Hemi-Synthesis and Anti-Oomycete Activity of Analogues of Isocordoin.
An efficient synthesis of a series of 4'-oxyalkyl-isocordoin analogues (2-8) is reported for the first time. Their structures were confirmed by ¹H-NMR, 13C-NMR, and HRMS. Their anti-oomycete activity was evaluated by mycelium and spores inhibition assay against two selected pathogenic oomycetes strains: Saprolegnia parasitica and Saprolegnia australis. The entire series of isocordoin derivatives (except compound 7) showed high inhibitory activity against these oomycete strains. Among them, compound 2 exhibited strong activity, with minimum inhibitory concentration (MIC) and minimum oomyceticidal concentration (MOC) values of 50 µg/mL and 75 µg/mL, respectively. The results showed that 4'-oxyalkylated analogues of isocordoin could be potential anti-oomycete agents.


MicroRNA-9 regulates neurogenesis in mouse telencephalon by targeting multiple transcription factors.
microRNA-9-2 and microRNA-9-3 double-mutant mice demonstrate that microRNA-9 (miR-9) controls neural progenitor proliferation and differentiation in the developing telencephalon by regulating the expression of multiple transcription factors. As suggested by our previous study, the Foxg1 expression was elevated, and the production of Cajal-Retzius cells and early-born neurons was suppressed in the miR-9-2/3 double-mutant pallium. At embryonic day 16.5 (E16.5), however, the Foxg1 expression was no longer elevated. The expression of an AU-rich RNA-binding protein Elavl2 increased at E16.5, Elav2 associated with Foxg1 3' untranslated region (UTR), and it countered the Foxg1 suppression by miR-9. Later, progenitor proliferation was reduced in the miR-9-2/3 double-mutant pallium with the decrease in Nr2e1 and Pax6 expression and the increase in Meis2 expression. The analyses suggest that microRNA-9 indirectly inhibits Pax6 expression by suppressing Meis2 expression. In contrast, together with Elavl1 and Msi1, microRNA-9 targets Nr2e1 mRNA 3' UTR to enhance the expression. Concomitantly, cortical layers were reduced, each cortical projection was malformed, and the tangential migration of interneurons into the pallium was impaired in the miR-9-2/3 double mutants. miR-9 also targets Gsh2 3' UTR, and Gsh2, as well as Foxg1, expression was elevated in the miR-9-2/3 double-mutant subpallium. The subpallium progenitor proliferation was enhanced, and the development of basal ganglia including striatum and globus pallidus was suppressed. Pallial/subpallial boundary shifted dorsally, and the ventral pallium was lost. Corridor was malformed, and thalamocortical and corticofugal axons were misrouted in the miR-9-2/3 double mutants.


The Werner syndrome protein is required for recruitment of chromatin assembly factor 1 following DNA damage.
The Werner syndrome protein (WRN) and chromatin assembly factor 1 (CAF-1) are both involved in the maintenance of genome stability. In response to DNA-damaging signals, both of these proteins relocate to sites where DNA synthesis occurs. However, the interaction between WRN and CAF-1 has not yet been investigated. In this report, we show that WRN interacts physically with the largest subunit of CAF-1, hp150, in vitro and in vivo. Although hp150 does not alter WRN catalytic activities in vitro, and the chromatin assembly activity of CAF-1 is not affected in the absence of WRN in vivo, this interaction may have an important role during the cellular response to DNA replication fork blockage and/or DNA damage signals. In hp150 RNA-mediated interference (RNAi) knockdown cells, WRN partially formed foci following hydroxyurea (HU) treatment. However, in the absence of WRN, hp150 did not relocate to form foci following exposure to HU and ultraviolet light. Thus, our results demonstrate that WRN responds to DNA damage before CAF-1 and suggest that WRN may recruit CAF-1, via interaction with hp150, to DNA damage sites during DNA synthesis.


Label-free flow cytometry using multiplex coherent anti-Stokes Raman scattering (MCARS) for the analysis of biological specimens.
We present the first demonstration, to our knowledge, of a label-free flow cytometer for the analysis of biological specimens using multiplex coherent anti-Stokes Raman scattering (MCARS) and elastic scatter measurements. The MCARS system probes the Raman vibrational energy levels and the elastic scatter provides morphological information. We demonstrate these capabilities by probing a culture of Saccharomyces cerevisiae at 100 spectra/s and constructing a background-free Raman reconstruction using a Kramers-Kronig relation. A theoretical analysis shows that this system could operate at speeds of 10 kHz with appropriate hardware; thus facilitating integration into commercial flow cytometers or use as a high-speed, stand-alone device.


Medical Marijuana and Opioids (MEMO) Study: protocol of a longitudinal cohort study to examine if medical cannabis reduces opioid use among adults with chronic pain.
In the USA, opioid analgesic use and overdoses have increased dramatically. One rapidly expanding strategy to manage chronic pain in the context of this epidemic is medical cannabis. Cannabis has analgesic effects, but it also has potential adverse effects. Further, its impact on opioid analgesic use is not well studied. Managing pain in people living with HIV is particularly challenging, given the high prevalence of opioid analgesic and cannabis use. This study's overarching goal is to understand how medical cannabis use affects opioid analgesic use, with attention to Δ9-tetrahydrocannabinol and cannabidiol content, HIV outcomes and adverse events. We are conducting a cohort study of 250 adults with and without HIV infection with (a) severe or chronic pain, (b) current opioid use and (c) who are newly certified for medical cannabis in New York. Over 18 months, we collect data via in-person visits every 3 months and web-based questionnaires every 2 weeks. Data sources include: questionnaires; medical, pharmacy and Prescription Monitoring Program records; urine and blood samples; and physical function tests. Using marginal structural models and comparisons within participants' 2-week time periods (unit of analysis), we will examine how medical cannabis use (primary exposure) affects (1) opioid analgesic use (primary outcome), (2) HIV outcomes (HIV viral load, CD4 count, antiretroviral adherence, HIV risk behaviours) and (3) adverse events (cannabis use disorder, illicit drug use, diversion, overdose/deaths, accidents/injuries, acute care utilisation). This study is approved by the Montefiore Medical Center/Albert Einstein College of Medicine institutional review board. Findings will be disseminated through conferences, peer-reviewed publications and meetings with medical cannabis stakeholders. ClinicalTrials.gov Registry (NCT03268551); Pre-results.


Elements in the transcriptional regulatory region flanking herpes simplex virus type 1 oriS stimulate origin function.
Like other DNA-containing viruses, the three origins of herpes simplex virus type 1 (HSV-1) DNA replication are flanked by sequences containing transcriptional regulatory elements. In a transient plasmid replication assay, deletion of sequences comprising the transcriptional regulatory elements of ICP4 and ICP22/47, which flank oriS, resulted in a greater than 80-fold decrease in origin function compared with a plasmid, pOS-822, which retains these sequences. In an effort to identify specific cis-acting elements responsible for this effect, we conducted systematic deletion analysis of the flanking region with plasmid pOS-822 and tested the resulting mutant plasmids for origin function. Stimulation by cis-acting elements was shown to be both distance and orientation dependent, as changes in either parameter resulted in a decrease in oriS function. Additional evidence for the stimulatory effect of flanking sequences on origin function was demonstrated by replacement of these sequences with the cytomegalovirus immediate-early promoter, resulting in nearly wild-type levels of oriS function. In competition experiments, cotransfection of cells with the test plasmid, pOS-822, and increasing molar concentrations of a competitor plasmid which contained the ICP4 and ICP22/47 transcriptional regulatory regions but lacked core origin sequences resulted in a significant reduction in the replication efficiency of pOS-822, demonstrating that factors which bind specifically to the oriS-flanking sequences are likely involved as auxiliary proteins in oriS function. Together, these studies demonstrate that trans-acting factors and the sites to which they bind play a critical role in the efficiency of HSV-1 DNA replication from oriS in transient-replication assays.


Dopamine transporter availability in clinically normal aging is associated with individual differences in white matter integrity.
Aging-related differences in white matter integrity, the presence of amyloid plaques, and density of biomarkers indicative of dopamine functions can be detected and quantified with in vivo human imaging. The primary aim of the present study was to investigate whether these imaging-based measures constitute independent imaging biomarkers in older adults, which would speak to the hypothesis that the aging brain is characterized by multiple independent neurobiological cascades. We assessed MRI-based markers of white matter integrity and PET-based marker of dopamine transporter density and amyloid deposition in the same set of 53 clinically normal individuals (age 65-87). A multiple regression analysis demonstrated that dopamine transporter availability is predicted by white matter integrity, which was detectable even after controlling for chronological age. Further post-hoc exploration revealed that dopamine transporter availability was further associated with systolic blood pressure, mirroring the established association between cardiovascular health and white matter integrity. Dopamine transporter availability was not associated with the presence of amyloid burden. Neurobiological correlates of dopamine transporter measures in aging are therefore likely unrelated to Alzheimer's disease but are aligned with white matter integrity and cardiovascular risk. More generally, these results suggest that two common imaging markers of the aging brain that are typically investigated separately do not reflect independent neurobiological processes. Hum Brain Mapp 37:621-631, 2016. © 2015 Wiley Periodicals, Inc.


Information reconstruction in educational institutions data from the European tertiary education registry.
Universities and other organizations providing higher level education are collectively called Higher Education Institutions. Their detail data, for instance number of students, number of graduates, etc., constitute the basis for several important analyses of the educational systems. This work provides data of the European Tertiary Education Register (ETER), which describes the Educational Institutions of Europe. These data have been gathered through the National Statistical Authorities of all the Countries participant in the ETER Project. However, they include many scattered missing values. Therefore, we have developed and applied an imputation methodology (see "Imputation Techniques for the Reconstruction of Missing Interconnected Data from Higher Educational Institutions, Bruni et al. [3]) to replace the missing values with feasible values being as similar as possible to the original values that have been lost and are now unknown. Thus, we also provide the imputed version of the same dataset, which allows more in-depth analyses of the European Higher Education Institutions. Both datasets (before and after imputation) are provided in two versions: with or without bibliometric information for the Institutions, so the user can also consider these additional information if interested.


