The (mis)estimation of neighborhood effects: causal inference for a practicable social epidemiology.
The resurgence of interest in the effect of neighborhood contexts on health outcomes, motivated by advances in social epidemiology, multilevel theories and sophisticated statistical models, too often fails to confront the enormous methodological problems associated with causal inference. This paper employs the counterfactual causal framework to illuminate fundamental obstacles in the identification, explanation, and usefulness of multilevel neighborhood effect studies. We show that identifying useful independent neighborhood effect parameters, as currently conceptualized with observational data, to be impossible. Along with the development of a dependency-based methodology and theories of social interaction, randomized community trials are advocated as a superior research strategy, one that may help social epidemiology answer the causal questions necessary for remediating disparities and otherwise improving the public's health.


Pimozide: delayed onset of action at rat striatal pre- and postsynaptic dopamine receptors.
It has been reported that the antipsychotic drug, pimozide, is unique in that it blocks postsynaptic dopamine (DA) receptors, but not presynaptic DA receptors. This was examined by comparing pimozide with haloperidol for time of onset of action in several experimental paradigms designed to demonstrate blockade of pre- and postsynaptic striatal DA receptors. Haloperidol (1.0 mg/kg s.c.) caused near maximum catalepsy scores within 90 min after injection, a time when twice as much pimozide had yet to produce catalepsy. Pimozide consistently exhibited a delayed onset of action on several dopaminergic biochemical parameters including: increased striatal DA metabolism, increased DA receptors. In electrophysiological studies, pimozide did not block the ability of apomorphine to inhibit DA impulse flow if given 5 to 10 min before apomorphine, but was effective if longer pretreatment times were allowed. These data indicate that a delay or pimozide action occurs at both postsynaptic and presynaptic DA receptors. It is known that pimozide binds with high affinity to neuroleptic binding sites (in vitro) and rapidly enters the brain after systemic injection. Pretreatment of animals with SKF 525-A, an inhibitor of liver mixed-function oxidase enzymes, had little or no effect on pimoxide's actions, suggesting that formation of an active metabolite is not the cause of pimozide's delayed actions. The reason for the delayed action is unclear, but pimozide will interact with both pre- and postsynaptic DA receptors if given sufficient time.


Divergent Hypoglycemic Effects of Hepatic-Directed Prandial Insulin: A 6-Month Phase 2b Study in Type 1 Diabetes.
Hepatic-directed vesicle insulin (HDV) uses a hepatocyte-targeting moiety passively attaching free insulin, improving subcutaneous insulin's hepatic biodistribution. We assessed HDV-insulin lispro (HDV-L) versus insulin lispro (LIS) in type 1 diabetes (T1D). Insulin Liver Effect (ISLE-1) was a 26-week, phase 2b, multicenter, randomized, double-blind, noninferiority trial. Among 176 randomized participants (HDV-L n = 118, LIS n = 58), the difference in change from baseline A1C was 0.09% (95% CI -0.18% to 0.35%), confirming noninferiority (prespecified margin ≤0.4%). Overall, there were no statistically significant differences between treatments for hypoglycemia or insulin dosing. However, baseline A1C modified the treatment group effect (interaction P < 0.001) on clinically apparent hypoglycemia designated by treatment-blinded investigators as severe. Thus, at higher baseline A1C, there was less hypoglycemia and lower insulin dosing with similar A1C outcomes during HDV-L versus LIS, whereas greater risk of hypoglycemia despite similar A1C outcomes and insulin doses was observed with lower baseline A1C. Among poorly controlled participants (A1C ≥8.5%), incidence rates of severe hypoglycemia in the HDV-L and LIS arms were 69 and 97 events/100 person-years, respectively (P = 0.03), whereas with A1C <8.5%, respective rates were 191 and 21 events/100 person-years (P = 0.001). Similar A1C-dependent trends in hypoglycemia were seen with continuous glucose monitoring. Among poorly controlled participants, bolus insulin doses at end point were ∼25% lower with HDV-L (P = 0.02), despite similar A1C outcomes; in better-controlled participants, insulin doses and A1Cs were stable over time in both subgroups. No safety signals were identified. Hepatic biodistribution of HDV-L appears to potentiate insulin effect in T1D, with divergent clinical outcomes in hypoglycemia dependent on baseline A1C.


Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.
Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established. To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant. In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase. Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group. Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test. Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo. For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo. ClinicalTrials.gov identifier: NCT02493868.


Reactive dynamics in confined liquids: ultrafast torsional dynamics of auramine O in nanoconfined water in aerosol OT reverse micelles.
The effects of confinement on the ultrafast torsional reaction of auramine O in aqueous solution are investigated through ultrafast fluorescence up-conversion with 50 fs time resolution. The aqueous solution is confined in nanoscale water droplets by an ionic surfactant. The torsional motion is orders of magnitude slower in the confined droplets than in bulk aqueous solution. The dynamics become faster with increasing radius of the nanodroplet but never reach the bulk value, even when the radius is as large as 10 nm. Time-dependent fluorescence spectra were constructed and subsequently analyzed using a one-dimensional generalized Smoluchowski equation. An accurate description of the data was achieved using a time-dependent diffusion coefficient. This is suggested to arise because the medium friction reflects dynamics on a broad range of time scales spanning the reaction dynamics. The friction recovered suggests strongly hindered motion in the confined droplet and can be qualitatively related to solvation dynamics measured in AOT, consistent with auramine O torsional dynamics being accompanied by intramolecular charge redistribution.


Neuropeptide-mediated calcium signaling in the suprachiasmatic nucleus network.
Neuroactive peptides and the intracellular calcium concentration ([Ca(2+) ](i) ) play important roles in light-induced modulation of gene expression in the suprachiasmatic nucleus (SCN) neurons that ultimately control behavioral rhythms. Vasoactive intestinal peptide (VIP) and arginine vasopressin (AVP) are expressed rhythmically within populations of SCN neurons. Pituitary adenylate cyclase-activating peptide (PACAP) is released from retinohypothalamic tract (RHT) terminals synapsing on SCN neurons. Nociceptin/orphanin FQ (OFQ) receptors are functionally expressed in the SCN. We examined the role of several neuropeptides on Ca(2+) signaling, simultaneously imaging multiple neurons within the SCN neural network. VIP reduced the [Ca(2+) ](i) in populations of SCN neurons during the day, but had little effect at night. Stimulation of the RHT at frequencies that simulate light input signaling evoked transient [Ca(2+) ](i) elevations that were not altered by VIP. AVP elevated the [Ca(2+) ](i) during both the day and night, PACAP produced variable responses, and OFQ induced a reduction in the [Ca(2+) ](i) similar to VIP. During the day, VIP lowered the [Ca(2+) ](i) to near nighttime levels, while AVP elevated [Ca(2+) ](i) during both the day and night, suggesting that the VIP effects on [Ca(2+) ](i) were dependent, and the AVP effects independent of the action potential firing activity state of the neuron. We hypothesize that VIP and AVP regulate, at least in part, Ca(2+) homeostasis in SCN neurons and may be a major point of regulation for SCN neuronal synchronization.


Persistent Night Sweats: Diagnostic Evaluation.
Night sweats are a nonspecific symptom that patients commonly experience but rarely discuss with their physicians without prompting. Although many life-threatening causes such as malignancies or infections have been described, most patients who report persistent night sweats in the primary care setting do not have a serious underlying disorder. Conditions commonly associated with night sweats include menopause, mood disorders, gastroesophageal reflux disease, hyperthyroidism, and obesity. If a clinical diagnosis is apparent based on the initial history and physical examination, specific treatment for four to eight weeks may be offered. When the history and physical examination do not reveal a specific cause, physicians should proceed with a systematic and cost-conscious strategy that uses readily available laboratory and imaging studies, such as a complete blood count, tuberculosis testing, thyroid-stimulating hormone levels, HIV testing, C-reactive protein level, and chest radiography. Additional tests that could be considered selectively include computed tomography of the chest and/or abdomen, bone marrow biopsy, polysomnography, and/or additional laboratory studies if indicated. If these results are normal, and no additional disorders are suspected, reassurance and continued monitoring are recommended. The presence of night sweats alone does not indicate an increased risk of death.


Hydrologic response and radionuclide transport following fire at semiarid sites.
Infrequent, high-impact events such as wildfires, droughts, biological shifts, floods, and mechanical disturbances can greatly change land surfaces, including vegetative cover and soil characteristics, which in turn can trigger high rates of hydrologic erosion and associated transport of sediments and sediment-sorbed contaminants. Where persistent soil contamination exists, infrequent mobilization of contaminants may dominate in determining long-term risks to human and ecological receptors. Among these infrequent events, fire stands out as having the capacity to cause large increases in sediment transport. This study measured runoff, sediment yield, and mobility of sediment-sorbed contamination (137Cs) on burned and unburned plots at the Waste Isolation Pilot Plant, New Mexico (WIPP), and the Rocky Flats Environmental Technology Site, Colorado (RFETS). Results showed that 137Cs transport from burned plots was up to 22 times greater than that from unburned plots at WIPP and 4 times greater at RFETS. Associated runoff was up to 12 times greater on burned plots at WIPP and sediment yields up to 6 times greater. Further, 137Cs concentrations in transported sediments were enriched compared with parent soils (expressed as enrichment ratio) by a factor of 2.3 at WIPP, and 1.3 at RFETS. However, enrichment ratios were not significantly different in sediments from burned and unburned plots. Our results provide new data on the effects of fire on the transport of sediment-sorbed contaminants, and demonstrate that rare events such as fire can greatly increase contaminant mobility.


