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Chronic hypercapnic respiratory failure occurs in several conditions associated with hypoventilation. The mechanisms underlying the development of chronic hypercapnia include a combination of processes that increase metabolic CO2 production, reduce minute ventilation (V'e), or increase dead space fraction (Vd/Vt). Fundamental to the pathophysiology is a mismatch between increased load and a reduction in the capacity of the respiratory pump to compensate. Though neural respiratory drive may be decreased in a subset of central hypoventilation disorders, it is more commonly increased in attempting to maintain the load-capacity homeostatic balance.

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Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are the standard treatment for selected patients with peritoneal malignancy. The optimal means of assessing risk prior to these complex operations is not known. This study explored the associations between preoperative cardiopulmonary exercise testing (CPET) variables and postoperative outcomes following elective CRS and HIPEC. This study included patients who underwent routine preoperative CPET prior to elective CRS and HIPEC at Royal Prince Alfred Hospital in Sydney between July 2017 and July 2020. CPET was performed using a cycle ergometer and measured peak oxygen uptake (VO2 peak) and anaerobic threshold (AT). Outcomes included in-hospital morbidity, length of intensive care unit (ICU) stay and hospital stay. The associations between preoperative CPET variables and postoperative morbidity were assessed using univariate and multivariate analyses. A total of 129 patients were included. Mean age was 56 years (standard deviation (SD) 12.5 years), and colorectal cancer was the most common indication for CRS and HIPEC. The overall complication rate was 69%, and two (1.6%) patients died in hospital. Patients who did not develop any postoperative complication had slightly higher preoperative AT and VO2 peak and shorter length of hospital stay. Data in this study support the role of CPET prior to CRS and HIPEC as an adjunct to improve risk assessment.

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Inland sources of particulate chloride for atmospheric nitryl chloride (ClNO2) formation remain unknown and unquantified, hindering air quality assessments. Globally each winter, tens of millions of tons of road salt are spread on roadways for deicing. Here, we identify road salt aerosol as the primary chloride aerosol source, accounting for 80-100% of ClNO2 formation, at an inland urban area in the wintertime. This study provides experimental evidence of the connection between road salt and air quality through the production of this important reservoir for nitrogen oxides and chlorine radicals, which significantly impact atmospheric composition and pollutant fates. A numerical model was employed to quantify the contributions of chloride sources to ClNO2 production. The traditional method for simulating ClNO2 considers chloride to be homogeneously distributed across the atmospheric particle population; yet, we show that only a fraction of the particulate surface area contains chloride. Our new single-particle parametrization considers this heterogeneity, dramatically lowering overestimations of ClNO2 levels that have been routinely reported using the prevailing methods. The identification of road salt as a ClNO2 source links this common deicing practice to atmospheric composition and air quality in the urban wintertime environment.

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Atomic chlorine (Cl) is a strong atmospheric oxidant that shortens the lifetimes of pollutants and methane in the springtime Arctic, where the molecular halogens Cl2 and BrCl are known Cl precursors. Here, we quantify the contributions of reactive chlorine trace gases and present the first observations, to our knowledge, of ClNO2 (another Cl precursor), N2O5, and HO2NO2 in the Arctic. During March - May 2016 near Utqiagvik, Alaska, up to 21 ppt of ClNO2, 154 ppt of Cl2, 27 ppt of ClO, 71 ppt of N2O5, 21 ppt of BrCl, and 153 ppt of HO2NO2 were measured using chemical ionization mass spectrometry. The main Cl precursor was calculated to be Cl2 (up to 73%) in March, while BrCl was a greater contributor (63%) in May, when total Cl production was lower. Elevated levels of ClNO2, N2O5, Cl2, and HO2NO2 coincided with pollution influence from the nearby town of Utqiagvik and the North Slope of Alaska (Prudhoe Bay) Oilfields. We propose a coupled mechanism linking NOx with Arctic chlorine chemistry. Enhanced Cl2 was likely the result of the multiphase reaction of Cl-(aq) with ClONO2, formed from the reaction of ClO and NO2. In addition to this NOx-enhanced chlorine chemistry, Cl2 and BrCl were observed under clean Arctic conditions from snowpack photochemical production. These connections between NOx and chlorine chemistry, and the role of snowpack recycling, are important given increasing shipping and fossil fuel extraction predicted to accompany Arctic sea ice loss.