Testing NF-kappa B1-p50 antibody specificity using knockout mice.
Cell extracts from knockout mice can provide definitive proof of antibody specificity. Two NF-kappa B1-p50 antibodies, sc-114 (a commercial antibody) and NR1157, were observed to recognize proteins having distinct electrophoretic mobilities of 52-55 kD and 50 kD, respectively, by Western blot analysis. In order to discriminate the specificity of these antibodies for NF-kappa B1-p50, whole cell extracts derived from NF-kappa B1-p105 knockout mice were employed. While the NR1157 antibody completely failed to recognize its 50 kD product in p105-/- knockout extracts, the sc-114 antibody still strongly recognized its 52-55 kD product. These data demonstrate that NR1157, but not sc-114, is highly specific for NF-kappa B1-p50 by Western blot analysis. In addition, these results highlight the utility of knockout cell extracts for discerning antibody specificity.


Highway proximity and black carbon from cookstoves as a risk factor for higher blood pressure in rural China.
Air pollution in China and other parts of Asia poses large health risks and is an important contributor to global climate change. Almost half of Chinese homes use biomass and coal fuels for cooking and heating. China's economic growth and infrastructure development has led to increased emissions from coal-fired power plants and an expanding fleet of motor vehicles. Black carbon (BC) from incomplete biomass and fossil fuel combustion is the most strongly light-absorbing component of particulate matter (PM) air pollution and the second most important climate-forcing human emission. PM composition and sources may also be related to its human health impact. We enrolled 280 women living in a rural area of northwestern Yunnan where biomass fuels are commonly used. We measured their blood pressure, distance from major traffic routes, and daily exposure to BC (pyrolytic biomass combustion), water-soluble organic aerosol (organic aerosol from biomass combustion), and, in a subset, hopane markers (motor vehicle emissions) in winter and summer. BC had the strongest association with systolic blood pressure (SBP) (4.3 mmHg; P < 0.001), followed by PM mass and water-soluble organic mass. The effect of BC on SBP was almost three times greater in women living near the highway [6.2 mmHg; 95% confidence interval (CI), 3.6 to 8.9 vs. 2.6 mmHg; 95% CI, 0.1 to 5.2]. Our findings suggest that BC from combustion emissions is more strongly associated with blood pressure than PM mass, and that BC's health effects may be larger among women living near a highway and with greater exposure to motor vehicle emissions.


Once a Week Resistance Training Improves Muscular Strength in Breast Cancer Survivors: A Randomized Controlled Trial.
Background: Exercise has been shown to reduce adverse outcomes related to breast cancer. However, the rate of adherence to physical exercise is very low among breast cancer survivors (BCS). This study investigated the effects of high supervision ratio resistance training (RT), once a week for 8 weeks, on changes in body composition and muscular strength in BCS. Methods: Twenty-five female BCS undergoing hormone therapy were randomized into resistance training group (TG, n = 12) or control (CG, n = 13) group. The TG performed 8 weeks of supervised RT, with 1 trainer per volunteer, once a week. Body composition was evaluated by dual-energy X-ray absorptiometry, and muscle strength was evaluated by 10 repetition maximum (10 RM) for leg press (45°) and bench press exercises. A 1-way analysis of variance was used to compare within-group effects at pre- and post-intervention. An analysis of covariance test was used to compare post-intervention values, using pre-intervention measures as covariates. The effect size (ES) was calculated by Cohen's d. Results: The TG improved muscle strength in 10 RM leg press (45°; Δ 33.75 ± 11.51 kg, P = .02; ES = 0.96) and bench press (Δ 4.08 ± 1.83 kg, P = .01; ES = 1.15). Adherence to training was more than 99%. Changes in body composition were not detected. There were no changes in the CG for any assessment. Conclusion: Once-weekly supervised RT could be an alternative to increase the adherence to exercise and improve muscular strength in BCS.


How we see ourselves and how we see others.
People see themselves differently from how they see others. They are immersed in their own sensations, emotions, and cognitions at the same time that their experience of others is dominated by what can be observed externally. This basic asymmetry has broad consequences. It leads people to judge themselves and their own behavior differently from how they judge others and those others' behavior. Often, those differences produce disagreement and conflict. Understanding the psychological basis of those differences may help mitigate some of their negative effects.


Smart instrumentation for determination of ligament stiffness and ligament balance in total knee arthroplasty.
Ligament balance is an important and subjective task performed during total knee arthroplasty (TKA) procedure. For this reason, it is desirable to develop instruments to quantitatively assess the soft-tissue balance since excessive imbalance can accelerate prosthesis wear and lead to early surgical revision. The instrumented distractor proposed in this study can assist surgeons on performing ligament balance by measuring the distraction gap and applied load. Also the device allows the determination of the ligament stiffness which can contribute a better understanding of the intrinsic mechanical behavior of the knee joint. Instrumentation of the device involved the use of hall-sensors for measuring the distractor displacement and strain gauges to transduce the force. The sensors were calibrated and tested to demonstrate their suitability for surgical use. Results show the distraction gap can be measured reliably with 0.1mm accuracy and the distractive loads could be assessed with an accuracy in the range of 4N. These characteristics are consistent with those have been proposed, in this work, for a device that could assist on performing ligament balance while permitting surgeons evaluation based on his experience. Preliminary results from in vitro tests were in accordance with expected stiffness values for medial collateral ligament (MCL) and lateral collateral ligament (LCL).


Efficacy and adverse effects of medical marijuana for chronic noncancer pain: Systematic review of randomized controlled trials.
To determine if medical marijuana provides pain relief for patients with chronic noncancer pain (CNCP) and to determine the therapeutic dose, adverse effects, and specific indications. In April 2014, MEDLINE and EMBASE searches were conducted using the terms chronic noncancer pain, smoked marijuana or cannabinoids, placebo and pain relief, or side effects or adverse events. An article was selected for inclusion if it evaluated the effect of smoked or vaporized cannabinoids (nonsynthetic) for CNCP; it was designed as a controlled study involving a comparison group, either concurrently or historically; and it was published in English in a peer-review journal. Outcome data on pain, function, dose, and adverse effects were collected, if available. All articles that were only available in abstract form were excluded. Synthesis A total of 6 randomized controlled trials (N = 226 patients) were included in this review; 5 of them assessed the use of medical marijuana in neuropathic pain as an adjunct to other concomitant analgesics including opioids and anticonvulsants. The 5 trials were considered to be of high quality; however, all of them had challenges with masking. Data could not be pooled owing to heterogeneity in delta-9-tetrahydrocannabinol potency by dried weight, differing frequency and duration of treatment, and variability in assessing outcomes. All experimental sessions in the studies were of short duration (maximum of 5 days) and reported statistically significant pain relief with nonserious side effects. There is evidence for the use of low-dose medical marijuana in refractory neuropathic pain in conjunction with traditional analgesics. However, trials were limited by short duration, variability in dosing and strength of delta-9-tetrahydrocannabinol, and lack of functional outcomes. Although well tolerated in the short term, the long-term effects of psychoactive and neurocognitive effects of medical marijuana remain unknown. Generalizing the use of medical marijuana to all CNCP conditions does not appear to be supported by existing evidence. Clinicians should exercise caution when prescribing medical marijuana for patients, especially in those with nonneuropathic CNCP.


Divergence in wine characteristics produced by wild and domesticated strains of Saccharomyces cerevisiae.
The budding yeast Saccharomyces cerevisiae is the primary species used by wine makers to convert sugar into alcohol during wine fermentation. Saccharomyces cerevisiae is found in vineyards, but is also found in association with oak trees and other natural sources. Although wild strains of S. cerevisiae as well as other Saccharomyces species are also capable of wine fermentation, a genetically distinct group of S. cerevisiae strains is primarily used to produce wine, consistent with the idea that wine making strains have been domesticated for wine production. In this study, we demonstrate that humans can distinguish between wines produced using wine strains and wild strains of S. cerevisiae as well as its sibling species, Saccharomyces paradoxus. Wine strains produced wine with fruity and floral characteristics, whereas wild strains produced wine with earthy and sulfurous characteristics. The differences that we observe between wine and wild strains provides further evidence that wine strains have evolved phenotypes that are distinct from their wild ancestors and relevant to their use in wine production.


Conjugated Thiophene-Fused Isatin Dyes through Intramolecular Direct Arylation.
We report on the design, synthesis, and properties of innovative, planar, π-conjugated compounds in which a thiophene ring is fused with the skeleton of the naturally occurring dye isatin. The synthesis is achieved in high yields making use of an intramolecular direct arylation reaction as the key step, making the overall process potentially scalable. The synthetic sequence has been demonstrated also for an isatin bearing fluorine substituents on the aromatic ring. NMR and X-ray studies demonstrate the crosstalk occurring between the fused, coplanar, and conjugated moieties, making these novel dyes with a donor-acceptor character. Cyclic voltammetry and UV-vis studies confirm very interesting HOMO-LUMO levels and energy gaps for the new compounds.


Recipient bed vascularity and the survival of ischaemic flaps.
The purpose of this study was to identify the length of the ischaemic period required to induce the 'no-reflow' phenomenon in a rat epigastric flap on an avascular recipient site. The vascularity of the recipient bed may affect flap survival in the early postischaemic stage after flap transfer. Initially, we designed epigastric flaps in 300-350 g Sprague-Dawley rats and separated the rats into four groups of 5 rats each (total 20 rats). In groups 1, 2, 3, the flaps were made ischaemic for 1 hour, 6 hours and 10 hours, respectively, by temporarily clipping the epigastric artery and vein. In group 4, the epigastric artery and vein were divided to create permanent ischaemia. In groups 1, 2 and 3, ischaemia was ended by removing the clips. After the ischaemic flaps were reperfused, their viability was studied by measuring the flap survival rate at postoperative day 7. Flap survival was studied by direct observations, laser Doppler flowmeter measurement of flap blood flow, histopathology, and carbon particle perfusion of the flap vasculature. Ischaemic flaps of groups 1 and 2 recovered almost completely after reperfusion due to the short period of ischaema. In a second series of experiments, in order to evaluate the contribution to flap survival of the recipient vascularised bed, another four groups of epigastric flaps (of 5 animals each, using the same time periods as above) were raised and a piece of Biobrane was interposed between the flap and the recipient bed before the flap wound was closed, to eliminate all nutrient supply from the recipient bed. THe results showed that the combined effect of the reperfused flap vasculature plus the metabolic contribution of the recipient bed significantly (P < 0.01) increased the extent of flap survival of the 6- and 10-hour ischaemic flaps as well as the divided pedicle flaps, which were never reperfused. An absolute 'no-reflow' rat model flap for further flap salvage studies was also developed.


