Effectiveness of pharmacotherapy for severe personality disorders: meta-analyses of randomized controlled trials.
There has been little systematic attempt to validate current pharmacologic treatment algorithms and guidelines for severe personality disorder. We evaluated studies on the effectiveness of psychoactive drugs on specific symptom domains for borderline and/or schizotypal personality disorder. The literature was searched for placebo-controlled randomized clinical trials (PC-RCTs) on the effectiveness of psychopharmacologic drugs in personality disorder patients. The PubMed, PsychINFO, PiCarta, Cochrane, and Web of Science databases were searched using the search terms borderline personality, schizotypal personality, personality disorder, cluster A, cluster B, treatment, drug, pharmacotherapy, antipsychotic, antidepressant, mood stabilizer, effect, outcome, review, and meta-analysis for studies published between 1980 and December 2007, and references were identified from bibliographies from articles and books. Placebo-controlled randomized clinical trials on the efficacy of antipsychotics, antidepressants, and mood stabilizers regarding cognitive-perceptual symptoms, impulsive-behavioral dyscontrol, and affective dysregulation (with subdomains depressed mood, anxiety, anger, and mood lability) were selected in patients with well defined borderline and/or schizotypal personality disorder. Studies whose primary emphasis was on the treatment of Axis I disorders were excluded. Meta-analyses were conducted using 21 retrieved studies. Antipsychotics have a moderate effect on cognitive-perceptual symptoms (5 PC-RCTs; standardized mean difference [SMD]=0.56) and a moderate to large effect on anger (4 PC-RCTs; SMD=0.69). Antidepressants have no significant effect on impulsive-behavioral dyscontrol and depressed mood. They have a small but significant effect on anxiety (5 PC-RCTs; SMD=0.30) and anger (4 PC-RCTs; SMD=0.34). Mood stabilizers have a very large effect on impulsive-behavioral dyscontrol (6 PC-RCTs; SMD=1.51) and anger (7 PC-RCTs; SMD=1.33), a large effect on anxiety (3 PC-RCTs; SMD=0.80), but a moderate effect on depressed mood (5 PC-RCTs; SMD=0.55). Mood lability as an outcome measure was seldomly assessed. Mood stabilizers have a more pronounced effect on global functioning (3 PC-RCTs; SMD=0.79) than have antipsychotics (5 PC-RCTs; SMD=0.37). The effect of antidepressants on global functioning is negligible. Drug therapy tailored to well-defined symptom domains can have a beneficial effect on patients with severe personality disorder. The findings from this study raise questions on current pharmacologic algorithms.


Female-mediated causes and consequences of status change in a social fish.
In highly social species, dominant individuals often monopolize reproduction, resulting in reproductive investment that is status dependent. Yet, for subordinates, who typically invest less in reproduction, social status can change and opportunities to ascend to dominant social positions are presented suddenly, requiring abrupt changes in behaviour and physiology. In this study, we examined male reproductive anatomy, physiology and behaviour following experimental manipulations of social status in the cooperatively breeding cichlid fish, Neolamprologus pulcher. This unusual fish species lives in permanent social groups composed of a dominant breeding pair and 1-20 subordinates that form a linear social dominance hierarchy. By removing male breeders, we created 18 breeding vacancies and thus provided an opportunity for subordinate males to ascend in status. Dominant females play an important role in regulating status change, as males successfully ascended to breeder status only when they were slightly larger than the female breeder in their social group. Ascending males rapidly assumed behavioural dominance, demonstrated elevated gonadal investment and androgen concentrations compared with males remaining socially subordinate. Interestingly, to increase gonadal investment ascending males appeared to temporarily restrain somatic growth. These results highlight the complex interactions between social status, reproductive physiology and group dynamics, and underscore a convergent pattern of reproductive investment among highly social, cooperative species.


Plasma 1-deoxysphingolipids are early predictors of incident type 2 diabetes mellitus.
1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids, which are formed in a side reaction during sphingolipid de-novo synthesis. Recently, we demonstrated that 1-deoxySLs are biomarkers for the prediction of T2DM in obese, non-diabetic patients. Here we investigated the relevance of 1-deoxySLs as long-term predictive biomarkers for the incidence of T2DM in an asymptomatic population. Here, we analyzed the plasma sphingoid base profile in a nested group of non-diabetic individuals (N = 605) selected from a population-based study including 5 year follow-up data (CoLaus study). 1-DeoxySLs at baseline were significantly elevated in individuals who developed T2DM during the follow-up (p<0.001), together with increased glucose (p<5.11E-14), triglycerides (p<0.001) and HOMA-IR indices (p<0.001). 1-Deoxy-sphinganine (1-deoxySA) and 1-deoxy-sphingosine (1-deoxySO) were predictive for T2DM, even after adjusting for fasting glucose levels in the binary regression analyses. The predictive value of the combined markers 1-deoxySA+glucose were superior to glucose alone in normal-weight subjects (p<0.001) but decreased substantially with increasing BMI. Instead, plasma adiponectin and waist-to-hip ratio appeared to be better risk predictors for obese individuals (BMI>30kg/m2). In conclusion, elevated plasma 1-deoxySL levels are strong and independent risk predictors of future T2DM, especially for non-obese individuals in the general population.


Increased NOS coupling by the metabolite tetrahydrobiopterin (BH4) reduces preeclampsia/IUGR consequences.
Preeclampsia (PE) is a high-prevalence pregnancy disease characterized by placental insufficiency, gestational hypertension, and proteinuria. Overexpression of the A isoform of the STOX1 transcription factor (STOX1A) recapitulates PE in mice, and STOX1A overexpressing trophoblasts recapitulate PE patients hallmarks in terms of gene expression and pathophysiology. STOX1 overexpression induces nitroso-redox imbalance and mitochondrial hyper-activation. Here, by a thorough analysis on cell models, we show that STOX1 overexpression in trophoblasts alters inducible nitric oxide synthase (iNOS), nitric oxide (NO) content, the nitroso-redox balance, the antioxidant defense, and mitochondrial function. This is accompanied by specific alterations of the Krebs cycle leading to reduced l-malate content. By increasing NOS coupling using the metabolite tetrahydrobiopterin (BH4) we restore this multi-step pathway in vitro. Moving in vivo on two different rodent models (STOX1 mice and RUPP rats, alike early onset and late onset preeclampsia, respectively), we show by transcriptomics that BH4 directly reverts STOX1-deregulated gene expression including glutathione metabolism, oxidative phosphorylation, cholesterol metabolism, inflammation, lipoprotein metabolism and platelet activation, successfully treating placental hypotrophy, gestational hypertension, proteinuria and heart hypertrophy. In the RUPP rats we show that the major fetal issue of preeclampsia, Intra Uterine Growth Restriction (IUGR), is efficiently corrected. Our work posits on solid bases BH4 as a novel potential therapy for preeclampsia.


Discovery of anion-π interactions in the recognition mechanism of inorganic anions by 1,2,3-triazolium rings.
A bis(triazolium)-based receptor designed for anion recognition is presented. NMR spectroscopic data indicate that one triazolium ring is acting as a hydrogen bond donor, whereas the second triazolium ring behaves as an anion-π receptor. The simultaneous presence of two noncovalent interactions allows us to achieve a highly selective binding of the hydrogenpyrophosphate anion.


Decisional pathways in breast augmentation: how to improve outcomes through accurate pre-operative planning.
Breast augmentation is the most commonly performed surgical procedure in aesthetic plastic surgery. Accurate pre-operative planning is crucial to obtain the best outcomes. We present our planning method deriving from a more than 30-year experience in aesthetic breast surgery, matching together patients tissues' characteristics and patients' wishes. We schematized our planning method in an easy-to-use flow diagram to help the decisional process in breast augmentation.


Three-Dimensional Networked Nanoporous Ta2O(5-x) Memory System for Ultrahigh Density Storage.
Oxide-based resistive memory systems have high near-term promise for use in nonvolatile memory. Here we introduce a memory system employing a three-dimensional (3D) networked nanoporous (NP) Ta2O5-x structure and graphene for ultrahigh density storage. The devices exhibit a self-embedded highly nonlinear I-V switching behavior with an extremely low leakage current (on the order of pA) and good endurance. Calculations indicated that this memory architecture could be scaled up to a ∼162 Gbit crossbar array without the need for selectors or diodes normally used in crossbar arrays. In addition, we demonstrate that the voltage point for a minimum current is systematically controlled by the applied set voltage, thereby offering a broad range of switching characteristics. The potential switching mechanism is suggested based upon the transformation from Schottky to Ohmic-like contacts, and vice versa, depending on the movement of oxygen vacancies at the interfaces induced by the voltage polarity, and the formation of oxygen ions in the pores by the electric field.


Livebirth after uterus transplantation from a deceased donor in a recipient with uterine infertility.
Uterus transplantation from live donors became a reality to treat infertility following a successful Swedish 2014 series, inspiring uterus transplantation centres and programmes worldwide. However, no case of livebirth via deceased donor uterus has, to our knowledge, been successfully achieved, raising doubts about its feasibility and viability, including whether the womb remains viable after prolonged ischaemia. In September, 2016, a 32-year-old woman with congenital uterine absence (Mayer-Rokitansky-Küster-Hauser [MRKH] syndrome) underwent uterine transplantation in Hospital das Clínicas, University of São Paulo, Brazil, from a donor who died of subarachnoid haemorrhage. The donor was 45 years old and had three previous vaginal deliveries. The recipient had one in-vitro fertilisation cycle 4 months before transplant, which yielded eight cryopreserved blastocysts. The recipient showed satisfactory postoperative recovery and was discharged after 8 days' observation in hospital. Immunosuppression was induced with prednisolone and thymoglobulin and continued via tacrolimus and mycophenalate mofetil (MMF), until 5 months post-transplantation, at which time azathioprine replaced MMF. First menstruation occurred 37 days post-transplantation, and regularly (every 26-32 days) thereafter. Pregnancy occurred after the first single embryo transfer 7 months post-transplantation. No blood flow velocity waveform abnormalities were detected by Doppler ultrasound of uterine arteries, fetal umbilical, or middle cerebral arteries, nor any fetal growth impairments during pregnancy. No rejection episodes occurred after transplantation or during gestation. Caesarean delivery occurred on Dec 15, 2017, near gestational week 36. The female baby weighed 2550 g at birth, appropriate for gestational age, with Apgar scores of 9 at 1 min, 10 at 5 min, and 10 at 10 min, and along with the mother remains healthy and developing normally 7 months post partum. The uterus was removed in the same surgical procedure as the livebirth and immunosuppressive therapy was suspended. We describe, to our knowledge, the first case worldwide of livebirth following uterine transplantation from a deceased donor in a patient with MRKH syndrome. The results establish proof-of-concept for treating uterine infertility by transplantation from a deceased donor, opening a path to healthy pregnancy for all women with uterine factor infertility, without need of living donors or live donor surgery. Fundação de Amparo à Pesquisa do Estado de São Paulo and Hospital das Clínicas, University of São Paulo, Brazil.