Shifting focus: The impacts of sustainable seafood certification.
Alongside government driven management initiatives to achieve sustainable fisheries management, there remains a role for market-based mechanisms to improve fisheries outcomes. Market-based mechanisms are intended to create positive economic incentives that improve the status and management of fisheries. Research to understand consumer demand for certified fish is central but needs to be mirrored by supply side understanding including why fisheries decide to gain or retain certification and the impact of certification on them and other stakeholders involved. We apply semi-structured interviews in seven different Marine Stewardship Council (MSC) certified fisheries that operate in (or from) Western Australia with the aim of better understanding fisheries sector participation in certification schemes (the supply side) and the impacts and unintended benefits and costs of certification. We find that any positive economic impacts of certification were only realised in a limited number of MSC fisheries in Western Australia, which may be explained by the fact that only a small proportion of Western Australian state-managed fisheries are sold with the MSC label and ex-vessel or consumer market price premiums are therefore mostly not obtained. Positive impacts of certification in these Western Australian fisheries are more of a social and institutional nature, for example, greater social acceptability and increased efficiency in the governance process respectively. However, opinion is divided on whether the combined non-monetary and monetary benefits outweigh the costs.


Structural origins of the selectivity of the trifunctional oxygenase clavaminic acid synthase.
Clavaminate synthase (CAS), a remarkable Fe(II)/2-oxoglutarate oxygenase, catalyzes three separate oxidative reactions in the biosynthesis of clavulanic acid, a clinically used inhibitor of serine beta-lactamases. The first CAS-catalyzed step (hydroxylation) is separated from the latter two (oxidative cyclization/desaturation) by the action of an amidinohydrolase. Here, we describe crystal structures of CAS in complex with Fe(II), 2-oxoglutarate (2OG) and substrates (N-alpha-acetyl-L-arginine and proclavaminic acid). They reveal how CAS catalyzes formation of the clavam nucleus, via a process unprecedented in synthetic organic chemistry, and suggest how it discriminates between substrates and controls reaction of its highly reactive ferryl intermediate. The presence of an unpredicted jelly roll beta-barrel core in CAS implies divergent evolution within the family of 2OG and related oxygenases. Comparison with other non-heme oxidases/oxygenases reveals flexibility in the position which dioxygen ligates to the iron, in contrast to the analogous heme-using enzymes.


Contribution of the Kv3.1 potassium channel to high-frequency firing in mouse auditory neurones.
1. Using a combination of patch-clamp, in situ hybridization and computer simulation techniques, we have analysed the contribution of potassium channels to the ability of a subset of mouse auditory neurones to fire at high frequencies. 2. Voltage-clamp recordings from the principal neurones of the medial nucleus of the trapezoid body (MNTB) revealed a low-threshold dendrotoxin (DTX)-sensitive current (ILT) and a high-threshold DTX-insensitive current (IHT). 3. IHT displayed rapid activation and deactivation kinetics, and was selectively blocked by a low concentration of tetraethylammonium (TEA; 1 mM). 4. The physiological and pharmacological properties of IHT very closely matched those of the Shaw family potassium channel Kv3.1 stably expressed in a CHO cell line. 5. An mRNA probe corresponding to the C-terminus of the Kv3.1 channel strongly labelled MNTB neurones, suggesting that this channel is expressed in these neurones. 6. TEA did not alter the ability of MNTB neurones to follow stimulation up to 200 Hz, but specifically reduced their ability to follow higher frequency impulses. 7. A computer simulation, using a model cell in which an outward current with the kinetics and voltage dependence of the Kv3.1 channel was incorporated, also confirmed that the Kv3.1- like current is essential for cells to respond to a sustained train of high-frequency stimuli. 8. We conclude that in mouse MNTB neurones the Kv3.1 channel contributes to the ability of these cells to lock their firing to high-frequency inputs.


Randomized trials addressing a similar question are commonly published after a trial stopped early for benefit.
We explored how investigators of ongoing or planned trials respond to the publication of a trial stopped early for benefit addressing a similar question. We searched multiple databases from the date of publication of the truncated trial through August, 2015. Independent reviewers selected trials and extracted data. We identified 207 trials truncated for early benefit; of which 102 (49%) were followed by subsequent trials (262 subsequent trials, median 2 per truncated trial, range 1-13). Only 99 (38%) provided a rationale justifying conducting a trial despite prior stopping. The top reasons were to address different population or setting (33%), skepticism of truncated trials findings because of small sample size (12%), inconsistency with other evidence (11%), or increased risk of bias (7%). We did not identify significant associations between subsequent trials and characteristics of truncated ones (risk of bias, precision, funding, or rigor of stopping decision). About half of the trials stopped early for benefit were followed by subsequent trials addressing a similar question. This suggests that future trialists may have been skeptic about the decision to stop prior trials. A more rigorous threshold for stopping early for benefit is needed.


Evaluation of nanoparticle-immobilized cellulase for improved ethanol yield in simultaneous saccharification and fermentation reactions.
Ethanol yields were 2.1 (P = 0.06) to 2.3 (P = 0.01) times higher in simultaneous saccharification and fermentation (SSF) reactions of microcrystalline cellulose when cellulase was physisorbed on silica nanoparticles compared to enzyme in solution. In SSF reactions, cellulose is hydrolyzed to glucose by cellulase while yeast simultaneously ferments glucose to ethanol. The 35°C temperature and the presence of ethanol in SSF reactions are not optimal conditions for cellulase. Immobilization onto solid supports can stabilize the enzyme and promote activity at non-optimum reaction conditions. Mock SSF reactions that did not contain yeast were used to measure saccharification products and identify the mechanism for the improved ethanol yield using immobilized cellulase. Cellulase adsorbed to 40 nm silica nanoparticles produced 1.6 times (P = 0.01) more glucose than cellulase in solution in 96 h at pH 4.8 and 35°C. There was no significant accumulation (<250 µg) of soluble cellooligomers in either the solution or immobilized enzyme reactions. This suggests that the mechanism for the immobilized enzyme's improved glucose yield compared to solution enzyme is the increased conversion of insoluble cellulose hydrolysis products to soluble cellooligomers at 35°C and in the presence of ethanol. The results show that silica-immobilized cellulase can be used to produce increased ethanol yields in the conversion of lignocellulosic materials by SSF.


Use of dental services by immigrant Canadians.
Although the health status and health behaviour of foreign-born residents of Canada have been well documented, little is known about their use of dental services. The authors, hypothesizing that foreign-born people would have lower utilization of dental care services than native-born Canadians, undertook this study to identify the factors associated with dental visits by Canadians aged 12 years and older and to compare the use of dental services by foreign-born and native-born populations. According to data derived from Statistics Canada"s 1996-97 National Population Health Survey, foreign-born people were somewhat more likely than native-born Canadians to have visited a dentist within the previous year. Higher levels of education, greater income adequacy, and the presence of dental insurance were associated with greater use of dental services, whereas increasing age was associated with lower use. Although immigrants reported greater use of dental services than native-born Canadians, a variety of barriers to care may be present in this population.


An annotated checklist of parasitic lice (Insecta: Phthiraptera) from the Galápagos Islands.
We list all described species and subspecies of parasitic lice from the Galápagos Islands, based on literature and specimen records. A total of eight families, 47 genera, and 104 species and subspecies of parasitic lice are listed, of which 26 are new species records and eight are new genus records. Also, we report 17 new host-louse associations. The checklist includes 17 endemic species (16 from birds, one from a mammal), 79 native species and subspecies (78 from birds, one from a mammal), and eight species and subspecies (five from birds, three from mammals) introduced by human agency. Nine species assigned in error to the Galápagos Islands in the literature are discussed and deleted from the fauna. For each valid species and subspecies we give information on its taxonomic history, type material, host associations, geographic distribution, biogeographical status, systematic relationships, and relevant literature references. We also give a brief summary of louse biology, and an account of the history of louse collecting, expeditions, collections, and research relating to Galápagos Islands lice. We include a host-parasite list, and a list of hosts which breed in the Galápagos Islands but without lice recorded from them. Also, we formally designate four lectotypes from the Kellogg Collection.


Gene-specific correlation of RNA and protein levels in human cells and tissues.
An important issue for molecular biology is to establish whether transcript levels of a given gene can be used as proxies for the corresponding protein levels. Here, we have developed a targeted proteomics approach for a set of human non-secreted proteins based on parallel reaction monitoring to measure, at steady-state conditions, absolute protein copy numbers across human tissues and cell lines and compared these levels with the corresponding mRNA levels using transcriptomics. The study shows that the transcript and protein levels do not correlate well unless a gene-specific RNA-to-protein (RTP) conversion factor independent of the tissue type is introduced, thus significantly enhancing the predictability of protein copy numbers from RNA levels. The results show that the RTP ratio varies significantly with a few hundred copies per mRNA molecule for some genes to several hundred thousands of protein copies per mRNA molecule for others. In conclusion, our data suggest that transcriptome analysis can be used as a tool to predict the protein copy numbers per cell, thus forming an attractive link between the field of genomics and proteomics.


Transjugular intrahepatic portosystemic shunt (TIPS); review of initial experience at Aga Khan University Hospital.
To retrospectively assess the therapeutic effectiveness and safety of transjugular intrahepafic portosystemic shunt (TIPS) in patients with portal hypertension related complications. Over a period of 7.5 years 19 patients (10 males and 9 females, age range 25-69 years) were referred for TIPS at our radiology department. Thirteen patients suffered from liver cirrhosis while 6 had Budd Chiari syndrome. All patients were evaluated with colour doppler ultrasonography and cross sectional imaging. Shunt procedures were performed under sedation or general anaesthesia through internal jugular approach. Metallic self expandable uncovered stents were placed in 15 patients and covered stent in 1 patient. Follow up of patency was evaluated with ultrasound in majority and by venography in some patients. Safety of the procedure and clinical outcome were analyzed. Indications of procedure included variceal bleeding (n=8), ascites (n=4), ascites and bleeding (n=1) and Budd-Chiari syndrome (n=6). Technical success rate was 84.21%. Complication rate was 10.53%. Three days mortality was 15.79%. Mean primary shunt patency was 306.62 +/- 533 days. During follow-up stent occlusion occurred in 5 patients (31.25%). Four of these patients underwent successful reintervention. Recurrence of symptoms occurred in 68.75% patients. TIPS is useful for management of complications of portal hypertension that are refractory to pharmacological and endoscopic treatment, however shunt stenosis or occlusion may cause recurrence of symptoms. Repeated interventions are often required to maintain shunt patency.


