An Evaluation of Critical Factors for the Cost-Effectiveness of Real-Time Computer-Aided Detection: Sensitivity and Threshold Analyses Using a Microsimulation Model.

BACKGROUND & AIMS: The use of computer-aided detection (CAD) increases the adenoma detection rates (ADRs) during colorectal cancer (CRC) screening/surveillance. This study aimed to evaluate the requirements for CAD to be cost-effective and the impact of CAD on adenoma detection by endoscopists with different ADRs. METHODS: We developed a semi-Markov microsimulation model to compare the effectiveness of traditional colonoscopy (mean ADR, 26%) to colonoscopy with CAD (mean ADR, 37%). CAD was modeled as having a $75 per-procedure cost. Extensive 1-way sensitivity and threshold analysis were performed to vary cost and ADR of CAD. Multiple scenarios evaluated the potential effect of CAD on endoscopists' ADRs. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay threshold of $100,000/quality-adjusted life year. RESULTS: When modeling CAD improved ADR for all endoscopists, the CAD cohort had 79 and 34 fewer lifetime CRC cases and deaths, respectively, per 10,000 persons. This scenario was dominant with a cost savings of $143 and incremental effectiveness of 0.01 quality-adjusted life years. Threshold analysis demonstrated that CAD would be cost-effective up to an additional cost of $579 per colonoscopy, or if it increases ADR from 26% to at least 30%. CAD reduced CRC incidence and mortality when limited to improving ADRs for low-ADR endoscopists (ADR <25%), with 67 fewer CRC cases and 28 CRC deaths per 10,000 persons compared with traditional colonoscopy. CONCLUSIONS: As CAD is implemented clinically, it needs to improve mean ADR from 26% to at least 30% or cost less than $579 per colonoscopy to be cost-effective when compared with traditional colonoscopy. Further studies are needed to understand the impact of CAD when used in community practice.

The Clinical Impact and Cost-Effectiveness of Surveillance of Incidentally Detected Gastric Intestinal Metaplasia: A Microsimulation Analysis.

BACKGROUND & AIMS: Gastric intestinal metaplasia (GIM) is associated with a higher risk of noncardia intestinal gastric adenocarcinoma (GA). The aim of this study was to estimate lifetime benefits, complications, and cost-effectiveness of GIM surveillance using esophagogastroduodenoscopy (EGD). METHODS: We developed a semi-Markov microsimulation model of patients with incidentally detected GIM, to compare the effectiveness of EGD surveillance with no surveillance at 10-year, 5-year, 3-year, 2-year, and 1-year intervals. We modeled a simulated cohort of 1,000,000 US individuals aged 50 with incidental GIM. Outcome measures were lifetime GA incidence, mortality, number of EGDs, complications, undiscounted life-years gained, and incremental cost-effectiveness ratio with a willingness-to-pay threshold of $100,000/quality-adjusted life-year (QALY). RESULTS: In the absence of surveillance, the model simulated 32.0 lifetime GA cases and 23.0 lifetime GA deaths per 1000 individuals with GIM, respectively. Among surveilled individuals, simulated lifetime GA incidence (per 1000) decreased with shorter surveillance intervals (10-year to 1-year, 11.2-6.1) as did GA mortality (7.4-3.6). Compared with no surveillance, all modeled surveillance intervals yielded greater life expectancy (87-190 undiscounted life-years gained per 1000); 5-year surveillance provided the greatest number of life-years gained per EGD performed and was the cost-effective strategy ($40,706/QALY). In individuals with risk factors of family history of GA or anatomically extensive, incomplete-type GIM intensified 3-year surveillance was cost-effective (incremental cost-effectiveness ratio $28,156/QALY and $87,020/QALY, respectively). CONCLUSIONS: Using microsimulation modeling, surveillance of incidentally detected GIM every 5 years is associated with reduced GA incidence/mortality and is cost-effective from a health care sector perspective. Real-world studies evaluating the impact of GIM surveillance on GA incidence and mortality in the United States are needed.

