Human-machine collaboration for improving semiconductor process development.

One of the bottlenecks to building semiconductor chips is the increasing cost required to develop chemical plasma processes that form the transistors and memory storage cells1,2. These processes are still developed manually using highly trained engineers searching for a combination of tool parameters that produces an acceptable result on the silicon wafer3. The challenge for computer algorithms is the availability of limited experimental data owing to the high cost of acquisition, making it difficult to form a predictive model with accuracy to the atomic scale. Here we study Bayesian optimization algorithms to investigate how artificial intelligence (AI) might decrease the cost of developing complex semiconductor chip processes. In particular, we create a controlled virtual process game to systematically benchmark the performance of humans and computers for the design of a semiconductor fabrication process. We find that human engineers excel in the early stages of development, whereas the algorithms are far more cost-efficient near the tight tolerances of the target. Furthermore, we show that a strategy using both human designers with high expertise and algorithms in a human first-computer last strategy can reduce the cost-to-target by half compared with only human designers. Finally, we highlight cultural challenges in partnering humans with computers that need to be addressed when introducing artificial intelligence in developing semiconductor processes.

Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico.

BACKGROUND: NVX-CoV2373 is an adjuvanted, recombinant spike protein nanoparticle vaccine that was shown to have clinical efficacy for the prevention of coronavirus disease 2019 (Covid-19) in phase 2b-3 trials in the United Kingdom and South Africa, but its efficacy had not yet been tested in North America. METHODS: We conducted a phase 3, randomized, observer-blinded, placebo-controlled trial in the United States and Mexico during the first half of 2021 to evaluate the efficacy and safety of NVX-CoV2373 in adults (≥18 years of age) who had not had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Participants were randomly assigned in a 2:1 ratio to receive two doses of NVX-CoV2373 or placebo 21 days apart. The primary objective was to determine vaccine efficacy against reverse-transcriptase-polymerase-chain-reaction-confirmed Covid-19 occurring at least 7 days after the second dose. Vaccine efficacy against moderate-to-severe disease and against different variants was also assessed. RESULTS: Of the 29,949 participants who underwent randomization between December 27, 2020, and February 18, 2021, a total of 29,582 (median age, 47 years; 12.6% ≥65 years of age) received at least one dose: 19,714 received vaccine and 9868 placebo. Over a period of 3 months, 77 cases of Covid-19 were noted - 14 among vaccine recipients and 63 among placebo recipients (vaccine efficacy, 90.4%; 95% confidence interval [CI], 82.9 to 94.6; P<0.001). Ten moderate and 4 severe cases occurred, all in placebo recipients, yielding vaccine efficacy against moderate-to-severe disease of 100% (95% CI, 87.0 to 100). Most sequenced viral genomes (48 of 61, 79%) were variants of concern or interest - largely B.1.1.7 (alpha) (31 of the 35 genomes for variants of concern, 89%). Vaccine efficacy against any variant of concern or interest was 92.6% (95% CI, 83.6 to 96.7). Reactogenicity was mostly mild to moderate and transient but was more frequent among NVX-CoV2373 recipients than among placebo recipients and was more frequent after the second dose than after the first dose. CONCLUSIONS: NVX-CoV2373 was safe and effective for the prevention of Covid-19. Most breakthrough cases were caused by contemporary variant strains. (Funded by Novavax and others; PREVENT-19 ClinicalTrials.gov number, NCT04611802.).

Identifying dose constraints for the parotid ducts to minimize patient-reported xerostomia: Is conventional mean dose sparing of the parotid glands sufficient?

