. Of the 56% allowing TOLAC, 10.8% report fewer than 3% VBAC births. Thus, national recommendations encouraging greater access to TOLAC had a minor effect in California.


Outcomes of planned home births with certified professional midwives: large prospective study in North America.
To evaluate the safety of home births in North America involving direct entry midwives, in jurisdictions where the practice is not well integrated into the healthcare system. Prospective cohort study. All home births involving certified professional midwives across the United States (98% of cohort) and Canada, 2000. All 5418 women expecting to deliver in 2000 supported by midwives with a common certification and who planned to deliver at home when labour began. Intrapartum and neonatal mortality, perinatal transfer to hospital care, medical intervention during labour, breast feeding, and maternal satisfaction. 655 (12.1%) women who intended to deliver at home when labour began were transferred to hospital. Medical intervention rates included epidural (4.7%), episiotomy (2.1%), forceps (1.0%), vacuum extraction (0.6%), and caesarean section (3.7%); these rates were substantially lower than for low risk US women having hospital births. The intrapartum and neonatal mortality among women considered at low risk at start of labour, excluding deaths concerning life threatening congenital anomalies, was 1.7 deaths per 1000 planned home births, similar to risks in other studies of low risk home and hospital births in North America. No mothers died. No discrepancies were found for perinatal outcomes independently validated. Planned home birth for low risk women in North America using certified professional midwives was associated with lower rates of medical intervention but similar intrapartum and neonatal mortality to that of low risk hospital births in the United States.


Surgical experts: born or made?
The concept of surgical expertise and the processes involved in its development are topical, and there is a constant drive to identify reliable measures of expert performance in surgery. This review explores the notion of whether surgical experts are "born" or "made", with reference to educational theory and pertinent literature. Peer-reviewed publications, books, and online resources on surgical education, expertise and training were reviewed. Important themes and aspects of expertise acquisition were identified in order to better understand the concept of a surgical expert. The definition of surgical expertise and several important aspects of its development are highlighted. Innate talent plays an important role, but is insufficient on its own to produce a surgical expert. Multiple theories that explore motor skill acquisition and memory are relevant, and Ericsson's theory of the development of competence followed by deliberate self-practice has been especially influential. Psychomotor and non-technical skills are necessary for progression in the current climate in light of our training curricula; surgical experts are adaptive experts who excel in these. The literature suggests that surgical expertise is reached through practice; surgical experts are made, not born. A deeper understanding of the nature of expert performance and its development will ensure that surgical education training programmes are of the highest possible quality. Surgical educators should aim to develop an expertise-based approach, with expert performance as the benchmark.


The many weak instruments problem and Mendelian randomization.
Instrumental variable estimates of causal effects can be biased when using many instruments that are only weakly associated with the exposure. We describe several techniques to reduce this bias and estimate corrected standard errors. We present our findings using a simulation study and an empirical application. For the latter, we estimate the effect of height on lung function, using genetic variants as instruments for height. Our simulation study demonstrates that, using many weak individual variants, two-stage least squares (2SLS) is biased, whereas the limited information maximum likelihood (LIML) and the continuously updating estimator (CUE) are unbiased and have accurate rejection frequencies when standard errors are corrected for the presence of many weak instruments. Our illustrative empirical example uses data on 3631 children from England. We used 180 genetic variants as instruments and compared conventional ordinary least squares estimates with results for the 2SLS, LIML, and CUE instrumental variable estimators using the individual height variants. We further compare these with instrumental variable estimates using an unweighted or weighted allele score as single instruments. In conclusion, the allele scores and CUE gave consistent estimates of the causal effect. In our empirical example, estimates using the allele score were more efficient. CUE with corrected standard errors, however, provides a useful additional statistical tool in applications with many weak instruments. The CUE may be preferred over an allele score if the population weights for the allele score are unknown or when the causal effects of multiple risk factors are estimated jointly.


Fibronectin promotes proliferation of naive and memory T cells by signaling through both the VLA-4 and VLA-5 integrin molecules.
The capacity of purified fibronectin to costimulate human T cell DNA synthesis was examined. Low concentrations of immobilized fibronectin, but not soluble fibronectin, augmented anti-CD3-induced proliferation of highly purified human T cells. In the absence of anti-CD3 stimulation, immobilized fibronectin did not induce T cell proliferation alone or in the presence of IL-2 or phorbol dibutyrate. Although fibronectin is present in high concentrations in the serum, immobilized fibronectin was able to costimulate T cell proliferation when cells were cultured in serum-containing medium. Immobilized collagen type I did not enhance anti-CD3 stimulated T cell responses, whereas gelatin (denatured collagen) and laminin were able to enhance anti-CD3 stimulated T cell responses modestly. The effects of gelatin, however, appeared to be indirect, because it could not enhance responses in medium devoid of fibronectin. Immobilized fibronectin enhanced anti-CD3 induced proliferation of both CD45RA dim and CD45RA bright subsets within both the CD4+ and CD8+ subpopulations of T cells, although cells with the CD45RA dim phenotype were costimulated by lower concentrations of immobilized fibronectin. Enhancement of anti-CD3 induced proliferation by immobilized fibronectin was completely inhibited by a mAb to CD29, the integrin beta 1-chain (4B4) and not by a variety of other mAb. In contrast to its effects on proliferation, 4B4 only partially blocked T cell binding to anti-CD3 and fibronectin-coated macrowells. These findings suggested that the interaction between fibronectin and its receptor transduced a signal to the T cell and did not merely stabilize the interaction between anti-CD3 and the CD3 complex. Further experiments confirmed this observation. Thus fibronectin could enhance anti-CD3 responses when it was immobilized to a separate surface. The augmentation of anti-CD3 stimulated proliferation induced by immobilized fibronectin was also inhibited partially by mAb to either VLA-4 or VLA-5 and completely by a combination of the two mAb. The mAb to VLA-4 not only blocked the capacity of immobilized fibronectin to enhance anti-CD3-induced T cell proliferation but also directly costimulated T cell responses. Thus, at least two fibronectin receptors are involved in fibronectin-mediated costimulation of T cell proliferation. These studies indicate that signals are transduced through the fibronectin receptors, VLA-4 and VLA-5, that augment T cell responses and therefore implicate the extracellular matrix protein fibronectin as an important influence regulating T cell responsiveness in vivo.