Fungi and bacteria in the beds of rural and urban infants correlate with later risk of atopic diseases.

INTRODUCTION: Rural children have a lower risk of asthma and atopic diseases than urban children. However, whether indoor microbiota in non-farming rural homes provides protection is unclear. METHODS: Here, we examine if microbes in the beds of rural and urban infants are associated with later development of atopic diseases. We studied fungi and bacteria in the beds of 6-month-old infants (n = 514) in association with the risk of asthma, allergic rhinitis, eczema and aeroallergen sensitization at 6 years of age in the prospective COPSAC2010 cohort. RESULTS: Both fungal and bacterial diversity were lower in the beds of children, who later developed allergic rhinitis (-0.22 [-0.43,-0.01], padj = .04 and -.24 [-0.42,-0.05], padj = .01 respectively) and lower bacterial richness was discovered in beds of children later developing asthma (-41.34 [-76.95,-5.73], padj = .02) or allergic rhinitis (-45.65 [-81.19,-10.10], padj = .01). Interestingly, higher fungal diversity and richness were discovered in the beds of children developing eczema (0.23 [0.02,0.43], padj = .03 and 29.21 [1.59,56.83], padj = .04 respectively). We defined a limited set of fungal and bacterial genera that predicted rural/urban environment. Some rural-associated bacterial genera such as Romboutsia and Bacillus and fungal genera Spegazzinia and Physcia were also associated with reduced risk of diseases, including eczema. These fungal and bacterial fingerprints predicting the living environment were associated with asthma and allergic rhinitis, but not eczema, with rural compositions being protective. The bed dust bacteria mediated 27% of the protective association of a rural living environment for allergic rhinitis (p = .04). CONCLUSIONS: Bed dust microbes can be differentially associated with airway- and skin-related diseases. The differing bed dust microbiota between rural and urban infants may influence their later risk of asthma and allergic rhinitis.

Quantum Contextuality Provides Communication Complexity Advantage.

Despite the conceptual importance of contextuality in quantum mechanics, there is a hitherto limited number of applications requiring contextuality but not entanglement. Here, we show that for any quantum state and observables of sufficiently small dimensions producing contextuality, there exists a communication task with quantum advantage. Conversely, any quantum advantage in this task admits a proof of contextuality whenever an additional condition holds. We further show that given any set of observables allowing for quantum state-independent contextuality, there exists a class of communication tasks wherein the difference between classical and quantum communication complexities increases as the number of inputs grows. Finally, we show how to convert each of these communication tasks into a semi-device-independent protocol for quantum key distribution.

Identification and molecular characterization of two recurrent missense mutations in the RS1 gene in two families with X-linked retinoschisis from North India.

X-linked retinoschisis (XLR) is a rare medical condition that involves in the splitting of neurosensory layers and the impairment of vision in the retina. In majority of the XLR cases, pathogenic variants in Retinoschisin 1 (RS1) gene have been implicated in males with an early age of onset during early childhood. In the present study, we have recruited two North Indian families having multiple affected male members, who were diagnosed with XLR. The entire protein-coding region of RS1 was screened by PCR-Sanger sequencing and two recurrent pathogenic variants (p.I81N and p.R102Q) were unraveled. The in vitro study of these variants demonstrated the aggregation of mutant RS1 within the endoplasmic reticulum. Furthermore, mutant forms of this protein showed significant intracellular retention, which was evident by the absence of retinoschisin protein fractions in the extracellular media. These inferences were also supported by extensive bioinformatics analysis of the mutants, which showed dramatic conformational changes in the local structure of retinoschisin. Thus, our study suggests that the identified pathogenic variants interfere with proper protein folding, leading to anomalous structural changes ultimately resulting in intracellular retention of retinoschisin within the retina.

Disulfiram Is Effective against Drug-Resistant Mycobacterium abscessus in a Zebrafish Embryo Infection Model.

