A Practical Classification System for Acute Cervical Spinal Cord Injury Based on a Three-Phased Modified Delphi Process From the AOSpine Spinal Cord Injury Knowledge Forum.
A modified Delphi study. To assess current practice patterns in the management of cervical spinal cord injury (SCI) and develop a simplified, practical classification system which offers ease of use in the acute setting, incorporates modern diagnostic tools and provides utility in determining treatment strategies for cervical SCI. A three-phase modified Delphi procedure was performed between April 2020 and December 2021. During the first phase, members of the AOSpine SCI Knowledge forum proposed variables of importance for classifying and treating cervical SCI. The second phase involved an international survey of spine surgeons gauging practices surrounding the role and timing of surgery for cervical SCI and opinions regarding factors which most influence these practices. For the third phase, information obtained from phases 1 and 2 were used to draft a new classification system. 396 surgeons responded to the survey. Neurological status, spinal stability and cord compression were the most important variables influencing decisions surrounding the role and timing of surgery. The majority (>50%) of respondents preferred to perform surgery within 24 hours post-SCI in clinical scenarios in which there was instability, severe cord compression or severe neurology. Situations in which <50% of respondents were inclined to operate early included: SCI with mild neurological impairments, with cord compression but without instability (with or without medical comorbidities), and SCI without cord compression or instability. Spinal stability, cord compression and neurological status are the most important variables influencing surgeons' practices surrounding the surgical management of cervical SCI. Based on these results, a simplified classification system for acute cervical SCI has been proposed.


Protease inhibitor levels in hair strongly predict virologic response to treatment.
Antiretroviral (ARV) therapies fail when behavioral or biologic factors lead to inadequate medication exposure. The currently available methods to assess ARV exposure are limited. Levels of ARVs in hair reflect plasma concentrations over weeks to months, and may provide a novel method for predicting therapeutic responses. The Women's Interagency HIV Study, a prospective cohort of HIV-infected women, provided the basis for developing and assessing methods to measure commonly prescribed protease inhibitors (lopinavir/ritonavir and atazanavir) in small hair samples. We examined the association between hair protease inhibitor levels and initial virologic responses to therapy in multivariate logistic regression models. ARV concentrations in hair were strongly and independently associated with treatment response for 224 women starting a new protease inhibitor-based regimen. For participants initiating lopinavir/ritonavir, the odds ratio (OR) for virologic suppression was 39.8 [95% confidence interval (CI) = 2.8-564] for those with lopinavir hair levels in the top tertile (>1.9 ng/mg) compared to the bottom (</=0.41 ng/mg) when controlling for self-reported adherence, age, race, starting viral load and CD4 cell count, and prior experience with protease inhibitors. For women starting atazanavir, the adjusted OR for virologic success was 7.7 (95% CI = 2.0-29.7) for those with hair concentrations in the top tertile (>3.4 ng/mg) compared to the lowest (</=1.2 ng/mg). Protease inhibitor levels in small hair samples were the strongest independent predictor of virologic success in a diverse group of HIV-infected adults. This non-invasive method for determining ARV exposure may have particular relevance for the epidemic in resource-poor settings due to the ease of collecting and storing hair.


EAACI guidelines on allergen immunotherapy: Prevention of allergy.
Allergic diseases are common and frequently coexist. Allergen immunotherapy (AIT) is a disease-modifying treatment for IgE-mediated allergic disease with effects beyond cessation of AIT that may include important preventive effects. The European Academy of Allergy and Clinical Immunology (EAACI) has developed a clinical practice guideline to provide evidence-based recommendations for AIT for the prevention of (i) development of allergic comorbidities in those with established allergic diseases, (ii) development of first allergic condition, and (iii) allergic sensitization. This guideline has been developed using the Appraisal of Guidelines for Research & Evaluation (AGREE II) framework, which involved a multidisciplinary expert working group, a systematic review of the underpinning evidence, and external peer-review of draft recommendations. Our key recommendation is that a 3-year course of subcutaneous or sublingual AIT can be recommended for children and adolescents with moderate-to-severe allergic rhinitis (AR) triggered by grass/birch pollen allergy to prevent asthma for up to 2 years post-AIT in addition to its sustained effect on AR symptoms and medication. Some trial data even suggest a preventive effect on asthma symptoms and medication more than 2 years post-AIT. We need more evidence concerning AIT for prevention in individuals with AR triggered by house dust mites or other allergens and for the prevention of allergic sensitization, the first allergic disease, or for the prevention of allergic comorbidities in those with other allergic conditions. Evidence for the preventive potential of AIT as disease-modifying treatment exists but there is an urgent need for more high-quality clinical trials.


Effects of replacing meat with soyabean in the diet on sex hormone concentrations in healthy adult males.
A randomised crossover dietary intervention study was performed to evaluate the effects of replacing meat protein in the diet with a soyabean product, tofu, on blood concentrations of testosterone, dihydrotestosterone, androstanediol glucuronide, oestradiol, sex hormone-binding globulin (SHBG), and the free androgen index (total testosterone concentration/SHBG concentration x 100; FAI). Forty-two healthy adult males aged 35-62 years were studied. Diets were isoenergetic, with either 150 g lean meat or 290 g tofu daily providing an equivalent amount of macronutrients, with only the source of protein differing between the two diets. Each diet lasted for 4 weeks, with a 2-week interval between interventions. Fasting blood samples were taken between 07.00 and 09.30 hours. Urinary excretion of genistein and daidzein was significantly higher after the tofu diet (P < 0.001). Blood concentrations of sex hormones did not differ after the two diets, but the mean testosterone:oestradiol value was 10% higher (P = 0.06) after the meat diet. SHBG was 3% higher (P = 0.07), whereas the FAI was 7% lower (P = 0.06), after the tofu diet compared with the meat diet. There was a significant correlation between the difference in SHBG and testosterone:oestradiol and weight change. Adjusting for weight change revealed SHBG to be 8.8% higher on the tofu diet (mean difference 3 (95% CI 0.7, 5.2) nmol/l; P = 0.01) and testosterone:oestradiol to be significantly lower, P = 0.049). Thus, replacement of meat protein with soyabean protein, as tofu, may have a minor effect on biologically-active sex hormones, which could influence prostate cancer risk. However, other factors or mechanisms may also be responsible for the different incidence rates in men on different diets.


REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants.
The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10-12) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046-0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027-0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale.


Association analysis of the extended MHC region in celiac disease implicates multiple independent susceptibility loci.
Celiac disease is a common autoimmune disease caused by sensitivity to the dietary protein gluten. Forty loci have been implicated in the disease. All disease loci have been characterized as low-penetrance, with the exception of the high-risk genotypes in the HLA-DQA1 and HLA-DQB1 genes, which are necessary but not sufficient to cause the disease. The very strong effects from the known HLA loci and the genetically complex nature of the major histocompatibility complex (MHC) have precluded a thorough investigation of the region. The purpose of this study was to test the hypothesis that additional celiac disease loci exist within the extended MHC (xMHC). A set of 1898 SNPs was analyzed for association across the 7.6 Mb xMHC region in 1668 confirmed celiac disease cases and 517 unaffected controls. Conditional recursive partitioning was used to create an informative indicator of the known HLA-DQA1 and HLA-DQB1 high-risk genotypes that was included in the association analysis to account for their effects. A linkage disequilibrium-based grouping procedure was utilized to estimate the number of independent celiac disease loci present in the xMHC after accounting for the known effects. There was significant statistical evidence for four new independent celiac disease loci within the classic MHC region. This study is the first comprehensive association analysis of the xMHC in celiac disease that specifically accounts for the known HLA disease genotypes and the genetic complexity of the region.


Effects of having a baby on weight gain.
Women often blame weight gain in early adulthood on having a baby. The aim was to estimate the weight gain attributable to having a baby, after disentangling the effects of other factors that influence weight change at this life stage. A longitudinal study of a randomly selected cohort of 6458 Australian women, aged 18-23 years in 1996, was conducted. Self-report mailed surveys were completed in 1996, 2000, 2003, and 2006, and data were analyzed in 2008. On average, women gained weight at the rate of 0.93% per year (95% CI=0.89, 0.98) or 605 g/year (95% CI=580, 635) for a 65-kg woman. Over the 10-year study period, partnered women with one baby gained almost 4 kg more, and those with a partner but no baby gained 1.8 kg more, than unpartnered childless women (after adjustment for other significant factors: initial BMI and age; physical activity, sitting time, energy intake (2003); education level, hours in paid work, and smoking). Having a baby has a marked effect on 10-year weight gain, but there is also an effect attributable to getting married or living with a partner. Social and lifestyle as well as energy balance variables should be considered when developing strategies to prevent weight gain in young adult women.


Modified Cut for Gap Arthroplasty in Temporomandibular Joint Ankylosis.
Temporomandibular joint ankylosis is a debilitating disease affecting the function, esthetics and psychology of the patient. Treatment of this condition aims at establishing not only the function and esthetics but also aims to prevent reankylosis. Among the different treatment modalities, interpositional gap arthroplasty followed by aggressive jaw physiotherapy is considered most effective. This is achieved by making two horizontal osteotomy cuts at a distance of 10-15 mm in the TMJ region. The gap is then interposed with an autogenous or alloplastic graft material. However, during the application of a jaw stretcher intraoperatively with the surgical site open and with the jaw wide open, a bony contact was seen to occur between the posterior aspect of the upper and lower osteotomy cuts. Taking this into consideration, the lower osteotomy cut is modified by making the posterior one-third cut divergent. This eliminates the bony contact during maximum mouth opening and thus prevents the chances of reankylosis as well.


