Mutations in sigma 70 transcription factor improves expression of functional eukaryotic membrane proteins in Escherichia coli.
Eukaryotic integral membrane proteins (IMPs) are difficult to study due to low functional expression levels. To investigate factors for efficient biogenesis of eukaryotic IMPs in the prokaryotic model organism Escherichia coli, important, e.g., for isotope-labeling for NMR, we selected for E. coli cells expressing high levels of functional G protein-coupled receptors (GPCRs) by FACS. Utilizing an E. coli strain library with all non-essential genes systematically deleted, we unexpectedly discovered upon whole-genome sequencing that the improved phenotype was not conferred by the deleted genes but by various subtle alterations in the "housekeeping" sigma 70 factor (RpoD). When analyzing effects of the rpoD mutations at the transcriptome level we found that toxic effects incurred on wild-type E. coli during receptor expression were diminished by two independent and synergistic effects: a slower but longer-lasting GPCR biosynthesis and an optimized transcriptional pattern, augmenting growth and expression at low temperature, setting the basis for further bacterial strain engineering.


Time delay associated with total reflection of a plane wave upon plasma mirror.
By employing both the ray model and the electromagnetic theory in a slab optical waveguide, we show that the Goos-Hänchen time, which has been recently argued in the literature, really exists and the time associated with total reflection of a plane wave upon nonabsorbing plasma mirror is exactly the sum of the group delay time and the Goos-Hänchen time. Based on this concept, it is also indicated that the causality is preserved not only for the frustrated Gires-Tournois interferometer case but also for the case of total reflection of a plane TM wave on a nonabsorbing plasma mirror.


Structure-function analysis of the mRNA cap methyltransferase of Saccharomyces cerevisiae.
The Saccharomyces cerevisiae mRNA cap methylating enzyme is a 436-amino acid protein encoded by the essential ABD1 gene. To identify structural features of ABD1 required for enzyme function, we introduced alanine mutations at 19 positions within a 205-amino acid region of similarity to the methyltransferase domain of the vaccinia capping enzyme. Three new recessive lethal mutations, E170A, D194A, and R206A, were identified. Structure-function relationships were clarified by introducing conservative substitutions at Glu-170, Asp-194, and Arg-206, and at Tyr-254 (an essential residue identified previously). Alleles E170D and D194E were viable, whereas E170Q and D194N were lethal; hence, acidic side chains were critical at both positions. R206K was viable, suggesting that a basic residue sufficed. Y254S was lethal, whereas Y254F was viable, albeit slow growing; thus, an aromatic side chain was important. The ABD1 mutations that were deleterious in vivo elicited catalytic defects in vitro. By studying the effects of amino- and carboxyl-terminal deletions, we defined a fully active catalytic domain of ABD1 from residues 130 to 426. Residues 110-129 were dispensable for methyltransferase activity in vitro, but essential for function in vivo. This analysis allowed us to delineate a subfamily of ABD1-like proteins within the superfamily of AdoMet-dependent methyltransferases. In addition, we identify a candidate Caenorhabditis elegans gene encoding a putative cap methyltransferase. All residues essential for ABD1 activity are conserved in the C. elegans homologue.


Variations in CCL3L gene cluster sequence and non-specific gene copy numbers.
Copy number variations (CNVs) of the gene CC chemokine ligand 3-like1 (CCL3L1) have been implicated in HIV-1 susceptibility, but the association has been inconsistent. CCL3L1 shares homology with a cluster of genes localized to chromosome 17q12, namely CCL3, CCL3L2, and, CCL3L3. These genes are involved in host defense and inflammatory processes. Several CNV assays have been developed for the CCL3L1 gene. Through pairwise and multiple alignments of these genes, we have shown that the homology between these genes ranges from 50% to 99% in complete gene sequences and from 70-100% in the exonic regions, with CCL3L1 and CCL3L3 being identical. By use of MEGA 4 and BioEdit, we aligned sense primers, anti-sense primers, and probes used in several previously described assays against pre-multiple alignments of all four chemokine genes. Each set of probes and primers aligned and matched with overlapping sequences in at least two of the four genes, indicating that previously utilized RT-PCR based CNV assays are not specific for only CCL3L1. The four available assays measured median copies of 2 and 3-4 in European and African American, respectively. The concordance between the assays ranged from 0.44-0.83 suggesting individual discordant calls and inconsistencies with the assays from the expected gene coverage from the known sequence. This indicates that some of the inconsistencies in the association studies could be due to assays that provide heterogenous results. Sequence information to determine CNV of the three genes separately would allow to test whether their association with the pathogenesis of a human disease or phenotype is affected by an individual gene or by a combination of these genes.


p73 regulates neurodegeneration and phospho-tau accumulation during aging and Alzheimer's disease.
The genetic mechanisms that regulate neurodegeneration are only poorly understood. We show that the loss of one allele of the p53 family member, p73, makes mice susceptible to neurodegeneration as a consequence of aging or Alzheimer's disease (AD). Behavioral analyses demonstrated that old, but not young, p73+/- mice displayed reduced motor and cognitive function, CNS atrophy, and neuronal degeneration. Unexpectedly, brains of aged p73+/- mice demonstrated dramatic accumulations of phospho-tau (P-tau)-positive filaments. Moreover, when crossed to a mouse model of AD expressing a mutant amyloid precursor protein, brains of these mice showed neuronal degeneration and early and robust formation of tangle-like structures containing P-tau. The increase in P-tau was likely mediated by JNK; in p73+/- neurons, the activity of the p73 target JNK was enhanced, and JNK regulated P-tau levels. Thus, p73 is essential for preventing neurodegeneration, and haploinsufficiency for p73 may be a susceptibility factor for AD and other neurodegenerative disorders.


ECONOMIC GEOLOGY: Lessons Learned from Deep-Sea Mining.
The first attempt to exploit deep-sea manganese nodules ended in failure as a result of the collapse of world metal prices, the onerous provisions imposed by the U. N. Conference on the Law of the Sea (UNCLOS), and the overoptimistic assumptions about the viability of nodule mining. Attention then focused on cobalt-rich manganese crusts from seamounts. Since the mid-1980s, a number of new players have committed themselves to long-term programs to establish the viability of mining deep-sea manganese nodules. These programs require heavy subsidy by host governments. Gold-rich submarine hydrothermal deposits located at convergent plate margins are now emerging as a more promising prospect for mining than deep-sea manganese deposits.


Opportunistic computed tomography screening shows a high incidence of osteoporosis in ankylosing spondylitis patients with acute vertebral fractures.
Advanced ankylosing spondylitis is associated with reductions in bone mineral density (BMD), contributing to pain and predisposing to fractures. Quantifying this reduction is complicated because overgrowth of bone and loss of trabecular bone occur concurrently. Traditional methods such as dual-energy X-ray absorptiometry struggle to generate accurate estimates of BMD in these patients. The aim of this study was to evaluate the utility of computed tomography (CT) attenuation in generating estimates of BMD in patients with severe AS who had sustained vertebral fractures. Patients with severe AS and bridging syndesmophytes who presented, with acute fractures of the spine, were reviewed to assess whether they had a CT scan in the 6 mo before or after injury that included an image of the L1 vertebra; if it did, the scans were selected for analysis. A total of 17 patients were evaluated. Using a CT attenuation threshold of 135 HU balanced for sensitivity and specificity, 14 of 17 (82%) patients were osteoporotic. Using a CT attenuation threshold for higher sensitivity (160 HU), 15 of 17 (88%) patients were osteoporotic. Even using the L1 CT attenuation threshold of 110 HU for higher specificity, 14 of 17 (82%) patients were osteoporotic. CT attenuation demonstrates that a high proportion of AS patients who sustain fractures have osteoporosis. This overcomes some of the difficulties that have been encountered with the use of dual-energy X-ray absorptiometry in this group of patients. This simple and accessible method saves on time, cost, and exposure to radiation and can help in the planning of a patient's management.


Neural correlates of oddball detection in self-motion heading: a high-density event-related potential study of vestibular integration.
The perception of self-motion is a product of the integration of information from both visual and non-visual cues, to which the vestibular system is a central contributor. It is well documented that vestibular dysfunction leads to impaired movement and balance, dizziness and falls, and yet our knowledge of the neuronal processing of vestibular signals remains relatively sparse. In this study, high-density electroencephalographic recordings were deployed to investigate the neural processes associated with vestibular detection of changes in heading. To this end, a self-motion oddball paradigm was designed. Participants were translated linearly 7.8 cm on a motion platform using a one second motion profile, at a 45° angle leftward or rightward of straight ahead. These headings were presented with a stimulus probability of 80-20 %. Participants responded when they detected the infrequent direction change via button-press. Event-related potentials (ERPs) were calculated in response to the standard (80 %) and target (20 %) movement directions. Statistical parametric mapping showed that ERPs to standard and target movements differed significantly from 490 to 950 ms post-stimulus. Topographic analysis showed that this difference had a typical P3 topography. Individual participant bootstrap analysis revealed that 93.3 % of participants exhibited a clear P3 component. These results indicate that a perceived change in vestibular heading can readily elicit a P3 response, wholly similar to that evoked by oddball stimuli presented in other sensory modalities. This vestibular-evoked P3 response may provide a readily and robustly detectable objective measure for the evaluation of vestibular integrity in various disease models.


Clinical and Cost Implications of Inpatient Versus Outpatient Orthopedic Surgeries: A Systematic Review of the Published Literature.
The number of outpatient orthopedic surgeries performed within North America continues to increase. The impact of this change in services on patient outcomes is largely unknown. The objective of this review is to compare patient outcomes and associated costs for outpatient orthopedic surgeries traditionally performed in hospital to inpatient surgeries, as well as to summarize the eligibility and preoperative education requirements for outpatient orthopedic surgery in North America. We performed a systematic review of Medline, Pubmed and Embase databases for articles comparing the clinical and economic impact of outpatient orthopedic surgical procedures versus inpatient procedures in North America. We reported on requirements for inpatient versus outpatient care, preoperative education requirements, complications and patient outcomes, patient satisfaction, and when available total mean costs. Nine studies met the inclusion criteria for this review. Eligibility requirements for outpatient orthopedic surgery within the included studies varied, but generally included: patient consent, a caregiver at home following surgery, close proximity to an outpatient center, and no history of serious medical problems. Preoperative education programs were not always compulsory and practices varied between outpatient centers. All of the reviewed studies reported that outpatient surgeries had similar or improved level of pain and rates of nausea. Outpatients reported increased satisfaction with the care they received. As expected, outpatient procedures were less expensive than inpatient procedures. This review found that outpatient procedures in North America appear to be less expensive and safe alternatives to inpatient care for patients who are at lower risk for complications and procedures that do not necessarily require close hospital level care monitoring following same day surgery.