VISA is required for B cell expression of TLR7.
B cells play a critical role in the initialization and development of the systemic lupus erythematosus that is dependent on the expression of the endosomal ssRNA receptor TLR7. Previous studies have established that B cell expression of TLR7 is controlled by the type I IFN secreted by plasmacytoid dendritic cells. In this article, we report that VISA, also known as MAVS, IPS-1, and CardIf, essential for RIG-I/MDA5-mediated signaling following sensing of cytosolic RNA, regulate B cell expression of TLR7 and CD23. We found that B cells from a VISA(-/-) mouse express reduced TLR7 but normal basal levels of type I IFN. We also show that although IFN-β and TLR7 agonists synergize to promote TLR7 expression in VISA(-/-) B cells, they do not fully complement the defect seen in VISA(-/-) cells. Cell transfer experiments revealed that the observed effects of VISA(-/-) are B cell intrinsic. The reduced TLR7 expression in B cells is correlated with impaired TLR7 agonist-induced upregulation of activation markers CD69 and CD86, cell proliferation, production of IFN-α, TNF, and IL-12, and NF-κB activation. Finally, studies indicate that genetic background may influence the observed phenotype of our VISA(-/-) mice, because VISA(-/-) B cells differ in CD23 and TLR7 expression when on C57BL/6 versus 129Sv-C57BL/6 background. Thus, our findings suggest an unexpected link between VISA-mediated cytosolic RLR signaling and autoimmunity.


Indications for pediatric liver transplantation.
This review discusses the indications for orthotopic liver transplantation (OLT) in children and provides guidelines for the appropriate time to list children for transplant. The diseases for which OLT are indicated in children are divided into diagnostic categories with a focus on the natural history and appropriate medical and surgical therapy prior to transplantation. Contraindications to transplantation pertinent to specific diseases are outlined, with particular emphasis on complex metabolic defects with extrahepatic manifestations. The clinical conditions which indicate that listing for OLT is appropriate, as well as the relative and absolute contraindications, irrespective of diagnosis, are discussed. The importance of malnutrition and poor development as listing criteria is stressed. Special timing considerations for diagnoses relevant to the pediatric age group, e.g. urea cycle defects and Crigler-Najjar syndrome, are emphasized. Finally, the impact of co-existing extrahepatic disease on the decision to list children for OLT is reviewed.


Differentiation of Crohn's disease from intestinal tuberculosis in India in 2010.
Differentiating intestinal tuberculosis from Crohn's disease (CD) is an important clinical challenge of considerable therapeutic significance. The problem is of greatest magnitude in countries where tuberculosis continues to be highly prevalent, and where the incidence of CD is increasing. The final clinical diagnosis is based on a combination of the clinical history with endoscopic studies, culture and polymerase chain reaction for Mycobacterium tuberculosis, biopsy pathology, radiological investigations and response to therapy. In a subset of patients, surgery is required and intraoperative findings with pathological study of the resected bowel provide a definitive diagnosis. Awareness of the parameters useful in distinguishing these two disorders in each of the different diagnostic modalities is crucial to accurate decision making. Newer techniques, such as capsule endoscopy, small bowel enteroscopy and immunological assays for Mycobacterium tuberculosis, have a role to play in the differentiation of intestinal tuberculosis and CD. This review presents currently available evidence regarding the usefulness and limitations of all these different modalities available for the evaluation of these two disorders.


Induced Mist1 expression promotes remodeling of mouse pancreatic acinar cells.
Early embryogenesis involves cell fate decisions that define the body axes and establish pools of progenitor cells. Development does not stop once lineages are specified; cells continue to undergo specific maturation events, and changes in gene expression patterns lead to their unique physiological functions. Secretory pancreatic acinar cells mature postnatally to synthesize large amounts of protein, polarize, and communicate with other cells. The transcription factor MIST1 is expressed by only secretory cells and regulates maturation events. MIST1-deficient acinar cells in mice do not establish apical-basal polarity, properly position zymogen granules, or communicate with adjacent cells, disrupting pancreatic function. We investigated whether MIST1 directly induces and maintains the mature phenotype of acinar cells. We analyzed the effects of Cre-mediated expression of Mist1 in adult Mist1-deficient (Mist1(KO)) mice. Pancreatic tissues were collected and analyzed by light and electron microscopy, immunohistochemistry, real-time polymerase chain reaction analysis, and chromatin immunoprecipitation. Primary acini were isolated from mice and analyzed in amylase secretion assays. Induced expression of Mist1 in adult Mist1(KO) mice restored wild-type gene expression patterns in acinar cells. The acinar cells changed phenotypes, establishing apical-basal polarity, increasing the size of zymogen granules, reorganizing the cytoskeletal network, communicating intercellularly (by synthesizing gap junctions), and undergoing exocytosis. The exocrine pancreas of adult mice can be remodeled by re-expression of the transcription factor MIST1. MIST1 regulates acinar cell maturation and might be used to repair damaged pancreata in patients with pancreatic disorders.


Interrater Reliability of the Revised Cognitive Performance Test (CPT): Assessing Cognition in People With Neurocognitive Disorders.
The rigor of occupation-based standardized assessments that rely on observational scoring procedures depends on proven reliability among test administrators. This study measured interrater reliability of the Cognitive Performance Test (CPT), a standardized, occupation-based assessment that measures cognitive-functional capacity in older adults with neurocognitive disorders. To capture a range of experience among test administrators, two sets of raters-four expert and three novice-scored video recordings of 10 patients administered the CPT. Interrater reliability results were strong among all raters (intraclass correlation coefficient [ICC] = .93), with expert raters (ICC = .97) yielding higher coefficients than novice raters (ICC = .93). Spearman's ρ correlation coefficients were high among all raters (rs = .92-1.00). Practitioners can be confident that results of the CPT give accurate and consistent information to the health care team, family members, and patients when administered with fidelity using standardized protocols.


Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure.
Purpose Classical Hodgkin lymphoma (HL) frequently exhibits genetic alterations leading to overexpression of the programmed death-1 (PD-1) ligands, suggesting a possible vulnerability to PD-1 blockade. The phase Ib study KEYNOTE-013 (NCT01953692) tested the safety and efficacy of the anti-PD-1 antibody pembrolizumab in patients with hematologic malignancies. Based on its genetics, HL was included as an independent cohort. Methods We enrolled patients with relapsed or refractory HL whose disease progressed on or after treatment with brentuximab vedotin. Patients received pembrolizumab, 10 mg/kg every 2 weeks, until disease progression occurred. Response to treatment was assessed at week 12 and every 8 weeks thereafter. Principal end points were safety and complete remission (CR) rate. Results Thirty-one patients were enrolled; 55% had more than four lines of prior therapy, and 71% had relapsed after autologous stem cell transplantation. Five patients (16%) experienced grade 3 drug-related adverse events (AEs); there were no grade 4 AEs or deaths related to treatment. The CR rate was 16% (90% CI, 7% to 31%). In addition, 48% of patients achieved a partial remission, for an overall response rate of 65% (90% CI, 48% to 79%). Most of the responses (70%) lasted longer than 24 weeks (range, 0.14+ to 74+ weeks), with a median follow-up of 17 months. The progression-free survival rate was 69% at 24 weeks and 46% at 52 weeks. Biomarker analyses demonstrated a high prevalence of PD-L1 and PD-L2 expression, treatment-induced expansion of T cells and natural killer cells, and activation of interferon-γ, T-cell receptor, and expanded immune-related signaling pathways. Conclusions Pembrolizumab was associated with a favorable safety profile. Pembrolizumab treatment induced favorable responses in a heavily pretreated patient cohort, justifying further studies.


The accuracy of quantitative parameters in (99m) Tc-MAG3 dynamic renography: a national audit based on virtual image data.
Assessment of image analysis methods and computer software used in (99m) Tc-MAG3 dynamic renography is important to ensure reliable study results and ultimately the best possible care for patients. In this work, we present a national multicentre study of the quantification accuracy in (99m) Tc-MAG3 renography, utilizing virtual dynamic scintigraphic data obtained by Monte Carlo-simulated scintillation camera imaging of digital phantoms with time-varying activity distributions. Three digital phantom studies were distributed to the participating departments, and quantitative evaluation was performed with standard clinical software according to local routines. The differential renal function (DRF) and time to maximum renal activity (Tmax ) were reported by 21 of the 28 Swedish departments performing (99m) Tc-MAG3 studies as of 2012. The reported DRF estimates showed a significantly lower precision for the phantom with impaired renal uptake than for the phantom with normal uptake. The Tmax estimates showed a similar trend, but the difference was only significant for the right kidney. There was a significant bias in the measured DRF for all phantoms caused by different positions of the left and right kidney in the anterior-posterior direction. In conclusion, this study shows that virtual scintigraphic studies are applicable for quality assurance and that there is a considerable uncertainty associated with standard quantitative parameters in dynamic (99m) Tc-MAG3 renography, especially for patients with impaired renal function.