An amyloid-notch hypothesis for Alzheimer's disease.
For more than 20 years, the amyloid hypothesis has provided an important framework for Alzheimer's disease (AD) research, yet after 50,000 papers, the nonpathological function of beta-amyloid (Aβ) remains enigmatic. This mystery is compounded by an absence of gross abnormalities in amyloid precursor protein (APP)-deficient mice and zebrafish even though APP has been highly conserved throughout vertebrate evolution. Here, the author hypothesizes that vertebrate cells express APP and release Aβ as part of a mechanism to optimize blood vessel density with the metabolite removal needs of local tissue neighborhoods. High-gain feedback of Aβ production at the rate-limiting γ-secretase step reduces Aβ production and Notch activation. Notch inhibition causes endothelial cells to adopt a tip cell morphology that induces more highly branched blood vessels. In vivo, γ-secretase inhibitors block Notch signaling and induce dense capillary networks that are similar to those in the brains of AD patients and mice. Notch inhibition could also contribute to synapse loss by reducing EphB2 receptor expression. EphB receptors are critical for the maintenance of dendritic spine morphology, and deficiencies result in immature spines that lack synaptic activity. This revised amyloid-Notch hypothesis may also explain the disappointing results of recent clinical trials with γ-secretase inhibitors.


Tolbutamide increases hypothalamic serotonin activity in the rat.
Sulfonylureas are potent hypoglycemic agents; however, their mechanism of action remains incompletely understood. Recent data indicate that hypothalamic norepinephrine (NE) plays a major role in mediating the central neural regulation of blood glucose. We therefore examined whether the sulfonylurea tolbutamide might lower serum glucose via an effect on hypothalamic NE neuronal activity, and compared the effects with those of 2-deoxyglucose-induced neuroglycopenia and of chronic insulin administration. Serum glucose levels fell and serum insulin levels rose 10, 20, and 30 min after acute tolbutamide injection. Serum glucose concentrations were reduced after chronic tolbutamide administered in drinking water, but serum insulin did not change. Hypothalamic NE neuronal activity was increased 10 min after tolbutamide administration, but not at the later times, nor during chronic tolbutamide administration. However, consistent with a rise in serotonin (5-HT) neuronal activity, hypothalamic 5-hydroxyindoleacetic acid (5-HIAA) and the 5-HIAA/5-HT ratio rose 30 min after acute tolbutamide and during chronic tolbutamide administration. This rise was not due to neuroglycopenia per se, since hypothalamic NE neuronal activity was increased and hypothalamic 5-HT neuronal activity was reduced after 2-deoxyglucose-induced neuroglycopenia. Furthermore, the effect of chronic tolbutamide contrasted with that of chronic insulin administration where hypothalamic NE neuronal activity was increased, while hypothalamic 5-HT neuronal activity was unchanged. We conclude that tolbutamide does not lower serum glucose via a direct effect on hypothalamic NE neuronal activity; however, we note that tolbutamide specifically increases hypothalamic 5-HT neuronal activity.(ABSTRACT TRUNCATED AT 250 WORDS)


Persistent intraprostatic androgen concentrations after medical castration in healthy men.
The impact of serum androgen manipulation on prostate tissue hormone levels in normal men is unknown. Studies of men with prostate cancer have suggested that prostatic androgens are preserved in the setting of castration. Tissue androgens might stimulate prostate growth, producing adverse clinical consequences. The objective of the study was to determine the effect of serum androgen manipulation on intraprostatic androgens in normal men. Thirteen male volunteers ages 35-55 yr (prostate-specific antigen < 2.0 ng/ml; normal transrectal ultrasound) were randomly assigned to: 1) a long-acting GnRH-antagonist, acyline, every 2 wk; 2) acyline plus testosterone (T) gel (10 mg/d); or 3) placebo for 28 d. Serum hormones were assessed weekly. Prostate biopsies were obtained on d 28. Extracted androgens were measured by RIA, and immunohistochemistry for androgen-regulated proteins was performed. The mean decrease in serum T was 94%, whereas prostatic T and dihydrotestosterone levels were 70 and 80% lower, respectively, in subjects receiving acyline alone compared with controls (P < 0.05). Despite this decrease in prostate androgens, there were no detectable differences in prostate epithelial proliferation, apoptosis, prostate-specific antigen, and androgen receptor expression. In this small study of healthy subjects, despite a 94% decrease in serum T with medical castration, intraprostatic T and dihydrotestosterone levels remained 20-30% of control values, and prostate cell proliferation, apoptosis, and androgen-regulated protein expression were unaffected. Our data highlight the importance of assessing tissue hormone levels. The source of persistent prostate androgens associated with medical castration and their potential role in supporting prostate metabolism deserves further study.


Analysis of 'driver' and 'passenger' CD8+ T-cell responses against variable viruses.
Variable viruses, such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV), persist despite host immune responses directed against them. Numerous lines of evidence have suggested that antiviral CD8+ T-cell responses are key among these immune responses, but these vary widely in their ability to contain virus. We propose that only a proportion of responses may exert significant antiviral pressure ('driver' responses), leading to control over viral replication (protection) and/or, ultimately, selection of escape mutants. Another set of responses may exert only weak pressure on the virus ('passenger' responses): these neither protect nor select. To examine this we have analysed (using established databases of HIV and HCV sequences and cytotoxic T-lymphocyte (CTL) epitopes, and published experimental datasets) two important features--predicted binding of the epitope to major histocompatibility complex molecule and observed variability of the epitope--that might distinguish such responses. We find that a high predicted binding estimate could only explain a limited set of 'driver' responses associated with protection or selection. There is statistical evidence that readily defined (and non-protective) CTL responses target regions associated with lower levels of viral variability. Taken together, this suggests that a large number of well-documented responses may represent 'passengers' and we propose a mechanism that might explain their presence.


Mucinous cystadenocarcinoma of the breast coexisting with infiltrating ductal carcinoma.
A recently described and rare variant of breast carcinoma, mucinous cystadenocarcinoma (MCA), is reported in a 65-year-old post-menopausal woman. She presented with a gradually enlarged breast tumor. A well-circumscribed tumor measuring about 3 cm in diameter was noted in the mammographic and ultrasonographic examinations. The mammographic and ultrasonographic findings were indistinguishable from more common mucinous carcinoma (colloid carcinoma) of the breast. The gross appearance of the tumor was well-defined and cystic, consisting of abundant transparent to bloody mucin, as well as whitish solid parts. Microscopically, the tumor was characterized by abundant extracellular and intracellular mucin. It looked like a mucinous cystic neoplasm of the ovary and pancreas. Particularly, few microscopic foci of ordinary intermediate-grade infiltrating ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS) were observed around the main lesion in this case. A transition from ordinary DCIS to MCA in situ was found. It might indicate MCA derives from a metaplasia process of ordinary DCIS. MCA can be easily differentiated from mucinous carcinoma by quite different histologic and immunohistochemical findings. According to the previously reported and present cases, MCA of the breast more commonly affects elderly women and has a relatively favorable prognosis.


Is intracytoplasmic morphologically selected sperm injection effective in patients with infertility related to teratozoospermia or repeated implantation failure?
To evaluate the potential benefit of intracytoplasmic morphologically selected sperm injection (IMSI) in patients selected for either severe teratozoospermia or repeated implantation failure after conventional intracytoplasmic sperm injection (ICSI). Prospective nonrandomized observational study. University hospital assisted reproduction unit. Four hundred seventy-eight patients were enrolled to evaluate ICSI and IMSI results for two indications. The first group (T) was composed of patients with severe teratozoospermia (<10% normal spermatozoa in fresh ejaculated and selected semen, according to David classification) and no or one previous ICSI failure. In the second group (IF), patients with at least two previous failed ICSI attempts were enrolled in absence of severe male factor (>10% normal spermatozoa in fresh ejaculated semen and >20% in selected sperm). ICSI/IMSI, biologic, and clinical data collection. Live-birth rate (LBR). In group T, LBR was significantly higher when IMSI procedure was used compared with ICSI (38% [50/132] vs. 20% [25/126]). However, LBR observed in group IF was not significantly different between IMSI and ICSI procedures (21% [19/90] vs. 22% [28/130]). IMSI procedure is a valuable option for patients with severe teratozoospermia at their first or second attempts, but it does not improve pregnancy rate in patients with repeated ICSI failures in the absence of severe male factor.


Automated Broad-Range Molecular Detection of Bacteria in Clinical Samples.
Molecular detection methods, such as quantitative PCR (qPCR), have found their way into clinical microbiology laboratories for the detection of an array of pathogens. Most routinely used methods, however, are directed at specific species. Thus, anything that is not explicitly searched for will be missed. This greatly limits the flexibility and universal application of these techniques. We investigated the application of a rapid universal bacterial molecular identification method, IS-pro, to routine patient samples received in a clinical microbiology laboratory. IS-pro is a eubacterial technique based on the detection and categorization of 16S-23S rRNA gene interspace regions with lengths that are specific for each microbial species. As this is an open technique, clinicians do not need to decide in advance what to look for. We compared routine culture to IS-pro using 66 samples sent in for routine bacterial diagnostic testing. The samples were obtained from patients with infections in normally sterile sites (without a resident microbiota). The results were identical in 20 (30%) samples, IS-pro detected more bacterial species than culture in 31 (47%) samples, and five of the 10 culture-negative samples were positive with IS-pro. The case histories of the five patients from whom these culture-negative/IS-pro-positive samples were obtained suggest that the IS-pro findings are highly clinically relevant. Our findings indicate that an open molecular approach, such as IS-pro, may have a high added value for clinical practice.