Accessory left atrial diverticulae: contractile properties depicted with 64-slice cine-cardiac CT.
To assess the contractility of accessory left atrial appendages (LAAs) using multiphasic cardiac CT. We retrospectively analyzed the presence, location, size and contractile properties of accessory LAAs using multiphasic cardiac 64-slice CT in 102 consecutive patients (63 males, 39 females, mean age 57). Multiplanar reformats were used to create image planes in axial oblique, sagittal oblique and coronal oblique planes. For all appendages with an orifice diameter >or= 10 mm, axial and sagittal diameters and appendage volumes were recorded in atrial diastole and systole. Regression analysis was performed to assess which imaging appearances best predicted accessory appendage contractility. Twenty-three (23%) patients demonstrated an accessory LAA, all identified along the anterior LA wall. Dimensions for axial oblique (AOD) and sagittal oblique (SOD) diameters and sagittal oblique length (SOL) were 6.3-19, 3.4-20 and 5-21 mm, respectively. All appendages (>or=10 mm) demonstrated significant contraction during atrial systole (greatest diameter reduction was AOD [3.8 mm, 27%]). Significant correlations were noted between AOD-contraction and AOD (R = 0.57, P < 0.05) and SOD-contraction and AOD, SOD and SOL (R = 0.6, P < 0.05). Mean diverticulum volume in atrial diastole was 468.4 +/- 493 mm(3) and in systole was 171.2 +/- 122 mm(3), indicating a mean change in volume of 297.2 +/- 390 mm(3), P < 0.0001. Stepwise multiple regression analysis revealed SOL to be the strongest independent predictor of appendage contractility (R(2) = 0.86, P < 0.0001) followed by SOD (R(2) = 0.91, P < 0.0001). Accessory LAAs show significant contractile properties on cardiac CT. Those accessory LAAs with a large sagittal height or depth should be evaluated for contractile properties, and if present should be examined for ectopic activity during electrophysiological studies.


Social and Genetic Networks of HIV-1 Transmission in New York City.
Sexually transmitted infections spread across contact networks. Partner elicitation and notification are commonly used public health tools to identify, notify, and offer testing to persons linked in these contact networks. For HIV-1, a rapidly evolving pathogen with low per-contact transmission rates, viral genetic sequences are an additional source of data that can be used to infer or refine transmission networks. The New York City Department of Health and Mental Hygiene interviews individuals newly diagnosed with HIV and elicits names of sexual and injection drug using partners. By law, the Department of Health also receives HIV sequences when these individuals enter healthcare and their physicians order resistance testing. Our study used both HIV sequence and partner naming data from 1342 HIV-infected persons in New York City between 2006 and 2012 to infer and compare sexual/drug-use named partner and genetic transmission networks. Using these networks, we determined a range of genetic distance thresholds suitable for identifying potential transmission partners. In 48% of cases, named partners were infected with genetically closely related viruses, compatible with but not necessarily representing or implying, direct transmission. Partner pairs linked through the genetic similarity of their HIV sequences were also linked by naming in 53% of cases. Persons who reported high-risk heterosexual contact were more likely to name at least one partner with a genetically similar virus than those reporting their risk as injection drug use or men who have sex with men. We analyzed an unprecedentedly large and detailed partner tracing and HIV sequence dataset and determined an empirically justified range of genetic distance thresholds for identifying potential transmission partners. We conclude that genetic linkage provides more reliable evidence for identifying potential transmission partners than partner naming, highlighting the importance and complementarity of both epidemiological and molecular genetic surveillance for characterizing regional HIV-1 epidemics.


The Effects of In-Season, Low-Volume Sprint Interval Training With and Without Sport-Specific Actions on the Physical Characteristics of Elite Academy Rugby League Players
To determine the utility of running-only and rugby-specific, in-season sprint interval interventions in professional rugby league players. Thirty-one professional academy rugby players were assigned to a rugby-specific (SITr/s, n = 16) or running-only (SITr, n = 15) sprint interval training group. Measures of speed, power, change of direction ability, prone Yo-Yo Intermittent Recovery Test (Yo-Yo IR1) performance, and heart rate recovery were taken before and after the 2-week intervention as were submaximal responses to the prone Yo-Yo IR1. Internal, external, and perceptual responses were collected during SITr/s and SITr, with well-being and neuromuscular function assessed before each session. Despite contrasting (possible to most likely) internal, external, and perceptual responses to the SIT interventions, possible to most likely within-group improvements in physical characteristics, heart rate recovery, and submaximal responses to the prone Yo-Yo IR1 were observed after both interventions. Between-group analysis favored the SITr/s intervention (trivial to moderate) for changes in 10-m sprint time, countermovement jump, change of direction, and medicine ball throw as well as submaximal (280-440 m) high metabolic power, PlayerLoad™, and acceleration distance during the prone Yo-Yo IR1. Overall changes in well-being or neuromuscular function were unclear. Two weeks of SITr/s and SITr were effective for improving physical characteristics, heart rate recovery, and submaximal responses to the prone Yo-Yo IR1, with no clear change in well-being and neuromuscular function. Between-group analysis favored the SITr/s group, suggesting that the inclusion of sport-specific actions should be considered for in-season conditioning of rugby league players.