Mycobacterium abscessus is an emerging nontuberculous mycobacterium (NTM) pathogen infecting susceptible people with cystic fibrosis (CF) and non-CF bronchiectasis. Here, we demonstrated the activity of an FDA-approved drug, disulfiram, against drug-susceptible and drug-resistant M. abscessus strains utilizing in vitro and intracellular macrophage assays and a zebrafish embryo infection model. These data demonstrate effective antimicrobial activity of disulfiram against M. abscessus infection in vivo and strongly support further study of disulfiram in human NTM infections.

Simplified AIT for allergy to several tree pollens-Arguments from the immune outcome analyses following treatment with SQ tree SLIT-tablet.

BACKGROUND: The SQ tree SLIT-tablet (containing birch extract) proved clinically significant effects during the pollen season for birch as well as alder/hazel. Immune outcomes of this treatment for allergens from multiple birch homologous trees need further investigation. We hypothesize that birch pollen extract AIT modulates a highly cross-reactive immune response and that this may be the basis for the observed clinical cross-protection. METHODS: Blood samples were collected from 397 birch allergic patients during SQ tree SLIT-tablet or placebo treatment (1:1) for up to 40 weeks. Serum IgE and IgG4 specific to birch, and birch homologous tree pollens from alder, hazel, hornbeam, beech and chestnut were measured by ImmunoCAP. IgE-Blocking Factor (IgE-BF) for alder, birch and hazel during treatment was measured by Advia Centaur and blocking effects for birch and all these birch homologous tree pollens were further investigated by basophil activation (BAT). Antibody readouts were investigated in patient subsets. T-cell responses (proliferation) to allergen extracts and peptide pools (group 1 allergens) were investigated in T-cell lines from 29 untreated birch pollen-allergic individuals. RESULTS: Significant Pearson correlations between serum IgE towards birch, alder, hazel, hornbeam and beech were observed (r-values > .86). T-cell reactivity was observed throughout the birch homologous group. Almost identical kinetics for changes in IgE towards birch, alder and hazel were observed during treatment and similar species-specific changes were seen for serum-IgG4 . IgG4 reactivity towards birch and alder, hazel, hornbeam and beech correlated significantly at end-of-treatment (r-values > .72). Treatment resulted in similar IgE-BF kinetics for alder, birch, and hazel and blocking of BAT for multiple trees in most actively treated patients investigated. CONCLUSIONS: Systematic analyses of T-cell and antibody cross-reactivities before and during birch pollen extract AIT provide the immunological basis for the observed clinical effect of SQ tree SLIT-tablet treatment of tree pollen allergy induced by multiple trees in the birch homologous group.

Dual slot-mode NOEM phase shifter.

Photonic system component counts are increasing rapidly, particularly in CMOS-compatible silicon photonics processes. Large numbers of cascaded active photonic devices are difficult to implement when accounting for constraints on area, power dissipation, and response time. Plasma dispersion and the thermo-optic effect, both available in CMOS-compatible silicon processes, address a subset of these criteria. With the addition of a few back-end-of-line etch processing steps, silicon photonics platforms can support nano-opto-electro-mechanical (NOEM) phase shifters. Realizing NOEM phase shifters that operate at CMOS-compatible voltages (≤ 1.2 V) and with low insertion loss remains a challenge. Here, we introduce a novel NOEM phase shifter fabricated alongside 90 nanometer transistors that imparts 5.63 radians phase shift at 1.08 volts bias over an actuation length of 25µm with an insertion loss of less than 0.04 dB and 3 dB bandwidth of 0.26 MHz.

Differential Infrared Pyrometry for Determination of Microkelvin Temperature Variations.

