Abnormal Lung Point-of-Care Ultrasound (POCUS) in Suspected Cases of COVID-19 pneumonia with Normal Plain Chest Radiographs - A Case Series.

COVID-19 pneumonia produces a heterogeneous array of clinical, biochemical, and radiological findings. Over the last few months of global hurry to optimize a testing strategy, it has been suggested that bedside point-of-care lung ultrasound may have a diagnostic role. We present 3 patients with RT-PCR nasopharyngeal swab-confirmed COVID-19 pneumonia, who had an admission plain chest film reported to be normal by a consultant radiologist, but with significant sonographic abnormalities on bedside ultrasound performed within 24 hours of the chest radiograph. Lung ultrasound may better correlate with the oxygen requirement and overall condition of the patient than chest radiographs - a pertinent consideration given the imminent advance of the pandemic into resource-poor zones where timely access to roentgenological imaging may be sparse.

Fine-Scale Analysis of the Energy-Land-Water Nexus: Nitrate Leaching Implications of Biomass Cofiring in the Midwestern United States.

As scientists seek to better understand the linkages between energy, water, and land systems, they confront a critical question of scale for their analysis. Many studies exploring this nexus restrict themselves to a small area in order to capture fine-scale processes, whereas other studies focus on interactions between energy, water, and land over broader domains but apply coarse resolution methods. Detailed studies of a narrow domain can be misleading if the policy intervention considered is broad-based and has impacts on energy, land, and agricultural markets. Regional studies with aggregate low-resolution representations may miss critical feedbacks driven by the dynamic interactions between subsystems. This study applies a novel, gridded energy-land-water modeling system to analyze the local environmental impacts of biomass cofiring of coal power plants across the upper MISO region. We use this framework to examine the impacts of a hypothetical biomass cofiring technology mandate of coal-fired power plants using corn residues. We find that this scenario has a significant impact on land allocation, fertilizer applications, and nitrogen leaching. The effects also impact regions not involved in cofiring through agricultural markets. Further, some MISO coal-fired plants would cease generation because the competition for biomass increases the cost of this feedstock and because the higher operating costs of cofiring renders them uncompetitive with other generation sources. These factors are not captured by analyses undertaken at the level of an individual power plant. We also show that a region-wide analysis of this cofiring mandate would have registered only a modest increase in nitrate leaching (just +5% across the upper MISO region). Such aggregate analyses would have obscured the extremely large increases in leaching at particular locations, as much as +60%. Many of these locations are already pollution hotspots. Fine-scale analysis, nested within a broader framework, is necessary to capture these critical environmental interactions within the energy, land, and water nexus.

Regional air quality impacts of increased natural gas production and use in Texas.

Natural gas use in electricity generation in Texas was estimated, for gas prices ranging from $1.89 to $7.74 per MMBTU, using an optimal power flow model. Hourly estimates of electricity generation, for individual electricity generation units, from the model were used to estimate spatially resolved hourly emissions from electricity generation. Emissions from natural gas production activities in the Barnett Shale region were also estimated, with emissions scaled up or down to match demand in electricity generation as natural gas prices changed. As natural gas use increased, emissions decreased from electricity generation and increased from natural gas production. Overall, NOx and SO2 emissions decreased, while VOC emissions increased as natural gas use increased. To assess the effects of these changes in emissions on ozone and particulate matter concentrations, spatially and temporally resolved emissions were used in a month-long photochemical modeling episode. Over the month-long photochemical modeling episode, decreases in natural gas prices typical of those experienced from 2006 to 2012 led to net regional decreases in ozone (0.2-0.7 ppb) and fine particulate matter (PM) (0.1-0.7 µg/m(3)). Changes in PM were predominantly due to changes in regional PM sulfate formation. Changes in regional PM and ozone formation are primarily due to decreases in emissions from electricity generation. Increases in emissions from increased natural gas production were offset by decreasing emissions from electricity generation for all the scenarios considered.