BACKGROUND AND PURPOSE: The aim of this study was to identify dose constraints for the parotid ducts that limit patient-reported xerostomia and estimate whether these constraints are achieved during conventional parotid gland sparing radiation therapy (PGS-RT). METHODS AND MATERIALS: Thirty-eight oropharyngeal squamous cell carcinoma patients were treated prospectively on trial with MRI sialography-guided parotid duct sparing radiation therapy (PDS-RT). PDS-RT explicitly minimizes dose to the parotid ducts in addition to PGS-RT. Parotid duct dose constraints were identified that distinguished patients reporting high and low rates of xerostomia. Atlas-based parotid duct contours were generated on a retrospective cohort of similar patients where the parotid ducts were not contoured nor explicitly spared to estimate the dose received by the parotid ducts during PGS-RT. RESULTS: Patients whose intraglandular parotid ducts or total parotid ducts were planned for a mean dose < 14 Gy and < 12 Gy, respectively, reported significantly (p < 0.01) lower rates of xerostomia at 6 and 12 months post-RT. Patients receiving PDS-RT had average total and intraglandular duct doses of 11.6  and 13.6 Gy, respectively, compared to an estimated 23.8  and 22.1 Gy, for those receiving PGS-RT (p < 0.01). Only 6% (6/108) and 20% (22/108) of patients receiving PGS-RT were estimated to meet the dose constraints for the total ducts and intraglandular ducts, respectively. CONCLUSION: Parotid duct dose thresholds exist that appear to distinguish patients with and without xerostomia. The identified dose thresholds are frequently not met in PGS-RT plans. In addition to reducing the dose to the parotid gland(s), parotid duct sparing may also further reduce xerostomia.

Gastrointestinal neuroimmune disruption in a mouse model of Gulf War illness.

Gulf War illness (GWI) is a chronic multisymptom disorder that is prominent in Gulf War veterans. Major unexplained symptoms of GWI include functional gastrointestinal disorders and undiagnosed illnesses, including neurologic disorders. Exposure to the antinerve gas drug pyridostigmine bromide (PB) is linked to the development of GWI, but the exact mechanisms remain unclear. Here, we tested the hypothesis that PB alters gut function by disrupting the neural and immune systems of the intestine. We exposed male and female mice to physiologically comparable amounts of PB that match the dose, route, and time frame of exposure experienced by Gulf War veterans and assessed the acute and chronic impacts on gastrointestinal functions, the functional architecture of the enteric nervous system, and immune responses in the gut and brain. Exposure to PB drove acute alterations to colonic motility and structure in both male and female mice that transitioned to chronic changes in gut functions. PB drove acute alterations to enteric neural and glial activity, glial reactivity, and neuron survival with glial reactivity persisting into the chronic phase in male mice. Despite having no effect on colonic permeability, exposure to PB caused major shifts in the expression of proinflammatory cytokines and chemokines in the colon and brain that suggest immunosuppressive effects. Interestingly, immune disruption was still evident in the colon and brain in female animals at 1 mo following exposure to PB. Together, our results show that the paradigm of PB exposure experienced by veterans of the Persian Gulf War contributes to long-lasting pathophysiology by driving enteric neuroinflammation, promoting immunosuppression, and altering functional anatomy of the colon in a sex-dependent manner.-Hernandez, S., Fried, D. E., Grubisic, V., McClain, J. L., Gulbransen, B. D. Gastrointestinal neuroimmune disruption in a mouse model of Gulf War illness.

NTPDase1 and -2 are expressed by distinct cellular compartments in the mouse colon and differentially impact colonic physiology and function after DSS colitis.