Challenges and Errors in Genetic Testing: The Fifth Case Series.
In this ongoing case series, 33 genetic testing cases are documented in which tests were recommended, ordered, interpreted, or used incorrectly and/or in which clinicians faced challenges related to history/reports provided by patients or laboratories. An invitation to submit cases of challenges or errors in genetic testing was issued to the general National Society of Genetic Counselors Listserv, the National Society of Genetic Counselors Cancer Special Interest Group members, as part of a case series with Precision Oncology News, and via social media (i.e., Facebook, Twitter, LinkedIn). Deidentified clinical documentation was requested and reviewed when available. Thirty-three cases were submitted, reviewed, and accepted. A thematic analysis was performed. Submitters were asked to approve cases before submission. All cases took place in the United States, involved hereditary cancer testing and/or findings in cancer predisposition genes, and involved medical-grade genetic testing, direct-to-consumer testing, or research genetic testing. In 9 cases, test results were misinterpreted, leading to incorrect screening or risk-reducing procedures being performed/recommended. In 5 cases, incorrect or unnecessary testing was ordered/recommended. In 3 cases, incorrect clinical diagnoses were made, or opportunities for diagnoses were delayed. In 3 cases, errors or challenges arose related to medical intervention after testing or reported genetic diagnosis. In 2 cases, physicians provided incorrect information related to the inheritance pattern of a syndrome. In 2 cases, there were challenges related to the interpretation of genetic variants. In 2 cases, challenges arose after direct-to-consumer testing. One case involved test results that should never have been reported based on sample quality. In 1 case, a patient presented a falsified test result. In 5 cases, multiple errors were made. As genetic testing continues to become more complicated and common, it is critical that patients and nongenetics providers have access to accurate and timely genetic counseling information. Even as multiple medical bodies highlight the value of genetic counselors (GCs), tension exists in the genomics community as GCs work toward licensure and Medicare provider status. It is critical that health care communities leverage, rather than restrict, the expertise and experience of GCs so that patients can benefit from, and not be harmed by, genetic testing. In order to responsibly democratize genomics, it will be important for genetics and nongenetic health care providers to collaborate and use alternative service delivery models and technology solutions at point of care. To deliver on the promise of precision medicine, accurate resources and tools must be utilized.


Total testosterone and neuropsychiatric symptoms in elderly men with Alzheimer's disease.
There has been a significant increase in the use of testosterone in aging men, but little investigation into its impact on men with Alzheimer's disease (AD). The findings of the few studies that have been done are inconsistent. In the present study, we investigated the relationship between total testosterone (TT) and neuropsychiatric symptoms (NPS) in a well-characterized sample of elderly men with mild to moderate AD. The sample, which was drawn from the Texas Alzheimer's Research Care Consortium Longitudinal Research Cohort, included 87 men who met the criteria for mild to moderate AD. The occurrence of NPS was gathered from caregivers and/or family members with the Neuropsychiatric Inventory. TT was analyzed, and the sample was divided into a low-testosterone group (TT ≤2.5 ng/ml; n = 44) and a borderline/normal group (TT ≥2.6 ng/ml; n = 43). TT was correlated with symptoms of hallucinations, delusions, agitation, irritability and motor activity. The borderline/normal group was significantly more likely to have hallucinations (odds ratio (OR) = 5.56), delusions (OR = 3.87), motor activity (OR = 3.13) and irritability (OR = 2.77) than the low-testosterone group. Health status and apolipoprotein E ε4 status were not significant factors. The findings of the present study have implications for the use of testosterone replacement therapy in men with AD or the prodromal stage of the disease.


Development of isoform-specific sensors of polypeptide GalNAc-transferase activity.
Humans express up to 20 isoforms of GalNAc-transferase (herein T1-T20) that localize to the Golgi apparatus and initiate O-glycosylation. Regulation of this enzyme family affects a vast array of proteins transiting the secretory pathway and diseases arise upon misregulation of specific isoforms. Surprisingly, molecular probes to monitor GalNAc-transferase activity are lacking and there exist no effective global or isoform-specific inhibitors. Here we describe the development of T2- and T3-isoform specific fluorescence sensors that traffic in the secretory pathway. Each sensor yielded little signal when glycosylated but was strongly activated in the absence of its glycosylation. Specificity of each sensor was assessed in HEK cells with either the T2 or T3 enzymes deleted. Although the sensors are based on specific substrates of the T2 and T3 enzymes, elements in or near the enzyme recognition sequence influenced their activity and required modification, which we carried out based on previous in vitro work. Significantly, the modified T2 and T3 sensors were activated only in cells lacking their corresponding isozymes. Thus, we have developed T2- and T3-specific sensors that will be valuable in both the study of GalNAc-transferase regulation and in high-throughput screening for potential therapeutic regulators of specific GalNAc-transferases.


Cellular proliferative responses in squirrel monkeys immunized with recombinant and synthetic Plasmodium vivax circumsporozoite peptides.
The role of circulating peripheral blood momonuclear cells (PBMC) in mediating protective immunity was examined during an immunization trial in Saimiri monkeys. Three engineered constructs representing different but overlapping regions of the circumsporozoite (CS) protein of Plasmodium vivax were used to immunize the Saimiri monkeys. Monkeys were randomly placed into three immunization groups: rPvCS2, rPvCS3, and LCV3 (representing three different but overlapping portions of the P. vivax CS protein) and two control groups: an alum adjuvant control group and an unimmunized control group. Collections of PBMC were made throughout the study at weeks 0, 2, 8, challenge (week 16), and two weeks after challenge. Proliferative responses to all immunogens and pokeweed mitogen were measured in all monkeys. Fourteen of 18 monkeys immunized with either rPvCS2 or rPvCS3 responded on the day of challenge to the appropriate immunogen with a stimulation index less than 2. Immunization with LCV3, which represents the repeat region only, elicited a specific response in only one monkey. However monkeys in both control groups also responded to rPvCS2 and rPvCS3, regardless of immunization, suggesting the presence of epitopes in rPvCS2 and rPvCS3 capable of associating with differing MHC antigens. Furthermore, the frequency of these cells in the periphery was increased by immunization, as demonstrated by a greater number of responding monkeys in the rPvCS2 and rPvCS3 immunized groups.


What scatter-hoarding animals have taught us about small-scale navigation.
Many animals use cues for small-scale navigation, including beacons, landmarks, compasses and geometric properties. Scatter-hoarding animals are a unique system to study small-scale navigation. They have to remember and relocate many individual spatial locations, be fairly accurate in their searching and have to remember these locations for long stretches of time. In this article, we review what is known about cue use in both scatter-hoarding birds and rodents. We discuss the importance of local versus global cues, the encoding of bearings and geometric rules, the use of external compasses such as the Sun and the influence of the shape of experimental enclosures in relocating caches or hidden food. Scatter-hoarding animals are highly flexible in how and what they encode. There also appear to be differences in what scatter-hoarding birds and rodents encode, as well as what scatter-hoarding animals in general encode compared with other animals. Areas for future research with scatter-hoarding animals are discussed in light of what is currently known.


Molecular diagnostics of parapox virus infections.
The diagnosis of parapox virus infections relies primarily on a history of contact with infected animals. The clinical presentation is usually a non-specific necrotic ulcer. The histology may also be non-specific, especially with older lesions. Negative-staining electron microscopy (EM) is a fast and reliable diagnostic tool, but is not widely available. Serological tests and the time-consuming viral culture are also rarely used in Europe. The diagnostic procedure in two patients with ecthyma contagiosum and milker's nodule using polymerase chain reaction specific for orthopox, parapox and Orf virus is explained. Diagnostics included bacterial culture, viral culture, histology and EM. In addition to these, a polymerase chain reaction (PCR) was performed in both cases. The patient with ecthyma contagiosum was negative for ortho-, parapox-, and orf-virus on PCR, whereas the patient with milker's nodule had a PCR positive for parapoxvirus. PCR is a simple, fast, and standardized method of diagnosis that can distinguish between the subgroups of parapoxviruses. A diagnosis can be made even in cases of ambiguous history or unspecific clinical presentation. The method is limited by the necessity to sample native material or to use neutrally buffered formalin in case of PCR from paraffin material.


Adverse right ventricular remodelling, function, and stress responses in obesity: insights from cardiovascular magnetic resonance.
We aimed to determine the effect of increasing body weight upon right ventricular (RV) volumes, energetics, systolic function, and stress responses using cardiovascular magnetic resonance (CMR). We first determined the effects of World Health Organization class III obesity [body mass index (BMI) > 40 kg/m2, n = 54] vs. healthy weight (BMI < 25 kg/m2, n = 49) upon RV volumes, energetics and systolic function using CMR. In less severe obesity (BMI 35 ± 5 kg/m2, n = 18) and healthy weight controls (BMI 21 ± 1 kg/m2, n = 9), we next performed CMR before and during dobutamine to evaluate RV stress response. A subgroup undergoing bariatric surgery (n = 37) were rescanned at median 1 year to determine the effects of weight loss. When compared with healthy weight, class III obesity was associated with adverse RV remodelling (17% RV end-diastolic volume increase, P < 0.0001), impaired cardiac energetics (19% phosphocreatine to adenosine triphosphate ratio reduction, P < 0.001), and reduction in RV ejection fraction (by 3%, P = 0.01), which was related to impaired energetics (R = 0.3, P = 0.04). Participants with less severe obesity had impaired RV diastolic filling at rest and blunted RV systolic and diastolic responses to dobutamine compared with healthy weight. Surgical weight loss (34 ± 15 kg weight loss) was associated with improvement in RV end-diastolic volume (by 8%, P = 0.006) and systolic function (by 2%, P = 0.03). Increasing body weight is associated with significant alterations in RV volumes, energetic, systolic function, and stress responses. Adverse RV modelling is mitigated with weight loss. Randomized trials are needed to determine whether intentional weight loss improves symptoms and outcomes in patients with obesity and heart failure.


Three-Hand Endoscopic Endonasal Transsphenoidal Surgery: Experience With an Anatomy-Preserving Mononostril Approach Technique.
Variations on the endoscopic transsphenoidal approach present unique surgical techniques that have unique effects on surgical outcomes, extent of resection (EOR), and anatomical complications. To analyze the learning curve and perioperative outcomes of the 3-hand endoscopic endonasal mononostril transsphenoidal technique. Prospective case series and retrospective data analysis of patients who were treated with the 3-hand transsphenoidal technique between January 2007 and May 2015 by a single neurosurgeon. Patient characteristics, preoperative presentation, tumor characteristics, operative times, learning curve, and postoperative outcomes were analyzed. Volumetric EOR was evaluated, and a logistic regression analysis was used to assess predictors of EOR. Two hundred seventy-five patients underwent an endoscopic transsphenoidal surgery using the 3-hand technique. One hundred eighteen patients in the early group had surgery between 2007 and 2010, while 157 patients in the late group had surgery between 2011 and 2015. Operative time was significantly shorter in the late group (161.6 min) compared to the early group (211.3 min, P = .001). Both cohorts had similar EOR (early group 84.6% vs late group 85.5%, P = .846) and postoperative outcomes. The learning curve showed that it took 54 cases to achieve operative proficiency with the 3-handed technique. Multivariate modeling suggested that prior resections and preoperative tumor size are important predictors for EOR. We describe a 3-hand, mononostril endoscopic transsphenoidal technique performed by a single neurosurgeon that has minimal anatomic distortion and postoperative complications. During the learning curve of this technique, operative time can significantly decrease, while EOR, postoperative outcomes, and complications are not jeopardized.