Measuring the effectiveness of mentoring as a knowledge translation intervention for implementing empirical evidence: a systematic review.
Mentoring as a knowledge translation (KT) intervention uses social influence among healthcare professionals to increase use of evidence in clinical practice. To determine the effectiveness of mentoring as a KT intervention designed to increase healthcare professionals' use of evidence in clinical practice. A systematic review was conducted using electronic databases (i.e., MEDLINE, CINAHL), grey literature, and hand searching. Eligible studies evaluated mentoring of healthcare professionals responsible for patient care to enhance the uptake of evidence into practice. Mentoring is defined as (a) a mentor more experienced than mentee; (b) individualized support based on mentee's needs; and (c) involved in an interpersonal relationship as indicated by mutual benefit, engagement, and commitment. Two reviewers independently screened citations for eligibility, extracted data, and appraised quality of studies. Data were analyzed descriptively. Of 10,669 citations from 1988 to 2012, 10 studies were eligible. Mentoring as a KT intervention was evaluated in Canada, USA, and Australia. Exposure to mentoring compared to no mentoring improved some behavioral outcomes (one study). Compared to controls or other multifaceted interventions, multifaceted interventions with mentoring improved practitioners' knowledge (four of five studies), beliefs (four of six studies), and impact on organizational outcomes (three of four studies). There were mixed findings for changes in professionals' behaviors and impact on practitioners' and patients' outcomes: some outcomes improved, while others showed no difference. Only one study evaluated the effectiveness of mentoring alone as a KT intervention and showed improvement in some behavioral outcomes. The other nine studies that evaluated the effectiveness of mentoring as part of a multifaceted intervention showed mixed findings, making it difficult to determine the added effect of mentoring. Further research is needed to identify effective mentoring as a KT intervention.


Differential effects of catalase on apoptosis induction in human promonocytic cells. Relationships with heat-shock protein expression.
The administration of the H(2)O(2)-specific scavenger catalase attenuated the generation of apoptosis by the antitumor drugs etoposide, camptothecin, doxorubicin, and cisplatin in U-937 human promonocytic cells. By contrast, the antioxidant potentiated the generation of apoptosis by the inducers of the stress response, heat shock and cadmium, in this and other myeloid cell types. Catalase also increased the heat shock-provoked stimulation of caspase-3 and -9 activities, as well as the release of cytochrome c from mitochondria to the cytosol. The potentiation of cell death by catalase correlated with its capacity to inhibit the stress response, as demonstrated by the suppression of 70- or 27-kDa heat-shock protein expression and the inhibition of heat-shock transcription factor 1 binding activity. Conversely, the toxicity of catalase plus heat shock was attenuated when the cells were preconditioned with a soft heating, which elevated the 70-kDa heat-shock protein levels. By contrast with catalase, the antioxidants superoxide dismutase and probucol did not inhibit heat-shock protein expression or affect apoptosis in U-937 cells. Finally, it was observed that the antitumor drugs did not activate the stress response in U-937 cells and that catalase failed to inhibit HSP expression and to potentiate apoptosis in heat shock-treated RPMI 8866 lymphoblastic cells. Taken together, these results provide the first demonstration of a proapoptotic action of catalase, suggest that H(2)O(2) is a critical regulator of both apoptosis and the stress response, and corroborate the antiapoptotic action of heat-shock proteins in myeloid cells.


Characteristic features of kynurenine aminotransferase allosterically regulated by (alpha)-ketoglutarate in cooperation with kynurenine.
Kynurenine aminotransferase from Pyrococcus horikoshii OT3 (PhKAT), which is a homodimeric protein, catalyzes the conversion of kynurenine (KYN) to kynurenic acid (KYNA). We analyzed the transaminase reaction mechanisms of this protein with pyridoxal-5'-phosphate (PLP), KYN and α-ketoglutaric acid (2OG) or oxaloacetic acid (OXA). 2OG significantly inhibited KAT activities in kinetic analyses, suggesting that a KYNA biosynthesis is allosterically regulated by 2OG. Its inhibitions evidently were unlocked by KYN. 2OG and KYN functioned as an inhibitor and activator in response to changes in the concentrations of KYN and 2OG, respectively. The affinities of one subunit for PLP or 2OG were different from that of the other subunit, as confirmed by spectrophotometry and isothermal titration calorimetry, suggesting that the difference of affinities between subunits might play a role in regulations of the KAT reaction. Moreover, we identified two active and allosteric sites in the crystal structure of PhKAT-2OG complexes. The crystal structure of PhKAT in complex with four 2OGs demonstrates that two 2OGs in allosteric sites are effector molecules which inhibit the KYNA productions. Thus, the combined data lead to the conclusion that PhKAT probably is regulated by allosteric control machineries, with 2OG as the allosteric inhibitor.


Measurement properties of the Inventory of Cognitive Bias in Medicine (ICBM).
Understanding how doctors think may inform both undergraduate and postgraduate medical education. Developing such an understanding requires valid and reliable measurement tools. We examined the measurement properties of the Inventory of Cognitive Bias in Medicine (ICBM), designed to tap this domain with specific reference to medicine, but with previously questionable measurement properties. First year postgraduate entry medical students at Flinders University, and trainees (postgraduate doctors in any specialty) and consultants (N = 348) based at two teaching hospitals in Adelaide, Australia, completed the ICBM and a questionnaire measuring thinking styles (Rational Experiential Inventory). Questions with the lowest item-total correlation were deleted from the original 22 item ICBM, although the resultant 17 item scale only marginally improved internal consistency (Cronbach's alpha = 0.61 compared with 0.57). A factor analysis identified two scales, both achieving only alpha = 0.58. Construct validity was assessed by correlating Rational Experiential Inventory scores with the ICBM, with some positive correlations noted for students only, suggesting that those who are naïve to the knowledge base required to "successfully" respond to the ICBM may profit by a thinking style in tune with logical reasoning. The ICBM failed to demonstrate adequate content validity, internal consistency and construct validity. It is unlikely that improvements can be achieved without considered attention to both the audience for which it is designed and its item content. The latter may need to involve both removal of some items deemed to measure multiple biases and the addition of new items in the attempt to survey the range of biases that may compromise medical decision making.


Functional expression of transient receptor potential channels in human endometrial stromal cells during the luteal phase of the menstrual cycle.
Are members of the transient receptor potential (TRP) channel superfamily functionally expressed in the human endometrial stroma? The Ca(2+)-permeable ion channels TRPV2, TRPV4, TRPC6 and TRPM7 are functionally expressed in primary endometrial stromal cells. Intercellular communication between epithelial and stromal endometrial cells is required to initiate decidualization, a prerequisite for successful implantation. TRP channels are possible candidates as signal transducers involved in cell-cell communication, but no fingerprint is available of the functional distribution of TRP channels in the human endometrium during the luteal phase of the menstrual cycle. Endometrial biopsy samples (previously frozen) from patients of reproductive age with regular menstrual cycles, who were undergoing diagnostic laparoscopic surgery for pain and/or infertility, were analysed. Samples were obtained from the menstrual (Days 1-5, n = 3), follicular (Days 6-14, n = 6), early luteal (Days 15-20, n = 5) and late luteal (Days 21-28, n = 5) phases. In addition, a total of 13 patient samples taken during the luteal phase were used to set up primary cell cultures for further experiments. Quantitative real-time PCR (qRT-PCR), immunocytochemistry, Fura2-based Ca(2+)-microfluorimetry and whole-cell patch clamp experiments were performed to study the functional expression pattern of TRP channels. Specific pharmacological agents, such as Δ(9)-tetrahydrocannabinol, GSK1016790A and 1-oleoyl-2-acetyl-glycerol, were used to functionally assess the expression of TRPV2, TRPV4 and TRPC6, respectively. Expression of TRPV2, TRPV4, TRPC1, TRPC4, TRPC6, TRPM4 and TRPM7 was detected at the mRNA level in endometrial biopsies (n = 19) and in primary endometrial stromal cell cultures obtained from patients during the luteal phase (n = 5) of the menstrual cycle. Messenger RNA levels of TRPV2, TRPC4 and TRPC6 were significantly increased (P < 0.01) in the late luteal phase compared with the early luteal phase. Immunocytochemistry experiments showed a positive staining for TRPV2, TRPV4, TRPC6 and TRPM7 in the plasma membrane and in the cytoplasm of primary endometrial stromal cells. Ca(2+)-microfluorimetry revealed significant increases (P < 0.001) in intracellular Ca(2+) levels when stromal cells were incubated with specific activators of TRPV2, TRPV4 and TRPC6. Further functional characterization was performed using whole-cell patch clamp experiments. Taken together, these data provide evidence for the functional activity of TRPV2, TRPV4, TRPC6 and TRPM7 channels in primary stromal cell cultures. Although mRNA levels are detected for TRPV6, TRPC1, TRPC4 and TRPM4, the limited supply of specific antibodies and lack of selective pharmacological agents restricted any additional analysis of these ion channels. Embryo implantation is a dynamic developmental process that integrates many signalling molecules into a precisely orchestrated programme. Our findings identified certain members of the TRP superfamily as candidate sensors in the epithelial-stromal crosstalk. These results are very helpful to unravel the signalling cascade required for successful embryo implantation. In addition, this knowledge could lead to new strategies to correct implantation failure and facilitate the development of novel non-hormonal contraceptives. This work was supported by grants from the Research Foundation-Flanders (G.0856.13N to J.V.), the Research Council of the KU Leuven (OT/13/113 to J.V. and T.D. and PF-TRPLe to T.V.) and by the Planckaert-De Waele fund (to J.V.). K.D.C. and K.H. are funded by the FWO Belgium. None of the authors have a conflict of interest.