ATP is both an important mediator of physiological gut functions such as motility and epithelial function, and a key danger signal that mediates cell death and tissue damage. The actions of extracellular ATP are regulated through the catalytic functions extracellular nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), -2, -3, and -8, which ultimately generate nucleosides. Ectonucleotidases have distinct cellular associations, but the specific locations and functional roles of individual NTPDases in the intestine are still poorly understood. Here, we tested the hypothesis that differential and cell-selective regulation of purine hydrolysis by NTPDase1 and -2 plays important roles in gut physiology and disease. We studied Entpd1 and Entpd2 null mice in health and following colitis driven by 2% dextran sulfate sodium (DSS) administration using functional readouts of gut motility, epithelial barrier function, and neuromuscular communication. NTPDase1 is expressed by immune cells, and the ablation of Entpd1 altered glial numbers in the myenteric plexus. NTPDase2 is expressed by enteric glia, and the ablation of Entpd2 altered myenteric neuron numbers. Mice lacking either NTPDase1 or -2 exhibited decreased inhibitory neuromuscular transmission and altered components of inhibitory junction potentials. Ablation of Entpd2 increased gut permeability following inflammation. In conclusion, the location- and context-dependent extracellular nucleotide phosphohydrolysis by NTPDase1 and -2 substantially impacts gut function in health and disease.NEW & NOTEWORTHY Purines are important mediators of gastrointestinal physiology and pathophysiology. Nucleoside triphosphate diphosphohydrolases (NTPDases) regulate extracellular purines, but the roles of specific NTPDases in gut functions are poorly understood. Here, we used Entpd1- and Entpd2-deficient mice to show that the differential and cell-selective regulation of purine hydrolysis by NTPDase1 and -2 plays important roles in barrier function, gut motility, and neuromuscular communication in health and disease.

Effect of internal mammary vessels radiation dose on outcomes of free flap breast reconstruction.

To assess the impact of internal mammary (IM) vessels radiation dose on autologous free-flap based breast reconstruction outcomes. We retrospectively evaluated the medical records of breast cancer patients who underwent mastectomy and free-flap breast reconstruction after postoperative radiation therapy (RT) to the breast/chest wall with (n = 9) or without (n = 11) electively including the IM lymph nodes. Twenty patients were included. Median age at diagnosis was 50 years (range, 33-63). The median time interval between the start of RT and reconstructive surgery was 16 months (range, 6-45). The maximal IM vessels dose was not associated with the risk of all complications (P = 0.44) or fat necrosis (P = 0.31). The mean IM vessels dose was not significant for the risk of all complications (P = 0.13) but was significant for fat necrosis (P = 0.04). A high mean IM vessels dose was related to the occurrence of fat necrosis.

Cholinergic activation of enteric glia is a physiological mechanism that contributes to the regulation of gastrointestinal motility.

The reflexive activities of the gastrointestinal tract are regulated, in part, by precise interactions between neurons and glia in the enteric nervous system (ENS). Intraganglionic enteric glia are a unique type of peripheral glia that surround enteric neurons and regulate neuronal function, activity, and survival. Enteric glia express numerous neurotransmitter receptors that allow them to sense neuronal activity, but it is not clear if enteric glia monitor acetylcholine (ACh), the primary excitatory neurotransmitter in the ENS. Here, we tested the hypothesis that enteric glia detect ACh and that glial activation by ACh contributes to the physiological regulation of gut functions. Our results show that myenteric enteric glia express both the M3 and M5 subtypes of muscarinic receptors (MRs) and that muscarine drives intracellular calcium (Ca2+) signaling predominantly through M3R activation. To elucidate the functional effects of activation of glial M3Rs, we used GFAP::hM3Dq mice that express a modified human M3R (hM3Dq) exclusively on glial fibrillary acidic protein (GFAP) positive glia to directly activate glial hM3Dqs using clozapine- N-oxide. Using spatiotemporal mapping analysis, we found that the activation of glial hM3Dq receptors enhances motility reflexes ex vivo. Continuous stimulation of hM3Dq receptors in vivo, drove changes in gastrointestinal motility without affecting neuronal survival in the ENS and glial muscarinic receptor activation did not alter neuron survival in vitro. Our results provide the first evidence that GFAP intraganglionic enteric glia express functional muscarinic receptors and suggest that the activation of glial muscarinic receptors contributes to the physiological regulation of functions. NEW & NOTEWORTHY Enteric glia are emerging as novel regulators of enteric reflex circuits, but little is still known regarding the effects of specific transmitter pathways on glia and the resulting consequences on enteric reflexes. Here, we provide the first evidence that enteric glia monitor acetylcholine in the enteric nervous system and that glial activation by acetylcholine is a physiological mechanism that contributes to the functional regulation of intestinal reflexes.

SMN deficiency disrupts gastrointestinal and enteric nervous system function in mice.