Interference with thyroid histogenesis by inhibitors of collagen synthesis.
Histogenesis of thyroid follicles in the chick embryo begins with a penetration by cells of the mesenchymal capsule into a solid epithelial primordium. Before penetration occurs, slits containing fibrillar material form between the epithelial cells. The fibrillar material is an epithelial cell product as shown by its formation within channels that form in cultures of isolated epithelial primordia. The drugs L-azetidine-2-carboxylic acid (LACA) and alpha, alpha'-dipyridyl, which interfere with collagen synthesis, prevent the formation of fibrils in cultured epithelial primordia and in cultures of whole thyroids. Furthermore, mesenchymal cells do not invade when whole thyroid primordia are cultured in the presence of either drug. The effects of alpha, alpha'-dipyridyl are reversed by washing out the drug; the effects of LACA are reversed by incubation with equimolar or greater amounts of L-proline added to the medium along with the drug. The results are interpreted to mean that the fibrillar material is collagen of epithelial origin, that the collagen in some way plays a role in mesenchymal penetration of the epithelial primordium, and that the epithelium is responsible for the pattern of lobulation within the developing gland.


Flavobacterium ponti sp. nov., isolated from seawater.
A Gram-stain-negative, non-flagellated, non-gliding, yellow-pigmented and rod-shaped bacterial strain, designated GSW-R14(T), was isolated from seawater of Geoje Island in the South Sea, Korea. Strain GSW-R14(T) grew optimally at 25 °C, at pH 7.0-8.0 and in the presence of 2 % (w/v) NaCl. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain GSW-R14(T) belonged to the genus Flavobacterium, joining Flavobacterium gelidilacus LMG 21477(T) by a bootstrap resampling value of 100 %. Strain GSW-R14(T) exhibited 97.6 % 16S rRNA gene sequence similarity to F. gelidilacus LMG 21477(T) and similarities of 91.2-95.2 % to other members of the genus Flavobacterium. Strain GSW-R14(T) contained MK-6 as the predominant menaquinone. The fatty acid profile of strain GSW-R14(T) was similar to that of F. gelidilacus LMG 21477(T). The DNA G+C content of strain GSW-R14(T) was 31.4 mol% and its DNA-DNA relatedness with F. gelidilacus LMG 21477(T) was 31 %. Strain GSW-R14(T) could be distinguished from F. gelidilacus and the other species of the genus Flavobacterium by its phylogenetic and genetic distinctiveness and by several phenotypic properties. On the basis of these data, strain GSW-R14(T) is considered to represent a novel species of the genus Flavobacterium, for which the name Flavobacterium ponti sp. nov. is proposed; the type strain is GSW-R14(T) (=KCTC 22802(T) =CCUG 58402(T)).


Propolis add-on therapy alleviates depressive symptoms; A randomized placebo-controlled clinical trial.
Almost half of the treatments with common antidepressants are failed or result in a relapse of symptoms after cessation. Moreover, the antidepressants side effects rationalize the use of complementary medicine as an adjunctive therapy. This study aimed to evaluate the efficacy and safety of propolis in complementary therapy of depressive disorder. Chromatography technics were used to detect propolis components. A double-blind, randomized, placebo-controlled trial was designed, and 54 participants were randomly assigned to receive either propolis or Placebo for 6 weeks. Treatment was defined as a decrease in 17-item Hamilton Depression Scale (HAMD-17) and Beck depression inventory (BDI). On D42, there was a significant reduction in HAMD score in the propolis group compared with the placebo group (p < .0001). HAMD score significantly decreased in the propolis group from 20.92 ± 3.77 on D0 to 10.03 ± 5.55 on D42, and BDI score was improved from 29.25 ± 3.06 on D0 to 14.17 ± 4.86 on D42. Our findings confirmed that complementary treatment of propolis with SSRIs could safely attenuate symptoms of moderate-severe MDD. These antidepressant effects might result from the rich phenolic acids and flavonoids content of Azerbaijan propolis.


Molecular cloning and characterization of Antheraea mylitta cytoplasmic polyhedrosis virus genome segment 9.
Genome segment 9 of the 11-segment RNA genomes of three cytoplasmic polyhedrosis virus (CPV) isolates from Antheraea mylitta (AmCPV), Antheraea assamensis (AaCPV) and Antheraea proylei (ApCPV) were converted to cDNA, cloned and sequenced. In each case, this genome segment consists of 1473 nucleotides with one long ORF of 1035 bp and encodes a protein of 345 amino acids, termed NSP38, with a molecular mass of 38 kDa. Secondary structure prediction showed the presence of nine alpha-helices in the central and terminal domains with localized similarity to RNA-binding motifs of bluetongue virus and infectious bursal disease virus RNA polymerases. Nucleotide sequences were 99.6% identical between these three strains of CPVs, but no similarity was found to any other nucleotide or protein sequence in public databases. The ORF from AmCPV cDNA was expressed as a His-tagged fusion protein in E. coli and polyclonal antibody was raised against the purified protein. Immunoblot as well as immunofluorescence analysis with anti-NSP38 antibody showed that the protein was not present in polyhedra or uninfected cells but was present in AmCPV-infected host midgut cells. NSP38 was expressed in insect cells as soluble protein via a baculovirus expression vector and shown to possess the ability to bind poly(rI)-(rC) agarose, which was competitively removed by AmCPV viral RNA. These results indicate that NSP38 is expressed in virus-infected cells as a non-structural protein. By binding to viral RNA, it may play a role in the regulation of genomic RNA function and packaging.


Evaluation of a birth preparation program on lumbopelvic pain, urinary incontinence, anxiety and exercise: a randomized controlled trial.
Antenatal preparation programmes are recommended worldwide to promote a healthy pregnancy and greater autonomy during labor and delivery, prevent physical discomfort and high levels of anxiety. The objective of this study was to evaluate effectiveness and safety of a birth preparation programme to minimize lumbopelvic pain, urinary incontinence, anxiety, and increase physical activity during pregnancy as well as to compare its effects on perinatal outcomes comparing two groups of nulliparous women. A randomized controlled trial was conducted with 197 low risk nulliparous women aged 16 to 40 years, with gestational age ≥ 18 weeks. Participants were randomly allocated to participate in a birth preparation programme (BPP; n=97) or a control group (CG; n=100). The intervention was performed on the days of prenatal visits, and consisted of physical exercises, educational activities and instructions on exercises to be performed at home. The control group followed a routine of prenatal care. Primary outcomes were urinary incontinence, lumbopelvic pain, physical activity, and anxiety. Secondary outcomes were perinatal variables. The risk of urinary incontinence in BPP participants was significantly lower at 30 weeks of pregnancy (BPP 42.7%, CG 62.2%; relative risk [RR] 0.69; 95% confidence interval [CI] 0.51-0.93) and at 36 weeks of pregnancy (BPP 41.2%, CG 68.4%; RR 0.60; 95%CI 0.45-0.81). Participation in the BPP encouraged women to exercise during pregnancy (p=0.009). No difference was found between the groups regarding to anxiety level, lumbopelvic pain, type or duration of delivery and weight or vitality of the newborn infant. The BPP was effective in controlling urinary incontinence and to encourage the women to exercise during pregnancy with no adverse effects to pregnant women or the fetuses. Clinicaltrials.gov, (NCT01155804).


Design and performance of a high-flux electrospray ionization source for ion soft landing.
We report the design and evaluation of a new high-intensity electrospray ionization source for ion soft-landing experiments. The source incorporates a dual ion funnel, which enables operation with a higher gas load through an expanded diameter heated inlet into the additional first region of differential pumping. This capability allowed us to examine the effect of the inner diameter (ID) of the heated stainless steel inlet on the total ion current transmitted through the dual funnel interface and, more importantly, the mass-selected ion current delivered to the deposition target. The ion transmission of the dual funnel is similar to the transmission of the single funnel used in our previous soft landing studies. However, substantially higher ion currents were obtained using larger ID heated inlets and an orthogonal inlet geometry, in which the heated inlet was positioned perpendicular to the direction of ion propagation through the instrument. The highest ion currents were obtained using the orthogonal geometry and a 1.4 mm ID heated inlet. The corresponding stable deposition rate of ∼1 μg of mass-selected ions per day will facilitate future studies focused on the controlled deposition of complex molecules on substrates for studies in catalysis, energy storage, and self-assembly.


Structure and mechanism of human UDP-xylose synthase: evidence for a promoting role of sugar ring distortion in a three-step catalytic conversion of UDP-glucuronic acid.
UDP-xylose synthase (UXS) catalyzes decarboxylation of UDP-D-glucuronic acid to UDP-xylose. In mammals, UDP-xylose serves to initiate glycosaminoglycan synthesis on the protein core of extracellular matrix proteoglycans. Lack of UXS activity leads to a defective extracellular matrix, resulting in strong interference with cell signaling pathways. We present comprehensive structural and mechanistic characterization of the human form of UXS. The 1.26-Å crystal structure of the enzyme bound with NAD(+) and UDP reveals a homodimeric short-chain dehydrogenase/reductase (SDR), belonging to the NDP-sugar epimerases/dehydratases subclass. We show that enzymatic reaction proceeds in three chemical steps via UDP-4-keto-D-glucuronic acid and UDP-4-keto-pentose intermediates. Molecular dynamics simulations reveal that the D-glucuronyl ring accommodated by UXS features a marked (4)C(1) chair to B(O,3) boat distortion that facilitates catalysis in two different ways. It promotes oxidation at C(4) (step 1) by aligning the enzymatic base Tyr(147) with the reactive substrate hydroxyl and it brings the carboxylate group at C(5) into an almost fully axial position, ideal for decarboxylation of UDP-4-keto-D-glucuronic acid in the second chemical step. The protonated side chain of Tyr(147) stabilizes the enolate of decarboxylated C(4) keto species ((2)H(1) half-chair) that is then protonated from the Si face at C(5), involving water coordinated by Glu(120). Arg(277), which is positioned by a salt-link interaction with Glu(120), closes up the catalytic site and prevents release of the UDP-4-keto-pentose and NADH intermediates. Hydrogenation of the C(4) keto group by NADH, assisted by Tyr(147) as catalytic proton donor, yields UDP-xylose adopting the relaxed (4)C(1) chair conformation (step 3).