Precise measurement of temperature is important in studies of chemical and biological systems as reaction kinetics are almost universally sensitive to temperature. However, the use of conventional temperature probes can introduce an exogenous temperature disturbance resulting in measurement artifacts. Infrared pyrometry is a noninvasive technique for temperature measurement, however, the challenge for current infrared pyrometry is low sensitivity to small temperature variations, which in many cases precludes determination of key diagnostic information. Here, we report a sensitive differential infrared pyrometer based on spatial modulation using a resonant oscillating mirror, which enables a sensitivity to temperature variations on the microkelvin scale. The instrument is employed to monitor minuscule heat evolution in an acid-base reaction and the decomposition of H2O2 by bovine liver catalase. The instrument holds great promise for monitoring the dynamics of heat evolution in a range of chemical and biological systems in a completely noninvasive manner.

Semi-Supervised Recurrent Neural Network for Adverse Drug Reaction mention extraction.

BACKGROUND: Social media is a useful platform to share health-related information due to its vast reach. This makes it a good candidate for public-health monitoring tasks, specifically for pharmacovigilance. We study the problem of extraction of Adverse-Drug-Reaction (ADR) mentions from social media, particularly from Twitter. Medical information extraction from social media is challenging, mainly due to short and highly informal nature of text, as compared to more technical and formal medical reports. METHODS: Current methods in ADR mention extraction rely on supervised learning methods, which suffer from labeled data scarcity problem. The state-of-the-art method uses deep neural networks, specifically a class of Recurrent Neural Network (RNN) which is Long-Short-Term-Memory network (LSTM). Deep neural networks, due to their large number of free parameters rely heavily on large annotated corpora for learning the end task. But in the real-world, it is hard to get large labeled data, mainly due to the heavy cost associated with the manual annotation. RESULTS: To this end, we propose a novel semi-supervised learning based RNN model, which can leverage unlabeled data also present in abundance on social media. Through experiments we demonstrate the effectiveness of our method, achieving state-of-the-art performance in ADR mention extraction. CONCLUSION: In this study, we tackle the problem of labeled data scarcity for Adverse Drug Reaction mention extraction from social media and propose a novel semi-supervised learning based method which can leverage large unlabeled corpus available in abundance on the web. Through empirical study, we demonstrate that our proposed method outperforms fully supervised learning based baseline which relies on large manually annotated corpus for a good performance.

Bacterial subversion of cAMP signalling inhibits cathelicidin expression, which is required for innate resistance to Mycobacterium tuberculosis.

Antimicrobial peptides such as cathelicidins are important components of innate immune defence against inhaled microorganisms, and have shown antimicrobial activity against Mycobacterium tuberculosis in in vitro models. Despite this, little is known about the regulation and expression of cathelicidin during tuberculosis in vivo. We sought to determine whether the cathelicidin-related antimicrobial peptide gene (Cramp), the murine functional homologue of the human cathelicidin gene (CAMP or LL-37), is required for regulation of protective immunity during M. tuberculosis infection in vivo. We used Cramp-/- mice in a validated model of pulmonary tuberculosis, and conducted cell-based assays with macrophages from these mice. We evaluated the in vivo susceptibility of Cramp-/- mice to infection, and also dissected various pro-inflammatory immune responses against M. tuberculosis. We observed increased susceptibility of Cramp-/- mice to M. tuberculosis as compared with wild-type mice. Macrophages from Cramp-/- mice were unable to control M. tuberculosis growth in an in vitro infection model, were deficient in intracellular calcium influx, and were defective in stimulating T cells. Additionally, CD4+ and CD8+ T cells from Cramp-/- mice produced less interferon-ß upon stimulation. Furthermore, bacterial-derived cAMP modulated cathelicidin expression in macrophages. Our results demonstrate that cathelicidin is required for innate resistance to M. tuberculosis in a relevant animal model and is a key mediator in regulation of the levels of pro-inflammatory cytokines by calcium and cyclic nucleotides. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A comparison of phonatory outcome between trans-oral CO2 Laser cordectomy and radiotherapy in T1 glottic cancer.