High shear stress attenuates agonist-induced, glycoprotein IIb/IIIa-mediated platelet aggregation when von Willebrand factor binding to glycoprotein Ib/IX is blocked.
High shear stress facilitates von Willebrand factor (vWF) binding to platelet glycoprotein (GP) Ib/IX, causing activation of GPIIb/IIIa to induce platelet aggregation. Here we report that activated GPIIb/IIIa, even occupied by ligands, is not sufficient to mediate platelet aggregation under high shear stress conditions when vWF binding to GPIb/IX is blocked. Platelet rich plasma or washed platelet suspension supplemented with purified human fibrinogen at a concentration of 2 mg/mL were treated with an anti-vWF monoclonal antibody NMC-4 which blocks the binding of vWF to GPIb/IX. After addition of 10 mumol/L ADP, aggregation was continuously monitored under various shear stress conditions (0-108 dyne/cm2) using a cone-plate type aggregometer previously described (Ikeda Y et al J Clin Invest 1991; 87:1234). The extent of maximal aggregation of agonist-stimulated platelets in the presence of NMC-4 correlated inversely with the level of shear stress applied, with the virtual absence of aggregation at 108 dyne/cm2. Once aggregated by 10 mumol/L ADP under low shear stress (12 dyne/cm2), platelets could be disaggregated, in part, by the application of high shear stress (108 dyne/cm2), and reaggregated when shear stress was returned to 12 dyne/cm2. Flow cytometric analysis revealed that platelets stimulated with 10 mumol/L ADP at 108 dyne/cm2 bound fluorescein isothiocyanate (FITC)-labeled fibrinogen, although aggregation was absent in this experimental condition. These results demonstrate the dual effect of shear stress on platelet functions; a pro-aggregating activity that induces vWF-GPIb/IX interaction leading to platelet activation, and an anti-aggregating force to prevent the growth of platelet thrombi. It is suggested that the efficacy of vWF blockade is greater under high shear than low shear stress conditions, and that a selective inhibition of platelet functions can be possible.


Clinical use of erythropoietic stimulating agents in myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are heterogeneous clonal diseases characterized by cytopenias resulting from ineffective hemopoiesis. Anemia affects the vast majority of patients with MDS and contributes substantially to their symptoms. For more than 20 years, recombinant human erythropoietin has been available for clinical use, and it has been employed in an attempt to relieve MDS-related anemia. Erythropoietin-alpha, erythropoietin-beta, and more recently darbepoetin have been found to increase hemoglobin levels and abolish transfusion dependence in 19%-68% of MDS cases. This wide range in clinical response depends on several biological and clinical variables that allow the selection of patients with the highest probability of successful treatment. These agents are a mainstay in MDS therapy, but many issues are still open in terms of the initiation of therapy, the optimal dosage of erythropoietic stimulating agents (ESAs), the most efficient type of ESA, and the duration and outcome of such treatments. In this review, the mechanisms of response and predictive factors as well as an analysis of the clinical activity of ESAs in MDS therapy are presented.


A New Method to Sort Differentiating Osteoclasts into Defined Homogeneous Subgroups.
Osteoclasts regulate skeletal development but also drive pathological osteolysis, making them prime therapeutic targets. Osteoclast research is limited by the heterogeneity of osteoclast populations generated in vitro, where the mixture of undifferentiated monocytes, binuclear pre-osteoclasts and multinucleated osteoclasts has by necessity been considered a single osteoclast population. This study describes the differentiation of primary human CD14+ monocyte-derived osteoclasts in 3D collagen gels. These osteoclasts remained small (>95% with ≤5 nuclei) but were viable and active; when released from the gel with collagenase, they fused rapidly when reseeded onto solid substrates and resorbed dentine for 2-3 weeks. 3D-generated osteoclasts expressed cell surface markers of osteoclast differentiation (e.g., CD9, RANK, OSCAR, CD63, CD51/61) which, with their small size, enabled live cell sorting of highly enriched viable subpopulations of human osteoclasts that retained full functional resorption capacity. Low-yield osteoclast preparations were strongly enriched to remove undifferentiated cells (e.g., 13.3% CD51/61+ to 84.2% CD51/61+), and subpopulations of CD9+CD51/61- early osteoclasts and CD9+CD51/61+ mature cells were distinguished. This novel approach allows the study of selected populations of differentiating osteoclasts in vitro and opens the door to in-depth transcriptomic and proteomic analysis of these cells, increasing our ability to study human osteoclast molecular mechanisms relevant to development, aging and disease.


Role of cortactin homolog HS1 in transendothelial migration of natural killer cells.
Natural Killer (NK) cells perform many functions that depend on actin assembly, including adhesion, chemotaxis, lytic synapse assembly and cytolysis. HS1, the hematopoietic homolog of cortactin, binds to Arp2/3 complex and promotes actin assembly by helping to form and stabilize actin filament branches. We investigated the role of HS1 in transendothelial migration (TEM) by NK cells. Depletion of HS1 led to a decrease in the efficiency of TEM by NK cells, as measured by transwell assays with endothelial cell monolayers on porous filters. Transwell assays involve chemotaxis of NK cells across the filter, so to examine TEM more specifically, we imaged live-cell preparations and antibody-stained fixed preparations, with and without the chemoattractant SDF-1α. We found small to moderate effects of HS1 depletion on TEM, including whether the NK cells migrated via the transcellular or paracellular route. Expression of HS1 mutants indicated that phosphorylation of HS1 tyrosines at positions 222, 378 and 397 was required for rescue in the transwell assay, but HS1 mutations affecting interaction with Arp2/3 complex or SH3-domain ligands had no effect. The GEF Vav1, a ligand of HS1 phosphotyrosine, influenced NK cell transendothelial migration. HS1 and Vav1 also affected the speed of NK cells migrating across the surface of the endothelium. We conclude that HS1 has a role in transendothelial migration of NK cells and that HS1 tyrosine phosphorylation may signal through Vav1.


Determination of absorption coefficient based on laser beam thermal blooming in gas-filled tube.
Thermal blooming of a laser beam propagating in a gas-filled tube is investigated both analytically and experimentally. A self-consistent formulation taking into account heating of the gas and the resultant laser beam spreading (including diffraction) is presented. The heat equation is used to determine the temperature variation while the paraxial wave equation is solved in the eikonal approximation to determine the temporal and spatial variation of the Gaussian laser spot radius, Gouy phase (longitudinal phase delay), and wavefront curvature. The analysis is benchmarked against a thermal blooming experiment in the literature using a CO₂ laser beam propagating in a tube filled with air and propane. New experimental results are presented in which a CW fiber laser (1 μm) propagates in a tube filled with nitrogen and water vapor. By matching laboratory and theoretical results, the absorption coefficient of water vapor is found to agree with calculations using MODTRAN (the MODerate-resolution atmospheric TRANsmission molecular absorption database) and HITRAN (the HIgh-resolution atmospheric TRANsmission molecular absorption database).


Effects of ozone (O3) and ethylenediurea (EDU) on the ecological stoichiometry of a willow grown in a free-air exposure system.
Ground-level ozone (O3) concentrations have been elevating in the last century. While there has been a notable progress in understanding O3 effects on vegetation, O3 effects on ecological stoichiometry remain unclear, especially early in the oxidative stress. Ethyelenediurea (EDU) is a chemical compound widely applied in research projects as protectant of plants against O3 injury, however its mode of action remains unclear. To investigate O3 and EDU effects early in the stress, we sprayed willow (Salix sachalinensis) plants with 0, 200 or 400 mg EDU L-1, and exposed them to either low ambient O3 (AOZ) or elevated O3 (EOZ) levels during the daytime, for about one month, in a free air O3 controlled exposure (FACE); EDU treatment was repeated every nine days. We collected samples for analyses from basal, top, and shed leaves, before leaves develop visible O3 symptoms. We found that O3 altered the ecological stoichiometry, including impacts in nutrient resorption efficiency, early in the stress. The relation between P content and Fe content seemed to have a critical role in maintaining homeostasis in an effort to prevent O3-induced damage. Photosynthetic pigments and P content appeared to play an important role in EDU mode of action. This study provides novel insights on the stress biology which are of ecological and toxicological importance.


Fibreoptic bronchoscopic electrosurgery under local anaesthesia for rapid palliation in patients with central airway malignancies: a preliminary report.
Obstruction of a major airway by tumour causes serious morbidity. There is still scope for a widely applicable, simple and effective treatment to provide rapid palliation. A fibreoptic bronchoscope prototype with an insulated inner sheath was used under local anaesthesia in 17 patients with locally advanced tracheobronchial malignancies. An insulated flexible electro-surgery probe was used to coagulate intraluminal tumour mass using standard electrosurgery equipment. Immediate reopening of the airway was obtained in 15 of the 17 patients. Two appeared to have extraluminal disease. Eleven patients had an obvious bronchoscopic response in whom a > 75% reopening of the normal airway diameter was achieved. Eight patients had subjective improvement of their dyspnoea, but only in four cases was there an objective improvement in physiological parameters. Haemoptysis resolved in four. There were no deaths resulting from treatment. Minor bleeding occurred in one patient and an aspiration pneumonia occurred in one. Three patients received additional treatment. Fibreoptic bronchoscopic electrosurgery is a simple technique for rapid palliation and immediate tumour debulking in patients with central tracheobronchial tumours. Further work is needed to compare its efficacy with other techniques.


A behavioral test battery for mouse models of Angelman syndrome: a powerful tool for testing drugs and novel Ube3a mutants.
Angelman syndrome (AS) is a neurodevelopmental disorder caused by mutations affecting UBE3A function. AS is characterized by intellectual disability, impaired motor coordination, epilepsy, and behavioral abnormalities including autism spectrum disorder features. The development of treatments for AS heavily relies on the ability to test the efficacy of drugs in mouse models that show reliable, and preferably clinically relevant, phenotypes. We previously described a number of behavioral paradigms that assess phenotypes in the domains of motor performance, repetitive behavior, anxiety, and seizure susceptibility. Here, we set out to evaluate the robustness of these phenotypes when tested in a standardized test battery. We then used this behavioral test battery to assess the efficacy of minocycline and levodopa, which were recently tested in clinical trials of AS. We combined data of eight independent experiments involving 111 Ube3a mice and 120 wild-type littermate control mice. Using a meta-analysis, we determined the statistical power of the subtests and the effect of putative confounding factors, such as the effect of sex and of animal weight on rotarod performance. We further assessed the robustness of these phenotypes by comparing Ube3a mutants in different genetic backgrounds and by comparing the behavioral phenotypes of independently derived Ube3a-mutant lines. In addition, we investigated if the test battery allowed re-testing the same animals, which would allow a within-subject testing design. We find that the test battery is robust across different Ube3a-mutant lines, but confirm and extend earlier studies that several phenotypes are very sensitive to genetic background. We further found that the audiogenic seizure susceptibility phenotype is fully reversible upon pharmacological treatment and highly suitable for dose-finding studies. In agreement with the clinical trial results, we found that minocycline and levodopa treatment of Ube3a mice did not show any sign of improved performance in our test battery. Our study provides a useful tool for preclinical drug testing to identify treatments for Angelman syndrome. Since the phenotypes are observed in several independently derived Ube3a lines, the test battery can also be employed to investigate the effect of specific Ube3a mutations on these phenotypes.