Quality of life is impaired in men with chronic prostatitis: the Chronic Prostatitis Collaborative Research Network.
Health-related quality of life (HRQOL) impairment may be a central component of chronic prostatitis for men afflicted with this condition. Our objective was to examine HRQOL, and factors associated with HRQOL, using both general and condition-specific instruments. Chronic Prostatitis Cohort (CPC) study. Six clinical research centers across the United States and Canada. Two hundred seventy-eight men with chronic prostatitis. The Short Form 12 (SF-12) Mental Component Summary (MCS) and Physical Component Summary (PCS), and the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) were measures used. CPC subjects' MCS scores (44.0 +/- 9.8) were lower than those observed in the most severe subgroups of patients with congestive heart failure and diabetes mellitus, and PCS scores (46.4+/-9.5) were worse than those among the general U.S. male population. Decreasing scores were seen in both domains with worsening symptom severity (P < .01). History of psychiatric disease and younger age were strongly associated with worse MCS scores, whereas history of rheumatologic disease was associated with worse PCS scores. Predictors of more severe NIH-CPSI scores included lower educational level and lower income; history of rheumatic disease was associated with higher scores. Men with chronic prostatitis experience impairment in the mental and physical domains of general HRQOL, as well as condition-specific HRQOL. To optimize the care of men with this condition, clinicians should consider administering HRQOL instruments to their patients to better understand the impact of the condition on patients' lives.


Vitamin D Supplementation and Prevention of Type 2 Diabetes.
Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.).


The Rose model, revisited.
In 1946 and 1948, three very important papers by Albert Rose [J. Soc. Motion Pict. Eng. 47, 273 (1946); J. Opt. Soc. Am. 38, 196 (1948); L. Marton, ed. (Academic, New York, 1948)] were published on the role that photon fluctuations have in setting fundamental performance limits for both human vision and electronic imaging systems. The papers were important because Rose demonstrated that the performance of imaging devices can be evaluated with an absolute scale (quantum efficiency). The analysis of human visual signal detection used in these papers (developed before the formal theory of signal detectability) was based on an approach that has come to be known as the Rose model. In spite of its simplicity, the Rose model is a very good approximation of a Bayesian ideal observer for the carefully and narrowly defined conditions that Rose considered. This simple model can be used effectively for back-of-the-envelope calculations, but it needs to be used with care because of its limited range of validity. One important conclusion arising from Rose's investigations is that pixel signal-to-noise ratio is not a good figure of merit for imaging systems or components, even though it is still occasionally used as such by some researchers. In the present study, (1) aspects of signal detection theory are presented, (2) Rose's model is described and discussed, (3) pixel signal-to-noise ratio is discussed, and (4) progress on modeling human noise-limited performance is summarized. This study is intended to be a tutorial with presentation of the main ideas and provision of references to the (dispersed) technical literature.


[Evaluation of the frequency of accomplishment of the breast examination and of oncotic cervical cytology and the obstetrical ultrasound during the prenatal period. An inversion of values].
Although ultrasound examination is a frequent procedure during pregnancy, routine use has not been effective to reduce maternal or perinatal morbidity-mortality. Assess frequency of breast examination and of oncotic cervical cytology among prenatal exams and compare it to frequency of obstetrical ultrasound. This was a cross-sectional evaluation conducted in the city of Rio Grande, RS, Brazil between May and July 2007. Data obtained with a structured questionnaire were entered into the Epi-Info 6.04 program and analyzed using the SPSS software. Among the 230 puerperae interviewed, 99.1% had undergone an ultrasound during pregnancy, while 37.5% and 33.6% had been submitted to clinical examination of the breasts and cervical cytology, respectively. It was noted that a larger number of obstetrical echographies increased the probability that a patient would be submitted to clinical examination of the breasts. On the other hand, the number of cytopathological evaluations of the uterine cervix was not influenced by the number of ultrasound examinations. Obstetrical echography was given priority and performed as a routine exam, whereas clinical examination of the breasts and cervical cytopathological examination were not, although considered obligatory during the prenatal period. These data confirm the tendency documented in literature indicating an inversion of priorities, favoring ultrasonography over breast examination and cervical pathological exams. For this reason, further studies and evaluations of health programs, also of the real impact of this inversion on the population health indices are recommended.


Evaluation of Covid-19 vaccines: Pharmacoepidemiological aspects.
The marketing authorization granted to SARS-Cov-2 vaccines was accompanied by reinforced safety monitoring plans. These plans' implementation was part of the usual logic of post-marketing surveillance of new and innovative health products. It was especially adapted to the context of post-marketing monitoring of drugs developed according to the usual scientific quality standards but in an accelerated schedule. In Europe, the reinforced surveillance system relies on the complementary strengths of pharmacovigilance and pharmacoepidemiology. If the performances of pharmacovigilance monitoring are incomparable for the detection of safety signals relating to rare events of atypical presentation, it needs to be completed with pharmacoepidemiology activities for more common events, either multifactorial or frequently classified as idiopathic. The pharmacoepidemiological monitoring developed in Europe was elaborated before the first SARS-Cov-2 vaccines where marketed, taking into account the lessons learned from the vaccination campaign against 2009 A (H1N1) influenza. It includes numerous academic studies as well as studies performed within vaccines risk management plans. In terms of safety, those defined a priori mostly concerns a list of pre-established health events of specific interest. Aside of these planned activities, ad-hoc studies will be latter developed on purpose to investigate safety signals or potential signals that could be identified as the result of pharmacovigilance activities. Aside of these regulated activities, as for today, very few studies have been published regarding SARS-Cov-2 vaccines; most of the existing consist in preprints that should be considered with caution. Pharmacoepidemiology of vaccines is thought to allow near-real time monitoring that needs sufficient time to provide with valid results. In the constant urge for information that accompanies COVID-related science, it is important not to make haste the enemy of speed and to let pharmacoepidemiology provides with what it is expected to do: rock-solid scientific information contributing to evidence-based decision-making.


Characterization of chromosomal regions conserved in Yersinia pseudotuberculosis and lost by Yersinia pestis.
The transformation of the enteropathogenic bacterium Yersinia pseudotuberculosis into the plague bacillus, Yersinia pestis, has been accompanied by extensive genetic loss. This study focused on chromosomal regions conserved in Y. pseudotuberculosis and lost during its transformation into Y. pestis. An extensive PCR screening of 78 strains of the two species identified five regions (R1 to R5) and four open reading frames (ORFs; orf1 to orf4) that were conserved in Y. pseudotuberculosis and absent from Y. pestis. Their conservation in Y. pseudotuberculosis suggests a positive selective pressure and a role during the life cycle of this species. Attempts to delete two ORFs (orf3 and orf4) from the chromosome of strain IP32953 were unsuccessful, indicating that they are essential for its viability. The seven remaining loci were individually deleted from the IP32953 chromosome, and the ability of each mutant to grow in vitro and to kill mice upon intragastric infection was evaluated. Four loci (orf1, R2, R4, and R5) were not required for optimal growth or virulence of Y. pseudotuberculosis. In contrast, orf2, encoding a putative pseudouridylate synthase involved in RNA stability, was necessary for the optimal growth of IP32953 at 37 degrees C in a chemically defined medium (M63S). Deletion of R1, a region predicted to encode the methionine salvage pathway, altered the mutant pathogenicity, suggesting that the availability of free methionine is severely restricted in vivo. R3, a region composed mostly of genes of unknown functions, was necessary for both optimal growth of Y. pseudotuberculosis at 37 degrees C in M63S and for virulence. Therefore, despite their loss in Y. pestis, five of the nine Y. pseudotuberculosis-specific chromosomal loci studied play a role in the survival, growth, or virulence of this species.


Association of intensity of ventilation with 28-day mortality in COVID-19 patients with acute respiratory failure: insights from the PRoVENT-COVID study.
The intensity of ventilation, reflected by driving pressure (ΔP) and mechanical power (MP), has an association with outcome in invasively ventilated patients with or without acute respiratory distress syndrome (ARDS). It is uncertain if a similar association exists in coronavirus disease 2019 (COVID-19) patients with acute respiratory failure. We aimed to investigate the impact of intensity of ventilation on patient outcome. The PRoVENT-COVID study is a national multicenter observational study in COVID-19 patients receiving invasive ventilation. Ventilator parameters were collected a fixed time points on the first calendar day of invasive ventilation. Mean dynamic ΔP and MP were calculated for individual patients at time points without evidence of spontaneous breathing. A Cox proportional hazard model, and a double stratification analysis adjusted for confounders were used to estimate the independent associations of ΔP and MP with outcome. The primary endpoint was 28-day mortality. In 825 patients included in this analysis, 28-day mortality was 27.5%. ΔP was not independently associated with mortality (HR 1.02 [95% confidence interval 0.88-1.18]; P = 0.750). MP, however, was independently associated with 28-day mortality (HR 1.17 [95% CI 1.01-1.36]; P = 0.031), and increasing quartiles of MP, stratified on comparable levels of ΔP, had higher risks of 28-day mortality (HR 1.15 [95% CI 1.01-1.30]; P = 0.028). In this cohort of critically ill invasively ventilated COVID-19 patients with acute respiratory failure, we show an independent association of MP, but not ΔP with 28-day mortality. MP could serve as one prognostic biomarker in addition to ΔP in these patients. Efforts aiming at limiting both ΔP and MP could translate in a better outcome. Trial registration Clinicaltrials.gov (study identifier NCT04346342).