The 2007 Consensus Statement for Standard of Care in Spinal Muscular Atrophy (SMA) notes that patients suffer from gastroesophageal reflux, constipation and delayed gastric emptying. We used two mouse models of SMA to determine whether functional GI complications are a direct consequence of or are secondary to survival motor neuron (Smn) deficiency. Our results show that despite normal activity levels and food and water intake, Smn deficiency caused constipation, delayed gastric emptying, slow intestinal transit and reduced colonic motility without gross anatomical or histopathological abnormalities. These changes indicate alterations to the intrinsic neural control of gut functions mediated by the enteric nervous system (ENS). Indeed, Smn deficiency led to disrupted ENS signaling to the smooth muscle of the colon but did not cause enteric neuron loss. High-frequency electrical field stimulation (EFS) of distal colon segments produced up to a 10-fold greater contractile response in Smn deficient tissues. EFS responses were not corrected by the addition of a neuronal nitric oxide synthase inhibitor indicating that the increased contractility was due to hyperexcitability and not disinhibition of the circuitry. The GI symptoms observed in mice are similar to those reported in SMA patients. Together these data suggest that ENS cells are susceptible to Smn deficiency and may underlie the patient GI symptoms.

Ammonia modifies enteric neuromuscular transmission through glial γ-aminobutyric acid signaling.

Impaired gut motility may contribute, at least in part, to the development of systemic hyperammonemia and systemic neurological disorders in inherited metabolic disorders, or in severe liver and renal disease. It is not known whether enteric neurotransmission regulates intestinal luminal and hence systemic ammonia levels by induced changes in motility. Here, we propose and test the hypothesis that ammonia acts through specific enteric circuits to influence gut motility. We tested our hypothesis by recording the effects of ammonia on neuromuscular transmission in tissue samples from mice, pigs, and humans and investigated specific mechanisms using novel mutant mice, selective drugs, cellular imaging, and enzyme-linked immunosorbent assays. Exogenous ammonia increased neurogenic contractions and decreased neurogenic relaxations in segments of mouse, pig, and human intestine. Enteric glial cells responded to ammonia with intracellular Ca2+ responses. Inhibition of glutamine synthetase and the deletion of glial connexin-43 channels in hGFAP::CreERT2+/-/connexin43f/f mice potentiated the effects of ammonia on neuromuscular transmission. The effects of ammonia on neuromuscular transmission were blocked by GABAA receptor antagonists, and ammonia drove substantive GABA release as did the selective pharmacological activation of enteric glia in GFAP::hM3Dq transgenic mice. We propose a novel mechanism whereby local ammonia is operational through GABAergic glial signaling to influence enteric neuromuscular circuits that regulate intestinal motility. Therapeutic manipulation of these mechanisms may benefit a number of neurological, hepatic, and renal disorders manifesting hyperammonemia.NEW & NOTEWORTHY We propose that local circuits in the enteric nervous system sense and regulate intestinal ammonia. We show that ammonia modifies enteric neuromuscular transmission to increase motility in human, pig, and mouse intestine model systems. The mechanisms underlying the effects of ammonia on enteric neurotransmission include GABAergic pathways that are regulated by enteric glial cells. Our new data suggest that myenteric glial cells sense local ammonia and directly modify neurotransmission by releasing GABA.

The value of 18F-FDG PET before and after induction chemotherapy for the early prediction of a poor pathologic response to subsequent preoperative chemoradiotherapy in oesophageal adenocarcinoma.