Endothelial Rictor is crucial for midgestational development and sustained and extensive FGF2-induced neovascularization in the adult.
To explore the general requirement of endothelial mTORC2 during embryonic and adolescent development, we knocked out the essential mTORC2 component Rictor in the mouse endothelium in the embryo, during adolescence and in endothelial cells in vitro. During embryonic development, Rictor knockout resulted in growth retardation and lethality around embryonic day 12. We detected reduced peripheral vascularization and delayed ossification of developing fingers, toes and vertebrae during this confined midgestational period. Rictor knockout did not affect viability, weight gain, and vascular development during further adolescence. However during this period, Rictor knockout prevented skin capillaries to gain larger and heterogeneously sized diameters and remodeling into tortuous vessels in response to FGF2. Rictor knockout strongly reduced extensive FGF2-induced neovascularization and prevented hemorrhage in FGF2-loaded matrigel plugs. Rictor knockout also disabled the formation of capillary-like networks by FGF2-stimulated mouse aortic endothelial cells in vitro. Low RICTOR expression was detected in quiescent, confluent mouse aortic endothelial cells, whereas high doses of FGF2 induced high RICTOR expression that was associated with strong mTORC2-specific protein kinase Cα and AKT phosphorylation. We demonstrate that the endothelial FGF-RICTOR axis is not required during endothelial quiescence, but crucial for midgestational development and sustained and extensive neovascularization in the adult.


Micro Integral Membrane Protein (MIMP), a Newly Discovered Anti-Inflammatory Protein of Lactobacillus Plantarum, Enhances the Gut Barrier and Modulates Microbiota and Inflammatory Cytokines.
Recent studies have demonstrated that the manipulation of the gut microbiome represents a promising treatment for inflammatory bowel disease (IBD). We previously identified micro integral membrane protein (MIMP) as the smallest domain of surface layer protein from Lactobacillus Plantarum. However, the therapeutic relevance of MIMP in IBD remains unknown. We initially employed a dextran sodium sulphate (DSS)-induced colitis model and evaluated the effect of MIMP on the inflammation response, intestinal barrier and gut microbiota using histological examination, Fluorescein isothiocyanate-Dextran detection and pyrosequencing analysis respectively. We then established peripheral blood mononuclear cells (PBMCs) and an epithelial CaCO-2 co-culture model to investigate the regulatory role of MIMP in inflammatory cytokines. The level changes of inflammatory cytokines were detected using Enzyme-linked immunosorbent and real-time polymerase chain reaction assay. The involved regulatory mechanisms were investigated mainly using dual luciferase reporter and chromatin immunoprecipitation assay. In the DSS-induced colitis model, we observed that MIMP intervention effectively improved the body weight loss, increased the colon length and decreased disease activity index. Consistently, the inflammation scores in the MIMP treatment group were significantly lower than those in the DSS treatment group. Furthermore, MIMP intervention was found to successfully neutralize DSS treatment by decreasing the expression of pro-inflammatory cytokines (IFN-γ, IL-17 and IL-23) and increasing the expression of anti-inflammatory cytokines (IL-4 and IL-10). Notably, the permeability assay demonstrated that the MIMP treatment group was remarkably lower than that in the DSS treatment group. We also showed that MIMP improved gut microbiota dysbiosis caused by DSS-induced inflammation. Additionally, in PBMCs and the CaCO-2 co-culture model, MIMP showed an obvious suppressive effect on lipopolysaccharide-induced inflammation in a time- and dose-dependent manner. Furthermore, we revealed that MIMP could modulate inflammatory cytokine expression through the toll-like receptor 4 pathway and histone acetylation. Our results suggested that MIMP showed a significant anti-inflammatory effect through regulating the gut barrier, microbiota and inflammatory cytokines. MIMP may have translational relevance as clinically relevant therapy for IBD patients.


Coherence and indistinguishability.
It has long been known that the interference produced by two light beams is related both to their mutual coherence and also to the intrinsic indistinguishability of the photon paths. With the help of a decomposition of the density operator it is shown that the degree of indistinguishability equals the degree of coherence. This provides the fundamental link between the wave and the particle descriptions.


A logical data representation framework for electricity-driven bioproduction processes.
Microbial electrosynthesis (MES) is a process that uses electricity as an energy source for driving the production of chemicals and fuels using microorganisms and CO2 or organics as carbon sources. The development of this highly interdisciplinary technology on the interface between biotechnology and electrochemistry requires knowledge and expertise in a variety of scientific and technical areas. The rational development and commercialization of MES can be achieved at a faster pace if the research data and findings are reported in appropriate and uniformly accepted ways. Here we provide a framework for reporting on MES research and propose several pivotal performance indicators to describe these processes. Linked to this study is an online tool to perform necessary calculations and identify data gaps. A key consideration is the calculation of effective energy expenditure per unit product in a manner enabling cross comparison of studies irrespective of reactor design. We anticipate that the information provided here on different aspects of MES ranging from reactor and process parameters to chemical, electrochemical, and microbial functionality indicators will assist researchers in data presentation and ease data interpretation. Furthermore, a discussion on secondary MES aspects such as downstream processing, process economics and life cycle analysis is included.


A multilevel analysis of the relationship between parental migration and left-behind children's macronutrient intakes in rural China.
China's internal migration has left 61 million children living apart from their parent(s) in rural areas. The present study aimed to examine whether the relative contributions of macronutrients (protein, fat and carbohydrate) to total energy intake differ between children left behind by the father or mother, compared with children from intact families. Drawing on a longitudinal study, the China Health and Nutrition Survey (1997-2009), multilevel modelling analyses (level 1: occasions; level 2: children; level 3: villages) were performed. Data from rural communities in nine provinces in China. Rural children (n 975; 555 boys and 420 girls) from 140 villages. Among boys of school age, being left behind by the father tended to reduce the relative protein intake by 0·70 % (P<0·01) compared with boys from intact families. Being left behind by at least the mother was more detrimental for young boys under the age of 6 years than paternal migration, reducing relative protein intake by 1·14 % (P<0·05). Parental migration was associated with a significant increase in young boys' relative fat intake by 2·60 % (P<0·05). No significant associations were found for girls. Results suggest left-behind boys, especially in early life, are subject to a higher-fat and lower-protein diet compared with non-left-behind boys. This may put them at increased risk of being overweight or obese, or of suffering from stunted growth, when they grow up. Public health policies should recognise the influences of parental migration on boys, especially maternal migration, and encourage a more balanced diet for children in rural China.


Benefits and Challenges in Using Seroprevalence Data to Inform Models for Measles and Rubella Elimination.
Control efforts for measles and rubella are intensifying globally. It becomes increasingly important to identify and reach remaining susceptible populations as elimination is approached. Serological surveys for measles and rubella can potentially measure susceptibility directly, but their use remains rare. In this study, using simulations, we outline key subtleties in interpretation associated with the dynamic context of age-specific immunity, highlighting how the patterns of immunity predicted from disease surveillance and vaccination coverage data may be misleading. High-quality representative serosurveys could provide a more accurate assessment of immunity if challenges of conducting, analyzing, and interpreting them are overcome. We frame the core disease control and elimination questions that could be addressed by improved serological tools, discussing challenges and suggesting approaches to increase the feasibility and sustainability of the tool. Accounting for the dynamical context, serosurveys could play a key role in efforts to achieve and sustain elimination.


Fuel poverty and the health of older people: the role of local climate.
Fuel poverty is a risk factor for ill-health, particularly among older people. We hypothesized that both the risk of fuel poverty and the strength of its detrimental effects on health would be increased in areas of colder and wetter climate. Individual data on respiratory health, hypertension, depressive symptoms and self-rated health were derived from the 2008/09 wave of the English Longitudinal Study of Ageing. Climate data for 89 English counties and unitary authorities were obtained from the UK Met Office. Multilevel regression models (n = 7160) were used to test (i) the association between local climate and fuel poverty risk, and (ii) the association between local climate and the effect of fuel poverty on health (adjusted for age, gender, height, smoking status and household income). Individual risk of fuel poverty varied across counties. However, this variation was not explained by differences in climate. Fuel poverty was significantly related to worse health for two of the outcomes (respiratory health and depressive symptoms). However, there was no significant effect of climate on fuel poverty's association with these outcomes. Although there is regional variation in England in both the risk of fuel poverty and its effects on health, this variation is not explained by differences in rainfall and winter temperatures.


Oral water intoxication in infants. An American epidemic.
Between 1975 and 1990, a total of 34 patients with water intoxication were treated at St Louis (Mo) Children's Hospital, 24 of these in the last 3 years, indicating a marked increase in incidence of this previously rare condition. Thirty-one were infants living in poverty who ingested excessive amounts of water offered at home by their caretakers. Exhaustion of the supply of infant formula was the most common reason given for this substitution. Infants were treated by a single infusion of hypertonic saline or a slow infusion of isotonic saline. Central pontine myelinolysis was not observed as a complication of hypertonic saline therapy. Modification of the Special Supplemental Food Program for Women, Infants, and Children to provide sufficient formula for the growing infant and better education of mothers as to the hazards of excessive water ingestion might reduce the incidence of this preventable and life-threatening condition.