Single administration of GDNF into the striatum induced protection and repair of the nigrostriatal dopaminergic system in the intrastriatal 6-hydroxydopamine injection model of hemiparkinsonism.
Purpose: Neurotrophic factor delivery into the brain is a promising approach in the treatment of Parkinson's disease. Glial cell line-derived neurotrophic factor (GDNF) is one of the most potent neurotrophic factors for dopaminergic neurons. Although multiple injections of GDNF into the brain are commonly performed in experimental studies, the present study investigates the efficacy of using a single injection of GDNF, which may be useful in elinically applying this treatment. Methods: Unilateral 6-hydroxydoparnine (6-OHDA) administration into the striatum was perforrned in Sprague-Dawley rats to create a partial lesion of the nigrostriatal DA system. These parkinsonian model rats received a single injection of human recombinant GDNF into the same portion of the striatum either 24 h before or 4 weeks after 6-OHDA treatrnent. Results: GDNF injected into the striatum before 6-OHDA administration potently protected the dopaminergic system, as shown by the numbers of mesencephalic dopaminergie neuron cell bodies and dopaminergic nerve terminal densities in the striatum. Dopaminergic neuron cell bodies and fiber densities were also significantly restored when GDNF was given after 6-OHDA administration, although the degree of restoration was lower than in the protective experiment. ODNF administration ameliorated apomorphine-induced rotational behavior in animals receiving it either before or after 6-OHDA treatment. However, the degree of improvement was less prominent when GDNF was iniected after 6-OHDA. Conclusion: Intracerebral GDNF adininistration exerts both protective and regenerative effects on the nigrostriatal dopaminergic system, a finding which may have implications for the development of new treatment strategies for Parkinson's disease.


Visible Light-Driven Artificial Molecular Switch Actuated by Radical-Radical and Donor-Acceptor Interactions.
We describe a visible light-driven switchable [2]catenane, composed of a Ru(bpy)3(2+) tethered cyclobis(paraquat-p-phenylene) (CBPQT(4+)) ring that is interlocked mechanically with a macrocyclic polyether consisting of electron-rich 1,5-dioxynaphthalene (DNP) and electron-deficient 4,4'-bipyridinium (BIPY(2+)) units. In the oxidized state, the CBPQT(4+) ring encircles the DNP recognition site as a consequence of favorable donor-acceptor interactions. In the presence of an excess of triethanolamine (TEOA), visible light irradiation reduces the BIPY(2+) units to BIPY((•+)) radical cations under the influence of the photosensitizer Ru(bpy)3(2+), resulting in the movement of the CBPQT(2(•+)) ring from the DNP to the BIPY((•+)) recognition site as a consequence of the formation of the more energetically favorable trisradical complex, BIPY((•+)) ⊂ CBPQT(2(•+)). Upon introducing O2 in the dark, the BIPY((•+)) radical cations are oxidized back to BIPY(2+) dications, leading to the reinstatement of the CBPQT(4+) ring encircled around the DNP recognition site. Employing this strategy of redox control, we have demonstrated a prototypical molecular switch that can be manipulated photochemically and chemically by sequential reduction and oxidation.


In the absence of its cytosolic domain, the CD28 molecule still contributes to T cell activation.
The CD28 costimulatory receptor has a pivotal role in T cell biology as this molecule amplifies T cell receptor (TCR) signals to provide an efficient immune T cell response. There is a large debate about how CD28 mediates these signals. Here, we designed a CD28 gene-targeted knock-in mouse strain lacking the cytoplasmic tail of CD28. As is the case in CD28-deficient (CD28 knock-out) mice, regulatory T cell homeostasis and T cell activation are altered in these CD28 knock-in mice. Unexpectedly, the presence of a CD28 molecule deprived of its cytoplasmic tail could partially induce some early activation events in T cells such as signaling events or expression of early activation markers. These results unravel a new mechanism of T cell costimulation by CD28, independent of its cytoplasmic tail.


Driving Simulator Training Is Associated with Reduced Inhibitory Workload in Older Drivers.
In demanding cognitive tasks, older people mostly experience more problems than younger people, and their brain workload is higher. An overloaded or exhausted mental workload is frequently associated with unsafe driving behavior. In this paper, we hypothesize that 10 active training sessions in a driving simulator positively influence brain workload, which relates to a beneficial increase in on-road driving performance. Ninety-one healthy active drivers (62⁻87 years) were randomly assigned to: (a) a driving simulator-training group; (b) an attention-training group; or (c) a control group. The dependent variables of this training study were brain workload (theta Fz/alpha Pz), and performance in three tasks, for which inhibition of inadequate responses (Stroop, Negative Priming, and Flanker) is required. Seventy-seven participants (85% of the total sample) completed the training. Training gains were analyzed by using a multiple regression analysis with planned comparisons. The results revealed that the driving simulator training reduced brain workload during performance of the inhibition tasks. The performance of the simulator group during the inhibition tasks did not improve, but the participants completed the tasks with less brain workload compared to the attention-training group. Adding to our first paper on the Drive-Wise project, this paper now focuses on the superiority of the driving simulator training, compared to attention-training in regards to reducing brain workload. The change in brain workload seems to be associated with a positive change in drivers' behavior on the road. Hence, a driving simulator training lasting only ten sessions leads to beneficial neuroplastic changes. This demonstrates brain plasticity of older people and its possible positive influence in real driving behavior.


Tight junction proteins at the blood-brain barrier: far more than claudin-5.
At the blood-brain barrier (BBB), claudin (Cldn)-5 is thought to be the dominant tight junction (TJ) protein, with minor contributions from Cldn3 and -12, and occludin. However, the BBB appears ultrastructurally normal in Cldn5 knock-out mice, suggesting that further Cldns and/or TJ-associated marvel proteins (TAMPs) are involved. Microdissected human and murine brain capillaries, quickly frozen to recapitulate the in vivo situation, showed high transcript expression of Cldn5, -11, -12, and -25, and occludin, but also abundant levels of Cldn1 and -27 in man. Protein levels were quantified by a novel epitope dilution assay and confirmed the respective mRNA data. In contrast to the in vivo situation, Cldn5 dominates BBB expression in vitro, since all other TJ proteins are at comparably low levels or are not expressed. Cldn11 was highly abundant in vivo and contributed to paracellular tightness by homophilic oligomerization, but almost disappeared in vitro. Cldn25, also found at high levels, neither tightened the paracellular barrier nor interconnected opposing cells, but contributed to proper TJ strand morphology. Pathological conditions (in vivo ischemia and in vitro hypoxia) down-regulated Cldn1, -3, and -12, and occludin in cerebral capillaries, which was paralleled by up-regulation of Cldn5 after middle cerebral artery occlusion in rats. Cldn1 expression increased after Cldn5 knock-down. In conclusion, this complete Cldn/TAMP profile demonstrates the presence of up to a dozen TJ proteins in brain capillaries. Mouse and human share a similar and complex TJ profile in vivo, but this complexity is widely lost under in vitro conditions.


HIV treatment as prevention: optimising the impact of expanded HIV treatment programmes.
Until now, decisions about how to allocate ART have largely been based on maximising the therapeutic benefit of ART for patients. Since the results of the HPTN 052 study showed efficacy of antiretroviral therapy (ART) in preventing HIV transmission, there has been increased interest in the benefits of ART not only as treatment, but also in prevention. Resources for expanding ART in the short term may be limited, so the question is how to generate the most prevention benefit from realistic potential increases in the availability of ART. Although not a formal systematic review, here we review different ways in which access to ART could be expanded by prioritising access to particular groups based on clinical or behavioural factors. For each group we consider (i) the clinical and epidemiological benefits, (ii) the potential feasibility, acceptability, and equity, and (iii) the affordability and cost-effectiveness of prioritising ART access for that group. In re-evaluating the allocation of ART in light of the new data about ART preventing transmission, the goal should be to create policies that maximise epidemiological and clinical benefit while still being feasible, affordable, acceptable, and equitable.


Cell adhesion of Shewanella oneidensis to iron oxide minerals: Effect of different single crystal faces.
The results of experiments designed to test the hypothesis that near-surface molecular structure of iron oxide minerals influences adhesion of dissimilatory iron reducing bacteria are presented. These experiments involved the measurement, using atomic force microscopy, of interaction forces generated between Shewanella oneidensis MR-1 cells and single crystal growth faces of iron oxide minerals. Significantly different adhesive force was measured between cells and the (001) face of hematite, and the (100) and (111) faces of magnetite. A role for electrostatic interactions is apparent. The trend in relative forces of adhesion generated at the mineral surfaces is in agreement with predicted ferric site densities published previously. These results suggest that near-surface structure does indeed influence initial cell attachment to iron oxide surfaces; whether this is mediated via specific cell surface-mineral surface interactions or by more general interfacial phenomena remains untested.


Reappraisal of the relationship between the HIV-1-protective single-nucleotide polymorphism 35 kilobases upstream of the HLA-C gene and surface HLA-C expression.
Previous studies have found an association between a single-nucleotide polymorphism 35 kb upstream of the HLA-C locus (-35 SNP), HLA-C expression, and HIV-1 set point viral loads. We show that the difference in HLA-C expression across -35 SNP genotypes can be attributed primarily to the very low expression of a single allelic product, HLA-Cw7, which is a common HLA type. We suggest that association of the -35 SNP and HIV-1 load manifests as a result of linkage disequilibrium of this polymorphism with both favorable and unfavorable HLA-C and -B alleles.


