Learning chromatin states with factorized information criteria.
Recent studies have suggested that both the genome and the genome with epigenetic modifications, the so-called epigenome, play important roles in various biological functions, such as transcription and DNA replication, repair, and recombination. It is well known that specific combinations of histone modifications (e.g. methylations and acetylations) of nucleosomes induce chromatin states that correspond to specific functions of chromatin. Although the advent of next-generation sequencing (NGS) technologies enables measurement of epigenetic information for entire genomes at high-resolution, the variety of chromatin states has not been completely characterized. In this study, we propose a method to estimate the chromatin states indicated by genome-wide chromatin marks identified by NGS technologies. The proposed method automatically estimates the number of chromatin states and characterize each state on the basis of a hidden Markov model (HMM) in combination with a recently proposed model selection technique, factorized information criteria. The method is expected to provide an unbiased model because it relies on only two adjustable parameters and avoids heuristic procedures as much as possible. Computational experiments with simulated datasets show that our method automatically learns an appropriate model, even in cases where methods that rely on Bayesian information criteria fail to learn the model structures. In addition, we comprehensively compare our method to ChromHMM on three real datasets and show that our method estimates more chromatin states than ChromHMM for those datasets.


Gall Bladder Agenesis: A Rare Embryonic Cause of Recurrent Biliary Colic.
BACKGROUND Gallbladder agenesis (GA) is an extremely rare anatomic anomaly with a reported incidence of less than 0.5%. It is usually asymptomatic, but can present with features of biliary colic and cholecystitis. We present here a case of GA in a patient with recurrent biliary colic. CASE REPORT A 24-year-old African American woman presented with recurrent episodes of right upper-quadrant abdominal pain. During her first episode, she was found to have elevated transaminases and clinical features of cholecystitis, but ultrasound did not visualize a gallbladder and she was discharged with a diagnosis of biliary colic. She returned within a week with worsening liver enzymes, severe pain, and vomiting. A hepatobiliary iminodiacetic acid (HIDA) scan was done, which again did not show the gall bladder. On clinical suspicion of acute cholecystitis, she underwent laparoscopic surgery. Intraoperatively, the gall bladder fossa was empty and a diagnosis of gall bladder agenesis was made. She presented a third time with similar complaints and magnetic resonance cholangiopancreatography (MRCP) was done, which showed normal biliary tract anatomy and absent gall bladder. A diagnosis of sphincter of Oddi dysfunction was made and she was discharged on antispasmodics. CONCLUSIONS Diagnosing GA is challenging. The rarity of this entity combined with classic clinical features of cholecystitis and non-visualization of the gall bladder on routine investigation prompts unnecessary surgical intervention. Awareness of this condition, along with use of better imaging modalities like preoperative MRCP, can aide physicians to appropriately manage this uncommon clinical condition.


Patient-level performance evaluation of a smartphone-based malaria diagnostic application.
Microscopic examination is commonly used for malaria diagnosis in the field. However, the lack of well-trained microscopists in malaria-endemic areas impacted the most by the disease is a severe problem. Besides, the examination process is time-consuming and prone to human error. Automated diagnostic systems based on machine learning offer great potential to overcome these problems. This study aims to evaluate Malaria Screener, a smartphone-based application for malaria diagnosis. A total of 190 patients were recruited at two sites in rural areas near Khartoum, Sudan. The Malaria Screener mobile application was deployed to screen Giemsa-stained blood smears. Both expert microscopy and nested PCR were performed to use as reference standards. First, Malaria Screener was evaluated using the two reference standards. Then, during post-study experiments, the evaluation was repeated for a newly developed algorithm, PlasmodiumVF-Net. Malaria Screener reached 74.1% (95% CI 63.5-83.0) accuracy in detecting Plasmodium falciparum malaria using expert microscopy as the reference after a threshold calibration. It reached 71.8% (95% CI 61.0-81.0) accuracy when compared with PCR. The achieved accuracies meet the WHO Level 3 requirement for parasite detection. The processing time for each smear varies from 5 to 15 min, depending on the concentration of white blood cells (WBCs). In the post-study experiment, Malaria Screener reached 91.8% (95% CI 83.8-96.6) accuracy when patient-level results were calculated with a different method. This accuracy meets the WHO Level 1 requirement for parasite detection. In addition, PlasmodiumVF-Net, a newly developed algorithm, reached 83.1% (95% CI 77.0-88.1) accuracy when compared with expert microscopy and 81.0% (95% CI 74.6-86.3) accuracy when compared with PCR, reaching the WHO Level 2 requirement for detecting both Plasmodium falciparum and Plasmodium vivax malaria, without using the testing sites data for training or calibration. Results reported for both Malaria Screener and PlasmodiumVF-Net used thick smears for diagnosis. In this paper, both systems were not assessed in species identification and parasite counting, which are still under development. Malaria Screener showed the potential to be deployed in resource-limited areas to facilitate routine malaria screening. It is the first smartphone-based system for malaria diagnosis evaluated on the patient-level in a natural field environment. Thus, the results in the field reported here can serve as a reference for future studies.


Investigation of the spread of brucellosis among human and animal populations in southeastern Bulgaria, 2007.
Three human cases of brucellosis were reported in summer 2007 in the region of Haskovo in southeastern Bulgaria. Subsequently, the regional veterinary and public health authorities carried out investigations to determine the spread of infection in domestic animals and in the human population. As a result, over 90,000 animals were tested, and 410 were found infected with brucellosis. The screening of 561 people believed to have been at risk of infection yielded 47 positive results. The majority of these persons had direct contact with domestic animals or had consumed unpasteurised dairy products. The investigations revealed evidence of disease among animals in the region and a considerable risk to humans, thus emphasising the need for effective prevention and control programmes.


Voice modulation: from origin and mechanism to social impact.
Research on within-individual modulation of vocal cues is surprisingly scarce outside of human speech. Yet, voice modulation serves diverse functions in human and nonhuman nonverbal communication, from dynamically signalling motivation and emotion, to exaggerating physical traits such as body size and masculinity, to enabling song and musicality. The diversity of anatomical, neural, cognitive and behavioural adaptations necessary for the production and perception of voice modulation make it a critical target for research on the origins and functions of acoustic communication. This diversity also implicates voice modulation in numerous disciplines and technological applications. In this two-part theme issue comprising 21 articles from leading and emerging international researchers, we highlight the multidisciplinary nature of the voice sciences. Every article addresses at least two, if not several, critical topics: (i) development and mechanisms driving vocal control and modulation; (ii) cultural and other environmental factors affecting voice modulation; (iii) evolutionary origins and adaptive functions of vocal control including cross-species comparisons; (iv) social functions and real-world consequences of voice modulation; and (v) state-of-the-art in multidisciplinary methodologies and technologies in voice modulation research. With this collection of works, we aim to facilitate cross-talk across disciplines to further stimulate the burgeoning field of voice modulation. This article is part of the theme issue 'Voice modulation: from origin and mechanism to social impact (Part I)'.


Calcium stilbene complexes: structures and dual reactivity.
Addition of a calcium hydride complex to diphenylacetylene gave a complex in which the stilbene dianion symmetrically bridges two Ca2+ ions. DFT calculations discuss the effect of the metal stilbene coordination. The stilbene complex reacts as a base (with H2) or an electron donor (with I2) and catalyzes the reduction of diphenylacetylene.


Hypoxia inducible factors in liver disease and hepatocellular carcinoma: current understanding and future directions.
Hypoxia inducible transcription factors (HIFs) activate diverse pathways that regulate cellular metabolism, angiogenesis, proliferation, and migration, enabling a cell to respond to a low oxygen or hypoxic environment. HIFs are regulated by oxygen-dependent and independent signals including: mitochondrial dysfunction, reactive oxygen species, endoplasmic reticular stress, and viral infection. HIFs have been reported to play a role in the pathogenesis of liver disease of diverse aetiologies. This review explores the impact of HIFs on hepatocellular biology and inflammatory responses, highlighting the therapeutic potential of targeting HIFs for an array of liver pathologies.


Rapid advance of spring arrival dates in long-distance migratory birds.
Several bird species have advanced the timing of their spring migration in response to recent climate change. European short-distance migrants, wintering in temperate areas, have been assumed to be more affected by change in the European climate than long-distance migrants wintering in the tropics. However, we show that long-distance migrants have advanced their spring arrival in Scandinavia more than short-distance migrants. By analyzing a long-term data set from southern Italy, we show that long-distance migrants also pass through the Mediterranean region earlier. We argue that this may reflect a climate-driven evolutionary change in the timing of spring migration.


The chemotherapy of rodent malaria. LIV. Combinations of 'Fenozan B07' (Fenozan-50F), a difluorinated 3,3'-spirocyclopentane 1,2,4-trioxane, with other drugs against drug-sensitive and drug-resistant parasites.
Fenozan B07, a 1,2,4-trioxane endoperoxide with potent blood schizontocidal activity against drug-sensitive and drug-resistant rodent malaria parasites, exerted a modest potentiating action when administered with chloroquine (CQ) to mice infected with parasites of the CQ-resistant P. yoelii ssp. NS, but not when given to mice infected with the CQ-sensitive P. berghei N strain. The reason why this potentiation may be of particular value in the treatment of severe falciparum malaria is discussed. Mefloquine and halofantrine displayed a similar level of potentiation with Fenozan B07 against the CQ-resistant parasites. However, antagonism was shown by combinations of Fenozan B07 with pyronaridine or the 8-aminoquinoline WR 238 605 when used against CQ-resistant parasites. Mefloquine with Fenozan B07 is also antagonistic against a highly mefloquine-resistant line of P. yoelii ssp. NS. The reasons behind such antagonism are not known. The importance is stressed of using carefully selected drug combinations of novel antimalarials, rather than single drugs, in order to impede the selection of drug-resistant parasites, but only after adequate, preclinical, toxicity testing.