Limitations of lymph node counts as a measure of therapy.
For several cancers, the number of lymph nodes removed during surgery is associated with survival. Observational studies supporting this association have prompted considerable debate regarding the extent of lymphadenectomy, and in some dieases, absolute lymph node counts have been suggested as a measure of the quality of cancer care. However, for most cancers, lymph node counts may not directly influence survival in a causal manner. In fact, several randomized clinical trials addressing the question in lung, gastric, and pancreatic cancers have not shown more extensive lymph node dissections to be linked with improved survival. Despite this negative evidence, however, lymph node counts have remained a target process in quality initiatives. Misinterpretation of the evidence may be driving some of the pressure to broadly implement more extended lymph node dissections. As a process for more accurate disease staging and as a potential marker for the completeness of surgery, lymph node counts are likely linked to quality, at least indirectly. However, a causal association between lymph node counts (and extented lymphadenectomy) and survival is tenuous and has not been supported by high-level evidence.


Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders.
Over 150 different proteins attach to the plasma membrane using glycosylphosphatidylinositol (GPI) anchors. Mutations in 18 genes that encode components of GPI-anchor biogenesis result in a phenotypic spectrum that includes learning disability, epilepsy, microcephaly, congenital malformations and mild dysmorphic features. To determine the incidence of GPI-anchor defects, we analysed the exome data from 4293 parent-child trios recruited to the Deciphering Developmental Disorders (DDD) study. All probands recruited had a neurodevelopmental disorder. We searched for variants in 31 genes linked to GPI-anchor biogenesis and detected rare biallelic variants in PGAP3, PIGN, PIGT (n=2), PIGO and PIGL, providing a likely diagnosis for six families. In five families, the variants were in a compound heterozygous configuration while in a consanguineous Afghani kindred, a homozygous c.709G>C; p.(E237Q) variant in PIGT was identified within 10-12 Mb of autozygosity. Validation and segregation analysis was performed using Sanger sequencing. Across the six families, five siblings were available for testing and in all cases variants co-segregated consistent with them being causative. In four families, abnormal alkaline phosphatase results were observed in the direction expected. FACS analysis of knockout HEK293 cells that had been transfected with wild-type or mutant cDNA constructs demonstrated that the variants in PIGN, PIGT and PIGO all led to reduced activity. Splicing assays, performed using leucocyte RNA, showed that a c.336-2A>G variant in PIGL resulted in exon skipping and p.D113fs*2. Our results strengthen recently reported disease associations, suggest that defective GPI-anchor biogenesis may explain ~0.15% of individuals with developmental disorders and highlight the benefits of data sharing.


From landfills to landscapes-Nature-based solutions for water management taking into account legacy contamination.
Nature-based solutions (NBS) can be used in combination with the reopening of piped rivers to support area development. In certain cases, piped rivers can run through disused landfills. This presents a complicating factor because landfills provide the possibility for river water to be contaminated by waste. In Skien municipality, close to Oslo, Norway, NBS are being considered as part of a potential reopening of the Kjørbekk stream. A 4-km stretch of the stream is contained in an aging pipe infrastructure that is buried under two disused landfills. The pipe infrastructure does not have the physical capacity to cope with an increase in precipitation brought about by current climate change, and in certain areas, the pipe has started to leak. This means that surface water runoff that cannot be accommodated by the pipe, as well as water that leaks from the pipe, can become contaminated by the waste in the disused landfill. Furthermore, the water can be transported with the stream course to the final recipient, taking the contamination with it. Reopening the stream and providing new water pathways can alleviate these problems, but it must be carried out so that contamination is not allowed to spread. This case study reveals how certain NBS that focus on reducing the amount of water in contact with pollutants, reducing the amount of particle spreading, remediating contaminated water, and remediating contaminated soil could be implemented at the site and function as a catalyst for an incremental city development. Integr Environ Assess Manag 2022;18:99-107. © 2021 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).


Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX: direct evidence for the involvement of CRX in the development of photoreceptor function.
The CRX (cone-rod homeobox) gene is specifically expressed in developing and mature photoreceptors and encodes an otd/Otx-like paired homeodomain protein. Mutant alleles of the CRX gene have recently been associated with autosomal dominant cone-rod dystrophy (CORD) as well as dominant Leber congenital amaurosis (LCA). Since LCA is more commonly inherited in an autosomal recessive manner, we examined a cohort of recessive LCA patients for CRX mutations. A homozygous substitution of arginine (R) at codon 90 by tryptophan (W) was identified in the CRX homeodomain of one of the probands who was nearly blind from birth. A group of 48 control individuals and 190 previously characterized CORD probands did not reveal this sequence change. The mutant CRXR90W homeodomain demonstrated decreased binding to the previously identified cis sequence elements in the rhodopsin promoter. In transient transfection experiments, the mutant protein showed significantly reduced ability to transactivate the rhodopsin promoter, as well as lower synergistic activation with the bZIP transcription factor NRL. Heterozygosity of the mutant CRX (R90W) allele was detected in both parents and in an older sibling. Ophthalmologic examination and electro-retinography revealed a subtle abnormality of cone function in both the parents. These data suggest that the R90W mutation results in a CRX protein with reduced DNA binding and transcriptional regulatory activity and that the subsequent changes in photoreceptor gene expression lead to the very early onset severe visual impairment in LCA.