Induction chemotherapy followed by chemoradiation in locally advanced pancreatic cancer: an effective and well-tolerated treatment.

AIMS: The treatment of locally advanced pancreatic cancer varies enormously both within the UK and internationally. Although chemoradiation is the treatment of choice in the USA, in the UK this modality is used infrequently because of concerns regarding both its efficacy and its toxicity. We reviewed our experience with induction chemotherapy and selective chemoradiation in an attempt to show that it is a well-tolerated treatment that may be superior to chemotherapy alone. MATERIALS AND METHODS: Case notes of patients with locally advanced pancreatic cancer referred to the Velindre Cancer Centre between 1 March 2005 and 31 October 2007 were reviewed. Data on patient demographics, tumour characteristics, treatment and overall survival were collected retrospectively. Toxicity data during chemoradiation were collected prospectively. Patients who had non-progressive disease after 3 months of chemotherapy were planned for chemoradiation using three-dimensional conformal radiotherapy to a total dose of 4500-5040cGy in 25-28 daily fractions with gemcitabine as a radiosensitiser. RESULTS: Of the 91 referrals, 69 (76%) were fit for active oncological treatment; 43/69 (62%) patients were considered for induction chemotherapy followed by chemoradiation and 16/43 (37%) patients received chemoradiation. The median overall survival for patients receiving primary chemotherapy (n=26) was 9.2 (6.8-11.9) months and was 15.3 (11.6-upper limit not reached) months for patients who received chemoradiation (n=16). During the induction chemotherapy 8/16 (50%) patients experienced grade 3/4 toxicity and there were five hospital admissions. During chemoradiation there were 6/16 (37.5%) cases of grade 3/4 toxicity and two hospital admissions. There were no treatment-related deaths. Overall, 94.5% of the intended radiotherapy dose and 84% of the concurrent chemotherapy dose was delivered. CONCLUSIONS: In this UK network, about half of patients were considered for chemoradiation, but only 18% received it. Survival and treatment-related toxicity are consistent with data from other chemoradiation trials and in our series chemoradiation was tolerated better than chemotherapy alone. This supports the view that 'consolidation' chemoradiation is a viable treatment option that should be considered in selected patients with locally advanced non-metastatic pancreatic cancer.

Involvement of prefrontal cortex in visual search.

Visual search for target items embedded within a set of distracting items has consistently been shown to engage regions of occipital and parietal cortex, but the contribution of different regions of prefrontal cortex remains unclear. Here, we used fMRI to compare brain activity in 12 healthy participants performing efficient and inefficient search tasks in which target discriminability and the number of distractor items were manipulated. Matched baseline conditions were incorporated to control for visual and motor components of the tasks, allowing cortical activity associated with each type of search to be isolated. Region of interest analysis was applied to critical regions of prefrontal cortex to determine whether their involvement was common to both efficient and inefficient search, or unique to inefficient search alone. We found regions of the inferior and middle frontal cortex were only active during inefficient search, whereas an area in the superior frontal cortex (in the region of FEF) was active for both efficient and inefficient search. Thus, regions of ventral as well as dorsal prefrontal cortex are recruited during inefficient search, and we propose that this activity is related to processes that guide, control and monitor the allocation of selective attention.

Cognitive processes in saccade generation.