Factors accounting for misidentification of Candida species.
From April 15 through June 15, 1999, a total of 660 yeast isolates were collected from 22 hospitals in Taiwan to investigate factors determining the accuracy of yeast identification. The germ tube test was the method most frequently used by hospitals for yeast identification, followed by the API-32C, cornmeal agar window test, and assimilation method. All of the submitted isolates were re-speciated in the National Health Research Institutes laboratory. The frequencies of inconsistent identification of isolates between hospitals and the National Health Research Institutes laboratory varied with the location and the type of hospital. The sensitivity and specificity of the germ tube test were 95% and 98.6%, respectively. This study showed that hospitals using the germ tube test as the first step in yeast identification had fewer inconsistent identifications of isolates than those using other methods. The VITEK Yeast Biochemical Card and API-32C had a sensitivity of 92.6% and 98.3%, respectively. No single method consistently identified all yeast isolates. Thus, every laboratory should have at least 2 methods available for yeast identification.


Descriptive experiences and sexual vs. nurturant aspects of cuddling between adult romantic partners.
Touch is a critical factor in intimate bonds between romantic partners. Although cuddling is a key expression of intimacy, it has received little empirical attention. Past research suggests that cuddling has some sexual aspects (e.g., it increases testosterone [T]), but there are theoretical reasons to expect cuddling to also involve nurturant intimacy (which should decrease T). In this article, we examined the phenomenon of partner cuddling to: (1) provide a descriptive examination; (2) determine if cuddling involved only nurturant intimacy or also sexual intimacy; and (3) test whether cuddling was perceived as nurturant but experienced as sexual. Via an online questionnaire, 514 participants (338 women) responded to quantitative and qualitative questions about cuddling with their romantic partners. Results suggested that cuddling occurred frequently and for relatively long durations, and was viewed very positively. Findings also showed that cuddling was perceived as nurturant and non-sexual but was experienced as at least somewhat sexual, which may explain why past research had found that cuddling increased T. Correlational analyses linked cuddling frequency and enjoyment positively with partnered sexual activities, but negatively with solitary sexuality. Results were discussed relative to evolutionary theories of distinct but overlapping neurobiological systems underlying pair bonding that involve sexual and nurturant intimacy.


The epidemiology of long- and short-term cancer survivors. A population-based cohort study exploring denominators for rehabilitation and palliative care programs.
In this study, we present data from a population-based cohort of incident cancer patients separated in long- and short-term survivors. Our aim was to procure denominators for use in the planning of rehabilitation and palliative care programs. A registry-linkage cohort study. All cancer patients, diagnosed from 1993 to 2003 from a 470 000 large population, were followed individually from diagnosis to death or until 31 December 2008. Long-term survivors lived five years or more after the time of the cancer diagnosis (TOCD). Short-term survivors died less than five years after TOCD. The cohort comprised 24 162 incident cancer patients with 41% long-term survivors (N = 9813). Seventy percent of the cohort was 60 + years at TOCD. The 14 349 short-term survivors' median survival was 0.6 year, and 78% died less than two years after TOCD. A 12 years' difference in age at TOCD was seen between long- and short-term survivors, with median ages of 60 versus 72 years, respectively. Females comprised 64% of long-term, and 46% of short-term survivors. The proportion of breast and lung cancers differed between the groups: Long-term survivors: 31% breast cancer, 2.4% lung cancer. Short-term survivors: 21% lung cancer, 7.2% breast cancer. Chemotherapy was provided to 15% of all patients, and to 10% of the 60 + year olds. The epidemiology of long- and short-term survivors shows significant differences with regard to age at TOCD, cancer types and sex. Two-year crude cancer survival seems as a clinically relevant cut point for characterizing potential "denominators" for rehabilitation or palliative care programs. From this cohort of incident cancer patients, and using two-year survival as a cut point, it could be estimated that 54% would candidate to a "care trajectory" focusing on rehabilitation and 46% a "care trajectory" focusing on palliative care at TOCD.


Comparing withdrawal and non-withdrawal of life-sustaining treatment among patients who died from stroke.
In severe stroke, a decision to withdraw life-sustaining treatment is sometimes made in cooperation with the family. The aim of this study was to study the time from withdrawing life-sustaining treatment to death in patients with severe ischemic or hemorrhagic stroke. In total, 2,506 patients with stroke admitted to Haukeland University Hospital between 2006 and 2011 were prospectively registered in the Bergen NORSTROKE database. Risk factors, stroke severity, etiology, and blood analyses were registered. Retrospectively, the patients' records were examined to determine the number of days from withdrawing all life-sustaining treatment to death in patients who died from severe stroke during the hospital stay. Life-sustaining treatment was withheld in 50 patients with severe stroke. Median time to death after withdrawing life-sustaining treatment was 4 days, and a quarter lived at least 1 week (range =1-11 days). Cox regression analyses showed that short time from withdrawing life-sustaining treatment to death was associated with high age (Hazard ratio [HR] =1.05, P=0.07), male sex (HR =2.9, P=0.01), high C-reactive protein on admission (HR =1.01, P=0.001), and hemorrhagic stroke (versus ischemic stroke, HR =1.5, P=0.03). One week after withdrawing life-sustaining treatment, a quarter of our patients with severe stroke remained alive. Short time to death was associated with high age, male sex, hemorrhagic stroke, and high C-reactive protein on admittance.


The effect of correlated linguistic dimensions on speeded classification of visually presented trigrams.
The influence of two types of linguistic dimensions, word-nonword and consonant pronunciation, on classification speed of trigrams in card-sorting tasks of two levels of complexity was examined. In complex grouping tasks, which required the evaluation of more than one letter to classify each stimulus, sorting times were faster when the linguistic dimension was correlated with, rather than orthogonal to, the response categories. For tasks in which each stimulus could be classified on the basis of a single letter, no effect of the correlated vs orthogonal linguistic dimension was observed, even when performance was degraded by visual noise. These results provide further evidence that, while linguistic properties of visual stimuli may influence classification time in complex tasks, they are of little importance in the performance of tasks only requiring the discriminalion of a single visual feature.


Clinical opinion: Earlier employment of polytherapy in sequential pharmacotherapy of epilepsy.
Modern pharmacotherapy for epilepsy consists of orderly, sequential drug trials, in which antiepileptic drugs (AEDs) are chosen under the concept of individual patient-oriented (or - tailored) pharmacotherapy. Although monotherapy has been established as the preferred mode of AEDs therapy in both newly diagnosed and drug resistant epilepsies, there are still lack of evidence to favor either monotherapy or polytherapy in epilepsy, which has generated continuing controversies on the preferred mode of pharmacotherapy. However, each mode of pharmacotherapy may have both advantages and disadvantages, which are different and variable related to individual case scenario. We conducted a brief comparative overview between monotherapy and polytherapy to provide clues for earlier employment of polytherapy in each steps of sequential drug trials. Previous claims about the advantages of monotherapy over polytherapy are not supported but gradually losing its ground by the introduction of a large number of drugs carrying pharmacological advantages for combination therapy. Current evidence stresses the importance of combining drugs having synergistic interactions for better outcome of polytherapy, which has not been considered in previous clinical investigations comparing monotherapy and polytherapy. It is likely that a significant improvement in the outcome of current AEDs therapy is feasible by earlier employment of polytherapy as well as identification of combination drug regimens carrying synergistic interactions. At present, lamotrigine(LTG) and valproate(VPA) combination regimen is the only well documented synergistic regimen, but there are a long-list of candidate regimens requiring future trials in appropriate designs.


TP53 oncomorphic mutations predict resistance to platinum‑ and taxane‑based standard chemotherapy in patients diagnosed with advanced serous ovarian carcinoma.
Individual mutations in the tumor suppressor TP53 alter p53 protein function. Some mutations create a non-functional protein, whereas others confer oncogenic activity, which we term 'oncomorphic'. Since mutations in TP53 occur in nearly all ovarian tumors, the objective of this study was to determine the relationship of oncomorphic TP53 mutations with patient outcomes in advanced serous ovarian cancer patients. Clinical and molecular data from 264 high-grade serous ovarian cancer patients uniformly treated with standard platinum- and taxane-based adjuvant chemotherapy were downloaded from The Cancer Genome Atlas (TCGA) portal. Additionally, patient samples were obtained from the University of Iowa and individual mutations were analyzed in ovarian cancer cell lines. Mutations in the TP53 were annotated and categorized as oncomorphic, loss of function (LOF), or unclassified. Associations between mutation types, chemoresistance, recurrence, and progression-free survival (PFS) were calculated. Oncomorphic TP53 mutations were present in 21.3% of ovarian cancers in the TCGA dataset. Patients with oncomorphic TP53 mutations demonstrated significantly worse PFS, a 60% higher risk of recurrence (HR=1.60, 95% confidence intervals 1.09, 2.33, p=0.015), and higher rates of platinum resistance (χ(2) test p=0.0024) when compared with single nucleotide mutations not categorized as oncomorphic. Furthermore, tumors containing oncomorphic TP53 mutations displayed unique protein expression profiles, and some mutations conferred increased clonogenic capacity in ovarian cancer cell models. Our study reveals that oncomorphic TP53 mutations are associated with worse patient outcome. These data suggest that future studies should take into consideration the functional consequences of TP53 mutations when determining treatment options.


Evidence of redistribution of cerebral blood flow during treatment for an intracranial arteriovenous malformation.
The presence of an intracranial arteriovenous malformation has a dramatic impact on local circulatory dynamics. Treatment of some arteriovenous malformations can result in disastrous hyperemic states caused by redistribution of previously shunted blood. This report describes serial hemodynamic measurements of both cerebral blood flow and flow velocity in 3 patients during treatment for arteriovenous malformations. Measurements of cerebral blood flow were made by computed tomographic scan employing the stable xenon inhalation technique; flow velocity, including autoregulatory characteristics, was measured by transcranial Doppler ultrasonogram. Substantial hyperemia developed in one patient (Case 1) after resection and in another (Case 3) after embolization. Embolization resulted in restoration of normal regional cerebral blood flow in a patient who demonstrated hypoperfusion before treatment (Case 2). In Patient 1, postoperative hyperemia was associated with persistently elevated flow velocities, and may have been accompanied by hemispheric neurological deficits. Sequential hemodynamic measurements may predict patients at risk of perioperative complications, and may become useful clinical guidelines for the extent and timing of embolization and for the timing of surgery after intracranial hemorrhage or preoperative embolization procedures.