PURPOSE: This study aimed at comparing phonatory outcomes between Trans-oral Laser Surgery and Radiotherapy in T1 glottic cancer. INTRODUCTION: Early glottic carcinoma, i.e. T1 stage, can be treated using trans-oral surgery, radiotherapy, or partial open surgery. Trans-oral laser (TOL) surgical techniques and Radiotherapy (RT) have undergone significant advancement in the past few years leading to a decrease in open procedures. Various studies have been published comparing voice quality after TOL surgery and RT. There are few works which consider patients' opinions, i.e. subjective parameters regarding functional voice quality post treatment. This study uses both subjective and objective parameters to evaluate phonatory outcome of both treatment options. METHODS: Phonatory outcomes were measured in patients who underwent RT and CO2 Laser excision for early laryngeal cancer. VHI, GRBAS and MDVP were used to measure the vocal outcome of treatment modality after 1 year of cancer-free survival. A comparison was then made between the outcomes in the two groups. RESULTS: Superior vocal outcomes in G, R and S criteria of the GRBAS scale, a better VHI index, and better jitter, shimmer and NHR were found in patients who underwent CO2 laser excision as compared to patients who underwent RT. Other parameters were comparable between the two groups. CONCLUSIONS: TOL surgery provides excellent vocal outcome as compared to RT in management of early glottic cancer and should be considered as the first line of management for the same.

Suppressor Cell-Depleting Immunotherapy With Denileukin Diftitox is an Effective Host-Directed Therapy for Tuberculosis.

Host-directed therapies that augment host immune effector mechanisms may serve as important adjunctive therapies for tuberculosis treatment. We evaluated the activity of denileukin diftitox in an acute mouse model of tuberculosis (TB) infection and analyzed the cellular composition and bacterial burden in lungs and spleens. These in vivo studies show that denileukin diftitox potentiates standard TB treatment in the mouse model, an effect which may be due to depletion of T-regulatory and myeloid-derived suppressor cells during TB infection. Our results indicate that denileukin diftitox and other suppressor cell-depleting therapies may be useful adjunctive, host-directed therapies for TB.

S9A Serine Protease Engender Antigenic Gluten Catabolic Competence to the Human Gut Microbe.

The human gut microbiome has a significant role in host physiology; however its role in gluten catabolism is debatable. Present study explores the role of human gut microbes in gluten catabolism and a native human gut microbe Cellulomonas sp. HM71 was identified. SSU rDNA analysis has described human gut microbiome structure and also confirmed the permanent residentship of Cellulomonas sp. HM71. Catabolic potential of Cellulomonas sp. HM71 to cleave antigenic gluten peptides indicates presence of candidate gene encoding biocatalytic machinery. Genome analysis has identified the presence of gene encoding S9A serine protease family-prolyl endopeptidase, with Ser591, Asp664 and His685 signature residues. Cellulomonas sp. HM71 prolyl endopeptidase activity was found optimal at pH 7.0 and 37 °C with a KM of 35.53 µmol and specifically cleaves at proline residue. Current study describes the gluten catabolism potential of Cellulomonas sp. HM71 depicting possible role of human gut microbes in gluten catabolism to confer resistance mechanisms for the onset of celiac diseases in populations with gluten diet.

Whole exome sequencing: Uncovering causal genetic variants for ocular diseases.

Identification of causal genetic defects for human diseases took a significant leap when the first generation DNA sequencing technologies enabled biologists extract sequence-based genetic information from living beings. However, these sequencing methods had unavoidable constraints of throughput, scalability, rapidity, and resolution. In this direction, next-generation sequencing (NGS) since the time of its advent has revolutionized the process of gene discovery for both monogenic and multifactorial genetic diseases. Among several variations of NGS, whole exome sequencing (WES) has emerged as a smart strategy that enables identification of disease causing variants present within the coding region of the human genome. The current review focuses primarily on the application of WES in identification of causal variants for ocular diseases. WES has successfully revealed pathogenic variants in a variety of ocular diseases such as retinal degenerations, refractive errors, lens diseases, corneal dystrophies, and developmental ocular defects. It has demonstrated immense potential for molecular diagnosis of genetic ocular diseases. WES has been extensively used in Mendelian and complex cases, familial and sporadic cases, simplex and multiplex cases, and syndromic and non-syndromic cases of ocular diseases. Although many such ocular diseases have been investigated using WES, reports indicate that it has been employed overwhelmingly for heterogeneous retinal degenerations. WES, within a short period of time, has proved to be a cost-effective and promising approach for understanding the genetic basis of ocular diseases.