Research: questions and answers from academic trauma surgeons.
The impact of recent social and professional influences on trauma research is unclear. This study characterizes current research practices, opinions on research quality, and barriers to academic productivity, expressed by academic trauma surgeons. A survey tool was administered electronically to members of the Eastern Association for the Surgery of Trauma. Questions on demographics, current and past research experience, perceptions of research quality trends, and barriers to academic success were included. Response rate was 40% (322 of 815). The mean age of respondents was 45 with 73% reporting completion of a critical care fellowship and 63% practicing in a university setting. The majority of respondents agreed or strongly agreed that both basic science (75%) and clinical (82%) research have become more difficult to perform. Greater difficulty in obtaining funding from their institutions was reported by 69% and by 61% for industry or private sources. Approximately 70% agreed that Institutional review board (IRB) regulations, confidentiality and consent requirements have impeded their research efforts whereas 86% agreed that increasing clinical requirements have inhibited their research efforts. Factors seen as impeding multi-institutional research, in order, were funding, IRB issues, poor coordination, commitment of investigators, and logistics. Perceived barriers to a successful research career were insufficient protected time (42%), funding (25%), personal motivation (11%), and IRB issues (11%). Research is viewed as being more difficult to conduct. The primary barriers to research productivity are perceived to be decreased protected time, decreased funding availability, and increased regulatory requirements.


Comparison of blood and synovial fluid th17 and novel peptidase inhibitor 16 Treg cell subsets in juvenile idiopathic arthritis.
Early recognition and treatment of juvenile idiopathic arthritis (JIA) can prevent joint damage and minimize side effects of medication. The balance between proinflammatory and antiinflammatory mechanisms is known to be important in JIA, and we therefore investigated T cell subsets including Th cells, autoaggressive Th17 cells, and regulatory T cells (Treg), including a novel Treg subset in peripheral blood (PB) and synovial fluid (SF) of patients with JIA. Fifty children with JIA were enrolled in our study. Frequency, phenotype, and function of T lymphocytes in PB and SF were characterized using flow cytometry. Migration capabilities of PB and SF cells were compared. Synovial T cells showed different phenotype and function compared with PB T cells, with an increased proportion of memory T cells, expression of CCR4, CCR5, CXCR3, interleukin 23R, and an increased ratio of Th17 to Treg. Although Treg were increased in SF compared with the PB, we found a significant decrease in the numbers of peptidase inhibitor 16 (PI16)+ Treg in active joints compared with peripheral blood. Coexpression of CCR4 and CCR6 was reduced on PI16+ Treg in PB and SF of patients with JIA compared with healthy children, however the ability of these cells to migrate toward their ligands was unaffected. This is a comprehensive characterization of novel PI16+ Treg and Th17 cells in matched blood and synovial fluid samples of patients with JIA. Despite an increased number of Treg within the inflamed joint, lower numbers of PI16+ Treg but high numbers of Th17 cells might contribute to the inability to control disease.


Risk factors for infection in patients with traumatic lacerations.
Most of our knowledge of laceration management comes from studies in animal models or patients with closure of sterile postoperative surgical incisions. Traumatic laceration management has not been well studied. To determine which characteristics of traumatic lacerations were associated with the development of wound infection. A cross-sectional study of consecutive patients with traumatic lacerations repaired over a four-year period was conducted. Structured closed-question data sheets were prospectively completed at the time of laceration repair and suture removal. Infection was determined at the time of suture removal. Multivariate modeling was used to determine the adjusted odds ratio (OR) of infection. Five thousand five hundred twenty-one patients were enrolled; 195 patients developed an infection (3.5%). An increased likelihood of wound infection was associated with age (adjusted OR per year, 1.01; 95% CI = 1.0 to 1.02); history of diabetes mellitus (adjusted OR 6.7; 95% CI = 1.7 to 26.4); laceration width (adjusted OR 1.05 per mm; 95% CI = 1.02 to 1.08); and presence of foreign body (adjusted OR 2.6; 95% CI = 1.3 to 5.2). Laceration location on the head/neck was associated with a decreased risk of infection (adjusted OR 0.28; 95% CI = 0.18 to 0.45). Both patient and wound characteristics of traumatic lacerations have an influence on the likelihood of infection. This knowledge may be valuable for determining whether various methods of wound cleansing, debridement, and repair can improve the outcome of patients with traumatic lacerations.


Hybrid optical-electrical detection of donor electron spins with bound excitons in silicon.
Electrical detection of spins is an essential tool for understanding the dynamics of spins, with applications ranging from optoelectronics and spintronics, to quantum information processing. For electron spins bound to donors in silicon, bulk electrically detected magnetic resonance has relied on coupling to spin readout partners such as paramagnetic defects or conduction electrons, which fundamentally limits spin coherence times. Here we demonstrate electrical detection of donor electron spin resonance in an ensemble by transport through a silicon device, using optically driven donor-bound exciton transitions. We measure electron spin Rabi oscillations, and obtain long electron spin coherence times, limited only by the donor concentration. We also experimentally address critical issues such as non-resonant excitation, strain, and electric fields, laying the foundations for realizing a single-spin readout method with relaxed magnetic field and temperature requirements compared with spin-dependent tunnelling, enabling donor-based technologies such as quantum sensing.


Estimating physical activity energy expenditure with the Kinect Sensor in an exergaming environment.
Active video games that require physical exertion during game play have been shown to confer health benefits. Typically, energy expended during game play is measured using devices attached to players, such as accelerometers, or portable gas analyzers. Since 2010, active video gaming technology incorporates marker-less motion capture devices to simulate human movement into game play. Using the Kinect Sensor and Microsoft SDK this research aimed to estimate the mechanical work performed by the human body and estimate subsequent metabolic energy using predictive algorithmic models. Nineteen University students participated in a repeated measures experiment performing four fundamental movements (arm swings, standing jumps, body-weight squats, and jumping jacks). Metabolic energy was captured using a Cortex Metamax 3B automated gas analysis system with mechanical movement captured by the combined motion data from two Kinect cameras. Estimations of the body segment properties, such as segment mass, length, centre of mass position, and radius of gyration, were calculated from the Zatsiorsky-Seluyanov's equations of de Leva, with adjustment made for posture cost. GPML toolbox implementation of the Gaussian Process Regression, a locally weighted k-Nearest Neighbour Regression, and a linear regression technique were evaluated for their performance on predicting the metabolic cost from new feature vectors. The experimental results show that Gaussian Process Regression outperformed the other two techniques by a small margin. This study demonstrated that physical activity energy expenditure during exercise, using the Kinect camera as a motion capture system, can be estimated from segmental mechanical work. Estimates for high-energy activities, such as standing jumps and jumping jacks, can be made accurately, but for low-energy activities, such as squatting, the posture of static poses should be considered as a contributing factor. When translated into the active video gaming environment, the results could be incorporated into game play to more accurately control the energy expenditure requirements.


The relationship between asthma admission rates, routes of admission, and socioeconomic deprivation.
This study aimed to explore the relationship between hospital admissions for asthma and socioeconomic deprivation. A retrospective study examined one year of hospital admissions for asthma in the West Midlands region of England (n = 10,044), and in one of the region's wealthier districts, Worcester (n = 251). Age standardized admission ratios (SARs) for asthma, and the routes of hospital admission, were compared with the Towns- end Deprivation Index for the place of residence. Asthma SAR was strongly associated with deprivation as measured by the Towns end Index for the district of residence (Spearman rank correlation coefficient rho = 0.65; p = 0.004). Asthma admission rates for all age groups, except those aged over 65 yrs, were higher in poorer districts. A significantly greater proportion of emergency admissions in poorer districts came via Accident and Emergency departments, rather than general practitioner referrals (rho = 0.76; p < 0.001). Within Worcester District, SAR was associated with Townsend Index for the ward of residence (rho = 0.39; p < 0.001). This remained significant after excluding repeat admissions (rho = 0.45; p < 0.001). We conclude that asthma admissions are strongly associated with deprivation in the community. Differences in the health care received during acute exacerbations by asthma patients from different economic backgrounds is likely to be an important factor in this relationship.


En bloc resection of primary melanoma with regional lymph node dissection.
En bloc resection of the primary melanoma with the regional lymph node drainage basin as a method of controlling disease within the area was used in 281 patients with stage I or II melanoma arising on the extremities (proximal to wrist or ankle) or on the trunk from 1954 through 1964. The en bloc operation was performed in 212 patients with a five-year cure of 73.5% (156 of 212). Seventy-six percent had histologically negative nodes. Only 2% developed regional recurrence. Sixty-nine patients had a discontinuous dissection. The five-year cure was comparable: 68% (47 of 69). The incidence of histologically negative nodes was similar (77%), but the regional recurrence rate was 14%. This difference is significant at P < .01. The incontinuity or en bloc procedure appears highly effective for its designed purpose.


Photoantimicrobials-are we afraid of the light?
Although conventional antimicrobial drugs have been viewed as miraculous cure-alls for the past 80 years, increasing antimicrobial drug resistance requires a major and rapid intervention. However, the development of novel but still conventional systemic antimicrobial agents, having only a single mode or site of action, will not alleviate the situation because it is probably only a matter of time until any such agents will also become ineffective. To continue to produce new agents based on this notion is unacceptable, and there is an increasing need for alternative approaches to the problem. By contrast, light-activated molecules called photoantimicrobials act locally via the in-situ production of highly reactive oxygen species, which simultaneously attack various biomolecular sites in the pathogenic target and therefore offer both multiple and variable sites of action. This non-specificity at the target circumvents conventional mechanisms of resistance and inhibits the development of resistance to the agents themselves. Photoantimicrobial therapy is safe and easy to implement and, unlike conventional agents, the activity spectrum of photoantimicrobials covers bacteria, fungi, viruses, and protozoa. However, clinical trials of these new, truly broad-spectrum, and minimally toxic agents have been few, and the funding for research and development is almost non-existent. Photoantimicrobials constitute one of the few ways forward through the morass of drug-resistant infectious disease and should be fully explored. In this Personal View, we raise awareness of the novel photoantimicrobial technologies that offer a viable alternative to conventional drugs in many relevant application fields, and could thus slow the pace of resistance development.