Non-Covalent BTK Inhibitors-The New BTKids on the Block for B-Cell Malignancies.
The B-cell receptor signalling pathway plays a critical role in development of B-cell malignancies, and the central role of Bruton's tyrosine kinase (BTK) activation in this pathway provides compelling rationale for BTK inhibition as a therapeutic strategy for these conditions. Covalent BTK inhibitors (BTKi) have transformed the treatment landscape of B-cell malignancies, but adverse events and treatment resistance have emerged as therapeutic challenges, with the majority of patients eventually discontinuing treatment due to toxicity or disease progression. Non-covalent BTKi have alternative mechanisms of binding to BTK than covalent BTKi, and therefore offer a therapeutic alternative for patients with B-cell malignancies, including those who have been intolerant to, or experienced disease progression during treatment with a covalent BTKi. Here, we summarise the clinical data, adverse events and mechanisms of resistance observed with covalent BTKi and describe the emerging data for non-covalent BTKi as a novel treatment for B-cell malignancies.


Peripheral N-methyl-D-aspartate receptors modulate nonadrenergic noncholinergic lower esophageal sphincter relaxation in rabbits.
We investigated the role of peripheral N-methyl-D-aspartate (NMDA) receptors in the myenteric plexus in mediating nonadrenergic noncholinergic (NANC) nitrergic relaxation of the lower esophageal sphincter (LES). Isometric contraction of LES strips from Japanese White rabbits was measured. NANC relaxation was induced by KCl (30 mM) in the presence of atropine and guanethidine. The concentration of 3',5'-cyclic guanosine monophosphate (cGMP) was measured using a radioimmunoassay. The muscle strips were exposed to diethyldithiocarbamic acid (DETCA; 3 mM) to inactivate Cu/Zn superoxide dismutase. MK801 (5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine) inhibited NANC relaxation in a concentration-dependent manner (EC50 = 1.5 x 10(-5) M), accompanied by a decrease in cGMP production. NMDA induced a concentration-dependent relaxation, which was antagonized by MK801. NMDA stimulated cGMP production, which was inhibited by N(G)-nitro-L-arginine. Superoxide dismutase (100 U/mL) shifted the concentration-response relationship of MK801-mediated inhibition of NANC relaxation to the right (EC50 = 3.4 x 10(-5) M), whereas catalase did not. Treatment with DETCA shifted the concentration-response relationships of pyrogallol-, ketamine- and MK801-mediated inhibition of NANC relaxation to the left. These findings suggest that the peripheral NMDA receptors mediate NANC smooth muscle relaxation, and modulate it, in part, through extracellular production of superoxide anions, thus eliminating the relaxant effect of endogenous nitric oxide.


APC/C-Cdc20 mediates deprotection of centromeric cohesin at meiosis II in yeast.
Cells undergoing meiosis produce haploid gametes through one round of DNA replication followed by 2 rounds of chromosome segregation. This requires that cohesin complexes, which establish sister chromatid cohesion during S phase, are removed in a stepwise manner. At meiosis I, the separase protease triggers the segregation of homologous chromosomes by cleaving cohesin's Rec8 subunit on chromosome arms. Cohesin persists at centromeres because the PP2A phosphatase, recruited by the shugoshin protein, dephosphorylates Rec8 and thereby protects it from cleavage. While chromatids disjoin upon cleavage of centromeric Rec8 at meiosis II, it was unclear how and when centromeric Rec8 is liberated from its protector PP2A. One proposal is that bipolar spindle forces separate PP2A from Rec8 as cells enter metaphase II. We show here that sister centromere biorientation is not sufficient to "deprotect" Rec8 at meiosis II in yeast. Instead, our data suggest that the ubiquitin-ligase APC/CCdc20 removes PP2A from centromeres by targeting for degradation the shugoshin Sgo1 and the kinase Mps1. This implies that Rec8 remains protected until entry into anaphase II when it is phosphorylated concurrently with the activation of separase. Here, we provide further support for this model and speculate on its relevance to mammalian oocytes.


Study Protocol: A Cross-Sectional Examination of Socio-Demographic and Ecological Determinants of Nutrition and Disease Across Madagascar.
Madagascar has experienced significant environmental change since 1960, particularly through forest clearing for agricultural expansion. Climatic patterns are undergoing change in Madagascar as well, with increasing temperatures, droughts, and cyclonic activity. The impact of these environmental and climatic changes will pose threats to food availability, income generation, and local ecosystems, with significant potential effects on the spatial and temporal distribution of disease burden. This study seeks to describe the health status of a large sample of geographically and socially diverse Malagasy communities through multiple clinical measurements, detailed social surveys, and paired data on regional variation in local ecologies. With an increased understanding of the current patterns of variation in human health and nutrition, future studies will be better able to identify associations with climate and anticipate and mitigate the burdens expected from larger, longer-term changes. Our mixed-method approach included an observational cross-sectional study. Research subjects were men, women, and children from 1,125 households evenly distributed across 24 communities in four ecologically and socio-demographically distinct regions of Madagascar. For these 1,125 households, all persons of both sexes and all ages therein (for a total of 6,292 individuals) were recruited into the research study and a total of 5,882 individuals were enrolled. Through repeated social survey recalls and focus group meetings, we obtained social and demographic data, including broad categories of seasonal movements, and characterized the fluctuation of income generation, food production and dietary consumption. Through collection of clinical and biological samples for both point-of-care diagnoses and laboratory analyses, we obtained detailed occurrence (and importantly co-occurrence) data on micronutrient nutritional, infectious disease, and non-communicable disease status. Our research highlights the highly variable social, cultural, and environmental contexts of health conditions in Madagascar, and the tremendous inter-regional, inter-community, and intra-community variation in nutritional and disease status. More than 30% of the surveyed population was afflicted by anemia and 14% of the population had a current malaria infection. This type of rich metadata associated with a suite of biological samples and nutritional and disease outcome data should allow disentangling some of the underlying drivers of ill health across the changing landscapes of Madagascar.


How to estimate solid-electrolyte-interphase features when screening electrolyte materials.
Computational screening of battery electrolyte components is an extremely challenging task because very complex features like solid-electrolyte-interphase (SEI) formation and graphite exfoliation need to be taken into account at least in the final screening stage. We present estimators for both SEI formation and graphite exfoliation based on a combinatorial approach using quantum chemistry calculations on model system reactions, which can be applied automatically for a large number of compounds and thus allows for the systematic first assessment of the relevant properties using screening approaches. The thermodynamic effects are assessed using quantum mechanical calculations, while a more heuristic approach is used to estimate the kinetic effects.


Transcriptional profiling of layers of the primate cerebral cortex.
In this issue of Neuron, Bernard et al. (2012) report microarray-based transcriptional profiling of individually isolated layers from several cortical areas in adult Rhesus monkeys (Macaca mulatta). The resulting molecular signatures of neocortical organization are compared with human and mouse.


Parkinson's disease: clinical features and diagnosis.
Parkinson's disease (PD) is a progressive neurological disorder characterised by a large number of motor and non-motor features that can impact on function to a variable degree. This review describes the clinical characteristics of PD with emphasis on those features that differentiate the disease from other parkinsonian disorders. A MedLine search was performed to identify studies that assess the clinical characteristics of PD. Search terms included "Parkinson's disease", "diagnosis" and "signs and symptoms". Because there is no definitive test for the diagnosis of PD, the disease must be diagnosed based on clinical criteria. Rest tremor, bradykinesia, rigidity and loss of postural reflexes are generally considered the cardinal signs of PD. The presence and specific presentation of these features are used to differentiate PD from related parkinsonian disorders. Other clinical features include secondary motor symptoms (eg, hypomimia, dysarthria, dysphagia, sialorrhoea, micrographia, shuffling gait, festination, freezing, dystonia, glabellar reflexes), non-motor symptoms (eg, autonomic dysfunction, cognitive/neurobehavioral abnormalities, sleep disorders and sensory abnormalities such as anosmia, paresthesias and pain). Absence of rest tremor, early occurrence of gait difficulty, postural instability, dementia, hallucinations, and the presence of dysautonomia, ophthalmoparesis, ataxia and other atypical features, coupled with poor or no response to levodopa, suggest diagnoses other than PD. A thorough understanding of the broad spectrum of clinical manifestations of PD is essential to the proper diagnosis of the disease. Genetic mutations or variants, neuroimaging abnormalities and other tests are potential biomarkers that may improve diagnosis and allow the identification of persons at risk.


Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport.
The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons1-3. Major depression and anxiety disorders are treated using selective serotonin reuptake inhibitors-small molecules that competitively block substrate binding and thereby prolong neurotransmitter action2,4. The dopamine and noradrenaline transporters, together with SERT, are members of the neurotransmitter sodium symporter (NSS) family. The transport activities of NSSs can be inhibited or modulated by cocaine and amphetamines2,3, and genetic variants of NSSs are associated with several neuropsychiatric disorders including attention deficit hyperactivity disorder, autism and bipolar disorder2,5. Studies of bacterial NSS homologues-including LeuT-have shown how their transmembrane helices (TMs) undergo conformational changes during the transport cycle, exposing a central binding site to either side of the membrane1,6-12. However, the conformational changes associated with transport in NSSs remain unknown. To elucidate structure-based mechanisms for transport in SERT we investigated its complexes with ibogaine, a hallucinogenic natural product with psychoactive and anti-addictive properties13,14. Notably, ibogaine is a non-competitive inhibitor of transport but displays competitive binding towards selective serotonin reuptake inhibitors15,16. Here we report cryo-electron microscopy structures of SERT-ibogaine complexes captured in outward-open, occluded and inward-open conformations. Ibogaine binds to the central binding site, and closure of the extracellular gate largely involves movements of TMs 1b and 6a. Opening of the intracellular gate involves a hinge-like movement of TM1a and the partial unwinding of TM5, which together create a permeation pathway that enables substrate and ion diffusion to the cytoplasm. These structures define the structural rearrangements that occur from the outward-open to inward-open conformations, and provide insight into the mechanism of neurotransmitter transport and ibogaine inhibition.