Association of the rs1346044 Polymorphism of the Werner Syndrome Gene RECQL2 with Increased Risk and Premature Onset of Breast Cancer.
Like other RECQ helicases, WRN/RECQL2 plays a crucial role in DNA replication and the maintenance of genome stability. Inactivating mutations in RECQL2 lead to Werner syndrome, a rare autosomal disease associated with premature aging and an increased susceptibility to multiple cancer types. We analyzed the association of two coding single-nucleotide polymorphisms in WRN, Cys1367Arg (rs1346044), and Arg834Cys (rs3087425), with the risk, age at onset, and clinical subclasses of breast cancer in a hospital-based case-control study of an Austrian population of 272 breast cancer patients and 254 controls. Here we report that the rare homozygous CC genotype of rs1346044 was associated with an approximately two-fold elevated breast cancer risk. Moreover, patients with the CC genotype exhibited a significantly increased risk of developing breast cancer under the age of 55 in both recessive and log-additive genetic models. CC patients developed breast cancer at a mean age of 55.2 ± 13.3 years and TT patients at 60.2 ± 14.7 years. Consistently, the risk of breast cancer was increased in pre-menopausal patients in the recessive model. These findings suggest that the CC genotype of WRN rs1346044 may contribute to an increased risk and a premature onset of breast cancer.


Estimating the burden of Japanese encephalitis virus and other encephalitides in countries of the mekong region.
Diverse aetiologies of viral and bacterial encephalitis are widely recognized as significant yet neglected public health issues in the Mekong region. A robust analysis of the corresponding health burden is lacking. We retrieved 75 articles on encephalitis in the region published in English or in French from 1965 through 2011. Review of available data demonstrated that they are sparse and often derived from hospital-based studies with significant recruitment bias. Almost half (35 of 75) of articles were on Japanese encephalitis virus (JEV) alone or associated with dengue. In the Western Pacific region the WHO reported 30,000-50,000 annual JEV cases (15,000 deaths) between 1966 and 1996 and 4,633 cases (200 deaths) in 2008, a decline likely related to the introduction of JEV vaccination in China, Vietnam, or Thailand since the 1980s. Data on dengue, scrub typhus and rabies encephalitis, among other aetiologies, are also reviewed and discussed. Countries of the Mekong region are undergoing profound demographic, economic and ecological change. As the epidemiological aspects of Japanese encephalitis (JE) are transformed by vaccination in some countries, highly integrated expert collaborative research and objective data are needed to identify and prioritize the human health, animal health and economic burden due to JE and other pathogens associated with encephalitides.


Training the physician-scientist: views from program directors and aspiring young investigators.
There is growing concern that the physician-scientist is endangered due to a leaky training pipeline and prolonged time to scientific independence (1). The NIH Physician-Scientist Workforce Working Group has concluded that as many as 1,000 individuals will need to enter the pipeline each year to sustain the workforce (2). Moreover, surveys of postgraduate training programs document considerable variability in disposition and infrastructure (3). Programs can be broadly grouped into two classes: physician-scientist training programs (PSTPs) that span residency and fellowship training, and research-in-residency programs (RiRs), which are limited to residency but trainees are able to match into PSTPs upon transitioning to fellowship (Figure 1). Funding sources for RiRs and PSTPs are varied and include NIH KL2 and T32 awards, charitable foundations, philanthropy, and institutional support. Furthermore, standards for research training and tools for evaluating programmatic success are lacking. Here, we share consensus generated from iterative workshops hosted by the Alliance of Academic Internal Medicine (AAIM) and the student-led American Physician Scientists Association (APSA).


HIV-1 inhibits autophagy in bystander macrophage/monocytic cells through Src-Akt and STAT3.
Autophagy is a homeostatic mechanism of lysosomal degradation. Defective autophagy has been linked to various disorders such as impaired control of pathogens and neurodegeneration. Autophagy is regulated by a complex array of signaling pathways that act upstream of autophagy proteins. Little is known about the role of altered regulatory signaling in disorders associated with defective autophagy. In particular, it is not known if pathogens inhibit autophagy by modulation of upstream regulatory pathways. Cells infected with HIV-1 blocked rapamycin-induced autophagy and CD40-induced autophagic killing of Toxoplasma gondii in bystander (non-HIV-1 infected) macrophage/monocytic cells. Blockade of autophagy was dependent on Src-Akt and STAT3 triggered by HIV-1 Tat and IL-10. Neutralization of the upstream receptors VEGFR, beta-integrin or CXCR4, as well as of HIV-1 Tat or IL-10 restored autophagy in macrophage/monocytic cells exposed to HIV-1-infected cells. Defective autophagic killing of T. gondii was detected in monocyte-derived macrophages from a subset of HIV-1(+) patients. This defect was also reverted by neutralization of Tat or IL-10. These studies revealed that a pathogen can impair autophagy in non-infected cells by activating counter-regulatory pathways. The fact that pharmacologic manipulation of cell signaling restored autophagy in cells exposed to HIV-1-infected cells raises the possibility of therapeutic manipulation of cell signaling to restore autophagy in HIV-1 infection.


Bioinspired multi-responsive soft actuators controlled by laser tailored graphene structures.
By exploiting aligned cellulose fibrils as geometrically constraining structures, plants can achieve a complex programmable shape change in response to environmental stimuli. Inspired by this natural prototype, a series of manmade materials with aligned structures have been developed and employed in self-morphing materials. However, in these cases, the constraining materials are fabricated and aligned in separate processes. In botanic systems, a more efficient way is adopted, in which the aligned microstructures are simultaneously synthesized and aligned in one bottom-up process. Herein, we report a bioinspired bottom-up approach to fabricate laser induced graphene (LIG) structures which resemble the aligned microstructures of the cellulose fibrils in plants. Such LIG structures serve as geometrically constraining materials to precisely control the shape changing behaviors of soft actuators made from polymer and LIG layers. Meanwhile, the LIG structures also serve as functional materials to absorb photo and electrical energy to stimulate motions of the soft actuators. Taking advantage of the geometrically constraining effect from the aligned LIG structures, a series of programmable actuations stimulated by electricity, light, organic vapor, and moisture were demonstrated. Furthermore, the soft actuators also act as soft grippers and walking robots upon different stimuli, indicating their potential applications in soft robotics, electronics, microelectromechanical systems, and others.


Free radicals act as effectors in the growth inhibition and apoptosis of iron-treated Burkitt's lymphoma cells.
The addition of ferric citrate to Burkitt's lymphoma (BL) cell lines inhibits growth, leads to the accumulation of cells in the phase G(2)/M of the cell cycle and to the modulation of translocated c-myc expression. The increase in the labile iron pool (LIP) of iron-treated BL cells leads to cytotoxicity. Indeed, intracellular free iron catalyzes the formation of highly reactive compounds such as hydroxyl radicals and nitric oxide (NO) that damages macromolecular components of cells, eventually resulting in apoptosis. In this report, we have investigated the possible involvement of free radicals in the response of Ramos cells to iron. When added to Ramos cells, iron increased the intracellular levels of peroxide/peroxynitrite and NO. Moreover, the addition of free radicals scavengers (TROLOX and Carboxy-PTIO) neutralized the effects of iron on Ramos cells while addition of an NO donor or hydrogen peroxide (H2O2) to cells generated effects which partially mimicked those induced by iron addition. Collectively, our results suggest the involvement of free radicals as effectors in the iron specific growth inhibition of BL cells observed in vitro.


Diagnostic accuracy of cardiothoracic ratio on admission chest radiography to detect left or right ventricular systolic dysfunction: a retrospective study.
To determine the diagnostic accuracy of the cardiothoracic ratio on postero-anterior or antero-posterior chest radiographs in predicting left ventricular or right ventricular dysfunction on echocardiography in an inpatient population. Retrospective study. Two secondary care hospitals in the United Kingdom. Four hundred consecutive inpatient echocardiograms were screened for inclusion along with chest radiographs (both postero-anterior and antero-posterior). The cardiothoracic ratio was calculated from chest radiographs along with quantitative and qualitative measures of left ventricular or right ventricular dysfunction on echocardiography. Sensitivity and specificity of cardiothoracic ratio across a range of values to detect moderate/severe left ventricular and/or right ventricular dysfunction on echocardiography. Overall, 272 records met inclusion criteria. The prevalence of left ventricular/right ventricular dysfunction on echocardiography was 26% in an inpatient population with high clinical suspicion of cardiac disease referred for echocardiography. Over a range of cardiothoracic ratio values on postero-anterior films, a value of >0.55 yielded the best sensitivity (62.5%) and specificity (76.5%) for diagnosing left ventricular/right ventricular impairment (positive likelihood ratio 2.56), with a positive predictive value of 29.5%. Cardiothoracic ratio on antero-posterior film was not predictive of left ventricular/right ventricular impairment on echocardiography. In conclusion, in the context of an acute admission, cardiothoracic ratio measured on postero-anterior or antero-posterior films has limited value in detecting moderate left ventricular and/or right ventricular systolic dysfunction. Previously established absolute values may be unreliable by modern standards.


Non-local energy transport in tunneling and plasmonic structures.
Various definitions of the velocity of propagation of the electromagnetic field have been adopted in experimental and theoretical studies of tunneling and plasmonic systems. Tunneling problems are often analyzed by invoking the group delay (or dwell time) velocities. On the other hand, slow light and plasmonic systems are considered by using the wave packet group velocity. This paper discusses various definitions for the velocity of the electromagnetic wave propagation and compares them in applications to the problems of slow light and superluminality in resonant and tunneling structures. Energy propagation is, in general, a nonlocal quantity and depends on the global properties of the system, rather than being simply a local quantity. The energy propagation velocity takes into account the non-local characteristics of the wave propagation and offers a natural generalization for those situations when the group velocity is ill defined or gives unphysical results. It is shown that the group delay velocity, which may be superluminal away from the resonance, becomes equal to the energy velocity at the resonant point.