PURPOSE: The purpose of our study was to determine the value of 18F-FDG PET before and after induction chemotherapy in patients with oesophageal adenocarcinoma for the early prediction of a poor pathologic response to subsequent preoperative chemoradiotherapy (CRT). METHODS: In 70 consecutive patients receiving a three-step treatment strategy of induction chemotherapy and preoperative chemoradiotherapy for oesophageal adenocarcinoma, 18F-FDG PET scans were performed before and after induction chemotherapy (before preoperative CRT). SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were determined at these two time points. The predictive potential of (the change in) these parameters for a poor pathologic response, progression-free survival (PFS) and overall survival (OS) was assessed. RESULTS: A poor pathologic response after induction chemotherapy and preoperative CRT was found in 27 patients (39 %). Patients with a poor pathologic response experienced less of a reduction in TLG after induction chemotherapy (p < 0.01). The change in TLG was predictive for a poor pathologic response at a threshold of -26 % (sensitivity 67 %, specificity 84 %, accuracy 77 %, PPV 72 %, NPV 80 %), yielding an area-under-the-curve of 0.74 in ROC analysis. Also, patients with a decrease in TLG lower than 26 % had a significantly worse PFS (p = 0.02), but not OS (p = 0.18). CONCLUSIONS: 18F-FDG PET appears useful to predict a poor pathologic response as well as PFS early after induction chemotherapy in patients with oesophageal adenocarcinoma undergoing a three-step treatment strategy. As such, the early 18F-FDG PET response after induction chemotherapy could aid in individualizing treatment by modification or withdrawal of subsequent preoperative CRT in poor responders.

The incidence of radiation necrosis following stereotactic radiotherapy for melanoma brain metastases: the potential impact of immunotherapy.

Stereotactic radiotherapy (SRT) is the standard treatment for patients with limited number of brain metastases. In the past few years, newer immunotherapies (immune checkpoint inhibitors) have been proven to prolong survival in patients with metastatic melanoma. The safety of the combination of SRT and immunotherapy for brain metastases is unknown. We retrospectively identified patients with melanoma brain metastases treated with SRT between 2007 and 2015. Patients who did not have at least 3 months of follow-up with imaging after SRT were excluded from the analysis. Outcomes were compared between patients who were treated with or without immunotherapy. A total of 58 patients were included; of these, 29 were treated with SRT and immunotherapy. MAPK inhibitors (BRAF, MEK inhibitors) were used more often in the immunotherapy group (nine vs. two patients). There was a higher incidence of intracranial complications in patients treated with immunotherapy and SRT. Eight patients had radiation necrosis; all occurred in patients who were treated with immunotherapy. Nine patients had hemorrhage, of which seven occurred in patients who were treated with immunotherapy (P=0.08). However, patients treated with immunotherapy and SRT had a significant overall survival advantage compared with SRT without immunotherapy (15 vs. 6 months, P=0.0013). Patients treated with SRT and immunotherapy have a higher incidence/risk of intracranial complications, but a longer overall survival.

Assessment of PlanIQ Feasibility DVH for head and neck treatment planning.

INTRODUCTION: Designing a radiation plan that optimally delivers both target coverage and normal tissue sparing is challenging. There are limited tools to determine what is dosimetrically achievable and frequently the experience of the planner/physician is relied upon to make these determinations. PlanIQ software provides a tool that uses target and organ at risk (OAR) geometry to indicate the difficulty of achieving different points for organ dose-volume histograms (DVH). We hypothesized that PlanIQ Feasibility DVH may aid planners in reducing dose to OARs. METHODS AND MATERIALS: Clinically delivered head and neck treatments (clinical plan) were re-planned (re-plan) putting high emphasis on maximally sparing the contralateral parotid gland, contralateral submandibular gland, and larynx while maintaining routine clinical dosimetric objectives. The planner was blinded to the results of the clinically delivered plan as well as the Feasibility DVHs from PlanIQ. The re-plan treatments were designed using 3-arc VMAT in Raystation (RaySearch Laboratories, Sweden). The planner was then given the results from the PlanIQ Feasibility DVH analysis and developed an additional plan incorporating this information using 4-arc VMAT (IQ plan). The DVHs across the three treatment plans were compared with what was deemed "impossible" by PlanIQ's Feasibility DVH (Impossible DVH). The impossible DVH (red) is defined as the DVH generated using the minimal dose that any voxel outside the targets must receive given 100% target coverage. RESULTS: The re-plans performed blinded to PlanIQ Feasibilty DVH achieved superior sparing of aforementioned OARs compared to the clinically delivered plans and resulted in discrepancies from the impossible DVHs by an average of 200-700 cGy. Using the PlanIQ Feasibility DVH led to additionalOAR sparing compared to both the re-plans and clinical plans and reduced the discrepancies from the impossible DVHs to an average of approximately 100 cGy. The dose reduction from clinical to re-plan and re-plan to IQ plan were significantly different even when taking into account multiple hypothesis testing for both the contralateral parotid and the larynx (P < 0.004 for all comparisons). No significant differences were observed between the three plans for the contralateral parotid when considering multiple hypothesis testing. CONCLUSIONS: Clinical treatment plans and blinded re-plans were found to suboptimally spare OARs. PlanIQ could aid planners in generating treatment plans that push the limits of OAR sparing while maintaining routine clinical target coverage goals.