The analysis of saccades offers an opportunity to study a number of different cognitive processes, such as visuospatial attention, working memory, and volitional conflict. A study of saccades in patients with visuospatial hemineglect, who performed a visual search task, showed repeated fixations on targets previously discovered, yet they often failed to retain the information that a particular target had previously been discovered. High-resolution structural brain scanning showed that this abnormality was due either to a lesion in the right intraparietal sulcus or the right inferior frontal lobe. Detailed analysis of the scanpaths suggested that the former location was associated with an accumulating impairment in remapping target locations across saccades or impaired memory of previously inspected target locations, whereas the latter location was more consistent with a failure to inhibit responses to rightward locations. When combined with a spatial bias to the right, such deficits might explain why many neglect patients often reexamine rightward targets, at the expense of items to their left. The functions of the supplementary eye field (SEF), in the medial frontal lobe, in relation to saccade generation are controversial. A series of studies in a patient with a focal lesion of the right SEF has indicated an important role for the SEF in the rapid self-control of saccadic eye movements and in set-switching (i.e., implementing control in situations of response conflict when ongoing saccadic plans have to be changed rapidly), rather than monitoring errors. In a recent fMRI study of normal subjects, it was shown that the SEF is involved in implementing the resolution of any volitional conflict, whereas other presupplementary motor areas are involved in the generation of volitional plans and processing volitional conflict.

Orbitofrontal cortex mediates inhibition of return.

Recent accounts have proposed that orbitofrontal cerebral cortex mediates the control of behavior based on emotional feedback and its somatic correlates. Here, we describe the performance of a patient with circumscribed damage to orbitofrontal cortex during a task that requires switching between sensory-motor mappings, contingent on the occurrence of positive and negative reward feedbacks. In this test, normal subjects and other patients with prefrontal damage show an increase in latencies for eye movements towards locations at which a negative feedback was presented on the preceding trial. In contrast, our patient does not show this reward-dependent inhibition of return effect on saccades. She was also found to make an increased rate of ocular refixations during visual search and used a disorganized search strategy in a token foraging task. These findings suggest that orbital regions of the prefrontal cortex mediate an inhibitory effect on actions directed towards locations that have been subject to negative reinforcement. Further, this mechanism seems to play a role in controlling natural search and foraging behavior.

Quantifying uncertainties in climate system properties with the use of recent climate observations.

We derive joint probability density distributions for three key uncertain properties of the climate system, using an optimal fingerprinting approach to compare simulations of an intermediate complexity climate model with three distinct diagnostics of recent climate observations. On the basis of the marginal probability distributions, the 5 to 95% confidence intervals are 1.4 to 7.7 kelvin for climate sensitivity and -0.30 to -0.95 watt per square meter for the net aerosol forcing. The oceanic heat uptake is not well constrained, but ocean temperature observations do help to constrain climate sensitivity. The uncertainty in the net aerosol forcing is much smaller than the uncertainty range for the indirect aerosol forcing alone given in the Intergovernmental Panel on Climate Change Third Assessment Report.

Ocular flutter associated with a localized lesion in the paramedian pontine reticular formation.

Ocular flutter is a rare horizontal eye movement disorder characterized by rapid saccadic oscillations. It has been hypothesized that it is caused by loss of "pause" neuronal inhibition of "burst" neuron function in the paramedian pontine reticular formation (PPRF); however, there have been no imaging studies confirming such anatomical localization. We report the case of a woman with an acute attack of multiple sclerosis associated both with ocular flutter and a circumscribed pontine lesion, mainly involving the PPRF on magnetic resonance imaging. As she recovered from the attack, both the midline pontine lesion and the ocular flutter dramatically improved. This case is the first clear evidence that at least some cases of ocular flutter are due to lesions involving the PPRF.

Effect of acute exposure to ammonia on glutamate transport in glial cells isolated from the salamander retina.