Epidemiological, clinical and therapeutic associations of hepatitis C types in western European patients.
Different variants of hepatitis C virus might show different susceptibility to interferon alpha treatment, but it is important to understand whether this difference in sensitivity reflects an association with other factors, such as cirrhosis or age. We have used an enzyme-linked immunosorbent hepatitis C virus typing assay based upon the detection of antibody in patient's era to type-specific NS-4 antigens to investigate the effect of hepatitis C virus type in 610 patients with chronic hepatitis C virus infection. The influence of viral types and their interdependency with host factors were separately analyzed to establish which factors executed an independent effect on the probability of sustained response. There was a marked difference in the distribution of hepatitis C virus types with age: infection with type 3 was more common in younger patients. The distribution of hepatitis C virus type with age is accounted for by differences in risk-factors for infection in different age groups. The frequency of cirrhosis increased markedly with age. Even after standardization for age, center and the presence of cirrhosis, viral type was strongly related to the outcome of infection. Our data suggest that enzyme-linked immunosorbent hepatitis C virus typing could assist in patient selection for interferon treatment to improve sustained response rates. Together with measurement of viral load, hepatitis C virus typing may serve to indicate the probability of response in patients with chronic hepatitis C, and to elucidate antiviral mechanisms in the disease. The serotyping assay provides a relatively inexpensive screening method to determine the infecting hepatitis C virus type, which could facilitate therapeutic decisions and strategies in patients with chronic hepatitis C.


The biopersistence of brazilian chrysotile asbestos following inhalation.
With the initial understanding of the relationship of asbestos to disease, little information was available on whether the two different groups of minerals that are called asbestos were of similar or different potency in causing disease. Asbestos was often described as a durable fiber that if inhaled would remain in the lung and cause disease. It has been only more recently, with the development of a standardized protocol for evaluating the biopersistence of mineral fibers in the lung, that the clearance kinetics of the serpentine chrysotile have been shown to be dramatically different from those of amphibole asbestos, with chrysotile clearing rapidly from the lung. In addition, recent epidemiology studies also differentiate chrysotile from amphibole asbestos. The biopersistence studies mentioned have indicated that chrysotile from Canada and California clear rapidly from the lung once inhaled. However, variations in chrysotile mineralogy have been reported depending upon the region. This is most likely associated with variations in the forces which created the chrysotile fibers centuries ago. In the present study, the dynamics and rate of clearance of chrysotile from the Cana Brava mine in central Brazil was evaluated in a comparable inhalation biopersistence study in the rat. For synthetic vitreous fibers, the biopersistence of the fibers longer than 20 microm has been found to be directly related to their potential to cause disease. This study was designed to determine lung clearance (biopersistence) and translocation and distribution within the lung. As the long fibers have been shown to have the greatest potential for pathogenicity, the chrysotile samples were specifically chosen to have more than 450 fibers/cm(3) longer than 20 microm in length present in the exposure aerosol. For the fiber clearance study (lung digestions), at 1 day, 2 days, 7 days, 2 wk, 1 mo, 3 mo, 6 mo, and 12 mo following a 5-day (6 h/day) inhalation exposure, the lungs from groups of animals were digested by low-temperature plasma ashing and subsequently analyzed by transmission electron microscopy (at the GSA Corp.) for total chrysotile fiber number in the lungs and chrysotile fiber size (length and diameter) distribution in the lungs. This lung digestion procedure digests the entire lung with no possibility of identifying where in the lung the fibers are located. A fiber distribution study (with confocal microscopy) was included in order to identify where in the lung the fibers were located. At 2 days, 2 wk, 3 mo, 6 mo, and 12 mo postexposure, the lungs from groups of animals were analyzed by confocal microscopy to determine the anatomic fate, orientation, and distribution of the retained chrysotile fibrils deposited on airways and those fibers translocated to the broncho-associated lymphoid tissue (BALT) subjacent to bronchioles in rat lungs. While the translocation of fibers to the BALT and lymphatic tissue is considered important as in cases of human's with asbestos-related disease, there has been no report in the literature of pathological changes in the BALT and lymphatic tissue stemming from asbestos. Thus, if the fibers are removed to these tissues, they are effectively neutralized in the lung. Chrysotile was found to be rapidly removed from the lung. Fibers longer than 20 microm were cleared with a half-time of 1.3 days, most likely by dissolution and breakage into shorter fibers. Shorter fibers were also rapidly cleared from the lung with fibers 5-20 microm clearing even more rapidly (T1/2 = 2.4 days) than those < 5 microm in length (T1/2 weighted = 23. days). Breaking of the longer fibers would be expected to increase the short fiber pool and therefore could account for this difference in clearance rates. The short fibers were never found clumped together but appeared as separate, fine fibrils, occasionally unwound at one end. Short free fibers appeared in the corners of alveolar septa, and fibers or their fragments were found within alveolar macrophages. The same was true of fibers in lymphatics, as they appeared free or within phagocytic lymphocytes. These results support the evidence presented by McDonald and McDonald (1997) that the chrysotile fibers are rapidly cleared from the lung in marked contrast to amphibole fibers which persist.