Optical three dimensional coherent spectroscopy.
Optical multdimensional coherent spectroscopy has recently been the subject of significant activity. While two-dimensional spectroscopy is most common, it is possible to extend the method into three dimensions. This perspective reviews the different approaches to three-dimensional spectroscopy and the systems that have been studied with it. The advantages of adding an additional dimension are discussed and compared to the resulting experimental challenges.


Association of Preoperatively Diagnosed Patent Foramen Ovale With Perioperative Ischemic Stroke.
Perioperative stroke is a major complication for patients undergoing surgery. Patent foramen ovale (PFO) represents a possible anatomical link between venous thrombosis and stroke. To determine whether a preoperatively diagnosed PFO is associated with increased risk of perioperative ischemic stroke. Retrospective cohort study from Massachusetts General Hospital and 2 affiliated community hospitals between January 1, 2007, and December 31, 2015. Participants were 182 393 consecutive adults undergoing noncardiac surgery with general anesthesia. Preoperatively diagnosed PFO. Perioperative ischemic stroke occurring within 30 days of surgery; stroke subtype by Oxfordshire Community Stroke Project classification and stroke severity by National Institute of Health Stroke Scale (NIHSS). Among the 150 198 patient cases analyzed (median [SD] age, 55 [16] years), 1540 (1.0%) had a diagnosis of PFO before surgery. A total of 850 (0.6%) ischemic strokes occurred within 30 days of surgery (49 [3.2%] among patients with PFO and 801 [0.5%] among patients without PFO). In adjusted analyses, patients with PFO had an increased risk of ischemic stroke compared with patients without PFO (odds ratio, 2.66 [95% CI, 1.96-3.63]; P < .001). The estimated risks of stroke were 5.9 for every 1000 patients with PFO and 2.2 for every 1000 patients without PFO (adjusted absolute risk difference, 0.4% [95% CI, 0.2%-0.6%). Patients with PFO also had an increased risk of large vessel territory stroke (relative risk ratio, 3.14 [95% CI, 2.21-4.48]; P < .001) and a more severe stroke-related neurologic deficit measured by NIHSS (median, 4 [interquartile range {IQR}, 2-10] vs median, 3 [IQR, 1-6] for those without PFO; P = .02). Among adult patients undergoing noncardiac surgery at 3 hospitals, having a preoperatively diagnosed PFO was significantly associated with increased risk of perioperative ischemic stroke within 30 days after surgery. Further research is needed to confirm these findings and to determine whether interventions would decrease this risk.


Screening and prevention of neonatal glucose 6-phosphate dehydrogenase deficiency in Guangzhou, China.
We aimed to summarize the results of screening protocol and prevention of neonatal glucose 6-phosphate dehydrogenase (G6PD) deficiency during a 22-year-long period to provide a basis of reference for the screening of this disease. About 1,705,569 newborn subjects in Guangzhou City were screened for this deficiency. Specimens were collected according to the conventional method of specimen acquisition for "newborn dried bloodspot screening", preserved, and inspected. The specimens were studied with fluorescent spot test and quantitative fluorescence assay. Diagnosis was performed using the modified NBTG6PD/6PGD ratio method. Bloodspot filter paper specimens were sent to the laboratory within 24 h via EMS Express, and the G6PD test was performed on the same day. The G6PD deficiency-positive rate was 4.2% in the samples screened using the fluorescent spot test, while it was 5% in case of the quantitative fluorescence assay. Neonatal screening for G6PD deficiency for 11,437 cases (6117 boys and 5320 girls) showed positive results in 481 cases. About 420 cases (318 boys and 102 girls) of G6PD deficiency were confirmed with the modified Duchenne NBT ratio method. The total detection rate was 3.7:5.2% for boys and 1.9% for girls. Quantitative fluorescence assay improved the sensitivity and detection rate. Accelerating the speed of sample delivery by using Internet network systems and ensuring online availability of screening results can aid the screening and diagnosis of this deficiency within 1 week of birth.


Management of common bile duct stones with a biliary endoprosthesis. Report on 40 cases.
Endoscopic placement of a biliary endoprosthesis has been proposed for the management of choledocholithiasis when stone extraction is difficult or considered hazardous. Over a two year period this approach was used in 40 such patients. There were 24 women and 16 men with a median age of 76 years. In seven patients with severe cholangitis no attempt was made to extract the stones. Twenty three (57.5%) patients underwent a sphincterotomy and four (10%) needle knife papillotomy. The endoprosthesis insertion was considered a temporary measure in 13 (32.5%) patients and definitive treatment in 27 (67.5%). Bile duct drainage was established in all patients. Early complications occurred in six patients (15%), but were without sequelae. Late complications developed in eight (20%) of the patients and included biliary colic (four), cholangitis (three), and cholecystitis (one). Two patients (one cholangitis and one cholecystitis) died as a consequence of the complication. Only patients without a sphincterotomy developed cholangitis. A total of eight patients (20%) underwent surgery (one as an emergency) and nine a repeat endoscopic retrograde cholangio pancreatography (two as an emergency) to clear the duct. The remaining 23 patients are asymptomatic at a median of 13 months (range five to 24 months). Biliary endoprosthesis insertion for choledocholithiasis is an important alternative means of establishing drainage in selected cases, and is probably the optimum method of management for the elderly and or debilitated patients with previous cholecystectomy. Caution must be exercised, however, in patients with an in situ gall bladder.


Hemoglobin stability in patients with anemia, CKD, and type 2 diabetes: an analysis of the TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) placebo arm.
Sparse data are available about the natural history of hemoglobin (Hb) level trends in contemporary patients with anemia, chronic kidney disease (CKD), and type 2 diabetes mellitus. We intended to describe Hb level trends over time with no or minimal administration of erythropoiesis-stimulating agents. Prospective clinical trial cohort. 2,019 individuals with type 2 diabetes, moderate anemia, and CKD from the placebo arm of the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) followed up for 2.3 years with an average of 32 monthly Hb level determinations per patient. Darbepoetin alfa was administered only if Hb level decreased to <9 g/dL. Number of protocol-directed doses of darbepoetin alfa received due to an Hb level decrease to <9 g/dL. 1,106 (55%) placebo patients consistently maintained an Hb level ≥9 g/dL and received no protocol-directed darbepoetin alfa. The other patients received 1 (16%), 2-4 (16%), or 5 or more (13%) doses of darbepoetin alfa. Those who received no darbepoetin alfa doses had higher baseline Hb levels, higher estimated glomerular filtration rates (eGFRs), less proteinuria, and lower ferritin and transferrin saturation values. On average, Hb levels were stable or increased in all groups. Compared with individuals who received no darbepoetin alfa, those who received 5 or more doses were more likely to receive intravenous iron therapy and blood transfusions and progress to renal replacement therapy, but were not at higher risk of death. The strongest predictors of requiring 5 or more doses of darbepoetin alfa were lower baseline Hb level, lower eGFR, and higher proteinuria level. Post hoc analysis of a clinical trial of a specific population with diabetes, anemia, and non-dialysis-dependent CKD. In the TREAT placebo arm, Hb levels were stable with no or minimal protocol-directed darbepoetin alfa during 2.3 years of follow-up. Most patients with moderate anemia, non-dialysis-dependent CKD, and type 2 diabetes are able to maintain a stable Hb level without implementing long-term erythropoiesis-stimulating agent therapy.


The new synthesis in moral psychology.
People are selfish, yet morally motivated. Morality is universal, yet culturally variable. Such apparent contradictions are dissolving as research from many disciplines converges on a few shared principles, including the importance of moral intuitions, the socially functional (rather than truth-seeking) nature of moral thinking, and the coevolution of moral minds with cultural practices and institutions that create diverse moral communities. I propose a fourth principle to guide future research: Morality is about more than harm and fairness. More research is needed on the collective and religious parts of the moral domain, such as loyalty, authority, and spiritual purity.


The presence of HLA-directed antibodies after heart transplantation is associated with poor allograft outcome.
The clinical significance of HLA-directed antibodies newly detected after transplantation (HT) is controversial. Seventy-one HT recipients consented to enroll. Mean follow-up time was 28 months (range 6-48). Panel reactive antibody (PRA) analysis was performed on posttransplant sera (2 weeks, 1, 2, 3, 6, and 12 months and annually thereafter) using Flow-PRA. A mean of 6.9+/-1.2 serum samples per patient were obtained. Severity of cellular rejection was measured using the ISHLT grading system. Coronary angiography and intravascular ultrasound (IVUS) studies were performed annually to evaluate severity of allograft vasculopathy. Twenty-five recipients had newly detected HLA-directed antibodies during the first year postHT. HLA class I antibodies were detected in 18 patients (25.4%), and class II in 11 patients (15.5%). The majority of donor recipient pairs were HLA mismatched (4.6+/-1.2 of the six major HLA antigens). Only mismatches at HLA-A locus had significant association with de novo posttransplant antibody formation. Length of ischemia time was correlated with early and sustained presence of de novo HLA-directed antibodies postheart transplant. Importantly, an association between de novo HLA-directed antibodies and cellular rejection was notes (P=0.0002). De novo HLA class II directed antibodies are also associated with IVUS documented vasculopathy (P<0.002). Finally, death due to allograft failure is associated with the presence of de novo formed HLA class II directed antibodies (P=0.008). Identifying the formation of de novo HLA-directed antibodies following heart transplantation may predict allograft outcome. This, in turn, may serve as a tool for individualization of immunosuppression protocols in heart transplant recipients.