Fundamental rate-loss tradeoff for optical quantum key distribution.
Since 1984, various optical quantum key distribution (QKD) protocols have been proposed and examined. In all of them, the rate of secret key generation decays exponentially with distance. A natural and fundamental question is then whether there are yet-to-be discovered optical QKD protocols (without quantum repeaters) that could circumvent this rate-distance tradeoff. This paper provides a major step towards answering this question. Here we show that the secret key agreement capacity of a lossy and noisy optical channel assisted by unlimited two-way public classical communication is limited by an upper bound that is solely a function of the channel loss, regardless of how much optical power the protocol may use. Our result has major implications for understanding the secret key agreement capacity of optical channels-a long-standing open problem in optical quantum information theory-and strongly suggests a real need for quantum repeaters to perform QKD at high rates over long distances.


Arboreal Folivores Limit Their Energetic Output, All the Way to Slothfulness.
By exploiting unutilized resources, organisms expand into novel niches, which can lead to adaptive radiation. However, some groups fail to diversify despite the apparent opportunity to do so. Although arising multiple times, arboreal folivores are rare and have not radiated, presumably because of energetic constraints. To explore this hypothesis, we quantified the field metabolic rate (FMR), movement, and body temperature for syntopic two- and three-toed sloths, extreme arboreal folivores that differ in their degree of specialization. Both species expended little energy, but three-toed sloths (162 kJ/day*kg(0.734)) possessed the lowest FMR recorded for any mammal. Three-toed sloths were more heterothermic and moved less than two-toed sloths. We then compared FMRs and basal metabolic rates (BMRs) for 19 species of arboreal folivores along a spectrum of specialization. Overall, arboreal folivores had lower BMRs and FMRs than other mammals, and increasing specialization led to lower FMRs but not BMRs. Thus, reduced energetic expenditure in specialized species was the result of thermoregulatory and behavioral strategies, rather than simply a proportionate reduction in BMR. Altogether, our findings support the concept that arboreal folivores are tightly constrained by nutritional energetics and help to explain the lack of radiation among species exploiting a lifestyle in the trees.


Modifications of citric acid cycle activity and gluconeogenesis in streptozotocin-induced diabetes and effects of metformin.
To better define the modifications of liver gluconeogenesis and citric acid cycle, or Krebs' cycle, activity induced by insulin deficiency and the effects of metformin on these abnormalities, we infused livers isolated from postabsorptive or starved normal and streptozotocin-induced diabetic rats with pyruvate and lactate (labeled with [3-13C]lactate) with or without the simultaneous infusion of metformin. Lactate and pyruvate uptake and glucose production were calculated. The 13C-labeling pattern of liver glutamate was used to calculate, according to Magnusson's model, the relative fluxes through Krebs' cycle and gluconeogenesis. These relative fluxes were converted into absolute values using substrate balances. In normal rats, starvation increased gluconeogenesis, the flux through pyruvate carboxylase-phosphoenolpyruvate carboxykinase (PC-PEPCK), and the ratio of PC to pyruvate dehydrogenase (PDH) flux (P < 0.05); metformin induced only a moderate decrease in the PC:PDH ratio. Livers from postabsorptive diabetic rats had increased lactate and pyruvate uptakes (P < 0.05); their metabolic fluxes resembled those of starved control livers, with increased gluconeogenesis and flux through PC-PEPCK. Starvation induced no further modifications in the diabetic group. Metformin decreased glucose output from the liver of starved diabetic rats (P < 0.05). The flux through PC-PEPCK and also pyruvate kinase were decreased (P < 0.05) by metformin in both groups of diabetic rats. In conclusion, insulin deficiency increased in this model of diabetes gluconeogenesis through enhanced uptake of substrate and increased flux through PC-PEPCK; metformin decreased glucose production by reducing the flux through PC-PEPCK.


Pornography and attitudes supporting violence against women: revisiting the relationship in nonexperimental studies.
A meta-analysis was conducted to determine whether nonexperimental studies revealed an association between men's pornography consumption and their attitudes supporting violence against women. The meta-analysis corrected problems with a previously published meta-analysis and added more recent findings. In contrast to the earlier meta-analysis, the current results showed an overall significant positive association between pornography use and attitudes supporting violence against women in nonexperimental studies. In addition, such attitudes were found to correlate significantly higher with the use of sexually violent pornography than with the use of nonviolent pornography, although the latter relationship was also found to be significant. The study resolves what appeared to be a troubling discordance in the literature on pornography and aggressive attitudes by showing that the conclusions from nonexperimental studies in the area are in fact fully consistent with those of their counterpart experimental studies. This finding has important implications for the overall literature on pornography and aggression.


Highlights of the 16th St Gallen International Breast Cancer Conference, Vienna, Austria, 20-23 March 2019: personalised treatments for patients with early breast cancer.
The 16th St Gallen International Breast Cancer Conference took place in Vienna for the third time, from 20-23 March 2019. More than 3000 people from all over the world were invited to take part in this important bi-annual critical review of the 'state of the art' in the primary care of breast cancer (BC), independent of political and industrial pressure, with the aim to integrate the most recent research data and most important developments in BC therapies since St Gallen International Breast Cancer Conference 2017, with the ultimate goal of drawing up a consensus for the current optimal treatment and prevention of BC. This year, the St Gallen Breast Cancer Award was won by Monica Morrow (Memorial Sloan Kettering Cancer Center, USA) for her extraordinary contribution in research and practise development in the treatment of BC. She opened the session with the lecture 'Will surgery be a part of BC treatment in the future?' Improved systemic therapy has decreased BC mortality and increased pathologic complete response (pCR) rates after neoadjuvant chemotherapy (NACT). Improved imaging and increased screening uptake have led to detect smaller cancers. These factors have highlighted two possible scenarios to omit surgery: for patients with small low-grade ductal carcinoma in situ (DCIS) and for those who have received NACT and had a clinical and radiological complete response. However, considering that 7%-20% of `low-risk' DCIS patients have co-existing invasive cancer at diagnosis, that surgery has become progressively less morbid and less toxic than some systemic therapies with a lower cost-effectiveness ratio, and that identification of pathologic complete response (pCR) without surgery requires more intensive imaging follow-up (more biopsies, higher cost and more anxiety for the patient), surgery still appears to be an essential treatment for BC. The Umberto Veronesi Memorial Award went to Lesley Fallowfield (Brighton and Sussex Medical School, UK) for her important research and activity in the field of the development of patient outcome, of better communication skills and quality of life for women. In her lecture, she remarked on the importance of improving BC personalised treatments, especially through co-operation between scientists, always considering the whole woman and not just her breast disease. This award was given by Paolo Veronesi, after a moving introduction which culminated with the following words of Professor Umberto Veronesi: 'It is not possible to take care of the people's bodies without taking care of their mind. My duty, the duty of all doctors, is to listen and be part of the emotions of those we treat every day'.


Cortical surface shape analysis based on spherical wavelets.
In vivo quantification of neuroanatomical shape variations is possible due to recent advances in medical imaging and has proven useful in the study of neuropathology and neurodevelopment. In this paper, we apply a spherical wavelet transformation to extract shape features of cortical surfaces reconstructed from magnetic resonance images (MRIs) of a set of subjects. The spherical wavelet transformation can characterize the underlying functions in a local fashion in both space and frequency, in contrast to spherical harmonics that have a global basis set. We perform principal component analysis (PCA) on these wavelet shape features to study patterns of shape variation within normal population from coarse to fine resolution. In addition, we study the development of cortical folding in newborns using the Gompertz model in the wavelet domain, which allows us to characterize the order of development of large-scale and finer folding patterns independently. Given a limited amount of training data, we use a regularization framework to estimate the parameters of the Gompertz model to improve the prediction performance on new data. We develop an efficient method to estimate this regularized Gompertz model based on the Broyden-Fletcher-Goldfarb-Shannon (BFGS) approximation. Promising results are presented using both PCA and the folding development model in the wavelet domain. The cortical folding development model provides quantitative anatomic information regarding macroscopic cortical folding development and may be of potential use as a biomarker for early diagnosis of neurologic deficits in newborns.


Preparation and characterization of PSF/PEI/CaCO3 nanocomposite membranes for oil/water separation.
Ultrafiltration (UF) is one of the significant advanced processes for oily wastewater treatment due to its clear advantages, for instance, ease in operation and efficient separation. The main drawback of these processes is the fouling problem and many researchers' effort on fabrication of high-performance membranes with higher hydrophilicity and antifouling properties. In this study, flat-sheet polysulfone (PSF)/polyethylenimine (PEI)/CaCO3 nanocomposite membranes were prepared by phase inversion method for oil/water emulsion separation. Structural properties of membranes were characterized by SEM, FT-IR, contact angle, tensile strength, and atomic force microscopy analysis. Increasing the CaCO3 nanoparticle loading exhibited the increased the water flux and BSA rejection. PSF/PEI/10 wt% CaCO3 nanocomposite membranes have 145 L/m2 h water flux at 2 bar with a contact angle of 84° and with 92% BSA rejection. All prepared CaCO3 nanocomposite membranes reached similar oil rejections at above 90%. Besides the higher water flux and oil removal efficiencies, 10 wt% of CaCO3 nanoparticle-blended PSF membranes has notable antifouling capacity with the highest flux recovery ratio (FRR) and lowest flux decay ratio (DR) values. The results showed that there is a great potential to use PSF/PEI/CaCO3 nanocomposite membranes for the treatment of oil water emulsions with higher permeability and antifouling capacity.


Bayesian prospective detection of small area health anomalies using Kullback-Leibler divergence.
Early detection of unusual health events depends on the ability to rapidly detect any substantial changes in disease, thus facilitating timely public health interventions. To assist public health practitioners to make decisions, statistical methods are adopted to assess unusual events in real time. We introduce a surveillance Kullback-Leibler measure for timely detection of disease outbreaks for small area health data. The detection methods are compared with the surveillance conditional predictive ordinate within the framework of Bayesian hierarchical Poisson modeling and applied to a case study of a group of respiratory system diseases observed weekly in South Carolina counties. Properties of the proposed surveillance techniques including timeliness and detection precision are investigated using a simulation study.


Pre-target activity in visual cortex predicts behavioral performance on spatial and feature attention tasks.
Physiological studies in humans and monkeys have revealed that, in response to an instruction to attend, areas of sensory cortex that code the attributes of the expected stimulus exhibit increases in neural activity prior to the arrival of the stimulus. Models of selective visual attention posit that these increases in activity give attended stimuli a processing advantage over distracting stimuli. Here, we test two key predictions of this view by using functional magnetic resonance imaging to record human brain activity during a cued voluntary orienting task. First, we tested whether pre-stimulus modulations are observed during both cued spatial and cued feature attention. Secondly, we tested whether the magnitude of pre-stimulus modulations predicts behavioral performance. Our results indicate that cue-triggered expectation of targets with particular spatial or nonspatial features activates areas of the visual cortex selective for these features. Furthermore, the magnitude of the cue-triggered modulations correlated with behavioral measures, such that those subjects who exhibited relatively large pre-stimulus modulations of activity performed better on the behavioral task. These findings support the view that top-down control systems bias activity in sensory cortices to favor the processing of expected target features and that this bias is related to behavior.