A rise of brain ammonia level, as occurs in liver failure, initially increases glutamate accumulation in neurons and glial cells. We investigated the effect of acute exposure to ammonia on glutamate transporter currents in whole cell clamped glial cells from the salamander retina. Ammonia potentiated the current evoked by a saturating concentration of L-glutamate, and decreased the apparent affinity of the transporter for glutamate. The potentiation had a Michaelis-Menten dependence on ammonia concentration, with a K(m) of 1.4 mM and a maximum potentiation of 31%. Ammonia also potentiated the transporter current produced by D-aspartate. Potentiation of the glutamate transport current was seen even with glutamine synthetase inhibited, so ammonia does not act by speeding glutamine synthesis, contrary to a suggestion in the literature. The potentiation was unchanged in the absence of Cl(-) ions, showing that it is not an effect on the anion current gated by the glutamate transporter. Ammonium ions were unable to substitute for Na+ in driving glutamate transport. Although they can partially substitute for K+ at the cation counter-transport site of the transporter, their occupancy of these sites would produce a potentiation of < 1%. Ammonium, and the weak bases methylamine and trimethylamine, increased the intracellular pH by similar amounts, and intracellular alkalinization is known to increase glutamate uptake. Methylamine and trimethylamine potentiated the uptake current by the amount expected from the known pH dependence of uptake, but ammonia gave a potentiation that was larger than could be explained by the pH change, and some potentiation of uptake by ammonia was still seen when the internal pH was 8.8, at which pH further alkalinization does not increase uptake. These data suggest that ammonia speeds glutamate uptake both by increasing cytoplasmic pH and by a separate effect on the glutamate transporter. Approximately two-thirds of the speeding is due to the pH change.

Bilirubin does not modulate ionotropic glutamate receptors or glutamate transporters.

Bilirubin, a product of haemoglobin metabolism, has been suggested to damage neurons by increasing activation of N-methyl-D-aspartate (NMDA) receptors when it reaches high levels in the blood [15,19], as occurs in neonatal jaundice [7]. Bilirubin is also generated in the brain following synthesis of the messenger carbon monoxide (CO) by haem oxygenase, and haem oxygenase is upregulated in Alzheimer's disease [23]. We examined the effect of bilirubin on currents generated by NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in hippocampal pyramidal cells, and on glutamate transporter currents in retinal glial cells. Bilirubin did not modulate either receptor-gated currents or transporter currents. These data show the negative, but important result that bilirubin does not induce neuronal death by acting directly on NMDA or AMPA receptors, nor indirectly by blocking glutamate uptake and raising the extracellular concentration of glutamate.

Stereo-specific cytotoxic effects of gossypol enantiomers and gossypolone in tumour cell lines.

The naturally occurring compound, gossypol, has been previously used as a male oral contraceptive, for the treatment of benign gynaecological conditions and cancer patients. Long-term daily dosing with gossypol is associated with minimal side effects and no myelosuppression. Since gossypol exhibits atropisomerism due to the restricted rotation about the 2,2' carbon bond, we have isolated the l- and d-isomers by Schiff's base formation using a chiral amine and regenerated the enantiomers by acid hydrolysis. The enantiomers and the proposed oxidative metabolite, gossypolone, were characterized by HPLC, 1H-NMR and optical rotation. The cytotoxicity was assessed in cell cultures derived from melanoma, lung, breast, cervix, and leukaemia using the MTT viability assay. The cytotoxicity of gossypolone was similar to racemic gossypol in five out of the six cell lines studied. The l-enantiomer of gossypol induced a dose-dependent cell kill in all cell lines with a mean IC50 of 20 microM and was significantly more potent than racemic gossypol, the d-enantiomer of gossypol and gossypolone. In addition, when the leukaemia line was exposed to l-gossypol (0.5-10 microM) over a 4-day period, a schedule-dependent decrease in cell viability was observed. l-Gossypol was also compared with respective drugs used to treat patients with melanoma, lung cancer and leukaemia. The data indicate that l-gossypol was significantly more active than cisplatin, melphalan and dacarbazine in the two melanoma lines, cisplatin and daunorubicin in the lung line and hydroxyurea and busulphan in the leukaemia line. Preliminary studies using one melanoma line showed that the l-isomer induced cell shrinkage, membrane blebbing and DNA fragmentation, characteristics suggestive of apoptotic cell death.

Epirubicin, cisplatin and continuous infusion 5-fluorouracil (ECF) as neoadjuvant chemotherapy in gastro-oesophageal cancer.