Efficacy of botulinum toxin A for treatment of unilateral spasms of the eyelid and its prognosis.
To this date, only a small number of studies have described the long-term use of BTX in Hemifacial spasm. To assess the prognosis and long-term effectiveness of Botulinum toxin A (BTXA) in the treatment of unilateral spasms of the eyelid. From September 1998 to January 2006, 245 consecutive cases of unilateral spasms of the eyelid were included in this retrospective study. Among them, 143 patients (BTXA group) underwent BTXA injection treatment, and 102 patients did not receive any intervention (control group). BTXA injections were made subcutaneously around the eye with the dose of 2.5U other than the temporal canthus of 5U. Follow-up was performed for 1-7 years after the last injection. In BTXA treatment group, the complete remission rate was 78.3% (112/143), recurrence rate was 21.7% (31/143) and the incidence of hemifacial spasm (HFS) was 18.9% (27/143); complete remission rate for patients with disease duration less than 3 months was 96.6% (86/89); for patients with a 3-6 months disease history, complete remission rate was 75.8% (25/33), and patients having the disease course exceeding 6 months had a complete remission rate of 4.8% (1/21). In the control group, the complete remission rate was 12.7% (13/102), and the prevalence of HFS was 71.6% (73/102); 16.7% (9/56) of patients with the disease duration less than 3 months were remitted, but the complete remission rate was 12.9% (4/31) for patients with a 3-6 months disease history. None was in remission when the disease history exceeded 6 months. BTXA treatment can improve the complete remission rate and prevent further progression of unilateral spasms of the eyelid into HFS, especially in early stage.


Music interventions for people with dementia: a review of the literature.
This paper provides a qualitative review of 21 published articles of clinical empirical studies looking at the effects of a variety of music activities on the emotional and behavioural responses in people with dementia. General information is reviewed such as the setting and context of studies, research findings and explanatory variables. Methodological issues are also discussed, particularly in relation to observational methods, and theoretical frameworks such as the progressively lowered stress threshold model are evaluated. Music appears to have a range of applications in dementia care but previous reviews have highlighted methodological weaknesses of studies. Recommendations for future research include the use of continuous time sampling methodology and to record the duration of observed behaviours. This review paper also argues for the use of Kitwood's theory of personhood as a framework to inform and guide future research.


Prediction of individualized lifetime benefit from cholesterol lowering, blood pressure lowering, antithrombotic therapy, and smoking cessation in apparently healthy people.
The benefit an individual can expect from preventive therapy varies based on risk-factor burden, competing risks, and treatment duration. We developed and validated the LIFEtime-perspective CardioVascular Disease (LIFE-CVD) model for the estimation of individual-level 10 years and lifetime treatment-effects of cholesterol lowering, blood pressure lowering, antithrombotic therapy, and smoking cessation in apparently healthy people. Model development was conducted in the Multi-Ethnic Study of Atherosclerosis (n = 6715) using clinical predictors. The model consists of two complementary Fine and Gray competing-risk adjusted left-truncated subdistribution hazard functions: one for hard cardiovascular disease (CVD)-events, and one for non-CVD mortality. Therapy-effects were estimated by combining the functions with hazard ratios from preventive therapy trials. External validation was performed in the Atherosclerosis Risk in Communities (n = 9250), Heinz Nixdorf Recall (n = 4177), and the European Prospective Investigation into Cancer and Nutrition-Netherlands (n = 25 833), and Norfolk (n = 23 548) studies. Calibration of the LIFE-CVD model was good and c-statistics were 0.67-0.76. The output enables the comparison of short-term vs. long-term therapy-benefit. In two people aged 45 and 70 with otherwise identical risk-factors, the older patient has a greater 10-year absolute risk reduction (11.3% vs. 1.0%) but a smaller gain in life-years free of CVD (3.4 vs. 4.5 years) from the same therapy. The model was developed into an interactive online calculator available via www.U-Prevent.com. The model can accurately estimate individual-level prognosis and treatment-effects in terms of improved 10-year risk, lifetime risk, and life-expectancy free of CVD. The model is easily accessible and can be used to facilitate personalized-medicine and doctor-patient communication.


Functional characterization of SCN10A variants in several cases of sudden unexplained death.
Multiple genome-wide association studies (GWAS) and targeted gene sequencing have identified common variants in SCN10A in cases of PR and QRS duration abnormalities, atrial fibrillation and Brugada syndrome. The New York City Office of Chief Medical Examiner has now also identified five SCN10A variants of uncertain significance in six separate cases within a cohort of 330 sudden unexplained death events. The gene product of SCN10A is the Nav1.8 sodium channel. The purpose of this study was to characterize effects of these variants on Nav1.8 channel function to provide better information for the reclassification of these variants. Patch clamp studies were performed to assess effects of the variants on whole-cell Nav1.8 currents. We also performed RNA-seq analysis and immunofluorescence confocal microcopy to determine Nav1.8 expression in heart. We show that four of the five rare 'variants of unknown significance' (L388M, L867F, P1102S and V1518I) are associated with altered functional phenotypes. The R756W variant behaved similar to wild-type under our experimental conditions. We failed to detect Nav1.8 protein expression in immunofluorescence microscopy in rat heart. Furthermore, RNA-seq analysis failed to detect full-length SCN10A mRNA transcripts in human ventricle or mouse specialized cardiac conduction system, suggesting that the effect of Nav1.8 on cardiac function is likely to be extra-cardiac in origin. We have demonstrated that four of five SCN10A variants of uncertain significance, identified in unexplained death, have deleterious effects on channel function. These data extend the genetic testing of SUD cases, but significantly more clinical evidence is needed to satisfy the criteria needed to associate these variants with the onset of SUD.


The first set of universal nuclear protein-coding loci markers for avian phylogenetic and population genetic studies.
Multiple nuclear markers provide genetic polymorphism data for molecular systematics and population genetic studies. They are especially required for the coalescent-based analyses that can be used to accurately estimate species trees and infer population demographic histories. However, in avian evolutionary studies, these powerful coalescent-based methods are hindered by the lack of a sufficient number of markers. In this study, we designed PCR primers to amplify 136 nuclear protein-coding loci (NPCLs) by scanning the published Red Junglefowl (Gallus gallus) and Zebra Finch (Taeniopygia guttata) genomes. To test their utility, we amplified these loci in 41 bird species representing 23 Aves orders. The sixty-three best-performing NPCLs, based on high PCR success rates, were selected which had various mutation rates and were evenly distributed across 17 avian autosomal chromosomes and the Z chromosome. To test phylogenetic resolving power of these markers, we conducted a Neoavian phylogenies analysis using 63 concatenated NPCL markers derived from 48 whole genomes of birds. The resulting phylogenetic topology, to a large extent, is congruence with results resolved by previous whole genome data. To test the level of intraspecific polymorphism in these makers, we examined the genetic diversity in four populations of the Kentish Plover (Charadrius alexandrinus) at 17 of NPCL markers chosen at random. Our results showed that these NPCL markers exhibited a level of polymorphism comparable with mitochondrial loci. Therefore, this set of pan-avian nuclear protein-coding loci has great potential to facilitate studies in avian phylogenetics and population genetics.


Sub-100 attosecond timing jitter from low-noise passively mode-locked solid-state laser at telecom wavelength.
We report on the ultralow timing jitter of the 100 MHz pulse trains generated by two identical passively mode-locked diode-pumped solid-state lasers (DPSSLs) emitting at 1556 nm. Ultralow timing jitter of 83 as (integrated from 10 kHz to 50 MHz) for one laser has been measured with a balanced optical cross-correlator as timing discriminator. Extremely low intensity noise has been measured as well. Several measurement techniques have been used and show similar jitter results. Different possible noise sources have been theoretically investigated and compared to the measured jitter power spectral density. It is found that although the measured integrated jitter is quite low, it is still significantly above the quantum limit in the considered frequency span. Therefore, there is a substantial potential for technical improvements that could make passively mode-locked DPSSL outperform fiber lasers as source of microwaves with low phase noise.


Superstructured fiber-optic contact force sensor with minimal cosensitivity to temperature and axial strain.
In this work a new superstructured, in-fiber Bragg grating (FBG)-based, contact force sensor is presented that is based on birefringent D-shape optical fiber. The sensor superstructure comprises a polyimide sheath, a stress-concentrating feature, and an alignment feature that repeatably orients the sensor with respect to contact forces. A combination of plane elasticity and strain-optic models is used to predict sensor performance in terms of sensitivity to contact force and axial strain. Model predictions are validated through experimental calibration and indicate contact force, axial strain, and temperature sensitivities of 169.6 pm/(N/mm), 0.01 pm/με, and -1.12 pm/°C in terms of spectral separation. The sensor addresses challenges associated with contact force sensors that are based on FBGs in birefringent fiber, FBGs in conventional optical fiber, and tilted FBGs. Relative to other birefringent fiber sensors, the sensor has contact force sensitivity comparable to the highest sensitivity of commercially available birefringent fibers and, unlike other birefringent fiber sensors, is self-aligning with respect to contact forces. Unlike sensors based on Bragg gratings in conventional fiber and tilted Bragg gratings, the sensor has minimal cosensitivity to both axial strain and changes in temperature.


Double-blind, randomized, placebo-controlled Canadian multicenter trial of two doses of synthetic surfactant or air placebo in 224 infants weighing 500 to 749 grams with respiratory distress syndrome. Canadian Exosurf Neonatal Study Group.
In a multicenter, double-masked, placebo-controlled rescue trial conducted at 12 Canadian hospitals, two 5 ml/kg doses of a synthetic surfactant or air placebo were administered to 224 infants with birth weights of 500 to 749 gm who had established respiratory distress syndrome and an arterial/alveolar oxygen tension ratio of less than 0.22. The first dose was given between 2 and 24 hours of age; the second dose was given 12 hours later to the infants continuing to receive mechanical ventilation. Infants were stratified at study entry by birth weight and gender. Infants receiving synthetic surfactant showed significant improvements in alveolar-arterial oxygen tension gradient, arterial/alveolar oxygen tension ratio, and oxygen and ventilator requirements through day 7. In the group randomized to synthetic surfactant, significant improvements were seen in oxygen requirements at the first time point measured (2 hours; p = 0.02), in the alveolar-arterial oxygen tension gradient by the second time point measured (6 hours; p = 0.03), and in mean airway pressure after 6 hours. Overall mortality at 28 days was not significantly different in the two groups (50% vs 46%, air placebo group vs synthetic surfactant group; p = 0.586). Similarly, neither the incidence of bronchopulmonary dysplasia (37% vs 30%, air placebo group vs synthetic surfactant group; p = 0.089) nor the incidence of survival without BPD through 28 days (17% vs 26%, respectively; p = 0.070) was significantly different in the two groups. No significant differences in the incidence of safety-related outcomes or in adverse effects such as apnea or pulmonary hemorrhage were noted. These findings indicate that rescue therapy with synthetic surfactant results in physiologic improvements in very tiny premature infants, but improvements in overall mortality or other complications of respiratory distress syndrome were not documented in the sample evaluated.