Sexual activity after myocardial infarction: taboo or lack of knowledge?
Despite its clinical and social relevance, resumption of sexual activity after an acute coronary syndrome (ACS) is a subject that is poorly addressed by healthcare providers and one that is given scant emphasis during hospitalization. Erectile dysfunction is a common complaint among cardiac patients, and these patients are in doubt regarding the safety of resuming sexual activity after a cardiovascular event. To describe how well informed patients are in regard to acute an myocardial infarction (AMI) and what sort of guidance they receive regarding resumption of sexual activity. A cross-sectional study was performed from June to July 2005 with patients on the sixth day of AMI. A questionnaire was applied to assess not only patients' knowledge of AMI, but also their expectations regarding their resumption of sexual activity - and frequency of same - following hospital discharge. Ninety-six patients were included in the study (mean age 59 +/- 12); 70% of them were male and 80% had experienced their first AMI. Of these, 96% lacked any knowledge of AMI clinical manifestations and possible limitations, 63% reported an active sex life before the event, 60% were in doubt regarding their sex life following hospital discharge, and only 4% received sexual guidance from healthcare providers during their hospital stay. According to our findings, the recommendations patients receive during hospitalization are suboptimal in regard to both AMI and resumption of sexual activity. The updating of healthcare providers may change this situation. This is especially true for the nursing staff, since they spend more time with patients.


Current Challenges in Diagnosis and Assessment of the Response of Locally Advanced and Metastatic Renal Cell Carcinoma.
Locally advanced and metastatic renal cell carcinoma (RCC) present a specific set of challenges to the radiologist. The detection of metastatic disease is confounded by the ability of RCC to metastasize to virtually any part of the human body long after surgical resection of the primary tumor. This includes sites not commonly included in routine surveillance, which come to light after the patient becomes symptomatic. In the assessment of treatment response, the phenomenon of tumor heterogeneity, where clone selection through systemic therapy drives the growth of potentially more aggressive phenotypes, can result in oligoprogression despite overall disease control. Finally, advances in therapy have resulted in the development of immuno-oncologic agents that may result in changes that are not adequately evaluated with conventional size-based response criteria and may even be misinterpreted as progression. This article reviews the common challenges a radiologist may encounter in the evaluation of patients with locally advanced and metastatic RCC. ©RSNA, 2019.


DARPins and other repeat protein scaffolds: advances in engineering and applications.
Antibodies have long been regarded as the only class of binding proteins. With the emergence of protein engineering techniques, new binding proteins based on alternative scaffolds have been designed. Additionally, modern technologies for selection and evolution from libraries are independent of the antibody scaffold and could thus be readily used for obtaining specific binding proteins. One important group of alternative scaffolds is based on repeat proteins. Nature is widely using these proteins to modulate protein-protein interactions, and even in the adaptive immune system of jawless vertebrates; the step to their application as an alternative to antibodies seems therefore logical. In this review, progress on DARPins and other repeat protein scaffolds will be discussed. Advances in their design as well as novel applications will be highlighted.


Prefrontal cortex function in the representation of temporally complex events.
The frontal cortex and inferior temporal cortex are strongly functionally interconnected. Previous experiments on prefrontal function in monkeys have shown that a disconnection of prefrontal cortex from inferior temporal cortex impairs a variety of complex visual learning tasks but leaves simple concurrent object-reward association learning intact. We investigated the possibility that temporal components of visual learning tasks determine the sensitivity of those tasks to prefrontal-temporal disconnection by adding specific temporal components to the concurrent object-reward association learning task. Monkeys with crossed unilateral lesions of prefrontal cortex and inferior temporal cortex were impaired compared with unoperated controls at associating two-item sequences of visual objects with reward. The impairment was specific to the learning of visual sequences, because disconnection was without effect on object-reward association learning for an equivalent delayed reward. This result was replicated in monkeys with transection of the uncinate fascicle, thus determining the anatomical specificity of the dissociation. Previous behavioral results suggest that monkeys represent the two-item serial compound stimuli in a configural manner, similar to the way monkeys represent simultaneously presented compound stimuli. The representation of simultaneously presented configural stimuli depends on the perirhinal cortex. The present experiments show that the representation of serially presented compound stimuli depends on the interaction of prefrontal cortex and inferior temporal cortex. We suggest that prefrontal-temporal disconnection impairs a wide variety of learning tasks because in those tasks monkeys lay down similar temporally complex representations.


Getting to the Truth: Ethics, Trust, and Triage in the United States versus Europe during the Covid-19 Pandemic.
Ethical issues around triage have been at the forefront of debates during the Covid-19 pandemic. This essay compares both discussion and guidelines around triage and the reality of what happened in the United States and in Europe, both in anticipation of and during the first wave of the pandemic. Why did the issue generate so many vivid debates in the United States and so few in most European countries, although the latter were also affected by the rationing of health care resources? Are countries with socialized health care systems better equipped to face the hard choices of triaging? Important lessons in transparency, trust, and accountability for policy-makers can be drawn from this comparison, demonstrating that fostering public involvement and ethical debate remains a critical element for the sustained acceptance of any triage plan.


Comparison of outcomes from a phase 3 study of age-related macular degeneration with a matched, observational cohort.
To compare outcomes of intravitreal therapy from an observational study cohort with those of participants receiving treatment in the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab (MARINA) for the treatment of neovascular age-related macular degeneration (wet AMD). Database observational study. Participants in the observational cohort were chosen to match demographic features and entry criteria of the treatment group from MARINA. Outcomes over 12 months were compared. Eight hundred twenty-one anti-vascular endothelial growth factor (anti-VEGF)-naïve eyes treated with ranibizumab with 12 months or more of follow-up were included in the total Fight Retinal Blindness! (FRB-All) cohort, whereas a subset of this cohort of 401 eyes who were matched to the MARINA treatment group were included as the FRB-MARINA cohort. Intravitreal ranibizumab therapy of 0.5 mg for wet AMD. Visual acuity (VA) in logarithm of the minimum angle of resolution (logMAR) letters and treatments given were recorded continuously and anonymously in an electronic database for 12 months. Locally weighted scatterplot smoothing (LOESS) regression was used to plot change in visual acuity data over the course of 12 months for both the FRB-All cohort and the FRB-MARINA cohort, whereas results from the MARINA trial were taken from the published study report. Change in VA in logMAR letters over 12 months, treatment, and visit intensity. Mean visual acuity improvement after 12 months in FRB-MARINA (+5.5 letters) was similar to that of the 0.5-mg group from MARINA (+7.2 letters). Improvement in FRB-ALL was slightly less (+4.9 letters). Mean treatment effect compared with the MARINA control group was similar for the MARINA treated group (+17.6 letters) and the FRB-MARINA cohort (+15.9 letters). A mean of 7.3 injections in 12 months was received by the observational cohorts. Similarity of mean VA improvement in the matched observational cohort with that of the phase 3 clinical trial suggests that these results can be achieved in real-world clinical practice with a modified treatment regimen.


Selected faecal bacteria and nutrients essential for antagonism of Salmonella typhimurium in anaerobic continuous flow cultures.
As few as five of the species of bacteria commonly found in human faeces--Escherichia coli, Enterobacter aerogenes, Enterococcus faecalis, Bacteroides ovatus and Fusobacterium varium--when grown together in anaerobic continuous flow cultures exerted antagonistic effects on Salmonella typhimurium as great as those given by mixed bacteria from extracts of human faeces. In a single culture, the population of S. typhimurium was c. 10(8) cfu/ml but in mixed cultures with the five antagonistic bacteria or mixed faecal bacteria it was reduced to c. 10(3) cfu/ml. Antagonism appeared to be the result of competition for the growth limiting amino acids, arginine, serine, threonine and aspartic acid. Optimal manifestation of antagonism required the presence of carbon sources fermentable only by antagonistic bacteria, such as lactose 0.1%, w/v, sucrose 0.1% (w/v) and starch 0.2-0.3% w/v. These carbohydrates promoted the growth of the antagonistic bacteria, particularly E. coli and B. ovatus. However, an increase in concentration by several fold of any one of four growth-limiting amino acids in the medium diminished the antagonistic effects and the population of S. typhimurium rose 10(2)-10(3)-fold.


The acute management of trauma hemorrhage: a systematic review of randomized controlled trials.
Worldwide, trauma is a leading cause of death and disability. Haemorrhage is responsible for up to 40% of trauma deaths. Recent strategies to improve mortality rates have focused on optimal methods of early hemorrhage control and correction of coagulopathy. We undertook a systematic review of randomized controlled trials (RCT) which evaluated trauma patients with hemorrhagic shock within the first 24 hours of injury and appraised how the interventions affected three outcomes: bleeding and/or transfusion requirements; correction of trauma induced coagulopathy and mortality. Comprehensive searches were performed of MEDLINE, EMBASE, CENTRAL (The Cochrane Library Issue 7, 2010), Current Controlled Trials, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP) and the National Health Service Blood and Transplant Systematic Review Initiative (NHSBT SRI) RCT Handsearch Database. A total of 35 RCTs were identified which evaluated a wide range of clinical interventions in trauma hemorrhage. Many of the included studies were of low methodological quality and participant numbers were small. Bleeding outcomes were reported in 32 studies; 7 reported significantly reduced transfusion use following a variety of clinical interventions, but this was not accompanied by improved survival. Minimal information was found on traumatic coagulopathy across the identified RCTs. Overall survival was improved in only three RCTs: two small studies and a large study evaluating the use of tranexamic acid. Despite 35 RCTs there has been little improvement in outcomes over the last few decades. No clear correlation has been demonstrated between transfusion requirements and mortality. The global trauma community should consider a coordinated and strategic approach to conduct well designed studies with pragmatic endpoints.