Efficient ambipolar transport properties in alternate stacking donor-acceptor complexes: from experiment to theory.
Comprehensive investigations of crystal structures, electrical transport properties and theoretical simulations have been performed over a series of sulfur-bridged annulene-based donor-acceptor complexes with an alternate stacking motif. A remarkably high mobility, up to 1.57 cm(2) V(-1) s(-1) for holes and 0.47 cm(2) V(-1) s(-1) for electrons, was obtained using organic single crystal field-effect transistor devices, demonstrating the efficient ambipolar transport properties. These ambipolar properties arise from the fact that the electronic couplings for both holes and electrons have the same super-exchange nature along the alternate stacking direction. The magnitude of super-exchange coupling depends not only on the intermolecular stacking distance and pattern, but also the energy level alignments between the adjacent donor-acceptor moieties. The concluded transport mechanism and structure-property relationship from this research will provide an important guideline for the future design of organic semiconductors based on donor-acceptor complexes.


The influence of temperature and dose on antibacterial peptide response against lipopolysaccharide in the blue mussel, Mytilus edulis.
Blue mussels (Mytilus edulis) were inoculated with two different doses of lipopolysaccharides (LPS) or phosphate-saline (PS) buffer under different temperature conditions (6 and 20 degrees C). The activity of the antibacterial peptide fraction, purified through reverse phase chromatography from mussel haemolyph, was compared at different time intervals after the inoculation. The activity was determined as the minimal peptide concentration that inhibited growth of the Gram-negative bacteria Escherichia coli D21, by using radial diffusion assay. The antibacterial activity for mussels inoculated with LPS changed over time, both at 6 and 20 degrees C, but those inoculated with PS-buffer did not. The response was enhanced within a time course of 3h. The higher temperature did increase the inhibitory activity and made the mussel respond at an earlier stage, in comparison to that at 6 degrees C. At 20 degrees C, mussels inoculated with 10 microg of LPS responded faster than those inoculated with 0.1 microg of LPS. In addition, cytotoxic effects of LPS on mussel haemocytes were investigated in vitro, using a colorimetric assay. The survival index (SI%) for haemocytes decreased with 76% at 6 degrees C but increased with 100% at 20 degrees C, irrespective of the dose of LPS. This indicated that LPS did not influence the viability of the haemocytes but the high temperature increased their metabolic state. Likely, antibacterial response was provoked by LPS in a dose-dependent manner and favoured by higher metabolic state of the haemocytes, elicited at higher temperature. These results provide important considerations for variability in the internal defence of mussels and consequently, also the retention of viable human pathogens in mussels.


Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials.
Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF. Two pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20% protocol violations. No infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported. These two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment. CLINICALTRIALS.GOV: Pilot one: NCT number: 00598429 registered on 10 January 2008. Last updated: 3 February 2011. Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013.


Clinical outcomes of a 2-y soy isoflavone supplementation in menopausal women.
Soy isoflavones are naturally occurring phytochemicals with weak estrogenic cellular effects. Despite numerous clinical trials of short-term isoflavone supplementation, there is a paucity of data regarding longer-term outcomes and safety. Our aim was to evaluate the clinical outcomes of soy hypocotyl isoflavone supplementation in healthy menopausal women as a secondary outcome of a trial on bone health. A multicenter, randomized, double-blind, placebo-controlled 24-mo trial was conducted to assess the effects of daily supplementation with 80 or 120 mg aglycone equivalent soy hypocotyl isoflavones plus calcium and vitamin D on the health of 403 postmenopausal women. At baseline and after 1 and 2 y, clinical blood chemistry values were measured and a well-woman examination was conducted, which included a mammogram and a Papanicolaou test. A cohort also underwent transvaginal ultrasound measurements to assess endometrial thickness and fibroids. The baseline characteristics of the groups were similar. After 2 y of daily isoflavone exposure, all clinical chemistry values remained within the normal range. The only variable that changed significantly was blood urea nitrogen, which increased significantly after 2 y (P = 0.048) but not after 1 y (P = 0.343) in the supplementation groups. Isoflavone supplementation did not affect blood lymphocyte or serum free thyroxine concentrations. No significant differences in endometrial thickness or fibroids were observed between the groups. Two serious adverse events were detected (one case of breast cancer and one case of estrogen receptor-negative endometrial cancer), which was less than the expected population rate for these cancers. Daily supplementation for 2 y with 80-120 mg soy hypocotyl isoflavones has minimal risk in healthy menopausal women. This trial was registered at clinicaltrials.gov as NCT00665860.


Practice patterns of palliative radiation therapy in pediatric oncology patients in an international pediatric research consortium.
The practice of palliative radiation therapy (RT) is based on extrapolation from adult literature. We evaluated patterns of pediatric palliative RT to describe regimens used to identify opportunity for future pediatric-specific clinical trials. Six international institutions with pediatric expertise completed a 122-item survey evaluating patterns of palliative RT for patients ≤21 years old from 2010 to 2015. Two institutions use proton RT. Palliative RT was defined as treatment with the goal of symptom control or prevention of immediate life-threatening progression. Of 3,225 pediatric patients, 365 (11%) were treated with palliative intent to a total of 427 disease sites. Anesthesia was required in 10% of patients. Treatment was delivered to metastatic disease in 54% of patients. Histologies included neuroblastoma (30%), osteosarcoma (18%), leukemia/lymphoma (12%), rhabdomyosarcoma (12%), medulloblastoma/ependymoma (12%), Ewing sarcoma (8%), and other (8%). Indications included pain (43%), intracranial symptoms (23%), respiratory compromise (14%), cord compression (8%), and abdominal distention (6%). Sites included nonspine bone (35%), brain (16% primary tumors, 6% metastases), abdomen/pelvis (15%), spine (12%), head/neck (9%), and lung/mediastinum (5%). Re-irradiation comprised 16% of cases. Techniques employed three-dimensional conformal RT (41%), intensity-modulated RT (23%), conventional RT (26%), stereotactic body RT (6%), protons (1%), electrons (1%), and other (2%). The most common physician-reported barrier to consideration of palliative RT was the concern about treatment toxicity (83%). There is significant diversity of practice in pediatric palliative RT. Combined with ongoing research characterizing treatment response and toxicity, these data will inform the design of forthcoming clinical trials to establish effective regimens and minimize treatment toxicity for this patient population.


Vertical-cavity surface-emitting laser with liquid crystal overlay.
We perform a theoretical study of the spectral and polarization threshold characteristics of Vertical-Cavity Surface-Emitting Lasers with Liquid Crystal overlay (LC-VCSEL) in three different configurations of the LC cell. Our model predicts the possibility of selecting between two orthogonal directions of linear polarization (LP) of the fundamental mode (x or y LP) by choosing appropriate LC length. It further predicts very strong polarization discrimination with LP mode threshold gain difference as large as several times the threshold gain of the lasing mode. We also numerically demonstrate an active control of light polarization by electro-optically tuning the LC director and show that either polarization switching between x and y LP modes or continuous change of the LP direction would be possible. Finally, we numerically demonstrate that LC-VCSEL would be capable of efficient wavelength tuning.


Serum CD163 and TARC as disease response biomarkers in classical Hodgkin lymphoma.
Candidate circulating disease response biomarkers for classical Hodgkin lymphoma (cHL) might arise from Hodgkin-Reed-Sternberg (HRS) cells or nonmalignant tumor-infiltrating cells. HRS cells are sparse within the diseased node, whereas benign CD163(+) M2 tissue-associated macrophages (TAM) are prominent. CD163(+) cells within the malignant node may be prognostic, but there is no data on serum CD163 (sCD163). The HRS-specific serum protein sTARC shows promise as a disease response biomarker. Tumor-specific and tumor-infiltrating circulating biomarkers have not been compared previously. We prospectively measured sCD163 and sTARC in 221 samples from 47 patients with Hodgkin lymphoma and 21 healthy participants. Blood was taken at five fixed time-points prior, during, and after first-line therapy. Results were compared with radiological assessment and plasma Epstein-Barr virus DNA (EBV-DNA). Potential sources of circulating CD163 were investigated, along with immunosuppressive properties of CD163. Pretherapy, both sCD163 and sTARC were markedly elevated compared with healthy and complete remission samples. sCD163 better reflected tumor burden during therapy, whereas sTARC had greater value upon completion of therapy. sCD163 correlated with plasma EBV-DNA, and associated with B symptoms, stage, and lymphopenia. Circulating CD163(+) monocytes were elevated in patients, indicating that sCD163 are likely derived from circulating and intratumoral cells. Depletion of cHL CD163(+) monocytes markedly enhanced T-cell proliferation, implicating monocytes and/or TAMs as potential novel targets for immunotherapeutic manipulation. The combination of circulating tumor-infiltrate (sCD163) and tumor-specific (sTARC) proteins is more informative than either marker alone as disease response biomarkers in early and advanced disease during first-line therapy for cHL.


Tunable, high aspect ratio pillars on diverse substrates using copolymer micelle lithography: an interesting platform for applications.
We demonstrate the use of copolymer micelle lithography using polystyrene-block-poly(2-vinylpyridine) reverse micelle thin films in their as-coated form to create nanopillars with tunable dimensions and spacing, on different substrates such as silicon, silicon oxide, silicon nitride and quartz. The promise of the approach as a versatile application oriented platform is highlighted by demonstrating its utility for creating super-hydrophobic surfaces, fabrication of nanoporous polymeric membranes, and controlling the areal density of physical vapor deposition derived titanium nitride nanostructures.


Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques.
Neutralizing antibodies are thought to be crucial for HIV vaccine protection, but studies in animal models suggest that high antibody concentrations are required. This is a major potential hurdle for vaccine design. However, these studies typically apply a large virus inoculum to ensure infection in control animals in single-challenge experiments. In contrast, most human infection via sexual encounter probably involves repeated exposures to much lower doses of virus. Therefore, animal studies may have provided an overestimate of the levels of antibodies required for protection in humans. We investigated whether plasma concentrations of antibody corresponding to relatively modest neutralization titers in vitro could protect macaques from repeated intravaginal exposure to low doses of a simian immunodeficiency virus-HIV chimera (SHIV) that uses the CC chemokine receptor 5 (CCR5) co-receptor. An effector function-deficient variant of the neutralizing antibody was also included. The results show that a substantially larger number of challenges is required to infect macaques treated with neutralizing antibody than control antibody-treated macaques, and support the notion that effector function may contribute to antibody protection. Overall, the results imply that lower amounts of antibody than previously considered protective may provide benefit in the context of typical human exposure to HIV-1.


Influence of sodium chloride reduction and replacement with potassium chloride based salts on the sensory and physico-chemical characteristics of pork sausage patties.
This study evaluated the effects of sodium chloride reduction and replacement with potassium chloride or modified potassium chloride based salts using a weight or molar equivalent basis on the sensory and physico-chemical properties of pork sausage patties. Three independent replications of pork sausage patties were manufactured to compare five treatments: full sodium, reduced sodium, modified potassium chloride weight based replacement, modified potassium chloride molar based replacement, and standard potassium chloride weight based replacement. Salt replacement did not affect (P>0.05) moisture, protein, fat, textural properties, lipid oxidation, or redness. Sausage patties with modified potassium chloride were more acceptable than those with standard potassium chloride (P<0.001). Using modified potassium chloride replaced on a molar equivalent basis resulted in samples with more similar sensory characteristics to the full sodium control than replacement on a weight equivalent basis. The use of modified potassium chloride reduced sodium and improved sodium:potassium ratios while other changes in composition or physico-chemical characteristics were minimal.


Blood vessels restrain pancreas branching, differentiation and growth.
How organ size and form are controlled during development is a major question in biology. Blood vessels have been shown to be essential for early development of the liver and pancreas, and are fundamental to normal and pathological tissue growth. Here, we report that, surprisingly, non-nutritional signals from blood vessels act to restrain pancreas growth. Elimination of endothelial cells increases the size of embryonic pancreatic buds. Conversely, VEGF-induced hypervascularization decreases pancreas size. The growth phenotype results from vascular restriction of pancreatic tip cell formation, lateral branching and differentiation of the pancreatic epithelium into endocrine and acinar cells. The effects are seen both in vivo and ex vivo, indicating a perfusion-independent mechanism. Thus, the vasculature controls pancreas morphogenesis and growth by reducing branching and differentiation of primitive epithelial cells.


A geo-coded inventory of anophelines in the Afrotropical Region south of the Sahara: 1898-2016.
Background: Understanding the distribution of anopheline vectors of malaria is an important prelude to the design of national malaria control and elimination programmes. A single, geo-coded continental inventory of anophelines using all available published and unpublished data has not been undertaken since the 1960s. Methods: We have searched African, European and World Health Organization archives to identify unpublished reports on anopheline surveys in 48 sub-Saharan Africa countries. This search was supplemented by identification of reports that formed part of post-graduate theses, conference abstracts, regional insecticide resistance databases and more traditional bibliographic searches of peer-reviewed literature. Finally, a check was made against two recent repositories of dominant malaria vector species locations ( circa 2,500). Each report was used to extract information on the survey dates, village locations (geo-coded to provide a longitude and latitude), sampling methods, species identification methods and all anopheline species found present during the survey. Survey records were collapsed to a single site over time. Results: The search strategy took years and resulted in 13,331 unique, geo-coded survey locations of anopheline vector occurrence between 1898 and 2016. A total of 12,204 (92%) sites reported the presence of 10 dominant vector species/sibling species; 4,473 (37%) of these sites were sampled since 2005. 4,442 (33%) sites reported at least one of 13 possible secondary vector species; 1,107 (25%) of these sites were sampled since 2005. Distributions of dominant and secondary vectors conform to previous descriptions of the ecological ranges of these vectors. Conclusion: We have assembled the largest ever geo-coded database of anophelines in Africa, representing a legacy dataset for future updating and identification of knowledge gaps at national levels. The geo-coded database is available on Harvard Dataverse as a reference source for African national malaria control programmes planning their future control and elimination strategies.


Beyond mortality: future clinical research in acute lung injury.
Mortality in National Heart, Lung and Blood Institute-sponsored clinical trials of treatments for acute lung injury (ALI) has decreased dramatically during the past two decades. As a consequence, design of such trials based on a mortality outcome requires ever-increasing numbers of patients. Recognizing that advances in clinical trial design might be applicable to these trials and might allow trials with fewer patients, the National Heart, Lung and Blood Institute convened a workshop of extramural experts from several disciplines. The workshop assessed the current state of clinical research addressing ALI, identified research needs, and recommended: (1) continued performance of trials evaluating treatments of patients with ALI; (2) development of strategies to perform ALI prevention trials; (3) observational studies of patients without ALI undergoing prolonged mechanical ventilation; and (4) development of a standardized format for reporting methods, endpoints, and results of ALI trials.


Social networks and HIV/AIDs risk perceptions.
Understanding the determinants of individuals' perceptions of their risk of becoming infected with HIV and their perceptions of acceptable strategies of prevention is an essential step toward curtailing the spread of this disease. We focus in this article on learning and decision-making about AIDS in the context of high uncertainty about the disease and appropriate behavioral responses. We argue that social interactions are important for both. Using longitudinal survey data from rural Kenya and Malawi, we test this hypothesis. We investigate whether social interactions--and especially the extent to which social network partners perceive themselves to be at risk--exert causal influences on respondents' risk perceptions and on one approach to prevention, spousal communication about the threat of AIDS to the couple and their children. The study explicitly allows for the possibility that important characteristics, such as unobserved preferences or community characteristics, determine not only the outcomes of interest but also the size and composition of networks. The most important empirical result is that social networks have significant and substantial effects on risk perceptions and the adoption of new behaviors even after we control for unobserved factors.


The role of thyroid hormone administration in potential organ donors.
Levothyroxine sodium therapy should be used in brain-dead potential organ donors to reverse hemodynamic instability and to prevent cardiovascular collapse, leading to more available organs for transplantation. Prospective, before and after clinical study. A surgical intensive care unit of an academic county hospital. During a 12-month period (September 1, 1999, through August 31, 2000), we evaluated 19 hemodynamically unstable patients with traumatic and nontraumatic intracranial lesions, who were candidates for organ donation following brain death declaration. All patients were resuscitated aggressively for organ preservation by fluids, inotropic agents, and vasopressors. If, despite all measures, the patients remained hemodynamically unstable, a bolus of 1 ampule of 50% dextrose, 2 g of methylprednisolone sodium succinate, 20 U of insulin, and 20 microg of levothyroxine sodium was administered, followed by a continuous levothyroxine sodium infusion at 10 microg/h. There was a significant reduction in the total vasopressor requirement after levothyroxine therapy (mean +/- SD, 11.1 +/- 0.9 microg/kg per minute vs 6.4 +/- 1.4 microg/kg per minute, P =.02). Ten patients (53%) had complete discontinuation of vasopressors. There were no failures to reach organ donation due to cardiopulmonary arrest. Levothyroxine therapy plays an important role in the management of hemodynamically unstable potential organ donors by decreasing vasopressor requirements and preventing cardiovascular collapse. This may result in an increase in the quantity and quality of organs available for transplantation.


Reading LINEs within the cocaine addicted brain.
Long interspersed element (LINE)-1 (L1) is a type of retrotransposon capable of mobilizing into new genomic locations. Often studied in Mendelian diseases or cancer, L1s may also cause somatic mutation in the developing central nervous system. Recent reports showed L1 transcription was activated in brains of cocaine-treated mice, and L1 retrotransposition was increased in cocaine-treated neuronal cell cultures. We hypothesized that the predisposition to cocaine addiction may result from inherited L1s or somatic L1 mobilization in the brain. Postmortem medial prefrontal cortex (mPFC) tissue from 30 CA and 30 control individuals was studied. An Alexafluor488-labeled NeuN antibody and fluorescence activated nuclei sorting were used to separate neuronal from non-neuronal cell nuclei. L1s and their 3' flanking sequences were amplified from neuronal and non-neuronal genomic DNA (gDNA) using L1-seq. L1 DNA libraries from the neuronal gDNA were sequenced on an Illumina HiSeq2000. Sequences aligned to the hg19 human genome build were analyzed for L1 insertions using custom "L1-seq" bioinformatics programs. Previously uncataloged L1 insertions, some validated by PCR, were detected in neurons from both CA and control brain samples. Steady-state L1 mRNA levels in CA and control mPFC were also assessed. Gene ontology and pathway analyses were used to assess relationships between genes putatively disrupted by novel L1s in CA and control individuals. L1 insertions in CA samples were enriched in gene ontologies and pathways previously associated with CA. We conclude that neurons in the mPFC harbor L1 insertions that have the potential to influence predisposition to CA.