Collateral impacts of pandemic COVID-19 drive the nosocomial spread of antibiotic resistance: A modelling study.
Circulation of multidrug-resistant bacteria (MRB) in healthcare facilities is a major public health problem. These settings have been greatly impacted by the Coronavirus Disease 2019 (COVID-19) pandemic, notably due to surges in COVID-19 caseloads and the implementation of infection control measures. We sought to evaluate how such collateral impacts of COVID-19 impacted the nosocomial spread of MRB in an early pandemic context. We developed a mathematical model in which Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and MRB cocirculate among patients and staff in a theoretical hospital population. Responses to COVID-19 were captured mechanistically via a range of parameters that reflect impacts of SARS-CoV-2 outbreaks on factors relevant for pathogen transmission. COVID-19 responses include both "policy responses" willingly enacted to limit SARS-CoV-2 transmission (e.g., universal masking, patient lockdown, and reinforced hand hygiene) and "caseload responses" unwillingly resulting from surges in COVID-19 caseloads (e.g., abandonment of antibiotic stewardship, disorganization of infection control programmes, and extended length of stay for COVID-19 patients). We conducted 2 main sets of model simulations, in which we quantified impacts of SARS-CoV-2 outbreaks on MRB colonization incidence and antibiotic resistance rates (the share of colonization due to antibiotic-resistant versus antibiotic-sensitive strains). The first set of simulations represents diverse MRB and nosocomial environments, accounting for high levels of heterogeneity across bacterial parameters (e.g., rates of transmission, antibiotic sensitivity, and colonization prevalence among newly admitted patients) and hospital parameters (e.g., rates of interindividual contact, antibiotic exposure, and patient admission/discharge). On average, COVID-19 control policies coincided with MRB prevention, including 28.2% [95% uncertainty interval: 2.5%, 60.2%] fewer incident cases of patient MRB colonization. Conversely, surges in COVID-19 caseloads favoured MRB transmission, resulting in a 13.8% [-3.5%, 77.0%] increase in colonization incidence and a 10.4% [0.2%, 46.9%] increase in antibiotic resistance rates in the absence of concomitant COVID-19 control policies. When COVID-19 policy responses and caseload responses were combined, MRB colonization incidence decreased by 24.2% [-7.8%, 59.3%], while resistance rates increased by 2.9% [-5.4%, 23.2%]. Impacts of COVID-19 responses varied across patients and staff and their respective routes of pathogen acquisition. The second set of simulations was tailored to specific hospital wards and nosocomial bacteria (methicillin-resistant Staphylococcus aureus, extended-spectrum beta-lactamase producing Escherichia coli). Consequences of nosocomial SARS-CoV-2 outbreaks were found to be highly context specific, with impacts depending on the specific ward and bacteria evaluated. In particular, SARS-CoV-2 outbreaks significantly impacted patient MRB colonization only in settings with high underlying risk of bacterial transmission. Yet across settings and species, antibiotic resistance burden was reduced in facilities with timelier implementation of effective COVID-19 control policies. Our model suggests that surges in nosocomial SARS-CoV-2 transmission generate selection for the spread of antibiotic-resistant bacteria. Timely implementation of efficient COVID-19 control measures thus has 2-fold benefits, preventing the transmission of both SARS-CoV-2 and MRB, and highlighting antibiotic resistance control as a collateral benefit of pandemic preparedness.


Urinary pellet sample preparation for shotgun proteomic analysis of microbial infection and host-pathogen interactions.
Urine is one of the most important biofluids in clinical proteomics, and in the past decades many potential disease biomarkers have been identified using mass spectrometry-based proteomics. Current studies mainly perform analyses of the urine supernatant devoid of cells and cell debris, and the pellet (or sediment) fraction is discarded. However, the pellet fraction is biologically of interest. It may contain whole human cells shed into the urine from anatomically proximal tissues and organs (e.g., kidney, prostate, bladder, urothelium, and genitals), disintegrated cells and cell aggregates derived from such tissues, viruses and microbial organisms which colonize or infect the urogenital tract. Knowledge of the function, abundance, and tissue of origin of such proteins can explain a pathological process, identify a microbe as the cause of urinary tract infection, and measure the human immune response to the infection-associated pathogen(s). Successful detection of microbial species in the urinary pellet via proteomics can serve as a clinical diagnostic alternative to traditional cell culture-based laboratory tests. Filter-aided sample preparation (FASP) has been widely used in shotgun proteomics. The methodology presented here implements an effective lysis of cells present in urinary pellets, solubilizes the majority of the proteins derived from microbial and human cells, and generates enzymatic digestion-compatible protein mixtures using FASP followed by optimized desalting procedures to provide a peptide fraction for sensitive and comprehensive LC-MS/MS analysis. A highly parallel sample preparation method in 96-well plates to allow scaling up such experiments is discussed as well. Separating peptides by nano-LC in one dimension followed by online MS/MS analysis on a Q-Exactive mass spectrometer, we have shown that more than 1,000 distinct microbial proteins and 1,000 distinct human proteins can be identified from a single experiment.


Health-related quality-of-life improvements in CIDP with immune globulin IV 10%: the ICE Study.
Chronic inflammatory demyelinating polyradiculoneuropathy trials have demonstrated the efficacy of IV immunoglobulin vs placebo. However, these trails have not addressed the long-term impact on health-related quality of life (HRQoL). One hundred seventeen patients in a randomized, double-blind, response-conditional crossover trial received immune globulin IV, 10% caprylate/chromatography purified (IGIV-C [Gamunex(R)]), or placebo every 3 weeks for up to 24 weeks in the first period (FP). Participants whose inflammatory neuropathy cause and treatment disability score did not improve by >/=1 point received alternate treatment in a 24-week crossover period (CP). In either period, participants who improved and completed treatment were eligible to be randomly reassigned to a blinded 24-week extension phase (EP). HRQoL analyses were conducted using the Short Form-36(R) (SF-36) and the Rotterdam Handicap Scale (RHS). In the FP, greater improvements in both SF-36 physical and mental component scores were observed with IGIV-C vs placebo, with a significant improvement in the physical component score (difference 4.4 points; 95% confidence interval [CI] 0.7-8.0). Improvements in all SF-36 domains favored IGIV-C vs placebo, with physical functioning, role-physical, social functioning, and mental health reaching significance. Participants receiving IGIV-C experienced a larger improvement in RHS vs those receiving placebo (difference 3.4 points; 95% CI 1.4-5.5; p = 0.001). In the CP, similar general trends were observed. In the EP, mean SF-36 improvements were generally improved or maintained in participants who continued IGIV-C therapy; however, worsening was observed in participants re-randomized to placebo. Long-term therapy with immune globulin IV, 10% caprylate/chromatography purified, improves and maintains health-related quality of life in chronic inflammatory demyelinating polyradiculoneuropathy.


Cytotoxicity of lonidamine alone and in combination with other drugs against murine RIF-1 and human HT1080 cells in vitro.
Lonidamine is an agent that is reported to inhibit recovery from potentially lethal damage. By itself, it has only mild anticancer activity. We have examined the ability of lonidamine to enhance the cytotoxicity of several drugs against a mouse and a human fibrosarcoma cell line in vitro. By itself, lonidamine showed only a limited cytotoxic effect with drug exposure up to 100 micrograms/ml and 24-h duration. Lower concentrations and shorter term exposures were not toxic to either of these tumor cell lines. When tested against the mouse line, the cytotoxicity of 5-fluorouracil, methotrexate, and etoposide was enhanced by lonidamine if the latter drug was given either before or after the exposure of the cells to the cytotoxic agents. For cisplatinum, bleomycin, mitomycin C, doxorubicin, and Actinomycin D, cytotoxicity was also enhanced, but only if lonidamine followed the other agents. In contrast, potentiation of 1,3-bis(2-chloroethyl)-1-nitrosourea toxicity was maximum when lonidamine preceded the nitrosourea. The human cells were more resistant to lonidamine and to the combination treatments than were the mouse cells. Nevertheless, substantial enhancement was seen particularly for cisplatin and mitomycin C. We examined in more detail the enhancement of cisplatin. Maximum interaction was obtained when lonidamine was given immediately following (or in conjunction with) the platinum agent. Our results suggest that lonidamine enhances the effects of several other agents in a time- and concentration-dependent manner and indicate a potential usefulness for lonidamine in multidrug therapy.


Mating activity of Bactrocera cacuminata (Hering) (Diptera: Tephritidae) on its larval host plant Solanum mauritianum Scopoli in southeast Queensland.
A detailed study was conducted on the mating behaviour of Bactrocera cacuminata (Hering) (Diptera: Tephritidae) in nature. Plant tissues from Solanum mauritianum Scopoli, the primary larval host for B. cacuminata, were also analysed for methyl eugenol content. In the field, over a 15 month period, 44,171 observations of adult B. cacuminata individuals were made including 1109 mating pairs on S. mauritianum. Calling behaviour consisting of wing fanning and anus beating by males was also consistently observed on the underside of leaves of S. mauritianum after sunset. Female flies that arrived into these groups of 10-15 calling males were mated and often remained coupled until dawn. No methyl eugenol was detected from the analysis of leaves, flowers and fruits of S. mauritianum. Thus, B. cacuminata does not need to aggregate at sites where methyl eugenol is present and the hypothesis that this chemical plays a role in the selection of mating sites by B. cacuminata is not supported by the current study. It is concluded that S. mauritianum is the primary site of mating for B. cacuminata in nature and that the concept that the larval host plant is the centre of activity for dacine fruit flies remains robust, being fully supported by the results of this study.