A disease-mediated trophic cascade in the Serengeti and its implications for ecosystem C.
Tree cover is a fundamental structural characteristic and driver of ecosystem processes in terrestrial ecosystems, and trees are a major global carbon (C) sink. Fire and herbivores have been hypothesized to play dominant roles in regulating trees in African savannas, but the evidence for this is conflicting. Moving up a trophic scale, the factors that regulate fire occurrence and herbivores, such as disease and predation, are poorly understood for any given ecosystem. We used a Bayesian state-space model to show that the wildebeest population eruption that followed disease (rinderpest) eradication in the Serengeti ecosystem of East Africa led to a widespread reduction in the extent of fire and an ongoing recovery of the tree population. This supports the hypothesis that disease has played a key role in the regulation of this ecosystem. We then link our state-space model with theoretical and empirical results quantifying the effects of grazing and fire on soil carbon to predict that this cascade may have led to important shifts in the size of pools of C stored in soil and biomass. Our results suggest that the dynamics of herbivores and fire are tightly coupled at landscape scales, that fire exerts clear top-down effects on tree density, and that disease outbreaks in dominant herbivores can lead to complex trophic cascades in savanna ecosystems. We propose that the long-term status of the Serengeti and other intensely grazed savannas as sources or sinks for C may be fundamentally linked to the control of disease outbreaks and poaching.


Studies of the ferroxidase activity of native and chemically modified xanthine oxidoreductase.
The O2-utilizing (type O, oxidase) form of xanthine oxidoreductase is primarily responsible for its ferroxidase activity. This form of xanthine oxidoreductase has 1000 times the ferroxidase activity of the serum ferroxidase caeruloplasmin. It has the ability to catalyse the oxidative incorporation of iron into transferrin at very low Fe2+ and O2 concentrations. Furthermore, the pH optimum of the ferroxidase activity of the enzyme is compatible with the conditions of pH that normally exist in the intestinal mucosa, where it has been proposed that xanthine oxidoreductase may facilitate the absorption of ionic iron. Modification of the molybdenum (Mb) centres of the enzyme in vitro by treatment with cyanide, methanol or allopurinol completely abolishes its ferroxidase activity. The feeding of dietary tungsten to rats, which prevents the incorporation of molybdenum into newly synthesized intestinal xanthine oxidoreductase, results in the progressive loss of the ferroxidase activity of intestinal-mucosa homogenates. Removal of the flavin centres from the enzyme also results in the complete loss of ferroxidase activity; however, the ferroxidase activity of the flavin-free form of the enzyme can be restored with artificial electron acceptors that interact with the molybdenum or non-haem iron centres. The presence of superoxide dismutase or catalase in the assay system results in little inhibition of the ferroxidase activity of xanthine oxidoreductase.


Gastrointestinal Symptoms and Feeding Problems and Their Associations with Dietary Interventions, Food Supplement Use, and Behavioral Characteristics in a Sample of Children and Adolescents with Autism Spectrum Disorders.
Autism spectrum disorders (ASD) are characterized by impairments in social interaction, communication, and restricted, stereotyped behavior. Gastrointestinal (GI), nutritional, and feeding problems are often reported in ASD. We investigated the prevalence of GI symptoms, food selectivity, and mealtime difficulties, and their associations with dietary interventions, food supplement use, and behavioral characteristics in a sample involving 247 participants with ASD and 267 controls aged 2-18 years. Data were collected by a questionnaire. GI symptoms were observed in 88.9% of children and adolescents with ASD, more often in girls than in boys. High rates of food selectivity (69.1%) and mealtime problems (64.3%) were found. Food supplements were used by 66.7% of individuals, mainly vitamins/minerals, probiotics, and omega-3 fatty acids. In the ASD sample, 21.2% of subjects followed a diet, mostly based on gluten and milk restriction, including individuals exhibiting food selectivity. Frequency of GI symptoms, food selectivity, and mealtime problems correlated weakly, but significantly with behavioral characteristics in the ASD group, but not with food supplement use. The study demonstrated that higher frequency of GI symptoms, food selectivity, and mealtime problems are a common problem in pre-schoolers, schoolchildren, and adolescents with ASD, and together with dietary modification, they are significantly associated with ASD.


Excitonic condensation under spin-orbit coupling and BEC-BCS crossover.
The condensation of electron-hole pairs is studied at zero temperature and in the presence of a weak spin-orbit coupling (SOC) in coupled quantum wells. Under realistic conditions, a perturbative SOC can have observable effects in the order parameter of the condensate. First, the fermion exchange symmetry is absent. As a result, the condensate spin has no definite parity. Additionally, the excitonic SOC breaks the rotational symmetry yielding a complex order parameter in an unconventional way; i.e., the phase pattern of the order parameter is a function of the condensate density. This is manifested through finite off-diagonal components of the static spin susceptibility, suggesting a new experimental method to confirm an excitonic condensate.


Pregnancy-induced Low Back Pain in Indian Women: Prevalence, Risk Factors, and Correlation with Serum Calcium Levels.
Pregnancy-induced low back pain (LBP) is a common problem during the pregnancy which usually begins between the 20th and the 28th weeks of gestation, and the exact duration varies. The aim of this study is to determine the prevalence of LBP including pelvic girdle pain (PGP) and its various aspects such as nature, intensity, character, radiation, circadian pattern, and its correlation with serum calcium levels. This was a cross-sectional survey conducted in a tertiary care hospital in the capital of Delhi. In this cross-sectional study, 200 pregnant women completed a questionnaire and also underwent clinical examinations if PGP is suspected. The clinical examination included various pain provocation tests including active straight leg raise test. Venous blood samples were drawn to evaluate the serum calcium levels in pregnant women complaining of back pain. Possible associating factors were studied by nonparametric tests and logistic regression analysis. Bivariant correlation of serum calcium levels, total duration of pain, and Visual Analog Scale score was done with various factors such as parity, socioeconomic status, and nature of pain. The point prevalence of LBP was found to be 80% with a significantly lower prevalence of PGP, i.e., 2%, when compared to the international figures. Majority of women graded their pain as dull aching type (47.5%) and moderate to severe in intensity. The circadian rhythm of back pain was observed in 56% of the patients, and out of that, insomnia was complained by 33% of the patients. Limitation of physical activity was observed in 62.5% of the patients. A negative correlation was observed between the serum calcium levels and parity; however, a positive correlation between the intensity of pain and parity was observed.


The forensic medical aspects of thromboembolic risk in orthopaedic surgery.
The correct balance between risk factors for the patient and those related to the type of surgery performed is an essential requirement when proposing appropriate anti-thrombosis prophylaxis, which is not always without risks. The guidelines consist in the essential parameter with which the surgeon must be inspired. Nonetheless, their acceptance cannot be totally uninfluenced but must be submitted to a critical analysis, as it cannot constitute, in terms of so-called defensive medicine, a hypothetical refuge to avoid responsabilities nor can it be an acritical parameter in a legal situation. In recent years, cases in this field have increased so that it seems useful to suggest greater involvement by the coagulation specialist, at least in the most complex cases. Legal suits frequently involve a lack of prophylaxis, inadequate prophylaxis, lack of monitoring of coagulative parameters, insufficient duration of prophylaxis, lack of diagnostic testing to be used when DVT and PTE are suspected. Nonetheless, in order to avoid blame on the profession it is not enough to choose suitable and correct treatment; it is important to also keep iatrogenic injury from becoming the center of a legal action because of the lack of patient informed consent. The amount of data is directly proportional to the amount of risk. Furthermore, it is necessary to insist on the need to document data, as a preventive measure, so that the patient is also responsible for the risk taken. In court, the signing of forms cannot be valid proof that the patient was effectively and truly provided with all of the information required.


Do national policies for complaint handling in English hospitals support quality improvement? Lessons from a case study.
A range of public inquiries in the English National Health Service have indicated repeating failings in complaint handling, and patients are often left dissatisfied. The complex, bureaucratic nature of complaints systems is often cited as an obstacle to meaningful investigation and learning, but a detailed examination of how such bureaucratic rules, regulations, and infrastructure shape complaint handling, and where change is most needed, remains relatively unexplored. We sought to examine how national policies structure local practices of complaint handling, how they are understood by those responsible for enacting them, and if there are any discrepancies between policies-as-intended and their reality in local practice. Case study involving staff interviews and documentary analysis. A large acute and multi-site NHS Trust in England. Clinical, managerial, complaints, and patient advocacy staff involved in complaint handling at the participating NHS Trust (n=20). Not applicable. Findings illustrate four areas of practice where national policies and regulations can have adverse consequences within local practices, and partly function to undermine an improvement-focused approach to complaints. These include muddled routes for raising formal complaints, investigative procedures structured to scrutinize the 'validity' of complaints, futile data collection systems, and adverse incentives and workarounds resulting from bureaucratic performance targets. This study demonstrates how national policies and regulations for complaint handling can impede, rather than promote, quality improvement in local settings. Accordingly, we propose a number of necessary reforms, including patient involvement in complaints investigations, the establishment of independent investigation bodies, and more meaningful data analysis strategies to uncover and address systemic causes behind recurring complaints.