Molecular mechanisms underlying variations in lung function: a systems genetics analysis.
Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48,201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs. The SpiroMeta-CHARGE GWAS results were integrated with lung eQTLs to map eSNPs and the genes and pathways underlying the associations in lung tissue. For comparison, a similar analysis was done in peripheral blood. The lung mRNA expression levels of the eSNP-regulated genes were tested for associations with lung function measures in 727 individuals. Additional analyses identified the pleiotropic effects of eSNPs from the published GWAS catalogue, and mapped enrichment in regulatory regions from the ENCODE project. Finally, the Connectivity Map database was used to identify potential therapeutics in silico that could reverse the COPD lung tissue gene signature. SNPs associated with lung function measures were more likely to be eQTLs and vice versa. The integration mapped the specific genes underlying the GWAS signals in lung tissue. The eSNP-regulated genes were enriched for developmental and inflammatory pathways; by comparison, SNPs associated with lung function that were eQTLs in blood, but not in lung, were only involved in inflammatory pathways. Lung function eSNPs were enriched for regulatory elements and were over-represented among genes showing differential expression during fetal lung development. An mRNA gene expression signature for COPD was identified in lung tissue and compared with the Connectivity Map. This in-silico drug repurposing approach suggested several compounds that reverse the COPD gene expression signature, including a nicotine receptor antagonist. These findings represent novel therapeutic pathways for COPD. The system genetics approach identified lung tissue genes driving the variation in lung function and susceptibility to COPD. The identification of these genes and the pathways in which they are enriched is essential to understand the pathophysiology of airway obstruction and to identify novel therapeutic targets and biomarkers for COPD, including drugs that reverse the COPD gene signature in silico. The research reported in this article was not specifically funded by any agency. See Acknowledgments for a full list of funders of the lung eQTL study and the Spiro-Meta CHARGE GWAS.


Direct in vitro electrochemical measurement of dopamine overflow in intermediate pituitary: characterization and pharmacology.
The intermediate lobe of the pituitary (IL) is a promising model system for the study of dopaminergic neurotransmission. We sought to characterize the release of dopamine (DA) from the IL using electrochemical methods which provide increased spatial and temporal resolution compared to the superfusion techniques which had previously been employed to study this system. After pretreatment with monoamine oxidase (MAO) inhibitors, we were able to routinely measure DA overflow after 30-sec, 9-Hz electrical stimulation of the pituitary stalk. This effect was blocked by tetrodotoxin and Cd++ ions confirming that it was due to synaptic activation. Intracellular recording from the postsynaptic cells (melanotrophs) showed a postsynaptic hyperpolarization with a time course that was identical to that of DA overflow. Overflow was increased and prolonged by agents that inhibited DA uptake (nomifensine, mazindol or cocaine) and increased but not prolonged by a D2 antagonist (sulpiride), presumably acting via presynaptic autoreceptors. The DA precursor 3,4-dihydroxyphenylalanine also increased DA overflow gradually over a 45-min time period. In view of reports of possible colocalization of DA and gamma-aminobutyric acid in IL, we determined the possible effects of GABAergic agents on DA release. Neither agonists (muscimol or baclofen) nor antagonists (bicuculline or 2-hydroxysaclofen) had any effect on DA overflow. By using the MAOA-specific inhibitor clorgyline and the MAOB-specific inhibitor deprenyl we were able to confirm that the MAOA form of the enzyme is involved in DA metabolism in this preparation.


Blood product support in patients undergoing chemotherapy and autologous or allogeneic bone marrow transplantation for haematological malignancies.
Three groups of patients with leukaemia and myelodysplasia were assessed with regard to the blood product support they required during their period of bone marrow hypoplasia following treatment. One group received myelo-ablative remission-induction chemotherapy followed by appropriate consolidation therapy (two courses in patients with acute myeloid leukaemia and one or two intensification courses in patients with acute lymphoblastic leukaemia); whilst the other two had 'conditioning' with chemotherapy and radiotherapy prior to autologous bone marrow transplantation (auto-BMT) or T cell depleted allogeneic bone marrow transplantation (allo-BMT). There was no statistically significant difference in blood product requirements between the three groups. However, platelet requirements during remission-induction chemotherapy alone were significantly less than for allo-BMT or auto-BMT. Platelet requirements for patients undergoing auto-BMT were also significantly higher than for patients receiving consolidation chemotherapy; and were required for a longer period than for patients receiving allogeneic-BMT. There was no difference in blood product support between ABO matched and mismatched transplants within the allogeneic group, but the presence of graft versus host disease and/or cytomegalovirus infection did significantly increase the requirements for blood product support.


Perioperative changes in oral bacteria number in patients undergoing cardiac valve surgery.
Perioperative oral care can reduce the risk of postoperative infections. This study examined 1) changes in oral bacteria counts during the perioperative period and 2) differences in bacteria counts in patients with or without endotracheal intubation. 47 patients who visited our hospital dental clinic prior to cardiac valve surgery were prospectively recruited. The number of bacteria on the tongue, tooth surface, and buccal vestibule was measured on the day before and 1, 4, and 7 days after surgery. Oral bacteria counts were statistically compared among time points and between intubation and extubation statuses. The oral bacteria counts on the tooth surface and buccal vestibule significantly increased from the day before surgery to 1 day after surgery, and then decreased from 1 to 4 days after surgery. On the day after surgery, the bacteria counts on the tooth surface and buccal vestibule were significantly higher in the intubated compared with the extubated group. Our findings suggest that the oral bacteria count is elevated just after surgery, especially if the patient has endotracheal intubation, which may increase the risk of aspiration pneumonia. These results highlight the importance of perioperative oral care to prevent postoperative pneumonia.


Obesogenic environments in youth: concepts and methods from a longitudinal national sample.
To effectively prevent and reduce childhood obesity through healthy community design, it is essential to understand which neighborhood environment features influence weight gain in various age groups. However, most neighborhood environment research is cross-sectional, focuses on adults, and is often carried out in small, nongeneralizable geographic areas. Thus, there is a great need for longitudinal neighborhood environment research in diverse populations across the life cycle. This paper describes (1) insights and challenges of longitudinal neighborhood environment research and (2) advancements and remaining gaps in measurement and study design that examine individuals and neighborhoods within the context of the broader community. Literature-based research and findings from the Obesity and Neighborhood Environment Database (ONEdata), a unique longitudinal GIS that is spatially and temporally linked to data in the National Longitudinal Study of Adolescent Health (N=20,745), provide examples of current limitations in this area of research. Findings suggest a need for longitudinal methodologic advancements to better control for dynamic sources of bias, investigate and capture appropriate temporal frameworks, and address complex residential location processes within families. Development of improved neighborhood environment measures that capture relevant geographic areas within complex communities and investigation of differences across urbanicity and sociodemographic composition are needed. Further longitudinal research is needed to identify, refine, and evaluate national and local policies to most effectively reduce childhood obesity.


Evaluation of a decision-support system for inoperable non-small cell lung cancer.
The purpose of this study was to find out whether a decision-support system is able to assist a clinician in predicting patient outcome and in selecting optimal treatment in oncology. The domain of the evaluated decision-support prototype was primary therapeutic decision making in inoperable non-small cell lung cancer. The performance of the prototype was tested on retrospective material consisting of 112 patients treated by radiotherapy. Survival was the endpoint for examining whether the treatment decision proposed by the system was more accurate than the decision actually made by the clinician. Certain prognostic variables were used by the system to classify patients into two treatment groups, radical or palliative radiotherapy. The median survival times of these groups were 15 and 7 months, respectively, compared with 9 and 8 months in the corresponding groups classified by the clinician. Our results indicate that clinicians need support in treatment selection and that decision-support systems could be a potential answer.


Lateral Center-Edge Angle Is Not Predictive of Acetabular Articular Cartilage Surface Area: Anatomic Variation of the Lunate Fossa.
Surgical treatment of symptomatic femoroacetabular impingement (FAI) and dysplasia requires careful characterization of acetabular morphology. The lateral center-edge angle (LCEA) is often used to assess lateral acetabular anatomy. Previous work has questioned the LCEA as a surrogate for acetabular contact/articular cartilage surface area because of the variable morphology of the lunate fossa. We hypothesized that weightbearing articular cartilage of the acetabulum would poorly correlate with LCEA secondary to significant variation in the size of the lunate fossa. Cohort study (Diagnosis); Level of evidence, 3. Patients with 3D CT imaging undergoing either hip arthroscopy or periacetabular osteotomy for FAI or symptomatic hip instability were retrospectively identified. The LCEA and femoral head diameter were measured on an anteroposterior pelvis radiograph. Patients were grouped according to their lateral acetabular coverage as undercoverage (LCEA, <25°), normal coverage (LCEA, 25°-40°), or overcoverage (LCEA, >40°). Patients were randomly identified until each group contained 20 patients. The articular surface area was measured from preoperative 3D CT data. Linear regression analysis was performed to examine the relationship between articular surface area and LCEA. Continuous and categorical data were analyzed utilizing analysis of variance and chi-square analysis. Statistical significance was set at P < .05. No difference in age (P = .52), body mass index (BMI) (P = .75), or femoral head diameter (P = .66) was noted between groups. A significant difference in articular surface area was observed between patients with undercoverage and those with overcoverage (20.4 cm2 vs 24.5 cm2; P = .01). No significant difference was identified between the undercoverage and normal groups (20.4 cm2 vs 23.3 cm2; P = .09) or the normal and overcoverage groups (23.3 cm2 vs 24.5 cm2; P = .63). A moderate positive correlation was observed between LCEA and articular surface area across all patients (r = 0.38; P = .002) but not when patients with undercoverage were excluded (r = 0.02; P = .88). Significant variation in surface area was observed within each group such that no patient in any group was outside of 2 SDs of the means of the other groups. When patients were categorized into quartiles established by the articular surface area for the entire population, 40% of patients with overcoverage were observed in the first or second quartile (lower area). Lateral acetabular undercoverage based on the LCEA (<25°) correlates with decreased acetabular surface area. Normal or increased acetabular coverage (LCEA, >25°), however, is not predictive of increased, normal, or decreased acetabular surface area.