Does use of the adjuvant! model influence use of adjuvant therapy through better risk communication?
Adjuvant! is a model that provides recurrence and mortality risk predictions for patients with breast cancer considering adjuvant therapies. Although low-risk patients who saw Adjuvant! chose adjuvant therapy less frequently, whether this was because of educational or other aspects of the decision aid is unknown. The authors explored whether Adjuvant! affects choice of therapy through increased patient knowledge. A subset of data were analyzed from a cluster randomized trial in which oncology practices in 2 major United States cities were randomly assigned to use either Adjuvant! or an informational pamphlet to educate patients. Of 405 patients, 48 were low-risk, with 28 assigned to the decision aid and 20 to the pamphlet. Among the low-risk patients, using frequency tables and Fisher exact tests, the authors explored whether Adjuvant! was associated with more accurate patient estimates of survival; whether accuracy was associated with treatment choice; and whether, after controlling for accuracy, any remaining association was seen between Adjuvant! and treatment choice. Adjuvant! was associated with more accurate estimates of baseline prognosis compared with the pamphlet (57% vs. 25%; P = .04). Patients who had more accurate estimates of baseline prognosis were less likely to choose adjuvant therapy (62% vs. 89%; P = .04). After controlling for accuracy, no statistically significant association was found between the use of Adjuvant! and adjuvant therapy (P = .59 and P = .11 for inaccurate and accurate patients, respectively). Adjuvant! seems to influence patient choice through educational rather than other means of persuasion. However, many patients held inaccurate risk perceptions after viewing Adjuvant!.


Multiwavelength fiber laser using a spatial mode beating filter.
A multiwavelength comb is obtained from Er(3+) - and Nd(3+)-doped fiber lasers by incorporation of a section of multimode optical fiber into an otherwise single-mode fiber ring cavity. This combination of fiber types acts as a wavelength-dependent filter in the laser through spatial mode beating between the LP(01) and LP(11) modes in the multimode fiber.


Investigations into within- and between-subject resting-state amplitude variations.
The amplitudes of spontaneous fluctuations in brain activity may be a significant source of within-subject and between-subject variability, and this variability is likely to be carried through into functional connectivity (FC) estimates (whether directly or indirectly). Therefore, improving our understanding of amplitude fluctuations over the course of a resting state scan and variation in amplitude across individuals is of great relevance to the interpretation of FC findings. We investigate resting state amplitudes in two large-scale studies (HCP and UK Biobank), with the aim of determining between-subject and within-subject variability. Between-subject clustering distinguished between two groups of brain networks whose amplitude variation across subjects were highly correlated with each other, revealing a clear distinction between primary sensory and motor regions ('primary sensory/motor cluster') and cognitive networks. Within subjects, all networks in the primary sensory/motor cluster showed a consistent increase in amplitudes from the start to the end of the scan. In addition to the strong increases in primary sensory/motor amplitude, a large number of changes in FC were found when comparing the two scans acquired on the same day (HCP data). Additive signal change analysis confirmed that all of the observed FC changes could be fully explained by changes in amplitude. Between-subject correlations in UK Biobank data showed a negative correlation between primary sensory/motor amplitude and average sleep duration, suggesting a role of arousal. Our findings additionally reveal complex relationships between amplitude and head motion. These results suggest that network amplitude is a source of significant variability both across subjects, and within subjects on a within-session timescale. Future rfMRI studies may benefit from obtaining arousal-related (self report) measures, and may wish to consider the influence of amplitude changes on measures of (dynamic) functional connectivity.


Effect of body mass index in patients undergoing resection for gastric cancer: a single center US experience.
With rising obesity in the USA, the impact of body mass index (BMI) on survival in gastric cancer remains unclear. An institutional database of patients undergoing surgical evaluation for gastric cancer was reviewed. Patients were stratified by the following BMI: <18.5, 18.5-25, 25.1-30, and >30. Clinicopathologic factors and overall survival (OS) were analyzed. From 1997 to 2012, 222 patients underwent exploration for gastric adenocarcinoma. 186 (84%) had BMI recorded: nine (5%) <18.5, 72 (39%) 18.5-25, 62 (33%) 25.1-30, and 43 (23%) >30. One hundred thirty-five (73%) ultimately underwent resection. Although American Society of Anesthesiology score and blood loss were not associated with increasing BMI, operative time was longer, p = 0.02. Proximal location, perineural invasion, lymphovascular invasion, positive surgical margins, and positive lymph nodes (LN+) were all associated with worse OS but not with increased BMI. Although increased BMI was associated with a lower lymph node count, p = 0.004, the number of LN + and final pathologic stage were not associated with BMI. Additionally, use of neoadjuvant or adjuvant chemotherapy was not associated with BMI. Median OS was 22 months. Median OS was improved with increased BMI: 21 months for <18.5, 13 months 18.5-25, 28 months 25-30, and 34 months >30, p = 0.02. Disease-free survival (DFS) was similar: 2 months for <18.5, 7 months 18.5-25, 15 months 25.1-30, and 15 months >30, p = 0.02. Although BMI may impact the technical difficulty of resection for gastric cancer, increasing BMI is not associated with more advanced disease. In this experience, increased BMI does not adversely impact OS or DFS.


Oestrogen blocks the nuclear entry of SOX9 in the developing gonad of a marsupial mammal.
Hormones are critical for early gonadal development in nonmammalian vertebrates, and oestrogen is required for normal ovarian development. In contrast, mammals determine sex by the presence or absence of the SRY gene, and hormones are not thought to play a role in early gonadal development. Despite an XY sex-determining system in marsupial mammals, exposure to oestrogen can override SRY and induce ovarian development of XY gonads if administered early enough. Here we assess the effect of exogenous oestrogen on the molecular pathways of mammalian gonadal development. We examined the expression of key testicular (SRY, SOX9, AMH and FGF9) and ovarian (WNT4, RSPO1, FOXL2 and FST) markers during gonadal development in the marsupial tammar wallaby (Macropus eugenii) and used these data to determine the effect of oestrogen exposure on gonadal fate. During normal development, we observed male specific upregulation of AMH and SOX9 as in the mouse and human testis, but this upregulation was initiated before the peak in SRY expression and 4 days before testicular cord formation. Similarly, key genes for ovarian development in mouse and human were also upregulated during ovarian differentiation in the tammar. In particular, there was early sexually dimorphic expression of FOXL2 and WNT4, suggesting that these genes are key regulators of ovarian development in all therian mammals. We next examined the effect of exogenous oestrogen on the development of the mammalian XY gonad. Despite the presence of SRY, exogenous oestrogen blocked the key male transcription factor SOX9 from entering the nuclei of male somatic cells, preventing activation of the testicular pathway and permitting upregulation of key female genes, resulting in ovarian development of the XY gonad. We have uncovered a mechanism by which oestrogen can regulate gonadal development through the nucleocytoplasmic shuttling of SOX9. This may represent an underlying ancestral mechanism by which oestrogen promotes ovarian development in the gonads of nonmammalian vertebrates. Furthermore, oestrogen may retain this function in adult female mammals to maintain granulosa cell fate in the differentiated ovary by suppressing nuclear translocation of the SOX9 protein. See commentary: http://www.biomedcentral.com/1741-7007/8/110.


Improving Interprofessional Consistency in Electronic Fetal Heart Rate Interpretation.
Objective To determine if mandatory online training in electronic fetal monitoring (EFM) improved agreement in documentation between obstetric care providers and nurses on labor and delivery. Methods Health care professionals working in obstetrics at our institution were required to complete a course on EFM interpretation. We performed a retrospective chart review of 701 charts including patients delivered before and after the introduction of the course to evaluate agreement among providers in their documentation of their interpretations of the EFM tracings. Results Agreement between provider and nurse documentation at the time of admission improved for variability and accelerations (variability: 91.1 vs. 98.3%, p < 0.001; and accelerations: 75.2 vs. 87.7%, p < 0.001). Similarly, agreement improved at the time of the last note prior to delivery for documentation of variability and accelerations (variability: 82.1 vs. 90.6%, p = 0.001; and accelerations: 56.7 vs. 68.6%, p = 0.0012). Agreement in interpretation of decelerations both at the time of admission and at the time of delivery increased (86.3 vs. 90.6%, p = 0.0787, and 56.7 vs. 61.1%, p = 0.2314, respectively) but was not significant. Conclusion An online EFM course can significantly improve consistency in multidisciplinary documentation of fetal heart rate tracing interpretation.


The temperature behavior and mechanism of exciton luminescence in quantum dots.
The processes of direct and indirect optical excitation of spatially confined excitons in quantum dots (QDs) embedded in a silica thin-film matrix have been reported and discussed. A generalized scheme for the electronic transitions is employed for a detailed description of luminescence temperature behavior using various excitation methods. This scheme considers three different models of exciton relaxation and substantiates the occupation of the triplet radiative states as a result of singlet-triplet intersystem crossing or excitation energy transfer from free excitons of the matrix. Analytical expressions describing five types of different temperature curves were derived. It is established that their shapes are exactly defined by the excitation mechanism and the parameters involved in the numerical model. The conditions allowing the estimation of the energy and kinetic characteristics of QD photoluminescence are formulated. We have shown that the confinement effect causes a decrease in the thermal activation barriers and frequency characteristics for non-radiative transitions. An application of the developed concepts allows predicting and estimating the temperature dependences for direct and indirect optically excited QD luminescence employing silicon nanoclusters in a silica thin-film matrix as an example.