Lead, Zinc, Copper, and Cadmium Content of Water from South Australian Rainwater Tanks.
Rainwater is consumed for drinking water in many parts of Australia, either preferentially over municipal water or in regional or remote areas, because rainwater is the primary source of water. Previous rainwater studies in other areas in Australia have shown the levels of some metals to be above the Australian Drinking Water Guidelines (ADWG). This study assessed the level of metals in rainwater harvested in the Adelaide region. Water samples were collected from 53 tanks from three different sampling corridors. A total of 365 water samples were analysed for lead, zinc, copper, and cadmium using atomic absorption spectrophotometry. In 47 out of the 53 tanks, lead was above the ADWG of 0.01 ppm in at least one sample (with 180/365 samples above 0.01 ppm). Zinc was above the ADWG (3.0 ppm) in 53/365 samples, copper was above the ADWG (2.0 ppm) in eight samples out of 365 samples, and cadmium was above the ADWG (0.002 ppm) in 19 samples out of 365 samples. These data are consistent with other studies of rainwater quality in Australia. Comparisons of levels of metals and volume of rainfall in the sampling and preceding month, roof material, and tank material, the presence of a first-flush device, sampling corridor, and sample pH showed that the roof material was related to higher levels of metals. There was a significant relationship between sampling corridors and the levels of lead and zinc. Nine of the tanks surveyed had filters installed. There was a small, but statistically significant, decrease in the levels of metals that passed through a filter prior to collection but, in those samples, filters did not remove metals to below guideline concentrations. An estimate of exposure, and a brief discussion of health risks as a result of exposure to metals, is presented.


Prenatal diagnosis of beta-thalassemia in Egypt: implementing accurate high-tech methods did not reflect much on the outcome.
The clinical severity of thalassemia major makes it a priority genetic disease for prevention programs through prenatal diagnosis for carrier couples. Incorporation of automated DNA sequencing that enables the characterization of mutations not detected by other mutation specific detection procedures was a prime goal of this work. Automated DNA sequencing was offered on fetal tissues in 30 pregnancies during the year 2005. The pregnancies were at high risk for homozygosity or compound heterozygosity for beta-thalassemia based on mutation analysis of both parents before prenatal diagnosis. Both parents have beta-thalassemia trait. Fetal samples were collected by chorionic villus sampling (CVS) in the first trimester and by amniocentesis in the second trimester. The point mutations were characterized by PCR (ARMS). The absence of the expected fragment with all the mutant ARMS primers insinuated an uncharacterized DNA segment that was further subjected to direct automated fluorescent DNA sequencing in an attempt to know if the fetus was affected by parents' mutations. If no mutation was detected using the PCR ARMS, the sample was further analyzed using direct automated fluorescent DNA sequencing. The mean gestation when carrying out the invasive procedure was 14 (10 -18) weeks. All mothers had a previous affected pregnancy, and 13 had two or more previous affected pregnancies. Pregnancies were: 8 carrier fetuses (trait) and 22 affected fetuses in which 2 were homozygous and 20 double heterozygous. Fourteen parents of affected fetuses preferred to continue pregnancy and the babies were born as diagnosed. The other 8 parents decided on termination and DNA of the abortuses proved to be as previously diagnosed by DNA sequencing. The use of PCR amplification and direct sequencing have permitted the accurate characterization of unidentified alleles and successfully solved 100% of the examined samples. However, it has resulted in minor changes of the outcome as the majority of couples preferred continuation of pregnancy.


Processing of frequency-modulated sounds in the cat's anterior auditory field.
1. Single-neuron activity was recorded from the anterior auditory field (AAF) in the cortex of gas-anesthetized cats. 2. Tone bursts and broad-band complex sounds were used for auditory stimulation. Responses to frequency-modulated (FM) sounds, in particular, were studied systematically. 3. Linear FM sweeps were centered around the best frequency (BF) of a neuron and had an excursion large enough to cover its whole frequency tuning range. Rate and direction of change of the FM sweeps were varied. 4. In 69% of the FM responses, a peak was found at an instantaneous frequency that corresponded to the BF in the pure-tone response. Thirty-three percent of the units had multiple maxima in their FM response. These secondary maxima were not always reflected in the pure-tone response of the same neurons. 5. The vast majority of AAF neurons showed one of two types of selectivity for FM rate. Depending on the criterion, almost half of the cells (46%) preferred fast changes of > 200 Hz/ms (high-pass) in both FM directions. Forty-eight percent of all neurons showed band-pass behavior with a clear preference in the middle range of FM rates in one or both directions. Low-pass or all-pass neurons made up only a small proportion (4 and 1%, respectively) of AAF neurons. 6. When both directions of an FM sweep (low-to-high and high-to-low-frequency) were tested, 66% of the neurons clearly were selective for one direction. This selectivity was not present necessarily at the preferred FM rate. In general, FM direction selectivity was most pronounced at slower FM rates. 7. The selectivity of AAF neurons for the rate and direction of FM sounds makes these neurons suitable for the detection and analysis of communication sounds, which often contain FM components with a particular sweep rate and direction.


Total synthesis of macrodiolide ionophores aplasmomycin A and boromycin via double ring contraction.
The half structure of the symmetrical macrodiolide aplasmomycin A was synthesized by alkylation of a C3-C10 α-sulfonyl ketone subunit, prepared from (R)-pulegone and protected as a C3 ortholactone with (2R,3R)-butanediol, by a protected 15,16-dihydroxy (12E)-allylic chloride representing C11-C17. The latter was obtained from (2S,3R)-1,2-epoxy-3-butanol and propargyl alcohol. Regio- and stereoselective 5-exo-trig cyclization of the ene diol moiety in this segment, mediated by N-bromosuccinimide, led to the (2R,3S,5R)-tetrahydrofuran substructure of aplasmomycin A. Attachment of an α-acetic ester at the C3 carboxylic acid and esterification of the 3'-hydroxyl group of the tetrahydrofuran as its α-bromoacetate enabled coupling of two aplasmomycin half structures as an α-acyloxy acetate. Mukaiyama macrolactonization of this hydroxy acid afforded a symmetrical 36-membered diolide. Base-mediated double Chan rearrangement of this bis α-acyloxy dilactone caused ring contraction to the 34-membered macrocycle of desboroaplasmomycin A while generating the transannular 2-hydroxy-3-hemiketal motif of the natural product in the correct configuration. Final incorporation of boron into the tetraol core produced aplasmomycin A, isolated as its sodium borate. Extension of this route to the unsymmetrical macrodiolide boromycin was accomplished by modifications that included reversal of C12-C13 olefin geometry to (Z) for the southern half structure along with stereoselective hydride reductions of the C9 ketone that produced (9R) and (9S) alcohols for northern and southern half structures, respectively. Coupling of these half structures was made using an α-acyloxy ester linkage as for aplasmomycin A, but ring closure in this case was orchestrated via a blocked C16 alcohol that left open the C15 hydroxyl group of the southern half for Mukaiyama macrolactonization. A double Chan rearrangement of the resulting 35-membered macrocycle produced the 33-membered diolide of desborodesvalinylboromycin which had been obtained previously by degradation of natural boromycin. Insertion of boron into the tetraol core followed by esterification of the C16 alcohol with a masked d-valine and final deprotection furnished boromycin as its zwitterionic (Böeseken) complex.


Mitochondrial genetic variability of Didelphis albiventris (Didelphimorphia, Didelphidae) in Brazilian localities.
Didelphis albiventris is a well-known and common marsupial. Due to its high adaptability, this very widespread generalist species occurs under various environmental conditions, this even including protected regions and disturbed urban areas. We studied a 653 bp fragment of cytochrome oxidase c (COI) from 93 biological samples from seven Brazilian localities, with linear distances ranging between 58 and about 1800 km to analyze the effects of geographic distances on variability and genetic differentiation. The haplotype network presented nine haplotypes and two genetic clusters compatible with the two most distant geographic areas of the states of Minas Gerais, in the southeast, and Rio Grande do Sul, in the extreme south. As each cluster was characterized by low nucleotide and high haplotype diversities, their populations were obviously composed of closely related haplotypes. Surprisingly, moderate to high F(ST) differentiation values and a very weak phylogeographic signal characterizes interpopulation comparisons within Minas Gerais interdemes, these being correlated with the presence of privative haplotypes. On a large rgeographic scale, a comparison between demes from Minas Gerais and Rio Grande do Sul presented high F(ST) values and a robust phylogeographic pattern. This unexpected scenario implies that mtDNA gene flow was insufficient to maintain population cohesion, reflected by the observed high differentiation.


Nonconventional support of respiration.
Several alternative treatments have been proposed to decrease mortality of patients with acute respiratory distress syndrome (ARDS). We will discuss most recent trials and meta-analysis studies on nonconventional ventilatory and pharmacological treatments of ARDS patients. Nonconventional ventilatory treatments such as prone positioning, high frequency oscillatory ventilation (HFOV), and extracorporeal membrane oxygenation (ECMO) aim to restore gas exchange while further decreasing ventilator induced lung injury. Though randomized trials failed to prove survival benefits with the use of prone positioning or HFOV, recent meta-analyses have shown, for both treatments, a decrease in mortality in the subpopulation of more severe ARDS patients. In a randomized controlled trial, referral of ARDS patients in a center with experience on ECMO was associated with an improved survival rate. Promising results come from new miniaturized extracorporeal techniques optimized for effective CO(2) removal from low blood flow. These techniques should allow early application of superprotective ventilator strategies. Pharmacological treatments such as neuromuscular blocking and intravenous β2 agonist may be effective in specific times and subsets of patients. Existing data suggest that some of the available nonconventional treatments may be effective in more severe ARDS patients. New techniques and drugs that should facilitate prevention or healing of lung injury are under investigation.