Assessment of Single-Photon Ionization Mass Spectrometry for Online Monitoring of in Vitro Aerosol Exposure Experiments.
Chemical and physical characterization of transported evolving aerosols in an in vitro system is complex. The challenges include appropriate sampling sensitivity, measurement capabilities, and performing online measurements of constituents in the flowing aerosol during exposure. We assessed the performance of single-photon ionization mass spectrometry in measuring aerosol properties within an in vitro aerosol exposure system. The sampling efficiency of the instrument was studied under three protocols to capture the evolving aerosol process inside the exposure system, and it was evaluated using computational fluid dynamics modeling. The changes in the aerosol as dilution is applied show not only a reduction in concentration of the traced substances but also selective sampling due to evolution of the aerosol and (gas/liquid) phase partitioning of the substances forming the aerosol or a change in the aerosol properties. These effects have potentially a direct impact on the delivered dose, as aerosol deposition is dependent on particle size. Dilution affects the chemical concentration of the substances as well as the interconnected physical properties of the aerosol; therefore, the experimental design of in vitro studies should not only report the dilution flow rates but also details of the applied dilution protocol. This adds a layer of complexity to the design and comparison of studies. We also discuss the potential and limitations of single-photon ionization mass spectrometry as a tool in in vitro monitoring of aerosols.


A three-dimensional analysis of bilateral directional asymmetry in the human clavicle.
This study presents a novel three-dimensional analysis using statistical atlases and automated measurements to assess diaphyseal morphology of the clavicle and its relationship to muscle asymmetry. A sample of 505 individuals (285 males, 220 females) from the William McCormick Clavicle Collection was CT scanned, segmented, and added to a statistical bone atlas that captures correspondence between homologous points on the bone surfaces. Muscle attachment sites were localized on the atlas and then propagated across the entire population. Cross-sectional contours were extracted at 5% increments along the entire bone, as well as at muscle attachment sites and the clavicle waist; maximum and minimum dimensions of each cross-sectional contour were calculated. In addition, the entire three-dimensional surface was examined for asymmetry by analyzing the magnitude and directional differences between homologous points across all bone surfaces in the dataset. The results confirm the existing studies on clavicle asymmetry, namely that the left clavicle is longer than the right, but the right is more robust than the left. However, the patterns of asymmetry are sexually dimorphic. Males are significantly asymmetric in all dimensions and at muscle and ligament attachment sites (P < 0.05), whereas female asymmetry is more variable. We hypothesize that this is related to absolute and relative differences in male muscle strength compared to females. However, an area with no muscle attachments on the posterior midshaft was significantly asymmetric in both sexes. We suggest that this is a curvature difference caused by opposing muscle actions at the medial and lateral ends of the bone.


Multigene panel predicting survival of patients with colon cancer.
Objective: The purpose of this study was to investigate multigene panel markers to predict long-term survival in patients with colon cancer. Methods and materials: GSE39582 was randomly divided into a training set and a validation set, while TCGA-COAD and GSE17536 were treated as two independent validation cohorts. Survival-associated genes were included in elastic net penalized Cox proportional hazards regression (ENCPH) model. Based on the results of the ENCPH, a multigene panel was constructed. We evaluated predictive performance of the multigene panel by univariate and multivariate survival analysis, and time-dependent ROC analysis. Results: A total of 1025 colon cancer patients were included in the study, and 94 genes were showed to be related with the overall survival of colon cancer patients, of which 7 genes were integrated to construct a multigene panel according to ENCPH model. The multigene panel could stratify colon cancer patients into notably different risk groups in the training set and three verification cohort. Results of multivariable CPH model suggested that the multigene panel was an independent prognostication factor. The multigene-containing nomogram showed reliable prediction ability on the 3- and 5-year survival of colon cancer patients with internally and externally validated C-indexes exceeded 0.7. Conclusion: The multigene panel we introduced showed considerable prognosis performance in colon cancer, and the multigene panel containing nomogram would help clinicians assess long-term survival probability.


Recovering maxillofacial trauma patients: the hidden problems.
This longitudinal study highlights the psychological and functional problems that can result from maxillofacial trauma. This is the first study to report outcome at one year. A total of 147 patients admitted for surgery following facial trauma were recruited over a seven-month period. Three questionnaires were used to record patient-derived levels of dysfunction: the Hospital Anxiety Depression scale, a modified University of Washington Quality of Life questionnaire and five non-validated facial trauma items. At one year 46 patients (31%) responded. Although there were significant improvements in scores from pre-operatively to one year, with all patients being discharged from outpatient follow-up, there was a substantial level of subjective symptomatology. Most notable was the level of anxiety and depression, which were present in 30% of the sample at both time points. Health-care professionals tend to underestimate the long-term effects of maxillofacial trauma. To improve patient care, greater appreciation of these problems is required at the time of initial management.


Tissue selectivity and potential clinical applications of trenbolone (17beta-hydroxyestra-4,9,11-trien-3-one): A potent anabolic steroid with reduced androgenic and estrogenic activity.
Recently, the development of selective androgen receptor modulators (SARMs) has been suggested as a means of combating the deleterious catabolic effects of hypogonadism, especially in skeletal muscle and bone, without inducing the undesirable androgenic effects (e.g., prostate enlargement and polycythemia) associated with testosterone administration. 17beta-Hydroxyestra-4,9,11-trien-3-one (trenbolone; 17beta-TBOH), a synthetic analog of testosterone, may be capable of inducing SARM-like effects as it binds to androgen receptors (ARs) with approximately three times the affinity of testosterone and has been shown to augment skeletal muscle mass and bone growth and reduce adiposity in a variety of mammalian species. In addition to its direct actions through ARs, 17beta-TBOH may also exert anabolic effects by altering the action of endogenous growth factors or inhibiting the action of glucocorticoids. Compared to testosterone, 17beta-TBOH appears to induce less growth in androgen-sensitive organs which highly express the 5alpha reductase enzyme (e.g., prostate tissue and accessory sex organs). The reduced androgenic effects result from the fact that 17beta-TBOH is metabolized to less potent androgens in vivo; while testosterone undergoes tissue-specific biotransformation to more potent steroids, dihydrotestosterone and 17beta-estradiol, via the 5alpha-reductase and aromatase enzymes, respectively. Thus the metabolism of 17beta-TBOH provides a basis for future research evaluating its safety and efficacy as a means of combating muscle and bone wasting conditions, obesity, and/or androgen insensitivity syndromes in humans, similar to that of other SARMs which are currently in development.