Targeted Editing of the pp38 Gene in Marek's Disease Virus-Transformed Cell Lines Using CRISPR/Cas9 System.
Marek's disease virus (MDV), a lymphotropic α-herpesvirus associated with T-cell lymphomas in chickens, is an excellent model for herpesvirus biology and virus-induced oncogenesis. Marek's disease (MD) is also one of the cancers against which a vaccine was first used. In the lymphomas and lymphoblastoid cell lines (LCLs) derived from them, MDV establishes latent infection with limited gene expression. Although LCLs are valuable for interrogating viral and host gene functions, molecular determinants associated with the maintenance of MDV latency and lytic switch remain largely unknown, mainly due to the lack of tools for in situ manipulation of the genomes in these cell lines. Here we describe the first application of CRISPR/Cas9 editing approach for precise editing of the viral gene phosphoprotein 38 (pp38), a biomarker for latent/lytic switch in MDV-transformed LCLs MDCC-MSB-1 (Marek's disease cell line MSB-1) and MDCC-HP8. Contradictory to the previous reports suggesting that pp38 is involved in the maintenance of transformation of LCL MSB-1 cells, we show that pp38-deleted cells proliferated at a significant higher rate, suggesting that pp38 is dispensable for the transformed state of these cell lines. Application of CRISPR/Cas9-based gene editing of MDV-transformed cell lines in situ opens up further opportunities towards a better understanding of MDV pathogenesis and virus-host interactions.


Adaptation to fluctuating environments in a selection experiment with Drosophila melanogaster.
A fundamental question in life-history evolution is how organisms cope with fluctuating environments, including variation between stressful and benign conditions. For short-lived organisms, environments commonly vary between generations. Using a novel experimental design, we exposed wild-derived Drosophila melanogaster to three different selection regimes: one where generations alternated between starvation and benign conditions, and starvation was always preceded by early exposure to cold; another where starvation and benign conditions alternated in the same way, but cold shock sometimes preceded starvation and sometimes benign conditions; and a third where conditions were always benign. Using six replicate populations per selection regime, we found that selected flies increased their starvation resistance, most strongly for the regime where cold and starvation were reliably combined, and this occurred without decreased fecundity or extended developmental time. The selected flies became stress resistant, displayed a pronounced increase in early life food intake and resource storage. In contrast to previous experiments selecting for increased starvation resistance in D. melanogaster, we did not find increased storage of lipids as the main response, but instead that, in particular for females, storage of carbohydrates was more pronounced. We argue that faster mobilization of carbohydrates is advantageous in fluctuating environments and conclude that the phenotype that evolved in our experiment corresponds to a compromise between the requirements of stressful and benign environments.


IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs.
The series of events leading to tertiary lymphoid organ (TLO) formation in mucosal organs following tissue damage remain unclear. Using a virus-induced model of autoantibody formation in the salivary glands of adult mice, we demonstrate that IL-22 provides a mechanistic link between mucosal infection, B-cell recruitment, and humoral autoimmunity. IL-22 receptor engagement is necessary and sufficient to promote differential expression of chemokine (C-X-C motif) ligand 12 and chemokine (C-X-C motif) ligand 13 in epithelial and fibroblastic stromal cells that, in turn, is pivotal for B-cell recruitment and organization of the TLOs. Accordingly, genetic and therapeutic blockade of IL-22 impairs and reverses TLO formation and autoantibody production. Our work highlights a critical role for IL-22 in TLO-induced pathology and provides a rationale for the use of IL-22-blocking agents in B-cell-mediated autoimmune conditions.


Interdependence of CD3-Ti and CD2 activation pathways in human T lymphocytes.
Human T lymphocytes can be activated through either the antigen/MHC receptor complex T3-Ti (CD3-Ti) or the T11 (CD2) molecule to proliferate via an IL-2 dependent mechanism. To investigate the relationship of these pathways to one another, we generated and characterized Jurkat mutants which selectively express either surface CD3-Ti or CD2. Here we show that CD3-Ti- mutants fail to be stimulated by either pathway to increase phosphoinositide turnover, mobilize calcium or induce the IL-2 gene. The activation capacity of these mutants via CD2 as well as CD3-Ti can be restored following reconstitution of surface CD3-Ti expression upon appropriate DNA transfer (e.g. Ti beta subunit cDNA into Ti beta- Jurkat variants). Collectively, these results demonstrate that CD3-Ti and CD2 pathways are interdependent and that phosphoinositide turnover is linked to the CD3-Ti complex.


Controlled warm-up intensity enhances hip range of motion.
Acute effects of active and passive warm-up, proprioceptive neuromuscular facilitation (PNF), and ratings of perceived exertion (RPE) were compared during hip-joint range of motion (ROM). Two active warm-up treatments included (a) achieving a respiratory exchange ratio (RER) of 1.00 and (b) achieving 60% of heart rate reserve (HRR). Hydrocollator pads (HP) served as the passive warm-up treatment. These treatments and a control were randomly assigned to increase hamstring muscle temperature of the dominant leg. Warm-up treatments were administered to 12 men (mean 25.3 years) with a minimum of 24 hours interspersed between each treatment. A timed PNF (slow-reversal-hold) technique was conducted after each warm-up treatment. Tukey tests (p < 0.05) showed ROM for RER (107.4 degrees) was greater than all other treatments. ROM for HRR (102.8 degrees) and HP (103.4 degrees) did not differ from each other but were greater than the control (98.8 degrees). Ratings of perceived exertion were lowest for RER (4.0) and highest for control (8.5). Ratings of perceived exertion for HRR (6.0) and HP (6.5) were similar. In conclusion, an active warm-up before PNF stretching appears to be the most effective treatment to increase hip ROM. Results of RPE reinforce that active warm-up reduces the resistance to stretch. In a field setting, it is estimated that a warm-up of 70% of HRR would duplicate the muscle readiness equivalent to an RER of 1.00 before PNF stretching.


Determinants of serum concentrations of perfluoroalkyl acids (PFAAs) in school children and the contribution of low-level PFAA-contaminated drinking water.
Little is known about the demographic/life-style/physiological determinants explaining the variation of serum perfluoroalkyl acid (PFAA) concentrations in children. We identified significant determinants in children and investigated the influence of low-level PFAA-contaminated drinking water (DW) (<10 ng L-1 of single PFAAs) on serum concentrations. Four perfluorosulfonic acids (PFSAs) and 11 perfluorocarboxylic acids (PFCAs) were analyzed in serum from 5th grade children from 11 Swedish schools (N = 200; average age: 12 years) using liquid chromatography-tandem-mass-spectrometry. Data on demography and life-style/physiological factors were obtained by questionnaires. PFAA concentrations in raw and drinking water (DW) were obtained from the water works supplying DW to the schools. In multiple regression analyses school was the determinant contributing most to the variation in PFAA concentrations, with the lowest contribution for PFHpA (10%) and the highest for PFHxS (81%). Girls had lower adjusted mean concentrations of PFHxS, PFOS, PFNA and PFDA than boys, but a higher concentration of PFHxA. Girls reporting onset of menstruation had lower PFHxS and PFOA concentrations than other girls, suggesting menstrual bleeding elimination. Children born by mothers from less industrialized countries had lower mean concentrations of both PFSAs and PFCAs than children with mothers from highly industrialized countries, suggesting differences in early-life exposure. Life-style factors associated with paternal education levels appeared to influence PFAA concentrations differently than maternal education level. Already at an average DW PFHxS concentration of 2 ng L-1, children had a significantly higher adjusted mean serum PFHxS concentration than at an average DW concentration of <1.6 ng PFHxS L-1. Similar results were observed for PFOS and PFOA. The DW variable explained 16% (PFOA) to 78% (PFHxS) of the variation in serum PFAA concentrations, suggesting that low-level-contaminated DW is a significant source of exposure for children in Sweden. Although some of the associations, especially those with menstruation and maternal birth country, should be interpreted with extra caution due to the small size of the study, the results contribute to future work on identifying populations of children at risk of elevated PFAA exposures.


FDA Approval: Alectinib for the Treatment of Metastatic, ALK-Positive Non-Small Cell Lung Cancer Following Crizotinib.
On December 11, 2015, the FDA granted accelerated approval to alectinib (Alecensa; Genentech) for the treatment of patients with anaplastic lymphoma receptor tyrosine kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This approval was based on two single-arm trials including 225 patients treated with alectinib 600 mg orally twice daily. The objective response rates (ORR) by an independent review committee in these studies were 38% [95% confidence interval (CI), 28-49] and 44% (95% CI, 36-53); the median durations of response (DOR) were 7.5 months and 11.2 months. In a pooled analysis of 51 patients with measurable disease in the central nervous system (CNS) at baseline, the CNS ORR was 61% (95% CI, 46-74); the CNS DOR was 9.1 months. The primary safety analysis population included 253 patients. The most common adverse reactions were fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). The most common laboratory abnormalities were anemia (56%), increased aspartate aminotransferase (51%), increased alkaline phosphatase (47%), increased creatine phosphokinase (43%), hyperbilirubinemia (39%), hyperglycemia (36%), increased alanine aminotransferase (34%), and hypocalcemia (32%). Dose reductions due to adverse reactions occurred in 12% of patients, whereas 27% of patients had alectinib dosing interrupted for adverse reactions. Permanent discontinuation of alectinib due to adverse reactions occurred in only 6% of patients. With the clinically meaningful ORR and DOR as well as the safety profile observed in these trials, alectinib was determined to have a favorable benefit-risk profile for the treatment of the indicated population. Clin Cancer Res; 22(21); 5171-6. ©2016 AACR.


Isolation, cryotomography, and three-dimensional reconstruction of centrioles.
Centrioles and basal bodies (referred to hereafter as centrioles for simplicity) are microtubule-based cylindrical organelles that are typically ∼450-nm long and ∼250nm in diameter. The centriole is composed of three distinct regions: the distal part characterized by microtubule doublets, the central core that harbors microtubule triplets, which are also present in the proximal part that also contains the cartwheel, a structure crucial for centriole assembly. The cartwheel was initially revealed by conventional electron microscopy of resin-embedded samples and is thought to impart the near universal ninefold symmetry of centrioles. Deciphering the native architecture of the cartwheel has proven challenging owing to its small dimensions and the difficulties in isolating it. Here, we present a method to purify and analyze the structure of the exceptionally long Trichonympha centriole by cryotomography and subtomogram averaging. Using this method, we revealed the native architecture of the proximal cartwheel-containing region at ∼40Å-resolution. This method can be applied as a general strategy for uncovering the structure of centrioles in other species.