Diagnosis and management of mycosis fungoides.
Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is a low-grade cutaneous lymphoma characterized by skin-homing CD4+ T cells. It is notable for highly symptomatic progressive skin lesions, including patches, plaques, tumors, and erytheroderma, and has a poorer prognosis at later stages. Diagnosis remains difficult owing to MF's nonspecific skin presentation and identification of the optimal treatment strategy is challenging given the paucity of controlled trials and numerous and emerging treatment options. Management includes topical therapy with the addition of systemic therapy for patients with later-stage disease including tumors; erythroderma; and nodal, visceral, or blood involvement. Topical therapies include mechlorethamine (nitrogen mustard), carmustine (BCNU), steroids, bexarotene gel (Targretin Gel), psoralen plus ultraviolet A (PUVA), ultraviolet B (UVB), and either localized or total skin electron radiotherapy. Systemic therapies include interferon, retinoids, oral bexarotene (Targretin), denileukin diftitox (Ontak), vorinostat (Zolinza), extracorporeal photochemotherapy (photopheresis), and cytotoxic chemotherapy. Herein, we outline clinically relevant aspects of MF, including clinical presentation, pathology, diagnosis, and staging. We describe in detail existing and emerging therapeutics and offer specific recommendations for management of each stage of MF.


Glycemic response to stress is altered in euglycemic Pima Indians.
The aim of this work was to study the effects of a computer-driven mental arithmetic task on blood glucose in a group of four male and four female euglycemic Caucasians and a group of seven male and six female euglycemic Pima Indians. Approximately 60% of euglycemic Pima Indian Native Americans eventually develop type 2 diabetes, while only 5% of Caucasians develop the disease. All subjects had normal glucose tolerance. Subjects were given a standard breakfast; 2 h later, they were given a computerized mental arithmetic stress test for 10 min. Before, during and after the test, several variables were analyzed, including serum concentrations of glucose, insulin, glucagon and plasma cortisol and catecholamines. Heart rate, systolic and diastolic blood pressure and all the stress hormones increased during stress and decreased during recovery in all subjects. Blood glucose consistently declined one hour after the meal in all subjects. However, while it continued to decline following stress in seven out of eight Caucasian subjects, it consistently increased during and following stress in 10 out of 13 Pima Indians. Fasting serum glucose in Pima Indians and Caucasians was respectively 5.07 + 0.08 mM and 5.04 + 0.09 mM. Two-hour post-prandial values were 5.63 + 0.22 mM and 5.48 + 0.19 mM respectively, whereas post-stress values were 6.15 + 0.19 mM for Pima Indians and 5.22 + 0.20 mM for Caucasians. Both serum glucose means following stress (t = 3.1, P < 0.005) and the direction of change in serum glucose in response to mental arithmetic (chi 2 = 8.2, P < 0.01) clearly differentiated Pimas from Caucasians.(ABSTRACT TRUNCATED AT 250 WORDS)


Measurements of scattering of light from layered microspheres.
Experimental elastic-scattering characteristics of layered microspheres are reported. Single particles consisting of glass cores coated with glycerine are suspended in an evacuated quadrupole trap, and scattered light intensity is measured at a fixed angle as the glycerine evaporates. The results are compared with those calculated for concentric spheres using the Mie theory. Excellent agreement is obtained for glycerine layers of thickness less than 700 nm. For thicker layers, differences occur that are attributed to the effect of gravity on particle structure.


Features and outcomes of immunoglobulin therapy in patients with Good syndrome at Thailand's largest tertiary referral hospital.
Good syndrome (GS) is an adult-onset immunodeficiency characterized by coexisting thymoma and hypogammaglobulinemia. Clinical course after treatment with intravenous immunoglobulin (IVIg) has rarely been reported. To investigate and report the clinical course and outcomes of GS patients after treatment with IVIg at Thailand's largest national tertiary referral hospital METHODS: This retrospective chart review included patients diagnosed with GS and treated with IVIg during the 1 January 2005 to 31 December 2015 study period. Nine GS patients with a median age at diagnosis of 53 years were included. Pneumonia and sepsis were the most common clinical manifestations. Six infectious organisms suggestive of cell-mediated immunity defect occurred in six patients, including cytomegalovirus (CMV), Mycobacterium tuberculosis, Mycobacterium abscessus, Herpes simplex virus (HSV), Pneumocystis jirovecii, and Aspergillus. Mean serum IgG level was 317 mg/dL. Eight patients had very low to undetectable B-cells. Five patients had either low CD4 number or impaired T-cell function, and one patient had both. All patients received IVIg replacement therapy monthly at a dose of 0.4 g/kg. The mean trough IgG level was 881 mg/dL. After treatment with IVIg replacement, seven patients had favorable clinical outcomes. However, two patients expired due to septicemia. Clinical outcomes of patients with GS are more dependent on the severity of infections and associated hematologic and autoimmune diseases than on the severity of thymoma itself. Therefore, early recognition and prompt IVIg replacement may change the natural course of this condition and may be successful in keeping the patient infections free.


[Surgical treatment of giant emphysematous lung bullae].
Lack of Brazilian publications regarding this disease in Brazil led us to perform the current work to describe the historical evolution and to analyze results of the surgical treatment of Giant Emphysematous Lung Bullae at the Santa Casa de São Paulo. We have retrospectively assessed, between January 1979 and June 2005, the medical records of 83 patients submitted to one of four surgical modalities: the thoracoscopic bullectomy, VATS bullectomy, VATS bullae drainage and bullae drainage with local anesthesia, totaling 92 surgeries. Parameters analyzed were hospitalization time, post-surgical complications, perioperative and late mortality in addition to clinical and functional pre- and post- surgical parameters. Morbidity was 40.2% and early post-surgical mortality 4.3%. Post-surgical complications were associated to the patient's morbid history. Factors such as diffuse pulmonary emphysema, multiple bullae and age did not influence early complications. There was an improvement in the symptomatology and functional results in 94.5% of the patients. There was no return on he operated bullae. Mortality five years after surgery was of 18.3% and arose, primarily from clinical progression of the diffuse pulmonary emphysema. Several surgical modalities were performed to treat the emphysematous lung bullae, from bullectomy to thoracotomy, at the initial phase until drainage of the bullae with local anesthesia and sprayed talc, the currently preferred modality. Regardless of the method used, however, notwithstanding the relatively high morbidity, post-surgical results are highly favorable with low mortality and uncontestable clinical-functional improvement of the operated patients.


Novel Molecular Strategies and Targets for Opioid Drug Discovery for the Treatment of Chronic Pain.
Opioid drugs like morphine and fentanyl are the gold standard for treating moderate to severe acute and chronic pain. However, opioid drug use can be limited by serious side effects, including constipation, tolerance, respiratory suppression, and addiction. For more than 100 years, we have tried to develop opioids that decrease or eliminate these liabilities, with little success. Recent advances in understanding opioid receptor signal transduction have suggested new possibilities to activate the opioid receptors to cause analgesia, while reducing or eliminating unwanted side effects. These new approaches include designing functionally selective ligands, which activate desired signaling cascades while avoiding signaling cascades that are thought to provoke side effects. It may also be possible to directly modulate downstream signaling through the use of selective activators and inhibitors. Separate from downstream signal transduction, it has also been found that when the opioid system is stimulated, various negative feedback systems are upregulated to compensate, which can drive side effects. This has led to the development of multi-functional molecules that simultaneously activate the opioid receptor while blocking various negative feedback receptor systems including cholecystokinin and neurokinin-1. Other novel approaches include targeting heterodimers of the opioid and other receptor systems which may drive side effects, and making endogenous opioid peptides druggable, which may also reduce opioid mediated side effects. Taken together, these advances in our molecular understanding provide a path forward to break the barrier in producing an opioid with reduced or eliminated side effects, especially addiction, which may provide relief for millions of patients.


Reconstructing Austronesian population history in Island Southeast Asia.
Austronesian languages are spread across half the globe, from Easter Island to Madagascar. Evidence from linguistics and archaeology indicates that the 'Austronesian expansion,' which began 4,000-5,000 years ago, likely had roots in Taiwan, but the ancestry of present-day Austronesian-speaking populations remains controversial. Here, we analyse genome-wide data from 56 populations using new methods for tracing ancestral gene flow, focusing primarily on Island Southeast Asia. We show that all sampled Austronesian groups harbour ancestry that is more closely related to aboriginal Taiwanese than to any present-day mainland population. Surprisingly, western Island Southeast Asian populations have also inherited ancestry from a source nested within the variation of present-day populations speaking Austro-Asiatic languages, which have historically been nearly exclusive to the mainland. Thus, either there was once a substantial Austro-Asiatic presence in Island Southeast Asia, or Austronesian speakers migrated to and through the mainland, admixing there before continuing to western Indonesia.


First dengue haemorrhagic fever epidemic in the Americas, 1981: insights into the causative agent.
Historical records describe a disease in North America that clinically resembled dengue haemorrhagic fever during the latter part of the slave-trading period. However, the dengue epidemic that occurred in Cuba in 1981 was the first laboratory-confirmed and clinically diagnosed outbreak of dengue haemorrhagic fever in the Americas. At that time, the presumed source of the dengue type 2 strain isolated during this epidemic was considered controversial, partly because of the limited sequence data and partly because the origin of the virus appeared to be southern Asia. Here, we present a molecular characterisation at the whole-genome level of the original strains isolated at different time points during the epidemic. Phylogenetic trees constructed using Bayesian methods indicated that 1981 Cuban strains group within the Asian 2 genotype. In addition, the study revealed that viral evolution occurred during the epidemic - a fact that could be related to the increasing severity from month to month. Moreover, the Cuban strains exhibited particular amino acid substitutions that differentiate them from the New Guinea C prototype strain as well as from dengue type 2 strains isolated globally.