Fano-like resonance in an optically driven atomic force microscope cantilever.
We observe Fano-like resonance in the vibration spectrum of an optically driven atomic force microscope cantilever system. The vibration of the cantilever is photothermally induced by exciting it with a 780-nm laser diode. The asymmetry of the resonance curve strongly depends on the position of the excitation spot along the central axis of the cantilever. By using a simple physical model, we could extract and analyze the hidden resonance and continuous components in the vibration spectrum.


Challenges and prospects for dengue and malaria control in Thailand, Southeast Asia.
Despite significant advances in the search for potential dengue vaccines and new therapeutic schemes for malaria, the control of these diseases remains difficult. In Thailand, malaria incidence is falling whereas that of dengue is rising, with an increase in the proportion of reported severe cases. In the absence of antiviral therapeutic options for acute dengue, appropriate case management reduces mortality. However, the interruption of transmission still relies on vector control measures that are currently insufficient to curtail the cycle of epidemics. Drug resistance in malaria parasites is increasing, compromising malaria control and elimination. Deficiencies in our knowledge of vector biology and vectorial capacity also hinder public health efforts for vector control. Challenges to dengue and malaria control are discussed, and research priorities identified.


Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials.
Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.


Inhibition of neutral endopeptidase (EC 184.108.40.206) leads to an atrial natriuretic factor-mediated natriuretic, diuretic and antihypertensive response in rodents.
1. Atrial natriuretic factor is metabolized by neutral endopeptidase (atriopeptidase; EC 188.8.131.52) in vitro. Inhibitors of this enzyme have been reported to prolong the half-life of atrial natriuretic factor in vivo and to potentiate the renal and haemodynamic effects of exogenous atrial natriuretic factor. 2. (+/-)-Candoxatrilat, a selective neutral endopeptidase inhibitor, potentiated the natriuretic and diuretic response to volume loading in anaesthetized rats. Part of the response to volume loading and the potentiation by (+/-)-candoxatrilat was prevented by a polyclonal atrial natriuretic factor antiserum. The diuretic and natriuretic responses evoked by hydrochlorothiazide were not altered by the antiserum. 3. (+/-)-Candoxatrilat reduced systolic blood pressure of one-kidney deoxycorticosterone acetate-salt hypertensive rats for over 5 h. This response was abolished by pretreatment with atrial natriuretic factor antiserum. 4. These data demonstrate that the neutral endopeptidase inhibitor (+/-)-candoxatrilat has natriuretic/diuretic and antihypertensive effects in rodents, and that these effects are mediated via endogenous atrial natriuretic factor.


A holistic approach to dissecting SPARC family protein complexity reveals FSTL-1 as an inhibitor of pancreatic cancer cell growth.
SPARC is a matricellular protein that is involved in both pancreatic cancer and diabetes. It belongs to a wider family of proteins that share structural and functional similarities. Relatively little is known about this extended family, but evidence of regulatory interactions suggests the importance of a holistic approach to their study. We show that Hevin, SPOCKs, and SMOCs are strongly expressed within islets, ducts, and blood vessels, suggesting important roles for these proteins in the normal pancreas, while FSTL-1 expression is localised to the stromal compartment reminiscent of SPARC. In direct contrast to SPARC, however, FSTL-1 expression is reduced in pancreatic cancer. Consistent with this, FSTL-1 inhibited pancreatic cancer cell proliferation. The complexity of SPARC family proteins is further revealed by the detection of multiple cell-type specific isoforms that arise due to a combination of post-translational modification and alternative splicing. Identification of splice variants lacking a signal peptide suggests the existence of novel intracellular isoforms. This study underlines the importance of addressing the complexity of the SPARC family and provides a new framework to explain their controversial and contradictory effects. We also demonstrate for the first time that FSTL-1 suppresses pancreatic cancer cell growth.


Birefringence dispersion compensation demodulation algorithm for polarized low-coherence interferometry.
A demodulation algorithm based on the birefringence dispersion characteristics for a polarized low-coherence interferometer is proposed. With the birefringence dispersion parameter taken into account, the mathematical model of the polarized low-coherence interference fringes is established and used to extract phase shift information between the measured coherence envelope center and the zero-order fringe, which eliminates the interferometric 2 π ambiguity of locating the zero-order fringe. A pressure measurement experiment using an optical fiber Fabry-Perot pressure sensor was carried out to verify the effectiveness of the proposed algorithm. The experiment result showed that the demodulation precision was 0.077 kPa in the range of 210 kPa, which was improved by 23 times compared to the traditional envelope detection method.


Integrating Data On Social Determinants Of Health Into Electronic Health Records.
As population health becomes more of a focus of health care, providers are realizing that data outside of traditional clinical findings can provide a broader perspective on potential drivers of a patient's health status and can identify approaches to improving the effectiveness of care. However, many challenges remain before data related to the social determinants of health, such as environmental conditions and education levels, are as readily accessible and actionable as medical data are. Key challenges are a lack of consensus on standards for capturing or representing social determinants of health in electronic health records and insufficient evidence that once information on them has been collected, social determinants can be effectively addressed through referrals or other action tools. To address these challenges and effectively use social determinants in health care settings, we recommend creating national standards for representing data related to social determinants of health in electronic health records, incentivizing the collection of the data through financial or quality measures, and expanding the body of research that measures the impact of acting on the information collected.


Gender Differences in Medicare Payments Among Cardiologists.
Women cardiologists receive lower salaries than men; however, it is unknown whether US Centers for Medicare & Medicaid Services (CMS) reimbursement also differs by gender and contributes to the lower salaries. To determine whether gender differences exist in the reimbursements, charges, and reimbursement per charge from CMS. This cross-sectional analysis used the CMS database to obtain 2016 reimbursement data for US cardiologists. These included reimbursements to cardiologists, charges submitted, and unique billing codes. Gender differences in reimbursement for evaluation and management and procedural charges from both inpatient and outpatient settings were also assessed. Analysis took place between April 2019 and December 2020. Outcomes included median CMS payments received and median charges submitted in the inpatient and outpatient settings in 2016. In 2016, 17 524 cardiologists (2312 women [13%] and 15 212 men [87%]) received CMS payments in the inpatient setting, and 16 929 cardiologists (2151 women [13%] and 14 778 men [87%]) received CMS payments in the outpatient setting. Men received higher median payments in the inpatient (median [interquartile range], $62 897 [$30 904-$104 267] vs $45 288 [$21 371-$73 191]; P < .001) and outpatient (median [interquartile range], $91 053 [$34 820-$196 165] vs $51 975 [$15 622-$120 175]; P < .001) practice settings. Men submitted more median charges in the inpatient (median [interquartile range], 1190 [569-2093] charges vs 959 [569-2093] charges; P < .001) and outpatient settings (median [interquartile range], 1685 [644-3328] charges vs 870 [273-1988] charges; P < .001). In a multivariable-adjusted linear regression analysis, women received less CMS payments compared with men (log-scale β = -0.06; 95% CI, -0.11 to -0.02) after adjustment for number of charges, number of unique billing codes, complexity of patient panel, years since graduation of physicians, and physician subspecialty. Payment by billing codes, both inpatient and outpatient, did not differ by gender. There may be potential differences in CMS payments between men and women cardiologists, which appear to stem from gender differences in the number and types of charges submitted. The mechanisms behind these differences merit further research, both to understand why such gender differences exist and also to facilitate reductions in pay disparities.


Bilateral open sacroiliac joint fusion during adult spinal deformity surgery using triangular titanium implants: technique description and presentation of 21 cases.
Pelvic fixation enhances long constructs during deformity surgery. Subsequent loosening of iliac screws and pain at the pelvis occur in as many as 29% of patients. Concomitant sacroiliac (SI) fusion may prevent potential pain and failure. The objective of this study was to describe a novel surgical technique and a single institution's experience using bilateral SI fusion during adult deformity surgery with S2-alar-iliac (S2AI) screws and triangular titanium rods (TTRs) placed with navigation. The authors reviewed open SI joint fusions with TTR performed between August 2019 and March 2020. All patients underwent lumbosacral fusion through a midline approach and bilateral S2AI pelvic fixation in the caudal teardrop, followed by TTR placement just proximal and cephalad to the S2AI screws using intraoperative CT imaging guidance. Twenty-one patients were identified who received 42 TTRs, ranging in size from 7.0 × 65 mm to 7.0 × 90 mm. Three TTRs (7%) were malpositioned intraoperatively, and each was successfully repositioned during index surgery without negative sequelae. All breaches occurred in a medial and cephalad direction into the pelvis. Incremental operative time for adding TTR averaged 8 minutes and 33 seconds per implant. Image-guided open SI joint fusion with TTR during lumbosacral fusion is technically feasible. The bony corridor for implant placement is narrower cephalad, and implants tend to deviate medially into the pelvis. Detection of malpositioned implant is aided with intraoperative CT, but this can be salvaged. A prospective randomized clinical trial is underway that will better inform the impact of this technique on patient outcomes.


Dicer1 imparts essential survival cues in Notch-driven T-ALL via miR-21-mediated tumor suppressor Pdcd4 repression.
The modulatory function of individual microRNAs (miRNAs) in Notch-driven T-cell acute lymphoblastic leukemias (T-ALLs) has recently been established. Although protumorigenic and tumor-suppressive miRNAs are implicated in disease onset in murine models of Notch-driven T-cell leukemia, whether Dicer1-processed miRNAs are essential for Notch-driven T-ALL is currently unknown. Here we used conditional and inducible genetic loss-of-function approaches to test whether the development and maintenance of Notch-driven T-ALL was dependent on Dicer1 function. Mice with specific inactivation of both Dicer1 alleles in the T-cell lineage did not develop Notch-driven T-ALL. In contrast, loss of 1 functional Dicer1 allele did not significantly perturb T-ALL onset and tumor progression. Inducible inactivation of Dicer1 in early stage polyclonal T-ALL cells was sufficient to abrogate T-ALL progression in leukemic mice, whereas late-stage monoclonal T-ALL cells were counterselected against loss of Dicer1. Lineage-tracing experiments revealed that Dicer1 deficiency led to the induction of apoptosis in T-ALL cells, whereas cell cycle progression remained unaltered. Through microarray-based miRNA profiling, we identified miR-21 as a previously unrecognized miRNA deregulated in both mouse and human T-ALL. Herein, we demonstrate that miR-21 regulates T-ALL cell survival via repression of the tumor suppressor Pdcd4.