LRP10 variants in progressive supranuclear palsy.
The aim of this study was to explore whether variants in LRP10, recently associated with Parkinson's disease and dementia with Lewy bodies, are observed in 2 large cohorts (discovery and validation cohort) of patients with progressive supranuclear palsy (PSP). A total of 950 patients with PSP were enrolled: 246 patients with PSP (n = 85 possible (35%), n = 128 probable (52%), n = 33 definite (13%)) in the discovery cohort and 704 patients with definite PSP in the validation cohort. Sanger sequencing of all LRP10 exons and exon-intron boundaries was performed in the discovery cohort, and whole-exome sequencing was performed in the validation cohort. Two patients from the discovery cohort and 8 patients from the validation cohort carried a rare, heterozygous, and possibly pathogenic LRP10 variant (p.Gly326Asp, p.Asp389Asn, and p.Arg158His, p.Cys220Tyr, p.Thr278Ala, p.Gly306Asp, p.Glu486Asp, p.Arg554∗, p.Arg661Cys). In conclusion, possibly pathogenic LRP10 variants occur in a small fraction of patients with PSP and may be overrepresented in these patients compared with controls. This suggests that possibly pathogenic LRP10 variants may play a role in the development of PSP.


A novel mesoionic carbene based highly fluorescent Pd(ii) complex as an endoplasmic reticulum tracker in live cells.
A recent study advocates that endoplasmic reticulum (ER) dysfunction may be linked to critical neurotrauma and advanced tauopathy. In this regard, targeting the ER warrants urgent attention towards the therapeutic treatment of neurotrauma-related neurodegeneration. Herein, we report the synthesis of a new N-heterocyclic mesoionic carbene based highly fluorescent square-planar Pd(ii) complex 1, with a high quantum yield (0.737). Probe 1 is a non-toxic probe for selectively labeling the endoplasmic reticulum in live cells.


Preliminary Development of a Screening Tool for Pre-Clinical Dysphagia in Community Dwelling Older Adults.
Evidence suggests that community dwelling older adults (CDOA) are at risk for dysphagia (swallowing difficulties). Dysphagia is often unidentified until related morbidities like under nutrition or pneumonia occur. These cases of unidentified dysphagia, prior to any clinical intervention, may be termed 'pre-clinical dysphagia'. Identifying pre-clinical dysphagia is challenged by the lack of validated tools appropriate for CDOA. This study addresses preliminary development of a novel patient reported outcome (PRO) screening tool for pre-clinical dysphagia. Initially, 34 questions were developed from literature review and expert opinion. Following pilot testing (n = 53), the questionnaire was revised and tested on 335 additional CDOA. Face validity, content validity, item analysis, reliability (internal consistency), and construct validity (exploratory factor analysis) measures were completed. Psychometric validation resulted in a 17-question PRO tool. Construct analysis identified a three-factor model that explained 67.345% of the variance. Emergent factors represented swallowing effort, physical function, and cognitive function. The results revealed strong construct validity and internal consistency (Cronbach's α = 0.90). A novel, simple PRO incorporating multiple function domains associated with aging demonstrated strong preliminary psychometric properties. This tool is more comprehensive and aging-focused than existing dysphagia screening tools. Inclusion of multiple domains may be key in early identification of pre-clinical dysphagia.


A single dose of in situ gel formulation of antimalarial drug chloroquine phosphate as a sustained prophylactic candidate for COVID-19.
In the ongoing COVID-19 outbreak, a prophylactic drug is strongly needed to stop the spread of this disease. Chloroquine (CQ) has been proposed as a prophylactic for individuals who are likely to be exposed to the virus. This study aimed to study the ability of CQ to act as a prophylactic treatment for susceptible people. The pharmacokinetic profiles of in situ gel and free CQ phosphate were determined using high-performance liquid chromatography. The effects of both formulations were examined on both liver and kidney functions. CQ levels were sustained in the plasma of both free and in situ gel-treated groups. Thus, our study shows that the in situ gel of CQ provides sustained release of CQ that is given only as a single dose. However, it should be used cautiously in patients with liver or kidney dysfunction.


Nutrition and cancer: the current epidemiological evidence.
We have examined the current scientific evidence on the relationship between nutrition and the most frequent tumours in the Spanish population: lung, colorectal, prostate, breast and stomach. Consumption of fruit is negatively associated with cancer of the lung and stomach, possibly with colorectal cancer, but probably not with prostate cancer and breast cancer. Consumption of vegetables probably reduces the risk of colorectal and stomach cancer, but probably is not associated with cancer of the lung, prostate and breast. Consumption of red and processed meat is positively associated with colorectal cancer and probably with stomach cancer. Animal fat is possibly associated with colorectal cancer and probably with prostate and breast cancer. High alcohol intake increases the risk of colorectal and breast cancer, while dairy products and calcium seem to decrease the risk of colorectal cancer. Obesity is a recognised risk factor of colorectal cancer and breast cancer in postmenopausal women, while foods with a high glycaemic index and glycaemic load possibly increase the risk of colorectal and prostate cancer. The relevance of nutrition on the cancer process is evident. Nevertheless important issues remain to be solved and further studies are needed. This accumulative knowledge should be used by public health authorities to develop recommendations and activities to reduce overweight and obesity and to promote healthy dietary habits.


Ingredients for protist coexistence: competition, endosymbiosis and a pinch of biochemical interactions.
1. The interaction between mutualism, facilitation or interference and exploitation competition is of major interest as it may govern species coexistence. However, the interplay of these mechanisms has received little attention. This issue dates back to Gause, who experimentally explored competition using protists as a model [Gause, G.F. (1935) Vérifications expérimentales de la théorie mathématique de la lutte pour la vie. Actualités Scientifiques et Industrielles, 277]. He showed the coexistence of Paramecium caudatum with a potentially allelopathic species, Paramecium bursaria. 2. Paramecium bursaria hosts the green algae Chlorella vulgaris. Therefore, P. bursaria may benefit from carbohydrates synthesised by the algae. Studying endosymbiosis with P. bursaria is possible as it can be freed of its endosymbiont. In addition, C. vulgaris is known to produce allelochemicals, and P. bursaria may benefit also from allelopathic compounds. 3. We designed an experiment to separate the effects of resource exploitation, endosymbiosis and allelopathy and to assess their relative importance for the coexistence of P. bursaria with a competitor that exploits the same resource, bacteria. The experiment was repeated with two competitors, Colpidium striatum or Tetrahymena pyriformis. 4. Results show that the presence of the endosymbiont enables the coexistence of competitors, while its loss leads to competitive exclusion. These results are in agreement with predictions based on resource equilibrium density of monocultures (R*) supporting the idea that P. bursaria's endosymbiont is a resource provider for its host. When P. bursaria and T. pyriformis coexist, the density of the latter shows large variation that match the effects of culture medium of P. bursaria. Our experiment suggests these effects are because of biochemicals produced in P. bursaria culture. 5. Our results expose the hidden diversity of mechanisms that underlie competitive interactions. They thus support Gauses's speculation (1935) that allelopathic effects might have been involved in his competition experiments. We discuss how a species engaged both in competition for a resource and in costly interference such as allelopathy may counterbalance these costs with a resource-provider endosymbiont.


Accidental injury is a serious risk in children with typical absence epilepsy.
To determine if young adults with a history of typical absence epilepsy (AE) in childhood have a greater risk of accidental injury than controls with juvenile rheumatoid arthritis (JRA). To assess the nature and severity of these injuries. All patients with AE or JRA diagnosed between 1977 and 1985, who were 18 years or older at the onset of the study, were identified from review of pediatric electroencephalographic records for the province of Nova Scotia (AE) or review of the medical records database at the only tertiary care pediatric center for the province (JRA). Fifty-nine (86%) of 69 patients with AE and 61 (80%) of 76 patients with JRA participated in an interview in 1994 or 1995, assessing nature, severity, and treatment of prior accidental injuries. Patients with AE were further questioned about injuries sustained during an absence seizure. Sixteen (27%) of 59 patients with AE reported accidental injury during an absence seizure, with risk of injury being 9% per person-year of AE. Most injuries (81%) occurred during anti-epileptic drug therapy. Although the majority of injuries did not require treatment, 2 (13%) of 16 patients required minor treatment and 2 (13%) of 16 were admitted to hospital. The risk of accidental injury resulting from an absence seizure in person-years at risk was highest in juvenile myoclonic epilepsy (45%), moderate in juvenile AE (14%), and lowest in childhood AE (3%). Patients with AE had a greater number of overall accidental injuries than those with JRA (P<.04), but these differences were particularly marked for bicycle (P<.003) and car accidents (P<.05) and for mild head injuries (P=.05). Accidental injury is common in AE and usually occurs after anti-epileptic drug treatment is started. Injury prevention counseling is indicated both at diagnosis and follow-up. Bicycle accidents pose a special risk and helmet use should be mandatory.


Association between XRCC3 Thr241Met polymorphism and laryngeal cancer susceptibility in Turkish population.
DNA repair systems are essential for normal cell function. Genetic alterations in the DNA repair genes such as X-ray repair cross-complementing group 3 (XRCC3), can cause a change in protein activity which results in cancer susceptibility. The aim of this study was to investigate the association of XRCC3 Thr241Met single nucleotide polymorphism (SNP), smoking and alcohol consumption with the risk of laryngeal cancer in Turkish population. The frequencies of Thr241Met SNP were studied in 58 laryngeal cancer cases (SSC) and 67 healthy individuals. Genomic DNA was isolated from peripheral blood samples of both controls and laryngeal cancer cases. Thr241Met SNP was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The genotype and allele frequencies of Thr241Met polymorphism were not statistically significant between the laryngeal cancer and control groups. Carrying mutant allele was not associated with the risk of laryngeal cancer. On the other hand, smoking and chronic alcohol consumption were associated with the risk of laryngeal cancer but there is no association between Thr241Met, smoking and alcohol consumption in laryngeal cancer cases. These results indicate that Thr241Met polymorphism was not associated with the development of laryngeal cancer in Turkish population. However, it should be kept in mind that the association of a polymorphism with cancer susceptibility can differ due to several factors such as cancer type, selection criteria, ethnic differences and size of the studied population.