Authorship Inflation in Medical Publications.
The number of authors per manuscript in peer-reviewed medical journals has increased substantially in the last several decades. Several reasons have been offered to explain this authorship growth, including increased researcher collaboration, honorary authorship driven by increased pressures for funding and promotion, the belief that including senior authors will facilitate publication, and the growing complexity of medical research. It is unknown, however, whether authorship has grown over time due to growing complexity of published academic articles, in which case growth could be warranted, or whether it has grown due to pressures of funding and academic promotion, which have created "authorship inflation." To answer this question, we analyzed data on authorship count, study type, and size of study population for the first 50 original articles published in each decade during 1960-2010 in 3 major medical journals. Within each type of study we considered (eg, randomized trials, observational studies, etc), average authorship rose more than 3-fold during this period. Similar growth persisted after adjustment for changes in study population sizes over time. Our findings suggest that increasing research complexity is an inadequate explanation for authorship growth. Instead, growth in authorship appears inflationary.


Universal access: making health systems work for women.
Universal coverage by health services is one of the core obligations that any legitimate government should fulfil vis-à-vis its citizens. However, universal coverage may not in itself ensure universal access to health care. Among the many challenges to ensuring universal coverage as well as access to health care are structural inequalities by caste, race, ethnicity and gender. Based on a review of published literature and applying a gender-analysis framework, this paper highlights ways in which the policies aimed at promoting universal coverage may not benefit women to the same extent as men because of gender-based differentials and inequalities in societies. It also explores how 'gender-blind' organisation and delivery of health care services may deny universal access to women even when universal coverage has been nominally achieved. The paper then makes recommendations for addressing these.


Bond strength of a resin composite to a polyacid-modified resin composite under different conditions.
The aim of this in vitro study was to evaluate the tensile bond strength values between polyacid-modified resin composite ("compomer") and resin composite materials under different conditions. There were five experimental groups in the study. In group A, resin composite was placed directly on polyacid-modified resin composite surfaces. In group B, bonding agent was applied to polyacid-modified resin composite surfaces and then resin composite was placed on the compomer. In group C, compomer specimens were stored for 1 week and then resin composite was placed directly on these aged compomers. In group D, compomer specimens were again stored for 1 week, and then the bonding agent and resin composite were applied to the compomer surfaces. In group E, the surfaces of aged (1 week) compomers were roughened before the bonding agent was applied and the resin composite was placed on the prepared surfaces. A statistical analysis of the results was made with the Kruskal-Wallis test method. The mean tensile strength values of the groups were as follows: group A = 12.84 MPa; group B = 15.03 MPa; group C = 10.60 MPa; group D = 11.56 MPa; group E = 24.87 MPa. There were statistically significant differences between groups E and A; groups E and C; groups E and D; and groups C and B. Mechanical roughening of a polyacid-modified resin composite surface was found to be the most effective factor in increasing the tensile bond strength between an aged compomer and a resin composite.


Stray light characterization of an InGaAs anamorphic hyperspectral imager.
Compact hyperspectral sensors potentially have a wide range of applications, including machine vision, quality control, and surveillance from small Unmanned Aerial Vehicles (UAVs). With the development of Indium Gallium Arsenide (InGaAs) focal plane arrays, much of the Short Wave Infra-Red (SWIR) spectral regime can be accessed with a small hyperspectral imaging system, thereby substantially expanding hyperspectral sensing capabilities. To fully realize this potential, system performance must be well-understood. Here, stray light characterization of a recently-developed push-broom hyperspectral sensor sensitive in the 1 microm -1.7 microm spectral regime is described. The sensor utilizes anamorphic fore-optics that partially decouple image formation along the spatial and spectral axes of the instrument. This design benefits from a reduction in complexity over standard high-performance spectrometer optical designs while maintaining excellent aberration control and spatial and spectral distortion characteristics. The stray light performance characteristics of the anamorphic imaging spectrometer were measured using the spectral irradiance and radiance responsivity calibrations using uniform sources (SIRCUS) facility at the National Institute of Standards and Technology (NIST). A description of the measurements and results are presented. Additionally, a stray-light matrix was assembled for the instrument to improve the instrument's spectral accuracy. Transmittance of a silicon wafer was measured to validate this approach.


Job adjustment and absence from work in mid-pregnancy in the Norwegian Mother and Child Cohort Study (MoBa).
Pregnant women at work have special needs, and sick leave is common. However, job adjustment in pregnancy is addressed in European legislation. Our main objective was to examine if job adjustment was associated with reduced absence. This study is based on the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. 28,611 employed women filled in questionnaires in weeks 17 and 30 in pregnancy. The risk of absence for more than 2 weeks was studied among those who were not absent in week 17 (n = 22,932), and the probability of return to work in week 30 among those who were absent in week 17 (n = 5679). Data were based on self-report. The influence of job adjustment (three categories: not needed, needed but not obtained, needed and obtained) was analysed in additive models in multivariable binomial regression. Associations with other job characteristics and work environment factors were also analysed. The risk of absence for more than 2 weeks was 0.308 and the probability of return to work was 0.137. Compared with women who needed but did not achieve job adjustment, obtained job adjustment was associated with a 0.107 decreased risk of absence (95% confidence interval 0.090 to 0.125) in a model including other job characteristics and work environment factors. Job adjustment was correspondingly associated with a 0.041 (0.023 to 0.059) increased probability of return to work. Absence was associated with adverse work environment, whereas the opposite pattern was found for return to work among those who started off being absent. Job adjustment was associated with reduced absence from work in pregnancy. Results should be interpreted cautiously because of low participation in MoBa and potential information bias from self-reported data.


Coexistence of tumor-induced osteomalacia and primary hyperparathyroidism.
To present an unusual case of coexisting tumor-induced osteomalacia (TIO) and primary hyperparathyroidism (PHPT). We report the clinical features, imaging studies, and the results of laboratory investigations before and after surgical resection of both a soft-tissue tumor and a parathyroid adenoma. A 44-year-old woman was referred to the endocrinology department with a diagnosis of PHPT accompanied by unusually severe hypophosphatemia, despite having received treatment with cinacalcet. Debilitating muscle weakness and bone pain, severe phosphaturia and hypophosphatemia, inappropriately normal calcitriol, and elevated fibroblast growth factor-23 and intact parathyroid hormone levels raised the suspicion of coexisting TIO and PHPT. Imaging studies were negative, but histologic characteristics of a palpable subcutaneous mass from the patient's thigh revealed a phosphaturic mesenchymal tumor. Complete remission after surgical removal of both the soft-tissue tumor and the parathyroid adenoma confirmed the diagnosis. The coexistence of TIO and PHPT has not been described before and can cause life-threatening hypophosphatemia. Diagnosis and localization of the tumor is of paramount importance since surgery is the treatment of choice for both TIO and PHPT.


Design and characterisation of a pulsed neutron interrogation facility.
The Joint Research Centre recently obtained a license to operate a new experimental device intended for research in the field of nuclear safeguards. The research projects currently being planned for the new device includes mass determination of fissile materials in matrices and detection of contraband non-nuclear materials. The device incorporates a commercial pulsed neutron generator and a large graphite mantle surrounding the sample cavity. In this configuration, a relatively high thermal neutron flux with a long lifetime is achieved inside the sample cavity. By pulsing the neutron generator, a sample may be interrogated by a pure thermal neutron flux during repeated time periods. The paper reports on the design of the new device and the pulsed fast and thermal neutron source. The thermal neutron flux caused by the neutron generator and the graphite structure has been characterised by foil activation, fission chamber and (3)He proportional counter measurements.


Circulating endostatin and the incidence of heart failure.
Circulating levels of endostatin are elevated in many underlying conditions leading to heart failure such as hypertension, diabetes, chronic kidney disease and ischemic heart disease. Yet, the association between endostatin and the incidence of heart failure has not been reported previously in the community. We investigated the longitudinal association between serum endostatin levels and incident heart failure in two community-based cohorts of elderly: Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, n = 966; mean age 70 years, 51% women, 81 events, mean follow-up 10 years) and Uppsala Longitudinal Study of Adult Men (ULSAM, n = 747 men; mean age 78 years, 98 heart failure events, mean follow-up 8 years). We also investigated the cross-sectional association between endostatin and echocardiographic left ventricular systolic function and diastolic function (ejection fraction and E/A-ratio, respectively). Higher serum endostatin was associated with an increased risk for heart failure in both cohorts after adjustment for established heart failure risk factors, glomerular filtration rate and N-terminal pro-brain natriuretic peptide (NT-proBNP) (PIVUS: multivariable hazard ratio (HR) per 1-standard deviation (SD) increase, HR 1.46 (95%CI, 1.17-1.82, p < .001); ULSAM: HR 1.29 (95%CI, 1.00-1.68, p < .05). In cross-sectional analyses at baseline, higher endostatin was significantly associated with both worsened left ventricular systolic and diastolic function in both cohorts. Conclusion Higher serum endostatin was associated with left ventricular dysfunction and an increased heart failure risk in two community-based cohorts of elderly. Our findings encourage further experimental studies that investigate the role of endostatin in the development of heart failure.


Day-to-Day Test-Retest Reliability of EEG Profiles in Children With Autism Spectrum Disorder and Typical Development.
Biomarker development is currently a high priority in neurodevelopmental disorder research. For many types of biomarkers (particularly biomarkers of diagnosis), reliability over short periods is critically important. In the field of autism spectrum disorder (ASD), resting electroencephalography (EEG) power spectral densities (PSD) are well-studied for their potential as biomarkers. Classically, such data have been decomposed into pre-specified frequency bands (e.g., delta, theta, alpha, beta, and gamma). Recent technical advances, such as the Fitting Oscillations and One-Over-F (FOOOF) algorithm, allow for targeted characterization of the features that naturally emerge within an EEG PSD, permitting a more detailed characterization of the frequency band-agnostic shape of each individual's EEG PSD. Here, using two resting EEGs collected a median of 6 days apart from 22 children with ASD and 25 typically developing (TD) controls during the Feasibility Visit of the Autism Biomarkers Consortium for Clinical Trials, we estimate test-retest reliability based on the characterization of the PSD shape in two ways: (1) Using the FOOOF algorithm we estimate six parameters (offset, slope, number of peaks, and amplitude, center frequency and bandwidth of the largest alpha peak) that characterize the shape of the EEG PSD; and (2) using nonparametric functional data analyses, we decompose the shape of the EEG PSD into a reduced set of basis functions that characterize individual power spectrum shapes. We show that individuals exhibit idiosyncratic PSD signatures that are stable over recording sessions using both characterizations. Our data show that EEG activity from a brief 2-min recording provides an efficient window into characterizing brain activity at the single-subject level with desirable psychometric characteristics that persist across different analytical decomposition methods. This is a necessary step towards analytical validation of biomarkers based on the EEG PSD and provides insights into parameters of the PSD that offer short-term reliability (and thus promise as potential biomarkers of trait or diagnosis) vs. those that are more variable over the short term (and thus may index state or other rapidly dynamic measures of brain function). Future research should address the longer-term stability of the PSD, for purposes such as monitoring development or response to treatment.