High-fat diet-induced obesity alters nitric oxide-mediated neuromuscular transmission and smooth muscle excitability in the mouse distal colon.

We tested the hypothesis that colonic enteric neurotransmission and smooth muscle cell (SMC) function are altered in mice fed a high-fat diet (HFD). We used wild-type (WT) mice and mice lacking the ß1-subunit of the BK channel (BKß1 (-/-)). WT mice fed a HFD had increased myenteric plexus oxidative stress, a 28% decrease in nitrergic neurons, and a 20% decrease in basal nitric oxide (NO) levels. Circular muscle inhibitory junction potentials (IJPs) were reduced in HFD WT mice. The NO synthase inhibitor nitro-l-arginine (NLA) was less effective at inhibiting relaxations in HFD compared with control diet (CD) WT mice (11 vs. 37%, P < 0.05). SMCs from HFD WT mice had depolarized membrane potentials (-47 ± 2 mV) and continuous action potential firing compared with CD WT mice (-53 ± 2 mV, P < 0.05), which showed rhythmic firing. SMCs from HFD or CD fed BKß1 (-/-) mice fired action potentials continuously. NLA depolarized membrane potential and caused continuous firing only in SMCs from CD WT mice. Sodium nitroprusside (NO donor) hyperpolarized membrane potential and changed continuous to rhythmic action potential firing in SMCs from HFD WT and BKß1 (-/-) mice. Migrating motor complexes were disrupted in colons from BKß1 (-/-) mice and HFD WT mice. BK channel α-subunit protein and ß1-subunit mRNA expression were similar in CD and HFD WT mice. We conclude that HFD-induced obesity disrupts inhibitory neuromuscular transmission, SMC excitability, and colonic motility by promoting oxidative stress, loss of nitrergic neurons, and SMC BK channel dysfunction.

Stage III Non-Small Cell Lung Cancer: Prognostic Value of FDG PET Quantitative Imaging Features Combined with Clinical Prognostic Factors.

PURPOSE: To determine whether quantitative imaging features from pretreatment positron emission tomography (PET) can enhance patient overall survival risk stratification beyond what can be achieved with conventional prognostic factors in patients with stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The institutional review board approved this retrospective chart review study and waived the requirement to obtain informed consent. The authors retrospectively identified 195 patients with stage III NSCLC treated definitively with radiation therapy between January 2008 and January 2013. All patients underwent pretreatment PET/computed tomography before treatment. Conventional PET metrics, along with histogram, shape and volume, and co-occurrence matrix features, were extracted. Linear predictors of overall survival were developed from leave-one-out cross-validation. Predictive Kaplan-Meier curves were used to compare the linear predictors with both quantitative imaging features and conventional prognostic factors to those generated with conventional prognostic factors alone. The Harrell concordance index was used to quantify the discriminatory power of the linear predictors for survival differences of at least 0, 6, 12, 18, and 24 months. Models were generated with features present in more than 50% of the cross-validation folds. RESULTS: Linear predictors of overall survival generated with both quantitative imaging features and conventional prognostic factors demonstrated improved risk stratification compared with those generated with conventional prognostic factors alone in terms of log-rank statistic (P = .18 vs P = .0001, respectively) and concordance index (0.62 vs 0.58, respectively). The use of quantitative imaging features selected during cross-validation improved the model using conventional prognostic factors alone (P = .007). Disease solidity and primary tumor energy from the co-occurrence matrix were found to be selected in all folds of cross-validation. CONCLUSION: Pretreatment PET features were associated with overall survival when adjusting for conventional prognostic factors in patients with stage III NSCLC.