Changes in ocean health in British Columbia from 2001 to 2016.
Effective management of marine systems requires quantitative tools that can assess the state of the marine social-ecological system and are responsive to management actions and pressures. We applied the Ocean Health Index (OHI) framework to retrospectively assess ocean health in British Columbia annually from 2001 to 2016 for eight goals that represent the values of British Columbia's coastal communities. We found overall ocean health improved over the study period, from 75 (out of 100) in 2001 to 83 in 2016, with scores for inhabited regions ranging from 68 (North Coast, 2002) to 87 (West Vancouver Island, 2011). Highest-scoring goals were Tourism & Recreation (average 94 over the period) and Habitat Services (100); lowest-scoring goals were Sense of Place (61) and Food Provision (64). Significant increases in scores over the time period occurred for Food Provision (+1.7 per year), Sense of Place (+1.4 per year), and Coastal Livelihoods (+0.6 per year), while Habitat Services (-0.01 per year) and Biodiversity (-0.09 per year) showed modest but statistically significant declines. From the results of our time-series analysis, we used the OHI framework to evaluate impacts of a range of management actions. Despite challenges in data availability, we found evidence for the ability of management to reduce pressures on several goals, suggesting the potential of OHI as a tool for assessing the effectiveness of marine resource management to improve ocean health. Our OHI assessment provides an important comprehensive evaluation of ocean health in British Columbia, and our open and transparent process highlights opportunities for improving accessibility of social and ecological data to inform future assessment and management of ocean health.


Combining lexical and semantic methods of inter-terminology mapping using the UMLS.
The need for inter-terminology mapping is constantly increasing with the growth in the volume of electronically captured biomedical data and the demand to re-use the same data for secondary purposes. Using the UMLS as a knowledge base, semantically-based and lexically-based mappings were generated from SNOMED CT to ICD9CM terms and compared to a gold standard. Semantic mapping performed better than lexical mapping in terms of coverage, recall and precision. As the two mapping methods are orthogonal, the two sets of mappings can be used to validate and enhance each other. A method of combining the mappings based on the precision level of sub-categories in each method was derived. The combined method outperformed both methods, achieving coverage of 91%, recall of 43% and precision of 27%. It is also possible to customize the method of combination to optimize performance according to the task at hand.


Structural characterization of hemoglobins from Monilifera and Frenulata tubeworms (Siboglinids): first discovery of giant hexagonal-bilayer hemoglobin in the former "Pogonophora" group.
Siboglinids are symbiotic polychete annelids having hemoglobins as essential oxygen- and sulfide-carriers for their endosymbiotic bacteria. We analyzed the structure of the hemoglobins from two species of siboglinids: the monilifera Sclerolinum contortum and the frenulata Oligobrachia webbi (i.e. haakonmosbiensis) from Norwegian cold seeps. Measured by Multi-Angle Laser Light Scattering (MALLS), Sclerolinum shows a 3190+/-50 kDa hexagonal bilayer hemoglobin (HBL-Hb) and a 461+/-46 kDa ring-Hb, just as vestimentifera, whereas Oligobrachia has a 409+/-3.7 kDa ring-Hb only. Electrospray Ionization-Mass Spectrometry (ESI-MS) showed Sclerolinum HBL-Hb composed of seven monomeric globins (15-16 kDa), three disulfide-bonded globin heterodimers and three linkers. The heterodimers always contain globin-b (15814.4+/-1.5 Da). Sclerolinum ring-Hb is composed of globins and dimers with identical masses as its HBL-Hb, but lacks linkers. Oligobrachia ring-Hb has three globin monomers (14-15 kDa) only, with no disulfide-bonded dimers. Comparison of Sclerolinum hemoglobins between Storegga and Haakon Mosby Mud Volcano, using the normalized height of deconvoluted ESI-MS peaks, shows differences in globin monomers abundances that could reflect genetic differences or differential gene expression between distinct seep populations. The discovery of HBL-Hb in Sclerolinum is a new element supporting the hypothesis of monilifera being phylogenetically more closely related to vestimentifera, than to frenulata.


Ectopic expression of PAX5 promotes maintenance of biphenotypic myeloid progenitors coexpressing myeloid and B-cell lineage-associated genes.
The transcription factor PAX5 is a critical regulator of B-cell commitment and development. Although normally not expressed in myeloid progenitors, PAX5 has recently been shown to be frequently expressed in myeloid malignancies and to suppress expression of myeloid differentiation genes, compatible with an effect on the differentiation or maintenance of myeloid progenitors. However, previous studies in which PAX5 was ectopically expressed in normal myeloid progenitors in vivo and in vitro provided conflicting results as to the effect of PAX5 on myeloid development. Herein, we demonstrate that on ectopic expression of PAX5 in bone marrow multipotent stem/progenitor cells, cells with a biphenotypic B220(+)GR-1/MAC-1(+) phenotype are produced. These remain cytokine-dependent, but unlike control-transduced cells they sustain long-term generation of myeloid progenitors in vitro and remain capable of myeloid differentiation. Notably, PAX5(+)B220(+)GR-1/MAC-1(+) myeloid progenitors coexpress, at the single-cell level, myeloid genes and otherwise B-cell-specific PAX5 target genes. These findings establish that ectopic expression of PAX5 introduces extensive self-renewal properties in otherwise short-lived myeloid progenitors. Along with the established ectopic expression of PAX5 in acute myeloid leukemia, this motivates a careful investigation of the potential involvement of ectopic PAX5 expression in myeloid and biphenotypic leukemias.


High levels of messenger RNAs for tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in primary breast carcinomas are associated with development of distant metastases.
Tissue inhibitors of metalloproteinases (TIMPs) are believed to possess several cellular functions, particularly the contrasting activities of inhibiting tissue-degrading enzymes and promoting cellular growth. In attempts to elucidate which of these functions may prevail in breast cancer, expression of mRNAs for TIMP-1 and TIMP-2 in the primary carcinomas from 34 breast cancer patients was related to known prognostic parameters and the clinical outcome. High levels of TIMP-1 mRNA showed significant correlation with the presence of lymph node metastases (P = 0.0067), development of distant metastases (P = 0.014), and early death of the disease (P = 0.020). Elevated expression of TIMP-2 mRNA was associated with development of distant metastases (P = 0.0055). No correlations, however, were observed between mRNA levels of TIMPs and prognostic factors such as patient age, tumor size, grade of anaplasia, or steroid receptor status; neither were any correlations found between these clinicopathological characteristics and the mRNA expression of the collagenolytic enzymes matrix metalloproteinase-2 and matrix metalloproteinase-9. The present data suggest that high levels of TIMP-1 and TIMP-2 mRNAs in the primary carcinomas are strongly associated with development of metastasis in breast cancer.


Nanoplasmonics of prime number arrays.
In this paper, we investigate the plasmonic near-field localization and the far-field scattering properties of non-periodic arrays of Ag nanoparticles generated by prime number sequences in two spatial dimensions. In particular, we demonstrate that the engineering of plasmonic arrays with large spectral flatness and particle density is necessary to achieve a high density of electromagnetic hot spots over a broader frequency range and a larger area compared to strongly coupled periodic and quasi-periodic structures. Finally, we study the far-field scattering properties of prime number arrays illuminated by plane waves and we discuss their angular scattering properties. The study of prime number arrays of metal nanoparticles provides a novel strategy to achieve broadband enhancement and localization of plasmonic fields for the engineering of nanoscale nano-antenna arrays and active plasmonic structures.


Complete Genome Sequence of Edwardsiella piscicida Isolate S11-285 Recovered from Channel Catfish (Ictalurus punctatus) in Mississippi, USA.
Edwardsiella piscicida is a recently described Gram-negative facultative anaerobe and an important pathogen to many wild and cultured fish species worldwide. Here, we report the complete and annotated genome of E. piscicida isolate S11-285 recovered from channel catfish (Ictalurus punctatus), consisting of a chromosome of 3,923,603 bp and 1 plasmid.


Next-generation proteomics: towards an integrative view of proteome dynamics.
Next-generation sequencing allows the analysis of genomes, including those representing disease states. However, the causes of most disorders are multifactorial, and systems-level approaches, including the analysis of proteomes, are required for a more comprehensive understanding. The proteome is extremely multifaceted owing to splicing and protein modifications, and this is further amplified by the interconnectivity of proteins into complexes and signalling networks that are highly divergent in time and space. Proteome analysis heavily relies on mass spectrometry (MS). MS-based proteomics is starting to mature and to deliver through a combination of developments in instrumentation, sample preparation and computational analysis. Here we describe this emerging next generation of proteomics and highlight recent applications.


Transcription Factor Reprogramming in the Inner Ear: Turning on Cell Fate Switches to Regenerate Sensory Hair Cells.
Non-mammalian vertebrates can restore their auditory and vestibular hair cells naturally by triggering the regeneration of adjacent supporting cells. The transcription factor ATOH1 is a key regulator of hair cell development and regeneration in the inner ear. Following the death of hair cells, supporting cells upregulate ATOH1 and give rise to new hair cells. However, in the mature mammalian cochlea, such natural regeneration of hair cells is largely absent. Transcription factor reprogramming has been used in many tissues to convert one cell type into another, with the long-term hope of achieving tissue regeneration. Reprogramming transcription factors work by altering the transcriptomic and epigenetic landscapes in a target cell, resulting in a fate change to the desired cell type. Several studies have shown that ATOH1 is capable of reprogramming cochlear non-sensory tissue into cells resembling hair cells in young animals. However, the reprogramming ability of ATOH1 is lost with age, implying that the potency of individual hair cell-specific transcription factors may be reduced or lost over time by mechanisms that are still not clear. To circumvent this, combinations of key hair cell transcription factors have been used to promote hair cell regeneration in older animals. In this review, we summarize recent findings that have identified and studied these reprogramming factor combinations for hair cell regeneration. Finally, we discuss the important questions that emerge from these findings, particularly the feasibility of therapeutic strategies using reprogramming factors to restore human hearing in the future.