Recombinant larvicidal bacteria with markedly improved efficacy against culex vectors of west nile virus.
An urgent need exists for new agents to control mosquito vectors of disease. Mosquito larvicides based on the bacteria Bacillus thuringiensis subsp. israelensis (Bti) or B. sphaericus (Bs) are effective in many habitats, but use is limited by their high cost. Moreover, mosquito resistance evolves rapidly to Bs where it is used intensively. The efficacy of these bacteria is due to a binary protein (BsB) in Bs and four proteins (Cry4A, Cry4B, Cry11A, and Cyt1A) in Bti. Here we report the use of cyt1A promoters and a 5' mRNA stabilizing sequence to synthesize high levels of Bs2362 binary toxin in Bti strains. The recombinant BtiIPS-82/BsB showed high potency against fourth instars of Culex quinquefasciatus, a vector of West Nile virus, being 21-fold as potent as BtiIPS-82, and 32-fold as potent as Bs2362. Similar improved efficacy was obtained against larvae of Cx. tarsalis. Moreover, BtiIPS-82/BsB suppressed resistance to Bs2362 in Cx. quinquefasciatus.


Nutrient Stoichiometry Shapes Microbial Community Structure in an Evaporitic Shallow Pond.
Nutrient availability and ratios can play an important role in shaping microbial communities of freshwater ecosystems. The Cuatro Ciénegas Basin (CCB) in Mexico is a desert oasis where, perhaps paradoxically, high microbial diversity coincides with extreme oligotrophy. To better understand the effects of nutrients on microbial communities in CCB, a mesocosm experiment was implemented in a stoichiometrically imbalanced pond, Lagunita, which has an average TN:TP ratio of 122 (atomic). The experiment had four treatments, each with five spatial replicates - unamended controls and three fertilization treatments with different nitrogen:phosphorus (N:P) regimes (P only, N:P = 16 and N:P = 75 by atoms). In the water column, quantitative PCR of the 16S rRNA gene indicated that P enrichment alone favored proliferation of bacterial taxa with high rRNA gene copy number, consistent with a previously hypothesized but untested connection between rRNA gene copy number and P requirement. Bacterial and microbial eukaryotic community structure was investigated by pyrosequencing of 16S and 18S rRNA genes from the planktonic and surficial sediment samples. Nutrient enrichment shifted the composition of the planktonic community in a treatment-specific manner and promoted the growth of previously rare bacterial taxa at the expense of the more abundant, potentially endemic, taxa. The eukaryotic community was highly enriched with phototrophic populations in the fertilized treatment. The sediment microbial community exhibited high beta diversity among replicates within treatments, which obscured any changes due to fertilization. Overall, these results showed that nutrient stoichiometry can be an important factor in shaping microbial community structure.


Alterations in cardiac flow parameters in patients with polycystic ovarian syndrome.
The aim of this study was to examine the echocardiographic profiles of patients with polycystic ovarian syndrome (PCOS). Serum concentrations of follicle stimulating hormone, luteinizing hormone, androstenedione, free testosterone, prolactin, DHEA-SO(4) and 17-OH-progesterone, lipid profile (high and low density lipoproteins, triglyceride and total cholesterol) and basal and total insulin after a glucose tolerance test were measured in 35 patients with PCOS and 35 healthy controls matched for body mass index. Doppler, two dimensional M mode echocardiography was performed for the following indices: isovolumetric relaxation time (IVRT), E wave duration time (EVT), A wave duration time (AVT), E wave deceleration time (DT), peak early diastolic flow velocity (PEV), peak late diastolic flow velocity (PAV), E wave velocity time integral (FVI-E), A wave velocity time integral (FVI-A), atrial filling fraction (AFF), ejection fraction (EF), pre-ejection time (PEP), ejection time (ET) and aortic flow velocity time integral (FVI). Androstenedione, free testosterone, low density lipoproteins and cholesterol concentrations were significantly higher in patients with PCOS. There was no difference in basal and total insulin concentrations. IVRT, AVT, FVI-A, AFF, and PEP were higher in patients with PCOS, while PEV, FVI-E, EF, ET, EVT and EVT/AVT were higher in the control group. There was a positive correlation between basal insulin values and IVRT, and between total insulin values and EF. These changes are consistent with a non-restrictive type of diastolic dysfunction and left ventricular stiffness. PCOS may lead to diastolic dysfunction via hyperinsulinaemia and male type dyslipidaemia.


National mortality following upper gastrointestinal or cardiovascular events in older veterans with recent nonsteroidal anti-inflammatory drug use.
Upper gastrointestinal events (UGIE), myocardial infarction (MI) and cerebrovascular accident (CVA) are known morbidities among recent NSAID users. To assess all-cause mortality following UGIE, MI or CVA among recent NSAID users. Veterans >65 prescribed an NSAID at any Veterans Affairs (VA) facility were identified using prescription fill data and their records linked to a merged VA-Medicare database. Each person-day was assessed for NSAID, coxib or proton pump inhibitor (PPI) exposure. Incidence density ratios and hazard rates of death were calculated following UGIE, MI and CVA adjusting for demographics, co-morbidity, prescription channeling, geographic location and pharmacological covariates. Among 474 495 patients [97.8% male; 85.3% white; 73.9 years (s.d. 5.6)], death followed at a rate of 5.5 per 1000 person-years (95% CI: 5.4-5.6) post-UGIE, 17.7 per 1000 person-years (95% CI: 17.5-17.9) post-MI and 21.8 per 1000 person-years (95% CI: 21.6-22.0) post-CVA. CVA was associated with greatest risk of death [hazard ratio (HR) 12.4; 95% CI: 10.9-14.3] followed by MI (HR 10.7; 95% CI: 9.2-11.6) and UGIE (HR 3.3; 95% CI: 2.8-3.9). Predictors of mortality were advancing age and co-morbidity, increased use of coxibs and failure to ensure adequate gastroprotection. Among elderly veterans with recent NSAID use, an UGIE, MI or CVA is a clinically relevant premorbid event.


Incidence, Prevalence, and Clinical Epidemiology of Inflammatory Bowel Disease in the Arab World: A Systematic Review and Meta-Analysis.
Despite the recent findings of the rising incidence of inflammatory bowel disease (IBD) in Arab countries, there are limited data on the characteristics of IBD patients and the disease course in the Arab world. This systematic review aimed to investigate the incidence and epidemiology of IBD in the Arab world. We conducted a systematic literature review that utilized a comprehensive search of PubMed, Cochrane Central, SCOPUS, Google Scholar, and Web of Science from their inception till August 2020. We included cross-sectional, prospective, and retrospective studies that examined the prevalence and/or epidemiological characteristics of IBD in Arab countries. A total of 16 studies that examined IBD in Saudi Arabia, Egypt, Kuwait, the United Arab Emirates, Bahrain, Lebanon, and Oman were included. Generally, the included studies covered the period from the early 1990s to the late 2010s. A total of 1,627 ulcerative colitis (UC) patients and 1,588 Crohn's disease (CD) patients were included in this systematic review. The mean age at diagnosis ranged from 24.13 to 43.6 years in adult cases and from 4.5 to 16 years in pediatric cases. In most of the included studies, the majority of patients were male. The quantitative analysis revealed a pooled incidence rate of 2.33 (95% confidence interval [CI] 1.2-3.4) per 100,000 persons per year for UC in the Arab world. Likewise, the pooled incidence rate for CD in the Arab world was 1.46 (95% CI 1.03-1.89) per 100,000 persons per year. There is a growing incidence of IBD in the Arab world, while IBD patients from Arab countries may present with some different characteristics, compared to their counterparts in Europe.


Water oxidation and oxygen monitoring by cobalt-modified fluorine-doped tin oxide electrodes.
Electrocatalytic water oxidation occurs at fluoride-doped tin oxide (FTO) electrodes that have been surface-modified by addition of Co(II). On the basis of X-ray photoelectron spectroscopy and transmission electron microscopy measurements, the active surface site appears to be a single site or small-molecule assembly bound as Co(II), with no evidence for cobalt oxide film or cluster formation. On the basis of cyclic voltammetry measurements, surface-bound Co(II) undergoes a pH-dependent 1e(-)/1H(+) oxidation to Co(III), which is followed by pH-dependent catalytic water oxidation. O2 reduction at FTO occurs at -0.33 V vs NHE, allowing for in situ detection of oxygen as it is formed by water oxidation on the surface. Controlled-potential electrolysis at 1.61 V vs NHE at pH 7.2 resulted in sustained water oxidation catalysis at a current density of 0.16 mA/cm(2) with 29,000 turnovers per site over an electrolysis period of 2 h. The turnover frequency for oxygen production per Co site was 4 s(-1) at an overpotential of 800 mV at pH 7.2. Initial experiments with Co(II) on a mesoporous, high-surface-area nanoFTO electrode increased the current density by a factor of ~5.


Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis.
We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93-1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53-1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.