Ku can contribute to telomere lengthening in yeast at multiple positions in the telomerase RNP.
Unlike ribonucleoprotein complexes that have a highly ordered overall architecture, such as the ribosome, yeast telomerase appears to be much more loosely constrained. Here, we investigate the importance of positioning of the Ku subunit within the 1157-nt yeast telomerase RNA (TLC1). Deletion of the 48-nt Ku-binding hairpin in TLC1 RNA (tlc1Δ48) reduces telomere length, survival of cells with gross chromosomal rearrangements, and de novo telomere addition at a broken chromosome end. To test the function of Ku at novel positions in the telomerase RNP, we reintroduced its binding site into tlc1Δ48 RNA at position 446 or 1029. We found that Ku bound to these repositioned sites in vivo and telomere length increased slightly, but statistically significantly. The ability of telomerase to promote survival of cells with gross chromosomal rearrangements by healing damaged chromosome arms was also partially restored, whereas the kinetics of DNA addition to a specific chromosome break was delayed. Having two Ku sites in TLC1 caused progressive hyperelongation of a variable subset of telomeres, consistent with Ku's role in telomerase recruitment to chromosome ends. The number of Ku-binding sites in TLC1 contributed to telomerase RNA abundance in vivo but was only partially responsible for telomere length phenotypes. Thus, telomerase RNA levels and telomere length regulation can be modulated by the number of Ku sites in telomerase RNA. Furthermore, there is substantial flexibility in the relative positioning of Ku in the telomerase RNP for native telomere length maintenance, although not as much flexibility as for the essential Est1p subunit.


Gram (-) microorganisms DNA polymerase inhibition, antibacterial and chemical properties of fruit and leaf extracts of Sorbus acuparia and Sorbus caucasica var. yaltirikii.
Investigation of novel plant-based agents might provide alternative antibiotics and thus fight antibiotic resistance. Here, we measured the ability of fruit and leaf extracts of Sorbus aucuparia (Sauc) and endemic Sorbus caucasica var. yaltirikii (Scau) to inhibit nonreplicative (Klenow Fragment-KF and Bacillus Large Fragment-BLF) and replicative (DnaE and PolC) bacterial DNA polymerases along with their antimicrobial, DPPH free radical scavenging activity (RSA), and chemical contents by total phenolic content and HPLC-DAD analysis. We found that leaf extracts had nearly 10-fold higher RSA and 5-fold greater TPC than the corresponding fruit extracts. All extracts had large amounts of chlorogenic acid (CGA) and rutin, while fruit extracts had large amounts of quercetin. Hydrolysis of fruit extracts revealed mainly caffeic acid from CGA (caffeoylquinic acid) and quercetin from rutin (quercetin-3-O-rutinoside), as well as CGA and derivatives of CGA and p-coumaric acid. Plant extracts of Sorbus species showed antimicrobial activity against Gram-negative microorganisms. Scau leaf extracts exhibited strong inhibition of KF activity. Sauc and Scau leaf extracts also strongly inhibited two replicative DNA polymerases. Thus, these species can be considered a potential source of novel antimicrobial agents specific for Gram-negative bacteria.


The Effects of Caffeine Ingestion on Measures of Rowing Performance: A Systematic Review and Meta-Analysis.
The purpose of this paper was to conduct a systematic review and a meta-analysis of studies examining the acute effects of caffeine ingestion on measures of rowing performance. Crossover and placebo-controlled experiments that investigated the effects of caffeine ingestion on measures of rowing performance were included. The PEDro checklist was used to assess the methodological quality of the included studies. Seven studies of good and excellent methodological quality were included. None of the included studies examined on-water rowing. The majority of studies that were included in the meta-analysis used a 2000m rowing distance with only one using 1000m distance. Results of the main meta-analysis indicated that caffeine enhances performance on a rowing ergometer compared to placebo with a mean difference of -4.1 s (95% confidence interval (CI): -6.4, -1.8 s). These values remained consistent in the analysis in which the study that used a 1000m distance was excluded (mean difference: -4.3 s; 95% CI: -6.9, -1.8 s). We also found a significant increase in mean power (mean difference: 5.7 W; 95% CI: 2.1, 9.3 W) and minute ventilation (mean difference: 3.4 L/min; 95% CI: 1.7, 5.1 L/min) following caffeine ingestion. No significant differences between caffeine and placebo were found for the rating of perceived exertion, oxygen consumption, respiratory exchange ratio, and heart rate. This meta-analysis found that acute caffeine ingestion improves 2000m rowing ergometer performance by ~4 s. Our results support the use of caffeine pre-exercise as an ergogenic aid for rowing performance.


Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy.
Correct regulation of troponin and myosin contractile protein gene isoforms is a critical determinant of cardiac and skeletal striated muscle development and function, with misexpression frequently associated with impaired contractility or disease. Here we reveal a novel requirement for Prospero-related homeobox factor 1 (Prox1) during mouse heart development in the direct transcriptional repression of the fast-twitch skeletal muscle genes troponin T3, troponin I2, and myosin light chain 1. A proportion of cardiac-specific Prox1 knockout mice survive beyond birth with hearts characterized by marked overexpression of fast-twitch genes and postnatal development of a fatal dilated cardiomyopathy. Through conditional knockout of Prox1 from skeletal muscle, we demonstrate a conserved requirement for Prox1 in the repression of troponin T3, troponin I2, and myosin light chain 1 between cardiac and slow-twitch skeletal muscle and establish Prox1 ablation as sufficient to cause a switch from a slow- to fast-twitch muscle phenotype. Our study identifies conserved roles for Prox1 between cardiac and skeletal muscle, specifically implicated in slow-twitch fiber-type specification, function, and cardiomyopathic disease.


A critical role for Neurofascin in regulating action potential initiation through maintenance of the axon initial segment.
The axon initial segment (AIS) is critical for the initiation and propagation of action potentials. Assembly of the AIS requires interactions between scaffolding molecules and voltage-gated sodium channels, but the molecular mechanisms that stabilize the AIS are poorly understood. The neuronal isoform of Neurofascin, Nfasc186, clusters voltage-gated sodium channels at nodes of Ranvier in myelinated nerves: here, we investigate its role in AIS assembly and stabilization. Inactivation of the Nfasc gene in cerebellar Purkinje cells of adult mice causes rapid loss of Nfasc186 from the AIS but not from nodes of Ranvier. This causes AIS disintegration, impairment of motor learning and the abolition of the spontaneous tonic discharge typical of Purkinje cells. Nevertheless, action potentials with a modified waveform can still be evoked and basic motor abilities remain intact. We propose that Nfasc186 optimizes communication between mature neurons by anchoring the key elements of the adult AIS complex.


Genotype-Corrector: improved genotype calls for genetic mapping in F2 and RIL populations.
F2 and recombinant inbred lines (RILs) populations are very commonly used in plant genetic mapping studies. Although genome-wide genetic markers like single nucleotide polymorphisms (SNPs) can be readily identified by a wide array of methods, accurate genotype calling remains challenging, especially for heterozygous loci and missing data due to low sequencing coverage per individual. Therefore, we developed Genotype-Corrector, a program that corrects genotype calls and imputes missing data to improve the accuracy of genetic mapping. Genotype-Corrector can be applied in a wide variety of genetic mapping studies that are based on low coverage whole genome sequencing (WGS) or Genotyping-by-Sequencing (GBS) related techniques. Our results show that Genotype-Corrector achieves high accuracy when applied to both synthetic and real genotype data. Compared with using raw or only imputed genotype calls, the linkage groups built by corrected genotype data show much less noise and significant distortions can be corrected. Additionally, Genotype-Corrector compares favorably to the popular imputation software LinkImpute and Beagle in both F2 and RIL populations. Genotype-Corrector is publicly available on GitHub at https://github.com/freemao/Genotype-Corrector .


Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection.
Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers: Washington University School of Medicine (n=134) and Yale School of Medicine (n=49). We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza (n=54), and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV, n=22). We demonstrate that circulating markers of complement activation are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., angiopoietin-2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials.


The effect of grape-seed extract on 24 h energy intake in humans.
Since grape-seed extract has been shown to stimulate lipolysis in vitro and reduce food intake in rats, we assessed the efficacy of grape-seed extract with respect to energy intake (EI) and satiety. In a randomized, placebo-controlled, double-blind, cross-over study, 51 subjects (age 18-65 y, body mass index 22-30 kg/m2) ate an ad libitum lunch and dinner twice in the University Restaurant for 3 days. Standard breakfasts and snacks were provided. Supplements were taken 30-60 min prior to each meal. In the total study population, no difference in 24 h EI was found between the grape-seed extract and placebo. However, in the subgroup of subjects (n=23) with an energy requirement > or =the median of 7.5 MJ/day, EI was reduced by 4% (DeltaEI 352.1 kJ/24 h, P=0.05) after grape-seed extract compared to placebo treatment. Meanwhile, there were no significant differences in macronutrient composition, attitude towards eating, satiety, mood or tolerance. Grape seed reduced 24 h EI, with on average 4% in subjects who had an energy requirement > or =7.5 MJ/day, without further effects on satiety, mood or tolerance. These findings suggest that grape seed could be effective in reducing 24 h EI in normal to overweight dietary unrestrained subjects, and could, therefore, play a significant role in body-weight management.


Bird mercury concentrations change rapidly as chicks age: toxicological risk is highest at hatching and fledging.
Toxicological risk of methylmercury exposure to juvenile birds is complex due to the highly transient nature of mercury concentrations as chicks age. We examined total mercury and methylmercury concentrations in blood, liver, kidney, muscle, and feathers of 111 Forster's tern (Sterna forsteri), 69 black-necked stilt (Himantopus mexicanus), and 43 American avocet (Recurvirostra americana) chicks as they aged from hatching through postfledging at wetlands that had either low or high mercury contamination in San Francisco Bay, California. For each waterbird species, internal tissue, and wetland, total mercury and methylmercury concentrations changed rapidly as chicks aged and exhibited a quadratic, U-shaped pattern from hatching through postfledging. Mercury concentrations were highest immediately after hatching, due to maternally deposited mercury in eggs, then rapidly declined as chicks aged and diluted their mercury body burden through growth in size and mercury depuration into growing feathers. Mercury concentrations then increased during fledging when mass gain and feather growth slowed, while chicks continued to acquire dietary mercury. In contrast to mercury in internal tissues, mercury concentrations in chick feathers were highly variable and declined linearly with age. For 58 recaptured Forster's tern chicks, the proportional change in blood mercury concentration was negatively related to the proportional change in body mass, but not to the amount of feathers or wing length. Thus, mercury concentrations declined more in chicks that gained more mass between sampling events. The U-shaped pattern of mercury concentrations from hatching to fledging indicates that juvenile birds may be at highest risk to methylmercury toxicity shortly after hatching when maternally deposited mercury concentrations are still high and again after fledging when opportunities for mass dilution and mercury excretion into feathers are limited.