Preferences for masculinity in male bodies change across the menstrual cycle.
In human females cyclic shifts in preference have been documented for odour and physical and behavioral male traits. Women prefer the smell of dominant males, more masculine male faces and men behaving more dominantly when at peak fertility than at other times in their menstrual cycle. Here we examine variation in preferences for body sexual dimorphism. Across two studies, both between- and within-participant, we show that women prefer greater masculinity in male bodies at times when their fertility is likely highest, in the follicular phase of their cycle. Shifts were seen when rating for a short-term but not when rating for a long-term relationship. In line with studies showing similar effects for facial sexual dimorphism, we also show that women prefer greater masculinity when they think themselves attractive than when they think themselves less attractive. These results indicate that women's preferences for sexual dimorphism in male bodies follow a similar pattern as found for sexual dimorphism and dominance in other domains and such differences in preference may serve a similar function. Cyclic preferences could influence women to select partners when most likely to become pregnant that possess traits that may be most likely to maximize their offspring's quality via attraction to masculinity or serve to help acquire investment via attraction to femininity.


Epithelial-to-mesenchymal transition in cyst lining epithelial cells in an orthologous PCK rat model of autosomal-recessive polycystic kidney disease.
In polycystic kidney disease (PKD), cyst lining cells show polarity abnormalities. Recent studies have demonstrated loss of cell contact in cyst cells, suggesting induction of epithelial-to-mesenchymal transition (EMT). Recently, EMT has been implicated in the pathogenesis of PKD. To explore further evidence of EMT in PKD, we examined age- and segment-specific expression of adhesion molecules and mesenchymal markers in PCK rats, an orthologous model of human autosomal-recessive PKD. Kidneys from 5 male PCK and 5 control rats each at 0 days, 1, 3, 10, and 14 wk, and 4 mo of age were serially sectioned and stained with segment-specific markers and antibodies against E-cadherin, Snail1, β-catenin, and N-cadherin. mRNAs for E-cadherin and Snail1 were quantified by real-time PCR. Vimentin, fibronectin, and α-smooth muscle actin (α-SMA) expressions were assessed as mesenchymal markers. E-cadherin expression pattern was correlated with the disease pathology in that tubule segments showing the highest expression in control had much severer cyst formation in PCK rats. In PCK rats, E-cadherin and β-catenin in cystic tubules was attenuated and localized to lateral areas of cell-cell contact, whereas nuclear expression of Snail1 increased in parallel with cyst enlargement. Some epithelial cells in large cysts derived from these segments, especially in adjacent fibrotic areas, showed positive immunoreactivity for vimentin and fibronectin. In conclusion, these findings suggest that epithelial cells in cysts acquire mesenchymal features in response to cyst enlargement and participate in progressive renal fibrosis. Our study clarified the nephron segment-specific cyst profile related to EMT in PCK rats. EMT may play a key role in polycystic kidney disease.


Hematopoietic and reproductive hazards of Korean electronic workers exposed to solvents containing 2-bromopropane.
The purpose of this study was to describe hematopoietic and reproductive hazards of Korean electronic workers exposed to solvents containing 2-bromopropane. Detailed medical and occupational histories were taken and thorough physical examinations with clinical laboratory tests were done for 33 workers (8 men and 25 women). Previous and present exposure was investigated in detail by industrial hygienists. Of the 25 female workers, 16 were shown to have secondary amenorrhea with high follicle-stimulating hormone levels, normal prolactin levels, and hot flashes. A total of eight workers with amenorrhea concurrently showed findings of pancytopenia. Among eight male workers, two showed azoospermia and another four showed some degree of oligospermia (normal > 20 million. ml-1) or reduced sperm motility (normal > 50%). The bone marrow effects and the testis or ovarian failure was shown to be the main health hazards in this workplace. Except for the cleaning solution containing 97.4% 2-bromopropane, no other known physical or chemical agents could be identified as responsible for the gonadal and bone marrow effects, including ionizing radiation, lead, ethylene glycol ether and its acetates, benzene, and dibromochloropropane. No previous studies have reported human toxicity for 2-bromopropane, but the results of this study lead to the tentative conclusion that the causal agent for the gonadal and bone marrow effects among the workers might be 2-bromopropane.


Metatarsal Fracture Leading to Massive Pulmonary Embolism.
Immobilization and bed rest after fracture and orthopedic surgery are routinely advised protocol. Period of bed rest usually depends on the type of injury and orthopedic procedure, ranging from few days to weeks. The trauma, surgery, and immobilization with other contributing factors can lead to deep vein thrombosis and pulmonary embolism (PE) in these patients. Although there is high incidence of PE in such patients, it is difficult to diagnose, primarily because of the variety of nonspecific signs and symptoms. Here, we discuss a case of a 30-year-old female, who had suffered a trivial roadside accident leading to metatarsal bone fracture and later on presented in emergency with seizures, pulmonary edema, and cardiac arrest, after immobilization of just 5 days which was diagnosed to be result of massive PE. Here, we will discuss the pathophysiology, risk factors, and management of massive PE.


Teleost HoxD and HoxA genes: comparison with tetrapods and functional evolution of the HOXD complex.
In tetrapods, Hox genes are essential for the proper organization and development of axial structures. Experiments involving Hox gene inactivations have revealed their particularly important functions in the establishment of morphological transitions within metameric series such as the vertebral column. Teleost fish show a much simpler range of axial (trunk or appendicular) morphologies, which prompted us to investigate the nature of the Hox system in these lower vertebrates. Here, we show that fish have a family of Hox genes, very similar in both number and general organization, to that of tetrapods. Expression studies, carried out with HoxD and HoxA genes, showed that all vertebrates use the same general scheme, involving the colinear activation of gene expression in both space and time. Comparisons between tetrapods and fish allowed us to propose a model which accounts for the primary function of this gene family. In this model, a few ancestral Hox genes were involved in the determination of polarity in the digestive tract and were further recruited in more elaborate axial structures.


Genetic correlations and the coevolutionary dynamics of three-species systems.
The majority of species interact with at least several others. We develop simple genetic models of coevolution between three species where interactions are mediated by quantitative traits. We assume that one of the species has two quantitative traits, each of which governs its interaction with one of the other two species. We use this model to explore how genetic correlations between the two traits in the multivariate species shape the evolutionary dynamics and outcomes of three species interactions. Our results suggest that genetic correlations are most important when at least one of the interactions is between a predator and prey or parasite and host. In these cases, genetic correlations between traits lead to a wide variety of novel coevolutionary outcomes and dynamics. In particular, genetic correlations can affect the existence and stability of coevolutionary equilibrium points, and they can lead to recurrent or permanent maladaptation. When the three species interact only as competitors or mutualists, however, genetic correlations have no effect on the outcome of coevolution. In all cases, our results reveal the surprising conclusion that both positive and negative genetic correlations between traits have qualitatively identical effects on coevolutionary dynamics.


Interspecific voice discrimination in dogs.
Conspecific individual recognition using vocal cues has been shown in a wide range of species but there is no published evidence that dogs are able to recognize their owner based on his/her voice alone (interspecific individual recognition). In our test, dogs had to rely on vocal cues to find their hidden owner in a two-way choice task. From behind an opaque screen, both the owner and a control person uttered neutral speech (reading sentences from a receipt) before the dogs were allowed to make their choice. Correct choices were reinforced by food and by verbal praise. During the six-choice trials, dogs chose their owner's voice significantly more often than the control person's voice. There was no effect of learning throughout the trials, and dogs did not show side preference. Thus, dogs are able to discriminate interspecific voices, suggesting that they are able to identify their owner based on vocal cues alone. This experimental design allows exploration of the role of individual acoustic parameters (such as fundamental frequency) in voice discrimination.


The sociocultural appraisals, values, and emotions (SAVE) framework of prosociality: core processes from gene to meme.
The study of prosocial behavior--altruism, cooperation, trust, and the related moral emotions--has matured enough to produce general scholarly consensus that prosociality is widespread, intuitive, and rooted deeply within our biological makeup. Several evolutionary frameworks model the conditions under which prosocial behavior is evolutionarily viable, yet no unifying treatment exists of the psychological decision-making processes that result in prosociality. Here, we provide such a perspective in the form of the sociocultural appraisals, values, and emotions (SAVE) framework of prosociality. We review evidence for the components of our framework at four levels of analysis: intrapsychic, dyadic, group, and cultural. Within these levels, we consider how phenomena such as altruistic punishment, prosocial contagion, self-other similarity, and numerous others give rise to prosocial behavior. We then extend our reasoning to chart the biological underpinnings of prosociality and apply our framework to understand the role of social class in prosociality.


Aspirin plus heparin or aspirin alone in women with recurrent miscarriage.
Aspirin and low-molecular-weight heparin are prescribed for women with unexplained recurrent miscarriage, with the goal of improving the rate of live births, but limited data from randomized, controlled trials are available to support the use of these drugs. In this randomized trial, we enrolled 364 women between the ages of 18 and 42 years who had a history of unexplained recurrent miscarriage and were attempting to conceive or were less than 6 weeks pregnant. We then randomly assigned them to receive daily 80 mg of aspirin plus open-label subcutaneous nadroparin (at a dose of 2850 IU, starting as soon as a viable pregnancy was demonstrated), 80 mg of aspirin alone, or placebo. The primary outcome measure was the live-birth rate. Secondary outcomes included rates of miscarriage, obstetrical complications, and maternal and fetal adverse events. Live-birth rates did not differ significantly among the three study groups. The proportions of women who gave birth to a live infant were 54.5% in the group receiving aspirin plus nadroparin (combination-therapy group), 50.8% in the aspirin-only group, and 57.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, -2.6 percentage points; 95% confidence interval [CI], -15.0 to 9.9; aspirin only vs. placebo, -6.2 percentage points; 95% CI, -18.8 to 6.4). Among 299 women who became pregnant, the live-birth rates were 69.1% in the combination-therapy group, 61.6% in the aspirin-only group, and 67.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, 2.1 percentage points; 95% CI, -10.8 to 15.0; aspirin alone vs. placebo -5.4 percentage points; 95% CI, -18.6 to 7.8). An increased tendency to bruise and swelling or itching at the injection site occurred significantly more frequently in the combination-therapy group than in the other two study groups. Neither aspirin combined with nadroparin nor aspirin alone improved the live-birth rate, as compared with placebo, among women with unexplained recurrent miscarriage. (Current Controlled Trials number, ISRCTN58496168.)