Response-guided telaprevir combination treatment for hepatitis C virus infection.
Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often need 48 weeks of peginterferon-ribavirin treatment for a sustained virologic response. We designed a noninferiority trial (noninferiority margin, -10.5%) to compare rates of sustained virologic response among patients receiving two treatment durations. We enrolled patients with chronic infection with HCV genotype 1 who had not previously received treatment. All patients received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 μg per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon-ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48. Of the 540 patients, a total of 352 (65%) had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, -2 to 11), establishing noninferiority. Adverse events included rash (in 37% of patients, severe in 5%) and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was based on adverse events in 18% of patients overall, as well as in 1% of patients (all of whom were randomly assigned) in the T12PR24 group and 12% of the patients randomly assigned to the T12PR48 group (P<0.001). In this study, among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon-ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number, NCT00758043.).


Promising Trends in Access to Medicines.
It is a vast understatement to say that the problem of access to medicines in developing countries is complex. Access is limited by a range of factors including inability to pay, a lack of infrastructure, and corruption in some countries. Surrounding and exacerbating these structural and technological problems is the layer of legal rights created by patents and their licensing that complicate and render more expensive the preparation and delivery of needed medicines, particularly those that need to be adapted to the social, health and cultural environment of developing countries. This article provides a survey of innovative strategies that aim at maximizing the potential of patents to facilitate the development and delivery of medicines against diseases, the burden of which falls principally on developing country populations. To understand the context in which these strategies are being proposed and implemented, the article reviews the battles over access to medicines beginning in the late 1980s. It then surveys some of the principal suggestions put forward to better direct innovation systems in addressing the critical health needs of the world's majority including advance market commitments, patent buy-outs, prize funds, public-private partnerships and patent pools.


Safety profile of pneumococcal conjugate vaccines: systematic review of pre- and post-licensure data.
A 7-valent pneumococcal polysaccharide-protein conjugate vaccine (PCV7) was licensed in the United States of America in 2000, but no comprehensive postmarketing review of safety has been carried out. We conducted a systematic review of the safety of PCV7 and other pneumococcal conjugate vaccines. A total of 42 studies were included in the review. Reactogenicity data from some randomized trials suggest that PCV7 may result in more local reactions and fever than certain comparison vaccines. However, the reactions were mild and self-limited, and PCV7 did not carry an increased risk of severe injection-site reactions or high fever. Some, although not all, of the randomized trials in children found that mild local and systemic reactions associated with PCV7 may increase with the number of doses, at least over the three-dose primary series. In addition, PCV7 and other pneumococcal conjugate vaccines were found to have tolerable reactogenicity in Native American and African populations and in medically high-risk groups for which pneumococcal vaccination is recommended. Two of the largest studies of PCVs, one involving PCV7 and the other, PCV9, found a statistically significant increased risk of hospitalization for reactive airway disease, including asthma. Another large trial of PCV9, however, did not find an increased risk of asthma. In conclusion, this review of the evidence did not identify any major safety problems with PCV7 or any other pneumococcal conjugate vaccine, with the possible exception of reactive airway disease, which may bear further scrutiny as additional data become available.


Implementing a survivorship care plan for patients with breast cancer.
The growing number of cancer survivors challenges healthcare organizations to develop programs that support survivors' transition from active treatments to survivorship care. Many individuals and families continue to face complicated care issues resulting from cancer diagnosis and side effects long after completion of their treatments. This article describes a model of a survivorship care plan, Cancer Treatment Summary and Follow-Up Care Plan, piloted in an outpatient clinical setting in a community hospital for patients with breast cancer. The plan can be expanded to include other cancer types. The intent of the survivorship care plan is to strengthen the care connections and coordination of services for survivors of breast cancer to ensure that continuing care needs are met during the survivorship phase of the cancer trajectory. The survivorship care plan is a unique opportunity for oncology nurses to be catalysts for the interdisciplinary interactions that are required to develop survivorship care plans and to implement a change in oncology nursing practice. The intervention shifts the paradigm of cancer survivorship care from an acute care medical model to a wellness model for cancer survivors in the clinical setting.


Genetic association analyses of PHOX2B and ASCL1 in neuropsychiatric disorders: evidence for association of ASCL1 with Parkinson's disease.
We previously identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of PHOX2B (PMX2B), the gene for a transcription factor that plays important roles in the development of oculomotor nerves and catecholaminergic neurons and regulates the expression of both tyrosine hydroxylase and dopamine beta-hydroxylase genes. An association was detected between gene polymorphisms and overall schizophrenia, and more specifically, schizophrenia with ocular misalignment. These prior results implied the existence of other schizophrenia susceptibility genes that interact with PHOX2B to increase risk of the combined phenotype. ASCL1 was considered as a candidate interacting partner of PHOX2B, as ASCL1 is a transcription factor that co-regulates catecholamine-synthesizing enzymes with PHOX2B. The genetic contributions of PHOX2B and ASCL1 were examined separately, along with epistatic interactions with broader candidate phenotypes. These phenotypes included not only schizophrenia, but also bipolar affective disorder and Parkinson's disease (PD), each of which involve catecholaminergic function. The current case-control analyses detected nominal associations between polyglutamine length variations in ASCL1 and PD (P=0.018), but supported neither the previously observed weak association between PHOX2B and general schizophrenia, nor other gene-disease correlations. Logistic regression analysis revealed the effect of ASCL1 dominant x PHOX2B additive (P=0.008) as an epistatic gene-gene interaction increasing risk of PD. ASCL1 controls development of the locus coeruleus (LC), and accumulating evidence suggests that the LC confers protective effects against the dopaminergic neurodegeneration inherent in PD. The present genetic data may thus suggest that polyglutamine length polymorphisms in ASCL1 could influence predispositions to PD through the fine-tuning of LC integrity.