Neural Support for Contributions of Utility and Narrative Processing of Evidence in Juror Decision Making.
Efforts to explain complex human decisions have focused on competing theories emphasizing utility and narrative mechanisms. These are difficult to distinguish using behavior alone. Both narrative and utility theories have been proposed to explain juror decisions, which are among the most consequential complex decisions made in a modern society. Here, we asked jury-eligible male and female subjects to rate the strength of a series of criminal cases while recording the resulting patterns of brain activation. We compared patterns of brain activation associated with evidence accumulation to patterns of brain activation derived from a large neuroimaging database to look for signatures of the cognitive processes associated with different models of juror decision-making. Evidence accumulation correlated with multiple narrative processes, including reading and recall. Of the cognitive processes traditionally viewed as components of utility, activation patterns associated with uncertainty, but not value, were more active with stronger evidence. Independent of utility and narrative, activations linked to reasoning and relational logic also correlated with increasing evidence. Hierarchical modeling of cognitive processes associated with evidence accumulation supported a more prominent role for narrative in weighing evidence in complex decisions. However, utility processes were also associated with evidence accumulation. These complementary findings support an emerging view that integrates utility and narrative processes in complex decisions.SIGNIFICANCE STATEMENT The last decade has seen a sharply increased interest in narrative as a central cognitive process in human decision-making and as an important factor in the evolution of human societies. However, the roles of narrative versus utility models of decision-making remain hotly debated. While available models frequently produce similar behavioral predictions, they rely on different cognitive processes and so their roles can be separated using the right neural tests. Here, we use brain imaging during mock juror decisions to show that cognitive processes associated with narrative, and to a lesser extent utility, were engaged while subjects evaluated evidence. These results are consistent with interactions between narrative and utility processes during complex decision-making.


Implementing early infant diagnosis of HIV infection at the primary care level: experiences and challenges in Malawi.
Malawi's national guidelines recommend that infants exposed to the human immunodeficiency virus (HIV) be tested at 6 weeks of age. Rollout of services for early infant diagnosis has been limited and has resulted in the initiation of antiretroviral therapy (ART) in very few infants. An early infant diagnosis programme was launched. It included education of pregnant women on infant testing, community sensitization, free infant testing at 6 weeks of age, active tracing of HIV-positive infants and referral for treatment and care. The programme was established in two primary care facilities in Blantyre, Malawi. Of 1214 HIV-exposed infants, 71.6% presented for early diagnosis, and 14.5% of those who presented tested positive for HIV. Further testing of 103 of these 126 apparently HIV-positive infants confirmed infection in 88; the other 15 results were false positives. The initial polymerase chain reaction testing of dried blood spots had a positive predictive value (PPV) of 85.4%. Despite active tracing, only 87.3% (110/126) of the mothers of infants who initially tested positive were told their infants' test results. ART was initiated in 58% of the infants with confirmed HIV infection. Early infant diagnosis of HIV infection at the primary care level in a resource-poor setting is challenging. Many children in the HIV diagnosis and treatment programme were lost to follow-up at various stages. Diagnostic tools with higher PPV and point-of-care capacity and better infrastructures for administering ART are needed to improve the management of HIV-exposed and HIV-infected infants.


Alternatives to Carbon Dioxide-Taking Responsibility for Humanely Ending the Life of Animals.
Carbon dioxide (CO2) is commonly used to kill rodents. However, a large body of research has now established that CO2 is aversive to them. A multidisciplinary symposium organized by the Swiss Federal Food Safety and Veterinary Office discussed the drawbacks and alternatives to CO2 in euthanasia protocols for laboratory animals. Dialogue was facilitated by brainstorming sessions in small groups and a "World Café". A conclusion from this process was that alternatives to CO2 were urgently required, including a program of research and extension to meet the needs for humane killing of these animals. The next step will involve gathering a group of international experts to formulate, draft, and publish a research strategy on alternatives to CO2.


Risk determination and prevention of breast cancer.
Breast cancer is an increasing public health problem. Substantial advances have been made in the treatment of breast cancer, but the introduction of methods to predict women at elevated risk and prevent the disease has been less successful. Here, we summarize recent data on newer approaches to risk prediction, available approaches to prevention, how new approaches may be made, and the difficult problem of using what we already know to prevent breast cancer in populations. During 2012, the Breast Cancer Campaign facilitated a series of workshops, each covering a specialty area of breast cancer to identify gaps in our knowledge. The risk-and-prevention panel involved in this exercise was asked to expand and update its report and review recent relevant peer-reviewed literature. The enlarged position paper presented here highlights the key gaps in risk-and-prevention research that were identified, together with recommendations for action. The panel estimated from the relevant literature that potentially 50% of breast cancer could be prevented in the subgroup of women at high and moderate risk of breast cancer by using current chemoprevention (tamoxifen, raloxifene, exemestane, and anastrozole) and that, in all women, lifestyle measures, including weight control, exercise, and moderating alcohol intake, could reduce breast cancer risk by about 30%. Risk may be estimated by standard models potentially with the addition of, for example, mammographic density and appropriate single-nucleotide polymorphisms. This review expands on four areas: (a) the prediction of breast cancer risk, (b) the evidence for the effectiveness of preventive therapy and lifestyle approaches to prevention, (c) how understanding the biology of the breast may lead to new targets for prevention, and (d) a summary of published guidelines for preventive approaches and measures required for their implementation. We hope that efforts to fill these and other gaps will lead to considerable advances in our efforts to predict risk and prevent breast cancer over the next 10 years.


Olaparib increases the therapeutic index of hemithoracic irradiation compared with hemithoracic irradiation alone in a mouse lung cancer model.
The radiosensitising effect of the poly(ADP-ribose) polymerase inhibitor olaparib on tumours has been reported. However, its effect on normal tissues in combination with radiation has not been well studied. Herein, we investigated the therapeutic index of olaparib combined with hemithoracic radiation in a urethane-induced mouse lung cancer model. To assess tolerability, A/J mice were treated with olaparib plus whole thorax radiation (13 Gy), body weight changes were monitored and normal tissue effects were assessed by histology. In anti-tumour (intervention) studies, A/J mice were injected with urethane to induce lung tumours, and were then treated with olaparib alone, left thorax radiation alone or the combination of olaparib plus left thorax radiation at 8 weeks (early intervention) or 18 weeks (late intervention) after urethane injection. Anti-tumour efficacy and normal tissue effects were assessed by visual inspection, magnetic resonance imaging and histology. Enhanced body weight loss and oesophageal toxicity were observed when olaparib was combined with whole thorax but not hemithorax radiation. In both the early and late intervention studies, olaparib increased the anti-tumour effects of hemithoracic irradiation without increasing lung toxicity. The addition of olaparib increased the therapeutic index of hemithoracic radiation in a mouse model of lung cancer.


An old enemy not to be forgotten during PET CT scanning of cancer patients: tuberculosis.
Positron emission tomography-computed tomography (PET CT) scan is commonly used in current medical oncology practice as an imaging method. In this study we present data from cancer patients who were followed at our clinic and suspected of having tuberculosis during PET CT scanning. After the biopsy, they were diagnosed with concomitant tuberculosis. In this study, 14 patients who applied to our clinic and followed up due to cancer, and had PET CT scanning for the preliminary staging or further evaluation, were included. The patients were diagnosed with metastatic or recurrent disease, and their biopsy results revealed tuberculosis. The mean age was 57.8 years with SD (standard deviation) 13.1 years and gender distribution of 78.6% (n = 11) females and 21.4% (n = 3) males. None of the patients had tuberculosis in their personal history (0%). Among the patients, 5 (35.7%) were diagnosed with tuberculosis during the preliminary staging, whereas 9 (64.3%) were diagnosed during the follow-up after the treatment. The median time to tuberculosis diagnosis was 11 months (min-max: 3-24 months) after the treatment. The most commonly involved lymph nodes during PET CT scanning were mediastinal in 8 (64.3%), axillary in 3 (21.4%) and para-aortic in 3 (21.4%) patients. The mean SUVmax (maximum standardised uptake value) of lymph node involved by PET CT scanning was defined as 8.5 (SD 2.6). Despite all improvements in modern medicine, tuberculosis is still a serious public health problem. It should always be considered in differential diagnosis while evaluating PET CT scanning results of cancer patients, because it may cause false positive results.


Management of COVID-19: current status and future prospects.
COVID-19, a highly transmissible pandemic disease, is affecting millions of lives around the world. Severely infected patients show acute respiratory distress symptoms. Sustainable management strategies are required to save lives of the infected people and further preventing spread of the virus. Diagnosis, treatment, and vaccination development initiatives are already exhibited from the scientific community to fight against this virus. In this review, we primarily discuss the management strategies including prevention of spread, prophylaxis, vaccinations, and treatment for COVID-19. Further, analysis of vaccine development status and performance are also briefly discussed. Global socioeconomic impact of COVID-19 is also analyzed as part of this review.


Triple-negative breast cancer: the reality in Chile and in Latin America.
Breast cancer is the leading cause of cancer death among women worldwide. While triple-negative breast cancer is less common among various sub-types of breast cancer, it tends to affect younger women and is more aggressive, having a higher rate of early recurrence and mortality compared to other sub-types. We know about the association between triple-negative breast cancer and BRCA mutations, which are highly prevalent in founding populations of European origin, but the true prevalence of these mutations in Latin American populations is unknown. There is also very little information about the demographic and epidemiological aspects of triple-negative breast cancer in Latin America, which we will try to summarise in this article. In addition, we will try to provide a brief introduction to the most common recommendations for treating this histological class in Latin America.