Synthesis of Linear Acetylenic Carbon: The "sp" Carbon Allotrope.
A carbon allotrope based on "sp" hybridization containing alternating triple and single bonds (an acetylenic or linear carbon allotrope) has been prepared. Studies of small (8 to 28 carbon atoms) acetylenic carbon model compounds show that such species are quite stable (130 degrees to 140 degrees C) provided that nonreactive terminal groups or end caps (such as tert-butyl or trifluoromethyl) are present to stabilize these molecules against further reactions. In the presence of end capping groups, laser-based synthetic techniques similar to those normally used to generate fullerenes, produce thermally stable acetylenic carbon species capped with trifluoromethyl or nitrile groups with chain lengths in excess of 300 carbon atoms. Under these conditions, only a negligible quantity of fullerenes is produced. Acetylenic carbon compounds are not particularly moisture or oxygen sensitive but are moderately light sensitive.


Presence of a loner strain maintains cooperation and diversity in well-mixed bacterial communities.
Cooperation and diversity abound in nature despite cooperators risking exploitation from defectors and superior competitors displacing weaker ones. Understanding the persistence of cooperation and diversity is therefore a major problem for evolutionary ecology, especially in the context of well-mixed populations, where the potential for exploitation and displacement is greatest. Here, we demonstrate that a 'loner effect', described by economic game theorists, can maintain cooperation and diversity in real-world biological settings. We use mathematical models of public-good-producing bacteria to show that the presence of a loner strain, which produces an independent but relatively inefficient good, can lead to rock-paper-scissor dynamics, whereby cooperators outcompete loners, defectors outcompete cooperators and loners outcompete defectors. These model predictions are supported by our observations of evolutionary dynamics in well-mixed experimental communities of the bacterium Pseudomonas aeruginosa. We find that the coexistence of cooperators and defectors that produce and exploit, respectively, the iron-scavenging siderophore pyoverdine, is stabilized by the presence of loners with an independent iron-uptake mechanism. Our results establish the loner effect as a simple and general driver of cooperation and diversity in environments that would otherwise favour defection and the erosion of diversity.


Low bone mineral density is associated with metabolic syndrome in South Korean men but not in women: The 2008-2010 Korean National Health and Nutrition Examination Survey.
We examined the relationships between bone mineral density (BMD) and metabolic syndrome in 6,659 men and 7,826 women from South Korean. After adjusting for age, body mass index (BMI), tobacco and alcohol use, and regular exercise, low BMD is especially associated with metabolic syndrome in South Korean men. This study examined the relationships between BMD and metabolic syndrome (MS) in South Korean adults. A total of 14,485 adults (6,659 men and 7,826 women) in the Korea National Health and Nutrition Examination Survey conducted from 2008 to 2010 were analyzed. We used multivariable regression models to examine the relationship between low BMD and MS. We calculated homeostasis model assessment and insulin resistance (HOMA-IR). MS was defined according to AHA/NHLBI criteria for Asians. BMD was measured at the lumbar spine (LS), femur neck (FN), total hip (TH), trochanter, and intertrochanter. After adjustment for age, BMI, tobacco and alcohol use, and regular exercise, the TH and FN BMD were significantly lower in men with MS than in men without MS (p < 0.05). However, there were no differences in premenopausal and postmenopausal women. In men, BMD was positively correlated with BMI, and high density lipoprotein cholesterol, but was negatively correlated with insulin, HOMA-IR, and triglyceride at all three sites (p < 0.05). Along with an increase of BMD (0.1 g/cm²), the odds ratios (ORs) for obesity and abdominal obesity were all greater than 1 at all sites in both genders. The ORs for hypertension and MS were 0.937 (0.879-0.998) and 0.899 (0.840-0.962), respectively at FN, and the OR for diabetes mellitus was 1.103 (1.017-1.196) at LS in men. In postmenopausal women, the OR for hypertension was 1.133 (1.029-1.246) at LS. Low BMD was especially associated with MS in South Korean men.


Microarray analysis shows that recessive resistance to Watermelon mosaic virus in melon is associated with the induction of defense response genes.
Resistance to Watermelon mosaic virus (WMV) in melon (Cucumis melo L.) accession TGR-1551 is characterized by a significant reduction in virus titer, and is inherited as a recessive, loss-of-susceptibility allele. We measured virus RNA accumulation in TGR-1551 plants and a susceptible control ('Tendral') by real-time quantitative polymerase chain reaction, and also profiled the expression of 17,443 unigenes represented on a melon microarray over a 15-day time course. The virus accumulated to higher levels in cotyledons of the resistant variety up to 9 days postinoculation (dpi) but, thereafter, levels increased in the susceptible variety while those in the resistant variety declined. Microarray experiments looking at the early response to infection (1 and 3 dpi), as well as responses after 7 and 15 dpi, revealed more profound transcriptomic changes in resistant plants than susceptible ones. The gene expression profiles revealed deep and extensive transcriptome remodeling in TGR-1551 plants, often involving genes with pathogen response functions. Overall, our data suggested that resistance to WMV in TGR-1551 melon plants is associated with a defense response, which contrasts with the recessive nature of the resistance trait.


Quantifying the sol-gel process and detecting toxic gas in an array of anchored microfluidic droplets.
The detection of toxic gases is becoming an important element in tackling increased air pollution. This has led to the development of gas sensors based on porous solid materials, which are produced using sol-gel chemistry and functionalized to change their optical qualities when in contact with the gas. In this context it is interesting to explore how microfluidics can be used to miniaturize these sensors, to improve their sensitivity and dynamic range, or to multiplex many gas measurements on a single chip. In this article we show how the sol-gel process can be implemented using anchored droplet microfluidics. The sensor material is partitioned into droplets while in the sol phase and maintained using capillary anchors. The ability to hold the droplets in place first allows us to study the sol-gel process. We use an original rheology method, which consists of observing the flows within stationary droplets that are submitted to an external flow, to measure the gelation time of the droplets. These measurements show a gelation time that decreases from 50 minutes to below 10 minutes as the temperature increases from 20 to 50 °C. We also measure the shrinkage of individual gel beads after gelation and find that this syneresis process is nearly finished after about 12 hours, leading to a final bead size that is 50% smaller than the initial droplet. Finally, we show that the beads can be functionalized and used to detect the presence of formaldehyde. These results first provide a new way to observe the physics of the sol-gel process in a well-controlled and quantitative fashion. Moreover they highlight how the coupling of microfluidics and sol-gel chemistry can be used to detect toxic gases, in view of answering the challenges surrounding gas detection in real-world settings.


Which Orthopaedic Patients Are Infected with Gram-negative Non-fermenting Rods?
Background : 1st and 2nd generation cephalosporins used for perioperative prophylaxis in orthopaedic surgery do not cover non-fermenting Gram-negative rods (NFR). Methods: Epidemiological cohort study of adult patients operated for orthopedic infections between 2004 and 2014 with perioperative cefuroxim or vancomycin prophylaxis. Exclusion of polyneuropathic ischemic foot infections and septic bursitis cases. Results: Of the total 1840 surgical procedures in the study, 430 grew Gram-negative pathogens (23%), of which 194 (11%) were due to NFR and 143 (8%) to Pseudomonas aeruginosa. Overall, 634 episodes (35%) involved orthopaedic implants (321 arthroplasties, 135 plates, 53 nails, and others). In multivariate analysis and group comparisons, especially preoperative antibiotic use (124/194 vs. 531/1456; p<0.01) was significantly associated with NFR. Conclusions: Overall proportion of NFR oscillated between 9% and 13% among our orthopaedic infections. Variables associated with NFR were antibiotic use prior to hospitalization. The low infection rate of NFR following elective surgery and the community-based epidemiology, has led us to keep our standard perioperative prophylaxis unchanged.


Stick-slip patterning at low capillary numbers for an evaporating colloidal suspension.
Pattern formation from a silica colloidal suspension that is evaporating has been studied when a movement is imposed to the contact line. This article focuses on the stick-slip regime observed for very low contact line velocities. A capillary rise experiment has been specially designed for the observation and allows us to measure the pinning force that increases during the pinning of the contact line on the growing deposit. We report systematic measurements of this pinning force and derive scaling laws when the velocity of the contact line, the colloid concentration, and the evaporation rate are varied. Our analysis supports the idea that the pinning of the contact line results from a competition between the geometry of the growing deposit and the force due to gravity.


Meta-Analysis of Sulfonylurea Therapy on Long-Term Risk of Mortality and Cardiovascular Events Compared to Other Oral Glucose-Lowering Treatments.
Among the most pressing clinical decisions in type 2 diabetes treatments are which drugs should be used after metformin is no longer sufficient, and whether sulfonylureas (SUs) should remain as a suitable second-line treatment. In this article we summarize current evidence on the long-term safety risks associated with SU therapy relative to other oral glucose-lowering therapies. The MEDLINE database and Clinicaltrials.gov were searched for observational and experimental studies comparing the safety of SUs to that of other diabetes medications in people with type 2 diabetes mellitus through December 15, 2015. Studies with at least 1 year of follow-up, which explicitly examined major cardiovascular events or death in patients who showed no evidence of serious conditions at baseline, were selected for inclusion in meta-analyses. SU treatment was associated with an elevated risk relative to treatment with metformin (METF), thiazolidinedione (TZD), dipeptidyl peptidase-4 inhibitor (DPP-4), and glucagon-like peptide-1 (GLP-1) agonist classes, either when compared alone (as a monotherapy) or when used in combination with METF. Significant findings were almost entirely derived from nontrial data and not confirmed by smaller, efficacy designed randomized controlled trials whose effects were in the same direction but much more imprecise. Although much of the evidence is derived and will continue to come from observational studies, the methodological rigor of such studies is questionable. A key challenge for evaluators is the extent to which they should incorporate evidence from study designs that are quasi-experimental.