Ca2+ responses in enteric glia are mediated by connexin-43 hemichannels and modulate colonic transit in mice.

BACKGROUND & AIMS: In the enteric nervous system, neurotransmitters initiate changes in calcium (Ca(2+) responses) in glia, but it is not clear how this process affects intestinal function. We investigated whether Ca(2+)-mediated responses in enteric glia are required to maintain gastrointestinal function. METHODS: We used in situ Ca(2+) imaging to monitor glial Ca(2+) responses, which were manipulated with pharmacologic agents or via glia-specific disruption of the gene encoding connexin-43 (Cx43) (hGFAP::CreER(T2+/-)/Cx43(f/f) mice). Gastrointestinal function was assessed based on pellet output, total gut transit, colonic bead expulsion, and muscle tension recordings. Proteins were localized and quantified by immunohistochemistry, immunoblot, and reverse transcription polymerase chain reaction analyses. RESULTS: Ca(2+) responses in enteric glia of mice were mediated by Cx43 hemichannels. Cx43 immunoreactivity was confined to enteric glia within the myenteric plexus of the mouse colon; the Cx43 inhibitors carbenoxolone and 43Gap26 inhibited the ability of enteric glia to propagate Ca(2+) responses. In vivo attenuation of Ca(2+) responses in the enteric glial network slowed gut transit overall and delayed colonic transit--these changes are also observed during normal aging. Altered motility with increasing age was associated with reduced glial Ca(2+)-mediated responses and changes in glial expression of Cx43 messenger RNA and protein. CONCLUSIONS: Ca(2+)-mediated responses in enteric glia regulate gastrointestinal function in mice. Altered intercellular signaling between enteric glia and neurons might contribute to motility disorders.

Efficient matrix approach to optical wave propagation and Linear Canonical Transforms.

The Fresnel diffraction integral form of optical wave propagation and the more general Linear Canonical Transforms (LCT) are cast into a matrix transformation form. Taking advantage of recent efficient matrix multiply algorithms, this approach promises an efficient computational and analytical tool that is competitive with FFT based methods but offers better behavior in terms of aliasing, transparent boundary condition, and flexibility in number of sampling points and computational window sizes of the input and output planes being independent. This flexibility makes the method significantly faster than FFT based propagators when only a single point, as in Strehl metrics, or a limited number of points, as in power-in-the-bucket metrics, are needed in the output observation plane.

Signal-to-noise ratio limitations for intensity correlation imaging.