Drug release from glutaraldehyde-treated fibrin gels.
Glutaraldehyde treatment of dexamethasone-containing cylindrical fibrin gels (obtained by the thrombin-induced polymerization of fibrinogen in the presence of the drug) causes cross-linking of the gels and modification of the pore structure. The effect on the release of dexamethasone was assessed by measuring the diffusion coefficient of the drug across treated and untreated gels; diffusion across the treated gels was significantly decreased as compared with untreated gels, but was little affected by the concentration of glutaraldehyde used in the treatment. In biodegradable tests, the treated gels (all concentrations of glutaraldehyde) were resistant to digestion even in the presence of plasmin, but untreated gels were digested, and the digestion rate was accelerated by plasmin. The volume of the gels was progressively reduced as the concentration of glutaraldehyde was increased or the amount of fibrinogen was decreased, but the extent of the reduction did not correlate with the changes in the diffusion coefficient.


Treatment with supplementary arginine, vitamin C and zinc in patients with pressure ulcers: a randomised controlled trial.
Nutrients putatively implicated in pressure ulcer healing were evaluated in a clinical setting. Sixteen inpatients with a stage 2, 3 or 4 pressure ulcer randomised to receive daily a standard hospital diet; a standard diet plus two high-protein/energy supplements; or a standard diet plus two high-protein/energy supplements containing additional arginine (9 g), vitamin C (500 mg) and zinc (30 mg). Nutritional status measurements (dietary, anthropometric and biochemical) and pressure ulcer size and severity (by PUSH tool; Pressure Ulcer Scale for Healing; 0=completely healed, 17=greatest severity) were measured weekly for 3 weeks. Patients' age and BMI ranges were 37-92 years and 16.4-28.1 k g/m2) respectively. Baseline PUSH scores were similar between groups (8.7+/-0.5). Only patients receiving additional arginine, vitamin C and zinc demonstrated a clinically significant improvement in pressure ulcer healing (9.4+/-1.2 vs. 2.6+/-0.6; baseline and week 3, respectively; P<0.01). All patient groups presented with low serum albumin and zinc and elevated C-reactive protein. There were no significant changes in biochemical markers, oral dietary intake or weight in any group. In this small set of patients, supplementary arginine, vitamin C and zinc significantly improved the rate of pressure ulcer healing. The results need to be confirmed in a larger study.


Robust, directed assembly of fluorescent nanodiamonds.
Arrays of fluorescent nanoparticles are highly sought after for applications in sensing, nanophotonics and quantum communications. Here we present a simple and robust method of assembling fluorescent nanodiamonds into macroscopic arrays. Remarkably, the yield of this directed assembly process is greater than 90% and the assembled patterns withstand ultra-sonication for more than three hours. The assembly process is based on covalent bonding of carboxyl to amine functional carbon seeds and is applicable to any material, and to non-planar surfaces. Our results pave the way to directed assembly of sensors and nanophotonics devices.


High-intensity statins are associated with improved clinical activity of PD-1 inhibitors in malignant pleural mesothelioma and advanced non-small cell lung cancer patients.
In preclinical models, statins showed vaccine adjuvant activities and synergized with PD-1 inhibitors. We analyzed the impact of statin treatment on clinical outcome in thoracic cancer patients treated with PD-1 inhibitors. A total of 82 malignant pleural mesothelioma (MPM) and 179 advanced non-small cell lung cancer (aNSCLC) patients treated with PD-1 inhibitors as second or further line treatment were examined. Seventy-seven MPM patients treated with standard chemotherapy were analyzed as control cohort. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were calculated. Among 253 patients with available data, statin use was associated with increased ORR (32% versus 18%, P = .02), PFS (median 6.7 versus 2.9 months, hazard ratio [HR] 0.57, 95% CI 0.39-0.83, P < .01), and OS (median 13.1 versus 8.7 months, HR 0.67, 95% CI 0.45-1.00, P = .05). In the control MPM cohort treated with chemotherapy (n = 77), no association was found. MPM patients who used statins showed improved ORR (22% versus 6%, P = .05), PFS (median 6.7 versus 2.4 months, P < .01), and OS (median not reached versus 6.0 months, P = .01). In aNSCLC patients, statin use was associated with improved ORR (40% versus 22%, P = .04) and PFS (median 7.8 versus 3.6 months, P = .03), but no significant difference in OS was found (median 13.1 versus 10.1 months, P = .30). Multivariable analysis confirmed the correlation between statin use and better PFS and OS in MPM and better PFS in aNSCLC. In the whole cohort, high but not low/moderate-intensity statins were associated with better OS compared to no user (P = .02 and P = .59, respectively). Our study showed that statins are associated with better clinical outcome in MPM and aNSCLC patients treated with PD-1 inhibitors in an intensity-dependent manner.


Survival of small populations under demographic stochasticity.
We estimate the mean time to extinction of small populations in an environment with constant carrying capacity but under stochastic demography. In particular, we investigate the interaction of stochastic variation in fecundity and sex ratio under several different schemes of density dependent population growth regimes. The methods used include Markov chain theory, Monte Carlo simulations, and numerical simulations based on Markov chain theory. We find a strongly enhanced extinction risk if stochasticity in sex ratio and fluctuating population size act simultaneously as compared to the case where each mechanism acts alone. The distribution of extinction times deviates slightly from a geometric one, in particular for short extinction times. We also find that whether maximization of intrinsic growth rate decreases the risk of extinction or not depends strongly on the population regulation mechanism. If the population growth regime reduces populations above the carrying capacity to a size below the carrying capacity for large r (overshooting) then the extinction risk increases if the growth rate deviates from an optimal r-value.


Childhood adversity, adult stressful life events, and risk of past-year psychiatric disorder: a test of the stress sensitization hypothesis in a population-based sample of adults.
Childhood adversity (CA) is associated with adult mental disorders, but the mechanisms underlying this association remain inadequately understood. Stress sensitization, whereby CA increases vulnerability to mental disorders following adult stressful life events, has been proposed as a potential mechanism. We provide a test of the stress sensitization hypothesis in a national sample. We investigated whether the association between past-year stressful life events and the 12-month prevalence of major depression, post-traumatic stress disorder (PTSD), other anxiety disorders, and perceived stress varies according to exposure to CA. We used data from the National Epidemiological Survey of Alcohol and Related Conditions (NESARC) (n=34 653). Past-year stressful life events were associated with an increased risk of major depression, PTSD, anxiety disorders, and perceived stress. However, the magnitude of the increased risk varied according to respondents' history of CA. For example, past-year major stressors were associated with a 27.3% increase in the 12-month risk of depression among individuals with 3 CAs and a 14.8% increased risk among individuals without CAs. Stress sensitization effects were present for depression, PTSD, and other anxiety disorders in women and men, although gender differences were found in the threshold of past-year stress needed to trigger such effects. Stress sensitization was most evident among individuals with 3 CAs. CA is associated with increased vulnerability to the deleterious mental health effects of adult stressors in both men and women. High levels of CA may represent a general diathesis for multiple types of psychopathology that persists throughout the life course.


Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression.
Using a forward genetics ENU mutagenesis screen for recessive mutations that affect circadian rhythmicity in the mouse, we isolated a long period (approximately 26 hr) circadian mutant named Overtime (Ovtm). Positional cloning and genetic complementation reveal that Ovtm is encoded by the F-box protein FBXL3, a component of the SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligase complex. The Ovtm mutation causes an isoleucine to threonine (I364T) substitution leading to a loss of function in FBXL3, which interacts specifically with the CRYPTOCHROME (CRY) proteins. In Ovtm mice, expression of the PERIOD proteins PER1 and PER2 is reduced; however, the CRY proteins CRY1 and CRY2 are unchanged. The loss of FBXL3 function leads to a stabilization of the CRY proteins, which in turn leads to a global transcriptional repression of the Per and Cry genes. Thus, Fbxl3(Ovtm) defines a molecular link between CRY turnover and CLOCK/BMAL1-dependent circadian transcription to modulate circadian period.


High crystallization of a multiple cation perovskite absorber for low-temperature stable ZnO solar cells with high-efficiency of over 20.
ZnO as a promising electron transport layer (ETL) to TiO2 for perovskite solar cells (PSCs) has achieved a power conversion efficiency (PCE) of 18.9%; however, this is still lower than that obtained for TiO2-based PSCs (higher than 20%). Herein, we report the fabrication of high-efficiency methylammonium (MA) and Cs co-alloyed formamidinium (FA) triple cation perovskite based ZnO PSCs via delicate control of the cation compositions and annealing temperatures. By virtue of structural, morphological, spectral and electrochemical characterizations and analysis, we found that the incorporation of MA and Cs into FA perovskite enables the formation of a highly crystalline black phase perovskite with reduced surface roughness, which inhibits charge recombination and promotes electron transfer at the ZnO/perovskite/spiro-OMeTAD interfaces and hence improves Jsc and FF values of the cell. As a result, the ZnO PSC based on MA0.1FA0.75Cs0.15PbI3 annealed at 110 °C achieved a PCE as high as 20.09%, exceeding the previous highest efficiency recorded for ZnO ETL based PSCs. The optimized MA0.1FA0.75Cs0.15PbI3 material demonstrated excellent reproducibility and long-term cell durability under ambient conditions within 1000 h. Particularly, the incorporation of a small amount of Br into the triple cation perovskite, i.e., MA0.1FA0.75Cs0.15PbI2.9Br0.1 led to a further enhancement in PCE of up to 20.44%, which is comparable with the best-performing MA and Cs-containing FA-based lead halide TiO2 PSCs.


The clinicopathological impact of gross classification on solitary small hepatocellular carcinoma.
The aim of this retrospective study was to determine the effect of gross classification on the outcome of hepatic resection for small solitary hepatocellular carcinoma (HCC). This study consisted of 179 consecutive primary HCC patients who were not preoperatively diagnosed with vascular invasion or intrahepatic metastasis. The clinicopathological impact of gross classification was compared. Patients were classified into four groups, vaguely nodular (VN) type, single nodular (SN) type, single nodular type with extranodular growth (SNEG), and confluent multinodular (CMN) type, according to the gross classification of resected specimens. The SNEG and CMN types showed a significantly higher rate of MVI and intrahepatic metastasis than VN and SN type. Multivariate analysis showed SNEG and CMN type is independent predictor of MVI. The survival rates and the disease free survival rates of four groups were equal after curative hepatectomy. This study demonstrated that the gross classifications were correlated significantly with the prevalence of MVI or intrahepatic metastasis, and that aggressive tumor spread in the SNEG type and in the CMN type was observed even in patients with small solitary HCC.