Phase pure α-Mn2O3 prisms and their bifunctional electrocatalytic activity in oxygen evolution and reduction reactions.
Synthesizing manganese oxide materials with exact control of the nanoparticle shape and phase is difficult, making it challenging to understand the influence of the surface structure on electrocatalysis. Here we describe an inexpensive, low-temperature method to synthesize single-crystal orthorhombic phase α-Mn2O3 prisms bound by the {100} facets. The synthesis is the first method to use the cation bridging effect to assist in the creation of α-Mn2O3 prisms. According to structural analysis using X-ray diffraction, X-ray pair-distribution function (PDF) measurements and high resolution transmission electron microscopy, the material is composed exclusively of α-Mn2O3 prisms, and no additional amorphous or nanocrystalline phases are present. Heating the prisms transformed the material to a more symmetrical, cubic phase α-Mn2O3 that exhibited strong bifunctional electrocatalytic activity for the oxygen evolution (OER) and oxygen reduction (ORR) reactions. We compared the oxygen electrode activities (OEA) and found that the α-Mn2O3 prisms performed 79% better than commercially-produced α-Mn2O3 powders, indicating that these α-Mn2O3 prisms perform well as inexpensive, earth-abundant materials for reversible electrodes.


Graft-versus-leukemia reactions after bone marrow transplantation.
To determine whether graft-versus-leukemia (GVL) reactions are important in preventing leukemia recurrence after bone marrow transplantation, we studied 2,254 persons receiving HLA-identical sibling bone marrow transplants for acute myelogenous leukemia (AML) in first remission, acute lymphoblastic leukemia (ALL) in first remission, and chronic myelogenous leukemia (CML) in first chronic phase. Four groups were investigated in detail: recipients of non--T-cell depleted allografts without graft-versus-host disease (GVHD), recipients of non--T-cell depleted allografts with GVHD, recipients of T-cell depleted allografts, and recipients of genetically identical twin transplants. Decreased relapse was observed in recipients of non--T-cell depleted allografts with acute (relative risk 0.68, P = .03), chronic (relative risk 0.43, P = .01), and both acute and chronic GVDH (relative risk 0.33, P = .0001) as compared with recipients of non--T-cell depleted allografts without GVHD. These data support an antileukemia effect of GVHD. AML patients who received identical twin transplants had an increased probability of relapse (relative risk 2.58, P = .008) compared with allograft recipients without GVHD. These data support an antileukemia effect of allogeneic grafts independent of GVHD. CML patients who received T-cell depleted transplants with or without GVHD had higher probabilities of relapse (relative risks 4.45 and 6.91, respectively, P = .0001) than recipients of non--T-cell depleted allografts without GVHD. These data support an antileukemia effect independent of GVHD that is altered by T-cell depletion. These results explain the efficacy of allogeneic bone marrow transplantation in eradicating leukemia, provide evidence for a role of the immune system in controlling human cancers, and suggest future directions to improve leukemia therapy.


Low Cost Fabrication of Si NWs/CuI Heterostructures.
In this paper, we present the realization by a low cost approach compatible with silicon technology of new nanostructures, characterized by the presence of different materials, such as copper iodide (CuI) and silicon nanowires (Si NWs). Silicon is the principal material of the microelectronics field for its low cost, easy manufacturing and market stability. In particular, Si NWs emerged in the literature as the key materials for modern nanodevices. Copper iodide is a direct wide bandgap p-type semiconductor used for several applications as a transparent hole conducting layers for dye-sensitized solar cells, light emitting diodes and for environmental purification. We demonstrated the preparation of a solid system in which Si NWs are embedded in CuI material and the structural, electrical and optical characterization is presented. These new combined Si NWs/CuI systems have strong potentiality to obtain new nanostructures characterized by different doping, that is strategic for the possibility to realize p-n junction device. Moreover, the combination of these different materials opens the route to obtain multifunction devices characterized by promising absorption, light emission, and electrical conduction.


Bone mineral density and risk of breast cancer in older women: the study of osteoporotic fractures. Study of Osteoporotic Fractures Research Group.
To test the hypothesis that bone mineral density (BMD) is associated with the risk of developing breast cancer in older women. Prospective cohort study with mean (SD) follow-up of 3.2 (1.6) years. Four clinical centers, one each located in the following areas: Baltimore, Md; Minneapolis, Minn; Portland, Ore; and the Monongahela Valley in Pennsylvania. A total of 6854 nonblack women who were 65 years of age or older and enrolled in the Study of Osteoporotic Fractures. Radius and calcaneus BMD by single photon absorptiometry at baseline; hip and spine BMD by dual-energy x-ray absorptiometry 2 years later. Breast cancer confirmed by medical record review. A total of 97 women developed breast cancer. In the multivariate model, adjusting for age, the degree of obesity, and other important covariates, the risk of breast cancer was about 30% to 50% higher per 1 SD increase in BMD (relative risk, distal radius BMD=1.50; 95% confidence interval, 1.16-1.95). The age-adjusted incidence rate of breast cancer per 1000 person-years among women in the lowest quartile of distal radius BMD was 2.46, compared with 5.99 among women with the highest BMD. Women with BMD above the 25th percentile were at 2.0 to 2.5 times increased risk of breast cancer compared with women below the 25th percentile. Results were consistent across all BMD sites. Bone mineral density predicts the risk of breast cancer in older women. The magnitude of the association is similar to that observed between BMD and all fractures. Our findings suggest a link between 2 of the most common conditions affecting a woman's health. Identifying a common denominator for these conditions should substantially improve our understanding of their etiology and prevention.