Intensity correlation imaging (ICI) is a concept which has been considered for the task of providing images of satellites in geosynchronous orbit using ground-based equipment. This concept is based on the intensity interferometer principle first developed by Hanbury Brown and Twiss. It is the objective of this paper to establish that a sun-lit geosynchronous satellite is too faint a target object to allow intensity interferometry to be used in developing image information about it-at least not in a reasonable time and with a reasonable amount of equipment. An analytic treatment of the basic phenomena is presented. This is an analysis of one aspect of the statistics of the very high frequency random variations of a very narrow portion of the optical spectra of the incoherent (black-body like-actually reflected sunlight) radiation from the satellite, an analysis showing that the covariance of this radiation as measured by a pair of ground-based telescopes is directly proportional to the square of the magnitude of one component of the Fourier transform of the image of the satellite-the component being the one for a spatial frequency whose value is determined by the separation of the two telescopes. This analysis establishes the magnitude of the covariance. A second portion of the analysis considers shot-noise effects. It is shown that even with much less than one photodetection event (pde) per signal integration time an unbiased estimate of the covariance of the optical field's random variations can be developed. Also, a result is developed for the standard deviation to be associated with the estimated value of the covariance. From these results an expression is developed for what may be called the signal-to-noise ratio to be associated with an estimate of the covariance. This signal-to-noise ratio, it turns out, does not depend on the measurement's integration time, Δt (in seconds), or on the optical spectral bandwidth, Δν (in Hertz), utilized-so long as ΔtΔν≫1, which condition it would be hard to violate. It is estimated that for a D=3.16 m diameter satellite, with a pair of D=1.0 m diameter telescopes (which value of D probably represents an upper limit on allowable aperture diameter since the telescope aperture must be much too small to even resolve the size of the satellite) at least N=2.55×10(16) separate pairs of (one integration time, pde count) measurement values must be collected to achieve just a 10 dB signal-to-noise ratio. Working with 10 pairs of telescopes (all with the same separation), and with 10 nearly adjacent and each very narrow spectral bands extracted from the light collected by each of the telescope-so that for each measurement integration time there would be 100 pairs of measurement values available-and with an integration time as short as Δt=1 ns, it would take T=2.55×10(5) s or about 71 h to collect the data for just a single spatial frequency component of the image of the satellite. It is on this basis that it is concluded that the ICI concept does not seem likely to be able to provide a timely responsive capability for the imaging of geosynchronous satellites.

The efficacy and safety of Grafix(®) for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial.

In a randomised, controlled study, we compared the efficacy of Grafix(®) , a human viable wound matrix (hVWM) (N = 50), to standard wound care (n = 47) to heal diabetic foot ulcers (DFUs). The primary endpoint was the proportion of patients with complete wound closure by 12 weeks. Secondary endpoints included the time to wound closure, adverse events and wound closure in the crossover phase. The proportion of patients who achieved complete wound closure was significantly higher in patients who received Grafix (62%) compared with controls (21%, P = 0·0001). The median time to healing was 42 days in Grafix patients compared with 69·5 days in controls (P = 0·019). There were fewer Grafix patients with adverse events (44% versus 66%, P = 0·031) and fewer Grafix patients with wound-related infections (18% versus 36·2%, P = 0·044). Among the study subjects that healed, ulcers remained closed in 82·1% of patients (23 of 28 patients) in the Grafix group versus 70% (7 of 10 patients) in the control group (P = 0·419). Treatment with Grafix significantly improved DFU healing compared with standard wound therapy. Importantly, Grafix also reduced DFU-related complications. The results of this well-controlled study showed that Grafix is a safe and more effective therapy for treating DFUs than standard wound therapy.

Constipation and a low-fiber diet are not associated with diverticulosis.

BACKGROUND & AIMS: Asymptomatic diverticulosis is commonly attributed to constipation caused by a low-fiber diet, although evidence for this mechanism is limited. We examined the associations between constipation and low dietary fiber intake with risk of asymptomatic diverticulosis. METHODS: We performed a cross-sectional study that analyzed data from 539 individuals with diverticulosis and 1569 without (controls). Participants underwent colonoscopy and assessment of diet, physical activity, and bowel habits. Our analysis was limited to participants with no knowledge of their diverticular disease to reduce the risk of biased responses. RESULTS: Constipation was not associated with an increased risk of diverticulosis. Participants with less frequent bowel movements (<7/wk) had reduced odds of diverticulosis compared with those with regular bowel movements (7/wk) (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.40-0.80). Those reporting hard stools also had reduced odds (OR, 0.75; 95% CI, 0.55-1.02). There was no association between diverticulosis and straining (OR, 0.85; 95% CI, 0.59-1.22) or incomplete bowel movement (OR, 0.85; 95% CI, 0.61-1.20). We found no association between dietary fiber intake and diverticulosis (OR, 0.96; 95% CI, 0.71-1.30) in comparing the highest quartile with the lowest (mean intake, 25 vs 8 g/day). CONCLUSIONS: In our cross-sectional, colonoscopy-based study, neither constipation nor a low-fiber diet was associated with an increased risk of diverticulosis.