Contaminants of emerging concern in urban stormwater: Spatiotemporal patterns and removal by iron-enhanced sand filters (IESFs).
Numerous contaminants of emerging concern (CECs) typically occur in urban rivers. Wastewater effluents are a major source of many CECs. Urban runoff (stormwater) is a major urban water budget component and may constitute another major CEC pathway. Yet, stormwater-based CEC field studies are rare. This research investigated 384 CECs in 36 stormwater samples in Minneapolis-St. Paul, Minnesota, USA. Nine sampling sites included three large stormwater conveyances (pipes) and three paired iron-enhanced sand filters (IESFs; untreated inlets and treated outlets). The 123 detected compounds included commercial-consumer compounds, veterinary and human pharmaceuticals, lifestyle and personal care compounds, pesticides, and others. Thirty-one CECs were detected in ≥50% of samples. Individual samples contained a median of 35 targeted CECs (range: 18-54). Overall, median concentrations were ≥10 ng/L for 25 CECs and ≥100 ng/L for 9 CECs. Ranked, hierarchical linear modeling indicated significant seasonal- and site type-based concentration variability for 53 and 30 CECs, respectively, with observed patterns corresponding to CEC type, source, usage, and seasonal hydrology. A primarily warm-weather, diffuse, runoff-based profile included many herbicides. A second profile encompassed winter and/or late summer samples enriched with some recalcitrant, hydrophobic compounds (e.g., PAHs), especially at pipes, suggesting conservative, less runoff-dependent sources (e.g., sediments). A third profile, indicative of mixed conservative/non-runoff, runoff, and/or atmospheric sources and transport that collectively affect a variety of conditions, included various fungicides, lifestyle, non-prescription, and commercial-consumer CECs. Generally, pipe sites had large, diverse land-use catchments, and showed more frequent detections of diverse CECs, but often at lower concentrations; while untreated sites (with smaller, more residential-catchments) demonstrated greater detections of "pseudo-persistent" and other ubiquitous or residentially-associated CECs. Although untreated stormwater transports an array of CECs to receiving waters, IESF treatment significantly removed concentrations of 14 (29%) of the 48 most detected CECs; for these, median removal efficiencies were 26%-100%. Efficient removal of some hydrophobic (e.g., PAHs, bisphenol A) and polar-hydrophilic (e.g., caffeine, nicotine) compounds indicated particulate-bound contaminant filtration and for certain dissolved contaminants, sorption.


Degradation of 2-nitrodiphenylamine, a component of Otto Fuel II, by Clostridium spp.
Otto Fuel II, a propellant in torpedoes, is composed of 76% 1,2 propanediol dinitrate (PGDN), 22.5% di-n-butyl sebacate, and 1.5% 2-nitrodiphenylamine (NDPA), and is largely recalcitrant to aerobic microbial degradation. Anaerobic microbial degradation of Otto Fuel II was tested by inoculating anaerobic enrichment media, containing either 2% (vol:vol) complete Otto Fuel II or 2% of a 0.02% solution of Otto Fuel II in methanol, with soil and water from sites contaminated with munitions or with landfill leachate. Anaerobic bacterial growth was completely inhibited by 2% Otto Fuel II. Two mixed bacterial enrichments developed in anaerobic media containing 2% (v/v) of a 0.02% solution of Otto Fuel II in methanol. After incubation, PGDN could not be detected in either enrichment, but was also not detectable in sterile controls, suggesting abiotic degradation of low concentrations of PGDN in reduced anaerobic medium. NDPA did not degrade in either enrichment. Similarly, complete Otto Fuel was recalcitrant to degradation by highly reducing methanogenic biomass collected from an upflow anaerobic sludge blanket bioreactor (UASB). A comparison of the degradative ability of autoclaved and viable biomass showed that low concentrations of PGDN autodegraded, however unlike the autoclaved anaerobic biomass, the viable anaerobic biomass degraded the NDPA component of Otto Fuel II. Two strains of anaerobic clostridia, strains SP3 and SPF, that caused the disappearance of NDPA at its limit of solubility in culture media, were isolated from the UASB bioreactor biomass. SP3 and SPF were shown, by comparison of 16S rDNA sequences, to be most closely related to Clostridium butyricum and Clostridium cochlearium respectively. Although NDPA was lost from cultures of both strains, metabolic end products were not identified. Neither strain could degrade NDPA unless supplied with an alternative energy source. In the culture system used, NDPA stimulated the growth of SP3 but it had no appreciable effect on the growth of SPF. Both SP3 and SPF degraded low concentrations of trinitrotoluene (TNT), without the production of detectable concentrations of aromatic amines. A possible method for the remediation of small spills of Otto Fuel II is suggested.


Improving practice in community-based settings: a randomized trial of supervision - study protocol.
Evidence-based treatments for child mental health problems are not consistently available in public mental health settings. Expanding availability requires workforce training. However, research has demonstrated that training alone is not sufficient for changing provider behavior, suggesting that ongoing intervention-specific supervision or consultation is required. Supervision is notably under-investigated, particularly as provided in public mental health. The degree to which supervision in this setting includes 'gold standard' supervision elements from efficacy trials (e.g., session review, model fidelity, outcome monitoring, skill-building) is unknown. The current federally-funded investigation leverages the Washington State Trauma-focused Cognitive Behavioral Therapy Initiative to describe usual supervision practices and test the impact of systematic implementation of gold standard supervision strategies on treatment fidelity and clinical outcomes. The study has two phases. We will conduct an initial descriptive study (Phase I) of supervision practices within public mental health in Washington State followed by a randomized controlled trial of gold standard supervision strategies (Phase II), with randomization at the clinician level (i.e., supervisors provide both conditions). Study participants will be 35 supervisors and 130 clinicians in community mental health centers. We will enroll one child per clinician in Phase I (N = 130) and three children per clinician in Phase II (N = 390). We use a multi-level mixed within- and between-subjects longitudinal design. Audio recordings of supervision and therapy sessions will be collected and coded throughout both phases. Child outcome data will be collected at the beginning of treatment and at three and six months into treatment. This study will provide insight into how supervisors can optimally support clinicians delivering evidence-based treatments. Phase I will provide descriptive information, currently unavailable in the literature, about commonly used supervision strategies in community mental health. The Phase II randomized controlled trial of gold standard supervision strategies is, to our knowledge, the first experimental study of gold standard supervision strategies in community mental health and will yield needed information about how to leverage supervision to improve clinician fidelity and client outcomes. ClinicalTrials.gov NCT01800266.


Syndromic surveillance by veterinary practitioners: a pilot study in the pig sector.
Traditional indicator-based livestock surveillance has been focused on case definitions, definitive diagnoses and laboratory confirmation. The use of syndromic disease surveillance would increase the population base from which animal health data are captured and facilitate earlier detection of new and re-emerging threats to animal health. Veterinary practitioners could potentially play a vital role in such activities. In a pilot study, specialist private veterinary practitioners (PVP) working in the English pig industry were asked to collect and transfer background data and disease incident reports for pig farms visited during the study period. Baseline data from 110 pig farms were received, along with 68 disease incident reports. Reports took an average of approximately 25 minutes to complete. Feedback from the PVPs indicated that they saw value in syndromic surveillance. Maintenance of anonymity in the outputs would be essential, as would timely access for the PVPs to relevant information on syndromic trends. Further guidance and standardisation would also be required. Syndromic surveillance by PVPs is possible for the pig industry. It has potential to fill current gaps in the collection of animal health data, as long as the engagement and participation of data providers can be obtained and maintained.


LINAC-based spinal stereotactic radiosurgery.
The authors' report on the use of a prototype spinal stereotactic radiosurgery frame which was employed for the treatment of 9 patients who presented with recurrent neoplastic involvement of the spinal column. All patients had failed standard therapy consisting of surgery, external fractionated radiation therapy, and/or chemotherapy. Eight of the lesions represented metastatic tumors in the vertebral column, one of the lesions was a primary osteosarcoma involving multiple vertebral bodies. The lesions were found at multiple levels, from the cervical through the sacral region. Six out of the 9 patients presented with epidural compression: 4 of the 9 patients with evidence of myelopathy: 2 of the 9 patients with radicular symptoms secondary to compression from the tumor, and 1 patient was free of any compressive symptoms. All patients had pain requiring narcotics. Patients were treated with a median radiosurgical dose of 800 cGy (range 800-1.000) with a median of 1 isocenter (range 1-7 isocenters) and median normalization of 80% to the isodose contour (range 80-160). Median dose delivered to the already prior irradiated spinal cord was 179 cGy (range 52-320 cGy) with a median spinal cord dose of 34 (range 4-68). To date, there have been three minor complications: one radiation-induced esophagitis which was treated medically: one wound infection, and 1 patient requiring an additional 24 h of hospitalization stay. There have been no major complications. To date, 5 of the 9 patients have died, all from causes unrelated to the spinal radiosurgery. Three out of the 9 patients have been followed for more than 1 year. In all 3, there was radiographic regression of the tumor and epidural compression. In 2 patients, there was histologic confirmation of absence of tumor in the treated site: in 1 patient. no tumor was found at postmortem. 12 months after treatment, when the patient died of unrelated causes. Although the number of patients followed is limited, the phase I study clearly shows the technical feasibility of spinal radiosurgery for the control of metastatic involvement of the vertebral column even in the face of epidural compression.


Robust Optical Recognition of Cursive Pashto Script Using Scale, Rotation and Location Invariant Approach.
The presence of a large number of unique shapes called ligatures in cursive languages, along with variations due to scaling, orientation and location provides one of the most challenging pattern recognition problems. Recognition of the large number of ligatures is often a complicated task in oriental languages such as Pashto, Urdu, Persian and Arabic. Research on cursive script recognition often ignores the fact that scaling, orientation, location and font variations are common in printed cursive text. Therefore, these variations are not included in image databases and in experimental evaluations. This research uncovers challenges faced by Arabic cursive script recognition in a holistic framework by considering Pashto as a test case, because Pashto language has larger alphabet set than Arabic, Persian and Urdu. A database containing 8000 images of 1000 unique ligatures having scaling, orientation and location variations is introduced. In this article, a feature space based on scale invariant feature transform (SIFT) along with a segmentation framework has been proposed for overcoming the above mentioned challenges. The experimental results show a significantly improved performance of proposed scheme over traditional feature extraction techniques such as principal component analysis (PCA).