National trends in prescription drug expenditures and projections for 2017.
Historical trends and factors likely to influence future pharmaceutical expenditures are discussed, and projections are made for drug spending in 2017 in nonfederal hospitals, clinics, and overall (all sectors). Drug expenditure data through calendar year 2016 were obtained from the QuintilesIMS National Sales Perspectives database and analyzed. Other factors that may influence drug spending in hospitals and clinics in 2017, including new drug approvals and patent expirations, were also reviewed. Expenditure projections for 2017 for nonfederal hospitals, clinics, and overall (all sectors) were made based on a combination of quantitative analyses and expert opinion. Total U.S. prescription sales in the 2016 calendar year were $448.2 billion, a 5.8% increase compared with 2015. More than half of the increase resulted from price hikes of existing drugs. Adalimumab was the top drug overall in 2016 expenditures ($13.6 billion); in clinics and nonfederal hospitals, infliximab was the top drug. Prescription expenditures in clinics and nonfederal hospitals totaled $63.7 billion (an 11.9% increase from 2015) and $34.5 billion (a 3.3% increase from 2015), respectively. In nonfederal hospitals and clinics, growth in spending was driven primarily by price increases of existing drugs and increased volume, respectively. We project a 6.0-8.0% increase in total drug expenditures across all settings, an 11.0-13.0% increase in clinics, and a 3.0-5.0% increase in hospital drug spending in 2017. Health-system pharmacy leaders should carefully examine their own local drug utilization patterns to determine their own organization's anticipated spending in 2017.


New vaccine adoption: qualitative study of national decision-making processes in seven low- and middle-income countries.
As more new and improved vaccines become available, decisions on which to adopt into routine programmes become more frequent and complex. This qualitative study aimed to explore processes of national decision-making around new vaccine adoption and to understand the factors affecting these decisions. Ninety-five key informant interviews were conducted in seven low- and middle-income countries: Bangladesh, Cameroon, Ethiopia, Guatemala, Kenya, Mali and South Africa. Framework analysis was used to explore issues both within and between countries. The underlying driver for adoption decisions in GAVI-eligible countries was the desire to seize GAVI windows of opportunity for funding. By contrast, in South Africa and Guatemala, non-GAVI-eligible countries, the decision-making process was more rooted in internal and political dynamics. Decisions to adopt new vaccines are, by nature, political. The main drivers influencing decisions were the availability of funding, political prioritization of vaccination or the vaccine-preventable disease and the burden of disease. Other factors, such as financial sustainability and feasibility of introduction, were not as influential. Although GAVI procedures have established more formality in decision-making, they did not always result in consideration of all relevant factors. As familiarity with GAVI procedures increased, questioning by decision-makers about whether a country should apply for funding appeared to have diminished. This is one of the first studies to empirically investigate national processes of new vaccine adoption decision-making using rigorous methods. Our findings show that previous decision-making frameworks (developed to guide or study national decision-making) bore little resemblance to real-life decisions, which were dominated by domestic politics. Understanding the realities of vaccine policy decision-making is critical for developing strategies to encourage improved evidence-informed decision-making about new vaccine adoptions. The potential for international initiatives to encourage evidence-informed decision-making should be realised, not assumed.


Application of a Framework to Assess the Usefulness of Alternative Sepsis Criteria.
The current definition of sepsis is life-threatening, acute organ dysfunction secondary to a dysregulated host response to infection. Criteria to operationalize this definition can be judged by six domains of usefulness (reliability, content, construct and criterion validity, measurement burden, and timeliness). The relative importance of these six domains depends on the intended purpose for the criteria (clinical care, basic and clinical research, surveillance, or quality improvement [QI] and audit). For example, criteria for clinical care should have high content and construct validity, timeliness, and low measurement burden to facilitate prompt care. Criteria for surveillance or QI/audit place greater emphasis on reliability across individuals and sites and lower emphasis on timeliness. Criteria for clinical trials require timeliness to ensure prompt enrollment and reasonable reliability but can tolerate high measurement burden. Basic research also tolerates high measurement burden and may not need stability over time. In an illustrative case study, we compared examples of criteria designed for clinical care, surveillance and QI/audit among 396,241 patients admitted to 12 academic and community hospitals in an integrated health system. Case rates differed four-fold and mortality three-fold. Predictably, clinical care criteria, which emphasized timeliness and low burden and therefore used vital signs and routine laboratory tests, had the greater case identification with lowest mortality. QI/audit criteria, which emphasized reliability and criterion validity, used discharge information and had the lowest case identification with highest mortality. Using this framework to identify the purpose and apply domains of usefulness can help with the evaluation of existing sepsis diagnostic criteria and provide a roadmap for future work.


Bladder cancer risk: Use of the PLCO and NLST to identify a suitable screening cohort.
Bladder cancer (BC) screening is not accepted in part owing to low overall incidence. We used the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and National Lung Cancer Screening Trial (NLST) to identify optimal high-risk populations most likely to benefit from screening. Data were extracted from PLCO and NLST to stratify risk of BC by overall population, sex, race, age at inclusion, and smoking status. Incidence rates between groups were compared using chi-square test. BC was identified in 1,430/154,898 patients in PLCO and 439/53,173 patients in NLST. BCs were grade III/IV in 36.8% and 41.3%. Incidence rates were significantly higher in men than in women (PLCO: 1.4 vs. 0.31/1,000 person-years and NLST: 1.84 vs. 0.6/1,000 person-years, both P<0.0001). In proportional hazards models, male sex, higher age, and duration and intensity of smoking were associated with higher risk of BC (all P<0.0001). In men older than 70 years with smoking exposure of 30 pack-years (PY) and more, incidence rates were as high as 11.92 (PLCO) and 5.23 (NLST) (per 1,000 person-years). In current high-intensity smokers (≥50 PY), the sex disparity in incidence persists in both trials (0.78 vs. 2.99 per 1,000 person-years in PLCO and 1.12 vs. 2.65 per 1,000 person-years in NLST). Men older than 60 years with a smoking history of>30 PY had incidence rates of more than 2/1,000 person-years, which could serve as an excellent population for screening trials. Sex differences in the incidence of BC cannot be readily explained by the differences in exposure to tobacco, as sex disparity persisted regardless of smoking intensity.


Impaired allocentric spatial processing in posttraumatic stress disorder.
A neurobiological dual representation model of PTSD proposes that reduced hippocampus-dependent contextual processing contributes to intrusive imagery due to a loss of control over hippocampus-independent sensory and affective representations. We investigated whether PTSD sufferers show impaired allocentric spatial processing indicative of reduced hippocampal functioning. Trauma-exposed individuals with (N=29) and without (N=30) a diagnosis of PTSD completed two tests of spatial processing: a topographical recognition task comprising perceptual and memory components, and a test of memory for objects' locations within a virtual environment in which the test is from either the same viewpoint as presentation (solvable with egocentric memory) or a different viewpoint (requiring allocentric memory). Participants in the PTSD group performed significantly worse on allocentric spatial processing than trauma-exposed controls. Groups performed comparably on egocentric memory and non-spatial memory for lists of objects. Exposure to repeated incident trauma was also associated with significantly worse spatial processing in the PTSD group. Results show a selective impairment in allocentric spatial processing, implicating weak hippocampal functioning, as predicted by a neurobiological dual representation model of PTSD. These findings have important clinical implications for cognitive therapy.


Antibiotic prophylaxis in cutaneous surgery.
Postoperative wound infections, endocarditis, and late contamination of prosthetic implants are potential complications of cutaneous surgery. To review current American Heart Association guidelines and their application to cutaneous surgery, and to determine how practicing physicians approach this problem. Surveys were sent to dermatologists to determine what kind of preoperative screening was being done and how antibiotics were being used. The most common indications for prophylaxis were manipulation of infected tissue in patients undergoing any procedure, and any procedure in a patient with a prosthetic heart valve. Some respondents used antibiotic prophylaxis for all procedures, while others never used antibiotics in any surgical procedure. Cephalosporins and erythromycin were the most commonly used antibiotics and they were usually given orally, one dose before and one dose after surgery. Scientific literature supports the use of antibiotic prophylaxis for endocarditis in two situations: 1) surgical procedures on infected tissue in patients with a high risk cardiac lesion; and 2) any surgical procedure in a patient with a prosthetic heart valve. Our survey suggests that the majority of dermatologists obtain pertinent medical history and use appropriate antibiotic prophylaxis in these two situations. But the survey also suggests that antibiotic prophylaxis is used in a variety of situations where indications for use are not as clear, and sometimes prophylaxis is not used when it should be.


Changes in the uptake of antiretroviral therapy and survival in people with known duration of HIV infection in Europe: results from CASCADE.
To estimate the times from HIV seroconversion to death, and to the initiation of therapy and the mean CD4 cell count at initiation. Using Kaplan-Meier methods, allowing for late entry, we analysed CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe) data from HIV-infected individuals with known dates of seroconversion. We tested the association of time to initiation of therapy and of survival with: exposure category, age, sex, presentation during acute infection and calendar year at risk (as time-dependent) in Cox proportional hazards models, stratifying by study. We estimated the mean CD4 cell count at the initiation of therapy using interval regression. Of 5893 seroconverters, 1613 (27.4%) died. The risk of death was 65% lower (95% CI = 57-72%) in 1997-99 compared to previous years. Being at risk in earlier calendar years, older age and a short interval between negative and positive test dates were associated with shorter survival. At the same time from seroconversion, people at risk in 1997-99, older individuals and people with a short test interval were more likely to initiate therapy. Injecting drug users (IDUs) were less likely to initiate therapy compared to those exposed through sex between men (RR = 0.79, 95% CI = 0.69-0.89). The mean CD4 cell count at therapy initiation was 205 cells/mL, which increased significantly over time. Although the earlier initiation of therapy was consistent with longer survival in the 1997-99 period, we found no evidence of this in other calendar periods. We found a significant and substantial reduction in the risk of death and a significant trend of earlier initiation of antiretroviral therapy (ART) in the 1997-99 period. Although IDUs were less likely to initiate therapy their overall survival did not appear to differ from others. The increasing tendency to initiate ART closer to seroconversion has unknown long-term consequences which require monitoring.