Understanding entrapped molecular photosystem and metal-organic framework synergy for improved solar fuel production.
Artificial photosystems assembled from molecular complexes, such as the photocatalyst fac-ReBr(CO)3(4,4'-dcbpy) (dcbpy = dicarboxy-2,2'-bipyridine) and the photosensitiser Ru(bpy)2(5,5'-dcbpy)Cl2 (bpy = 2,2'-bipyridine), are a wide-spread approach for solar fuel production. Recently metal-organic framework (MOF) entrapping of such complexes was demonstrated as a promising concept for catalyst stabilisation and reaction environment optimisation in colloidal-based CO2 reduction. Building on this strategy, here we examined the influence of MIL-101-NH2(Al) MOF particle size, the electron donor source, and the presence of an organic base on the photocatalytic CO2-to-CO reduction performance, and the differences to homogeneous systems. A linear relation between smaller scaffold particle size and higher photocatalytic activity, longer system lifetimes for benign electron donors, and increased turnover numbers (TONs) with certain additive organic bases, were determined. This enabled understanding of key molecular catalysis phenomena and synergies in the nanoreactor-like host-guest assembly, and yielded TONs of ∼4300 over 96 h of photocatalysis under optimised conditions, surpassing homogeneous TON values and lifetimes.


Microorganisms Associated With Pneumonia in Children <5 Years of Age in Developing and Emerging Countries: The GABRIEL Pneumonia Multicenter, Prospective, Case-Control Study.
Pneumonia, the leading infectious cause of child mortality globally, mainly afflicts developing countries. This prospective observational study aimed to assess the microorganisms associated with pneumonia in children aged <5 years in developing and emerging countries. A multicenter, case-control study by the GABRIEL (Global Approach to Biological Research, Infectious diseases and Epidemics in Low-income countries) network was conducted between 2010 and 2014 in Cambodia, China, Haiti, India (2 sites), Madagascar, Mali, Mongolia, and Paraguay. Cases were hospitalized children with radiologically confirmed pneumonia; controls were children from the same setting without any features suggestive of pneumonia. Nasopharyngeal swabs were collected from all subjects; 19 viruses and 5 bacteria were identified by reverse-transcription polymerase chain reaction. Associations between microorganisms and pneumonia were quantified by calculating the adjusted population attributable fraction (aPAF) after multivariate logistic regression analysis adjusted for sex, age, time period, other pathogens, and site. Overall, 888 cases and 870 controls were analyzed; ≥1 microorganism was detected in respiratory samples in 93.0% of cases and 74.4% of controls (P < .001). Streptococcus pneumoniae, Mycoplasma pneumoniae, human metapneumovirus, rhinovirus, respiratory syncytial virus (RSV), parainfluenza virus 1, 3, and 4, and influenza virus A and B were independently associated with pneumonia; aPAF was 42.2% (95% confidence interval [CI], 35.5%-48.2%) for S. pneumoniae, 18.2% (95% CI, 17.4%-19.0%) for RSV, and 11.2% (95% CI, 7.5%-14.7%) for rhinovirus. Streptococcus pneumoniae, RSV, and rhinovirus may be the major microorganisms associated with pneumonia infections in children <5 years of age from developing and emerging countries. Increasing S. pneumoniae vaccination coverage may substantially reduce the burden of pneumonia among children in developing countries.


Pillararene-based supramolecular polymers: from molecular recognition to polymeric aggregates.
Pillar[n]arenes (P[n]As) and their derivatives, consisting of (substituted) hydroquinone units linked by methylene bridges at para-positions, are new type of cyclophane hosts developed in 2008. Their intrinsic characteristics and properties, such as facile preparation and flexible modification, symmetrical and columnar architectures, very rigid and π-rich cavities, as well as intriguing and peculiar guest complexation capability, make them ideal building blocks for the fabrication of polymeric supramolecules. This Feature Article provides an overview of the construction of pillararene-based supramolecular polymers and covers recent research endeavors of the marriage between pillararene-based host-guest pairs and polymeric aggregates. These polymers are classified into two major classes according to the different types of guest species: (1) supramolecular polymers relying on pillararene-based cationic guest recognition; (2) supramolecular polymers relying on pillararene-based neutral guest recognition. The host-guest motifs, building strategies, topological architectures, stimuli-responsiveness and functionalities are comprehensively discussed.


Concomitant Medication Use and New-Onset Diabetes Among Medicaid Beneficiaries with Chronic Obstructive Pulmonary Disease.
Use of multiple prescription medications is common among individuals with chronic obstructive pulmonary disease (COPD) because of coexisting inflammatory-related conditions. Specifically, the use of antidepressants, inhaled corticosteroids (ICSs), and statins may place individuals with COPD at high risk for new-onset diabetes. The objective was to examine the relationship between the use of antidepressants, ICSs, and statins and new-onset diabetes among Medicaid beneficiaries with COPD. This study used a retrospective longitudinal cohort design using multiple years (2005-2008) of Medicaid claims for beneficiaries with newly diagnosed COPD (n = 15,287), who were diabetes free at baseline. National Drug Codes were used to determine the receipt of antidepressants, ICSs, and statins, and International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to define new-onset diabetes (250.x2). Multivariable logistic regression was used to examine the adjusted relationship between medication use and new-onset diabetes. Overall, 6.3% of the study population was diagnosed with new-onset diabetes. After controlling for baseline characteristics, individuals using ICSs (adjusted odds ratio [AOR]: 1.23; 95% confidence interval [CI]: 1.07, 1.47) or statins (AOR: 1.48; 95% CI: 1.27, 1.72) had a greater risk of new-onset diabetes compared to those not given ICSs, statins, or antidepressants. Analyses using combined medication categories revealed that adults using statins in combination with both antidepressants and ICSs, or when combined with ICS, were more likely to have new-onset diabetes. These findings indicate that multiple medication use (ICSs and statins) was associated with increased rates of new-onset diabetes. Further research is warranted to understand this association.


Role of nitrogen fixation in the autecology of Polaromonas naphthalenivorans in contaminated sediments.
Polaromonas naphthalenivorans strain CJ2 is a Gram-negative betaproteobacterium that was identified, using stable isotope probing in 2003, as a dominant in situ degrader of naphthalene in coal tar-contaminated sediments. The sequenced genome of strain CJ2 revealed several genes conferring nitrogen fixation within a 65.6 kb region of strain CJ2's chromosome that is absent in the genome of its closest sequenced relative Polaromonas sp. strain JS666. Laboratory growth and nitrogenase assays verified that these genes are functional, providing an alternative source of nitrogen in N-free media when using naphthalene or pyruvate as carbon sources. Knowing this, we investigated if nitrogen-fixation activity could be detected in microcosms containing sediments from the field site where strain CJ2 was isolated. Inducing nitrogen limitation with the addition of glucose or naphthalene stimulated nitrogenase activity in amended sediments, as detected using the acetylene reduction assay. With the use of fluorescence microscopy, we screened the microcosm sediments for the presence of active strain CJ2 cells using a dual-labelling approach. When we examined the carbon-amended microcosm sediments stained with both a strain CJ2-specific fluorescent in situ hybridization probe and a polyclonal fluorescently tagged antibody, we were able to detect dual-labelled active cells. In contrast, in sediments that received no carbon addition (showing no nitrogenase activity), no dual-labelled cells were detected. Furthermore, the naphthalene amendment enhanced the proportion of active strain CJ2 cells in the sediment relative to a glucose amendment. Field experiments performed in sediments where strain CJ2 was isolated showed nitrogenase activity in response to dosing with naphthalene. Dual-label fluorescence staining of these sediments showed a fivefold increase in active strain CJ2 in the sediments dosed with naphthalene over those dosed with deionized water. These experiments show that nitrogen fixation may play an important role in naphthalene biodegradation by strain CJ2 and contribute to its ecological success.


Extended mechanical circulatory support with a continuous-flow rotary left ventricular assist device.
This study sought to evaluate the use of a continuous-flow rotary left ventricular assist device (LVAD) as a bridge to heart transplantation. LVAD therapy is an established treatment modality for patients with advanced heart failure. Pulsatile LVADs have limitations in design precluding their use for extended support. Continuous-flow rotary LVADs represent an innovative design with potential for small size and greater reliability by simplification of the pumping mechanism. In a prospective, multicenter study, 281 patients urgently listed (United Network of Organ Sharing status 1A or 1B) for heart transplantation underwent implantation of a continuous-flow LVAD. Survival and transplantation rates were assessed at 18 months. Patients were assessed for adverse events throughout the study and for quality of life, functional status, and organ function for 6 months. Of 281 patients, 222 (79%) underwent transplantation, LVAD removal for cardiac recovery, or had ongoing LVAD support at 18-month follow-up. Actuarial survival on support was 72% (95% confidence interval: 65% to 79%) at 18 months. At 6 months, there were significant improvements in functional status and 6-min walk test (from 0% to 83% of patients in New York Heart Association functional class I or II and from 13% to 89% of patients completing a 6-min walk test) and in quality of life (mean values improved 41% with Minnesota Living With Heart Failure and 75% with Kansas City Cardiomyopathy questionnaires). Major adverse events included bleeding, stroke, right heart failure, and percutaneous lead infection. Pump thrombosis occurred in 4 patients. A continuous-flow LVAD provides effective hemodynamic support for at least 18 months in patients awaiting transplantation, with improved functional status and quality of life. (Thoratec HeartMate II Left Ventricular Assist System [LVAS] for Bridge to Cardiac Transplantation; NCT00121472).