Characterization of spatially homogeneous regions based on temporal patterns of fine particulate matter in the continental United States.
Statistical analyses of time-series or spatial data have been widely used to investigate the behavior of ambient air pollutants. Because air pollution data are generally collected in a wide area of interest over a relatively long period, such analyses should take into account both spatial and temporal characteristics. The objective of this study is 2-fold: (1) to identify an efficient way to characterize the spatial variations of fine particulate matter (PM2.5) concentrations based solely upon their temporal patterns, and (2) to analyze the temporal and seasonal patterns of PM2.5 concentrations in spatially homogenous regions. This study used 24-hr average PM2.5 concentrations measured every third day during a period between 2001 and 2005 at 522 monitoring sites in the continental United States. A k-means clustering algorithm using the correlation distance was used to investigate the similarity in patterns between temporal profiles observed at the monitoring sites. A k-means clustering analysis produced six clusters of sites with distinct temporal patterns that were able to identify and characterize spatially homogeneous regions of the United States. The study also presents a rotated principal component analysis (RPCA) that has been used for characterizing spatial patterns of air pollution and discusses the difference between the clustering algorithm and RPCA.


Perioperative assessment for refractive cataract surgery.
As cataract surgery has evolved into lens-based refractive surgery, expectations for refractive outcomes continue to increase. During the past decade, advancements in technology have provided new ways to measure the cornea in preparation for cataract surgery. The increasing ability to accurately estimate corneal power allows determination of the most precise intraocular lens (IOL) for each patient. New equipment measures the anterior and posterior corneal surfaces to most accurately estimate corneal power and corneal aberrations. These measurements help surgeons make the best decisions regarding the power of the IOL to be implanted during cataract surgery. However, with all the available technology, it can be difficult to decipher which of the many technologies is necessary or best for patients and for practices. This article reviews currently available options for topography, tomography, keratometry, and biometry in preparation for cataract surgery. In addition, intraoperative aberrometry and integrated cataract suites are reviewed.


Fluorocarbene, fluoroolefin, and fluorocarbyne complexes of Rh.
The manuscript reports the synthesis, characterization, and analysis of electronic structure in a series of complexes of small perfluorocarbon ligands with the (PNP)Rh fragment (where PNP is a diarylamido/bis(phosphine) pincer ligand). Reactions of (PNP)Rh(TBE) as the source of (PNP)Rh with CHF3 and C2HF5 produced perfluoroalkylidene complexes (PNP)Rh[double bond, length as m-dash]CF2 and (PNP)Rh[double bond, length as m-dash]C(F)(CF3). (PNP)Rh[double bond, length as m-dash]CF2 could also be obtained via the reaction of (PNP)Rh(TBE) with Me3SiCF3/CsF, with an admixture of (PNP)Rh(C2F4), where TBE = tert-butylethylene. Abstraction of fluoride from these neutral (PNP)RhC x F y complexes was successful, although only abstraction from (PNP)Rh[double bond, length as m-dash]CF2 allowed unambiguous identification of the Rh product, [(PNP)Rh[triple bond, length as m-dash]CF]+. DFT computational studies allowed comparison of relative energies of (PNP)Rh(C2F4) and [(PNP)Rh(C2F3)]+ isomers as well as comparisons between the electronic structure of the [double bond, length as m-dash]CF2, C2F4, and [triple bond, length as m-dash]CF+ complexes and their hydrocarbon analogues.


Molecular cytogenetic comparison of apocrine hyperplasia and apocrine carcinoma of the breast.
The relationship of apocrine metaplasia to invasive breast cancer is controversial. Different authors have reported that apocrine differentiation in proliferative lesions may be a risk factor, a precursor lesion, or have no association with malignancy. The aim of this study was to compare the genetic alterations in benign apocrine hyperplasia with apocrine ductal carcinoma in situ (DCIS) and invasive apocrine carcinomas of the breast using comparative genomic hybridization. The mean number of alterations in apocrine hyperplasia was 4.1 (n = 10) compared to 10.2 in apocrine DCIS (n = 10) and 14.8 (n = 4) in invasive carcinoma. The most common alterations in apocrine hyperplasia were gains of 2q, 13q, and 1p and losses of 1p, 17q, 22q, 2p, 10q, and 16q. Apocrine DCIS and invasive carcinomas showed gains of 1q, 2q, 1p, and losses of 1p, 22q, 17q, 12q, and 16q as their most common DNA copy number changes. Apocrine hyperplasia is considered to be a benign lesion and its relationship to invasive carcinoma remains unclear. Our data suggest that some apocrine hyperplasias may be clonal proliferations. The mean number of alterations are lower in apocrine hyperplasia, however the changes show considerable overlap with those identified in in situ and invasive apocrine carcinoma. These alterations are also commonly seen in nonapocrine breast cancer. The data are consistent with apocrine hyperplasia as a putative nonobligate precursor of apocrine carcinoma.


Rewriting the bacterial glycocalyx via Suzuki-Miyaura cross-coupling.
Suzuki-Miyaura cross-coupling has been used to couple novel carbohydrate-based boronic acids, site-selectively, to the surface of E. coli at an unnatural amino acid. In this way, benign metal-catalyzed cellular switching allowed modulation of interactions with biomolecular partners via prokaryotic O-glycosylation mimics.


Effect of photodynamic therapy with posterior sub-tenon triamcinolone acetonide on predominantly classic choroidal neovascularization: one-year results.
The aim of this study was to compare the results of monotherapy (photodynamic therapy) and combined therapy (photo-dynamic therapy with posterior sub-Tenon triamcinolone acetonide) in age-related macular degeneration (AMD). Forty eyes from forty patients with diagnosed neovascular AMD were enrolled in this study during March-2005 - October-2008. All patients were grouped in either the study or the control group. Both the study and control groups consisted of 20 eyes from 20 patients. The study group was treated with posterior sub-Tenon triamcinolone acetonide (PSTA) along with their initial photodynamic therapy (PDT) treatment. The control group members were treated with PDT alone. All patients were examined at 1, 3, 6 and 12 months. Visual acuity (VA), lesion size and number of treatment sessions were recorded during each examination. The mean difference between pre- and post-treatment VA using the Snellen chart was +0.6 ± 1.7 in study group and -1.4 ± 1.7 in control. The difference for VA was significant in the study group as compared to control (p<0.05). The decrease in lesion size in the study group was 680±1195.2 µm, and the decrease was 32.75 ± 809.9 µm in the control. The difference with regard to the decrease in lesion sizes was significant in the study group as compared to the control (p<0.05). Total PDT treatment sessions were applied 1.2 times per patient in the study group and 1.9 times per patient in the control group. The difference was not significant (p>0.05). Our study showed that PSTA with PDT significantly reduces CNV growth, and improves VA at the 12-month follow-up in patients with AMD.


Fermented Foods as a Dietary Source of Live Organisms.
The popularity of fermented foods and beverages is due to their enhanced shelf-life, safety, functionality, sensory, and nutritional properties. The latter includes the presence of bioactive molecules, vitamins, and other constituents with increased availability due to the process of fermentation. Many fermented foods also contain live microorganisms that may improve gastrointestinal health and provide other health benefits, including lowering the risk of type two diabetes and cardiovascular diseases. The number of organisms in fermented foods can vary significantly, depending on how products were manufactured and processed, as well as conditions and duration of storage. In this review, we surveyed published studies in which lactic acid and other relevant bacteria were enumerated from the most commonly consumed fermented foods, including cultured dairy products, cheese, fermented sausage, fermented vegetables, soy-fermented foods, and fermented cereal products. Most of the reported data were based on retail food samples, rather than experimentally produced products made on a laboratory scale. Results indicated that many of these fermented foods contained 105-7 lactic acid bacteria per mL or gram, although there was considerable variation based on geographical region and sampling time. In general, cultured dairy products consistently contained higher levels, up to 109/mL or g. Although few specific recommendations and claim legislations for what constitutes a relevant dose exist, the findings from this survey revealed that many fermented foods are a good source of live lactic acid bacteria, including species that reportedly provide human health benefits.


A phase 1 study of tazarotene in adults with advanced cancer.
Tazarotene is an acetylenic retinoid which is metabolised to tazarotenic acid and which binds selectively to the retinoid receptors RARbeta and RARgamma. The safety, toxicity and pharmacokinetics of oral tazarotene were determined over 12 weeks of treatment in 34 patients with advanced cancer. Commonly seen toxicities were mucocutaneous symptoms, musculoskeletal pain and headache. Dose-limiting toxicities were hypercalcaemia, hypertriglyceridaemia and musculoskeletal pain. The maximum tolerated dose of tazarotene in this schedule is 25.2 mg day(-1). Plasma concentrations of tazarotenic acid were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly. The C(max) and AUC values on day 0, and weeks 2 and 4 were similar indicating no drug accumulation. The dose-normalised C(max) and AUC values at different dose levels and different study days appeared to be similar indicating linear pharmacokinetics. No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)). We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy.


Insulin binding to monocytes in trained athletes: changes in the resting state and after exercise.
Insulin binding to monocytes was examined in trained athletes (long distance runners) and in sedentary control subjects in the resting state and after 3 h of exercise at 40% of maximal aerobic power. At rest, specific binding of 125-I-insulin to monocytes was 69% higher in athletes than in sedentary controls and correlated with maximal aerobic power. The increase in insulin binding was primarily due to an increase in binding capacity. During acute exercise, insulin binding fell by 31% in athletes but rose by 35% in controls. The athletes had a smaller decline in plasma glucose and a lower respiratory exchange ratio during exercise than did controls. We conclude that physical training increases insulin binding to monocytes in the resting state but results in a fall in insulin binding during acute exercise. Changes in insulin binding in athletes thus may account for augmented insulin sensitivity at rest as well as a greater shift from carbohydrate to fat usage during exercise than is observed in untrained controls.


The evolution of sex differences in mate searching when females benefit: new theory and a comparative test.
Sexual selection is thought to have led to searching as a profitable, but risky way of males obtaining mates. While there is great variation in which sex searches, previous theory has not considered search evolution when both males and females benefit from multiple mating. We present new theory and link it with data to bridge this gap. Two different search protocols exist between species in the bush-cricket genus Poecilimon (Orthoptera): females search for calling males, or males search for calling females. Poecilimon males also transfer a costly nuptial food gift to their mates during mating. We relate variations in searching protocols to variation in nuptial gift size among 32 Poecilimon taxa. As predicted, taxa where females search produce significantly larger nuptial gifts than those where males search. Our model and results show that search roles can reverse when multiple mating brings about sufficiently strong material benefits to females.