High response rates have been reported in the treatment of advanced gastric cancer with epirubicin, cisplatin and continuous infusion 5-fluorouracil (ECF), including instances of unresectable disease being rendered operable by chemotherapy. We report our experience with ECF as neoadjuvant treatment in gastric and lower oesophageal carcinoma. Twenty-seven patients were treated, of whom ten (37%) had carcinoma of the stomach and 17 (63%) tumours of the lower oesophagus. Histology in the majority of cases, 21 (78%), was adenocarcinoma. Before chemotherapy ten patients (37%) had evidence of initially unresectable locally advanced disease, 16 (59%) had localised disease only and one patient (4%) had a localised primary with a single liver metastasis. Epirubicin (50 mg m(-2) i.v.) and cisplatin (60 mg m(-2) i.v.) were administered every 3 weeks for four cycles together with a continuous 12 week infusion of 5-fluorouracil (200 mg m(-2) day(-1)). Fifteen of 24 assessable patients (62%) had symptomatic improvement on chemotherapy. On combined surgical and/or radiological assessment, 15 of the 27 patients (56%) had objective evidence of tumour response. In all patients assessment for radical surgery was made following chemotherapy. Eighteen patients (67%) proceeded to operation: of these, 11 had complete resection of their disease, one had a histologically incomplete resection and six were found to have unresectable disease. No pathological complete responses were observed. Only one of the ten patients with locally advanced disease achieved complete surgical resection after chemotherapy. At a median follow-up of 36 months from date of diagnosis (range 30-47 months), 19 of the 27 patients (70%) have died. Of 11 patients who had a complete surgical resection, one died post-operatively, three have subsequently relapsed (of whom two have died) and seven remain disease free. Toxicity from treatment was mild and included emesis, myelosuppression, stomatitis and exfoliation. Myelosuppression caused modification of treatment in 14 of 108 chemotherapy cycles (13%). There was one surgical death but no chemotherapy-related deaths. These early results show encouraging symptomatic and objective responses of gastro-oesophageal carcinoma to ECF, but provide no instances of ECF achieving complete pathological response. Only randomised trials can establish the role of neoadjuvant ECF chemotherapy in both initially resectable and unresectable carcinoma of the stomach and lower oesophagus.

5-fluorouracil and folinic acid-induced mucositis: no effect of oral glutamine supplementation.

In some clinical situations the endogenous production of glutamine may be insufficient to maintain optimal tissue structure and function such that glutamine becomes a conditionally essential amino acid. Studies in laboratory animals have demonstrated that glutamine supplementation can reduce the incidence and severity of cytotoxic-induced mucositis. This study examined the role of oral glutamine supplementation in the management of mucositis caused by 5-fluorouracil (5-FU) and folinic acid. Twenty-eight patients with gastrointestinal cancers were randomised to receive 16 g of glutamine per day for 8 days, or placebo, in a randomised double-blind trial before crossing over to the alternative supplement during the second treatment cycle. The supplement was well tolerated with no apparent adverse effects, but failed to have any significant effect on oral mucositis assessed by the patients or investigator. The possible reasons for this apparent lack of benefit are discussed.

Length of follow-up in teratomas--results of a modification of Einhorn's regime in testicular teratomas.

A modification of Einhorn's original chemotherapy schedule was used to treat 40 patients with metastatic testicular teratomas. Each cycle of chemotherapy consisted of cisplatin (100 mg/m2), bleomycin (30 mg X 3) and vinblastine (5 mg/m2 X 2). Four patients failed to achieve a complete response and died with advanced disease. There was one treatment death. Only two of 14 patients who had residual masses resected still had active tumour. The 2-year actuarial disease free survival for patients in first remission was 85%, but this fell to 77% at 5 years as 3 patients relapsed (34, 36, 37 months). The results are comparable with other series but are associated with less toxicity. The need for continued follow-up is demonstrated in view of relapses occurring after 2 years.