Characterisation of foscarnet-resistant strains of human immunodeficiency virus type 1.
Foscarnet is a broad-spectrum viral DNA polymerase inhibitor active in vitro and in vivo against human immunodeficiency virus type 1 (HIV-1). Strains of HIV-1 resistant to foscarnet were selected by in vitro passage in increasing concentrations of drug. Reduced susceptibility to foscarnet was evident at the levels of both HIV-1 replication and reverse transcriptase. Biologically cloned, foscarnet-resistant strains with distinct genotypes were hypersensitive to zidovudine, azidodeoxyuridine, nevirapine, and R82913 but had unchanged susceptibility to zalcitibine and didanosine. The reverse transcriptase of foscarnet-resistant strains had unique substitutions Glu89-Lys, Leu92-Ile, or Ser156-Ala, the third being associated with six polymorphic changes. Introduction of these mutations into wild-type HIV-1 by site-directed mutagenesis confirmed their role in foscarnet resistance. In the three-dimensional structure of the reverse transcriptase enzyme these amino acids are located close to the template strand of the template primer and far away from the putative pyrophosphate binding site, suggesting that the mechanism by which HIV-1 becomes resistant to foscarnet is indirect. Foscarnet resistance is thus likely to be mediated through an altered interaction of the mutant enzyme with the template strand of the template primer which distorts the geometry of the polymerase active site and thereby decreases foscarnet binding.


A behavior genetic investigation of the relationship between leadership and personality.
Phenotypic research on leadership style has long considered the importance of individual differences in personality when identifying the behaviors associated with good leaders. Although leadership and many personality traits have been separately shown to be heritable, these constructs have not been examined with genetically informative data to identify common sources of heritability in the two domains. A logical extension to current research, therefore, is to examine the extent to which factors of personality are predictive of leadership dimensions and the extent to which unique genetic contributions to the relationship between personality and leadership style may be identified. Adult twin pairs (183 MZ and 64 same-sex DZ) completed the Multifactor Leadership Questionnaire (MLQ) and the Personality Research Form (PRF). Univariate analyses indicated that both leadership factors (transformational and transactional leadership) and all five of the "Big Five" factors (openness, conscientiousness, extraversion, disagreeableness, and neuroticism) were best fit by genetic models. Multivariate genetic analyses suggest that transformational leadership shows a statistically significant positive genetic correlation with conscientiousness, extraversion, and openness to experience. Transactional leadership shows a significant negative genetic correlation with conscientiousness and extraversion, and a significant positive genetic correlation with disagreeableness. These results underscore the importance of conscientiousness and extraversion in predicting leadership style, and illustrate important differences between transformational and transactional leaders.


FRAMe: Familial Risk Assessment of Melanoma-a risk prediction tool to guide CDKN2A germline mutation testing in Australian familial melanoma.
Germline mutations in CDKN2A greatly increase risk of developing cutaneous melanoma. We have constructed a risk prediction model, Familial Risk Assessment of Melanoma (FRAMe), for estimating the likelihood of carrying a heritable CDKN2A mutation among Australian families, where the prevalence of these mutations is low. Using logistic regression, we analysed characteristics of 299 Australian families recruited through the Sydney site of GenoMEL (international melanoma genetics consortium) with at least three cases of cutaneous melanoma (in situ and invasive) among first-degree blood relatives, for predictors of the presence of a pathogenic CDKN2A mutation. The final multivariable prediction model was externally validated in an independent cohort of 61 melanoma kindreds recruited through GenoMEL Queensland. Family variables independently associated with the presence of a CDKN2A mutation in a multivariable model were number of individuals diagnosed with melanoma under 40 years of age, number of individuals diagnosed with more than one primary melanoma, and number of individuals blood related to a melanoma case in the first degree diagnosed with any cancer excluding melanoma and non-melanoma skin cancer. The number of individuals diagnosed with pancreatic cancer was not independently associated with mutation status. The risk prediction model had an area under the receiver operating characteristic curve (AUC) of 0.851 (95% CI 0.793, 0.909) in the training dataset, and 0.745 (95%CI 0.612, 0.877) in the validation dataset. This model is the first to be developed and validated using only Australian data, which is important given the higher rate of melanoma in the population. This model will help to effectively identify families suitable for genetic counselling and testing in areas of high ambient ultraviolet radiation. A user-friendly electronic nomogram is available at www.melanomarisk.org.au .


Targeted therapy in soft tissue sarcoma-a novel direction in therapeutics.
Inherent or acquired resistance to chemotherapy is a significant problem in the treatment of soft tissue sarcomas. Over the past decade, the discovery and characterization of aberrant signaling pathways and the identification of agents that can specifically target them has led to their introduction as novel treatment options in soft-tissue sarcomas (STS). Trials of monotherapy with targeted agents have shown results below expectations often because of activation of alternative signaling pathways. This review examines the potential for tactical combinations of these drugs to overcome this problem.