Direct Bandgap Light Emission from Strained Germanium Nanowires Coupled with High-Q Nanophotonic Cavities.

A silicon-compatible light source is the final missing piece for completing high-speed, low-power on-chip optical interconnects. In this paper, we present a germanium nanowire light emitter that encompasses all the aspects of potential low-threshold lasers: highly strained germanium gain medium, strain-induced pseudoheterostructure, and high-Q nanophotonic cavity. Our nanowire structure presents greatly enhanced photoluminescence into cavity modes with measured quality factors of up to 2000. By varying the dimensions of the germanium nanowire, we tune the emission wavelength over more than 400 nm with a single lithography step. We find reduced optical loss in optical cavities formed with germanium under high (>2.3%) tensile strain. Our compact, high-strain cavities open up new possibilities for low-threshold germanium-based lasers for on-chip optical interconnects.

Wet-Chemically Synthesized Colloidal Semiconductor Nanostructures as Optical Gain Media.

An overview on the development of wet-chemically synthesized semiconductor nanostructures as optical gain materials is presented in this Review, beginning with the first demonstration of amplified spontaneous emission in zero-dimensional quantum dots and evolving to more sophisticated heterostructures such as one-dimensional core-seeded nanorods, branched core-seeded tetrapods and two-dimensional nanoplatelets. The advantages and challenges of utilizing strongly quantum-confined colloidal semiconductor materials as gain media are discussed, and a concerted effort is made to elaborate on how the progression towards more structurally complex architectures has allowed for dramatic improvements in performance and stability over the archetypal quantum dot.

Acute Antero-Inferior Wall Ischaemia with Acute Ischaemic Stroke Caused by Oral Ingestion of Cannabis in a Young Male.

Cannabis is a frequently used illicit recreational drug that is known to be associated with a variety of psychopharmacological effects. Negative somatic effects such as myocardial infarction and stroke have been reported, though, less frequently. Most of the literature available has focused on the complications due to smoked forms of cannabis (ganja and charas). Here we report a case of acute myocardial ischaemia with acute ischaemic stroke developing after oral ingestion of 'Bhang', a preparation of cannabis.

Verapamil increases the bactericidal activity of bedaquiline against Mycobacterium tuberculosis in a mouse model.

Bedaquiline is a newly approved drug for the treatment of multidrug-resistant tuberculosis, but there are concerns about its safety in humans. We found that the coadministration of verapamil with subinhibitory doses of bedaquiline gave the same bactericidal effect in mice as did the full human bioequivalent bedaquiline dosing. Adding verapamil to bedaquiline monotherapy also protected against the development of resistant mutants in vivo. The adjunctive use of verapamil may permit use of lower doses of bedaquiline to be used and thereby reduce its dose-related toxicities in tuberculosis patients.

Ge microdisk with lithographically-tunable strain using CMOS-compatible process.

We present germanium microdisk optical resonators under a large biaxial tensile strain using a CMOS-compatible fabrication process. Biaxial tensile strain of ~0.7% is achieved by means of a stress concentration technique that allows the strain level to be customized by carefully selecting certain lithographic dimensions. The partial strain relaxation at the edges of a patterned germanium microdisk is compensated by depositing compressively stressed silicon nitride layer. Two-dimensional Raman spectroscopy measurements along with finite-element method simulations confirm a relatively homogeneous strain distribution within the final microdisk structure. Photoluminescence results show clear optical resonances due to whispering gallery modes which are in good agreement with finite-difference time-domain optical simulations. Our bandgap-customizable microdisks present a new route towards an efficient germanium light source for on-chip optical interconnects.