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Bromine atoms play a central role in atmospheric reactive halogen chemistry, depleting ozone and elemental mercury, thereby enhancing deposition of toxic mercury, particularly in the Arctic near-surface troposphere. However, direct bromine atom measurements have been missing to date, due to the lack of analytical capability with sufficient sensitivity for ambient measurements. Here we present direct atmospheric bromine atom measurements, conducted in the springtime Arctic. Measured bromine atom levels reached 14 parts per trillion (ppt, pmol mol-1; 4.2 × 108 atoms per cm-3) and were up to 3-10 times higher than estimates using previous indirect measurements not considering the critical role of molecular bromine. Observed ozone and elemental mercury depletion rates are quantitatively explained by the measured bromine atoms, providing field validation of highly uncertain mercury chemistry. Following complete ozone depletion, elevated bromine concentrations are sustained by photochemical snowpack emissions of molecular bromine and nitrogen oxides, resulting in continued atmospheric mercury depletion. This study provides a breakthrough in quantitatively constraining bromine chemistry in the polar atmosphere, where this chemistry connects the rapidly changing surface to pollutant fate.

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We report two 3D printed devices that can be used for electrochemical detection. In both cases, the electrode is housed in commercially available, polymer-based fittings so that the various electrode materials (platinum, platinum black, carbon, gold, silver) can be easily added to a threaded receiving port printed on the device; this enables a module-like approach to the experimental design, where the electrodes are removable and can be easily repolished for reuse after exposure to biological samples. The first printed device represents a microfluidic platform with a 500 × 500 µm channel and a threaded receiving port to allow integration of either polyetheretherketone (PEEK) nut-encased glassy carbon or platinum black (Pt-black) electrodes for dopamine and nitric oxide (NO) detection, respectively. The embedded 1 mm glassy carbon electrode had a limit of detection (LOD) of 500 nM for dopamine and a linear response (R(2) = 0.99) for concentrations between 25-500 µM. When the glassy carbon electrode was coated with 0.05% Nafion, significant exclusion of nitrite was observed when compared to signal obtained from equimolar injections of dopamine. When using flow injection analysis with a Pt/Pt-black electrode and standards derived from NO gas, a linear correlation (R(2) = 0.99) over a wide range of concentrations (7.6-190 µM) was obtained, with the LOD for NO being 1 µM. The second application showcases a 3D printed fluidic device that allows collection of the biologically relevant analyte adenosine triphosphate (ATP) while simultaneously measuring the release stimulus (reduced oxygen concentration). The hypoxic sample (4.8 ± 0.5 ppm oxygen) released 2.4 ± 0.4 times more ATP than the normoxic sample (8.4 ± 0.6 ppm oxygen). Importantly, the results reported here verify the reproducible and transferable nature of using 3D printing as a fabrication technique, as devices and electrodes were moved between labs multiple times during completion of the study.

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OBJECTIVE: To correlate the planned dose to the nausea center (NC) - area postrema (AP) and dorsal vagal complex (DVC) - with nausea and vomiting symptoms in OPC patients treated with IMRT without chemotherapy. We also investigated whether it was possible to reduce doses to the NC without significant degradation of the clinically accepted treatment plan. METHODS: From 11/04 to 4/09, 37 OPC patients were treated with definitive or adjuvant IMRT without chemotherapy. Of these, only 23 patients had restorable plans and were included in this analysis. We contoured the NC with the assistance of an expert board-certified neuroradiologist. We searched for correlation between the delivered dose to the NC and patient-reported nausea and vomiting during IMRT. We used one-paired t-test: two-sample assuming equal variances to compare differences in dose to NC between symptomatic and asymptomatic patients. We then replanned each case to determine if reduced dose to the NC could be achieved without compromising coverage to target volumes, increasing unwarranted hotspots or increasing dose to surrounding critical normal tissues. RESULTS: Acute symptoms of nausea were as follows: Grade 0 (n=6), Grade 1 (n=13), Grade 2 (n=3), and Grade 3 (n=1). Patients with no complaints of nausea had a median dose to the DVC of 34.2 Gy (range 4.6-46.6 Gy) and AP of 32.6 Gy (range 7.0-41.4Gy); whereas those with any complaints of nausea had a median DVC dose of 40.4 Gy (range 19.3-49.4 Gy) and AP dose of 38.7 Gy (range 16.7-46.8 Gy) (p=0.04). Acute vomiting was as follows: Grade 0 (n=17), Grade 1 (n=4), Grade 2 (n=1), and Grade 3 (n=1). There was no significant difference in DVC or AP dose among those with and without vomiting symptoms (p=0.28).Upon replanning of each case to minimize dose to the NC, we were, on average, able to reduce the radiation dose to AP by 18% and DVC by 17%; while the average dose variations to the PTV coverage, brainstem, cord, temporal lobes, and cochlea were never greater than 3%. Hotspots increased by 2% for 3 patients while hotspots for remaining patients were less than 2% variation. CONCLUSION: For OPC cancer patients treated with IMRT without chemotherapy, dose to AP and DVC may be associated with development of nausea. We were able to show that reducing doses substantially to the NC is achievable without significant alteration of the clinically accepted plan and may reduce the incidence and grade of nausea. As symptoms of nausea can be devastating to patients, one can consider routine contouring and constraining of the NC to minimize chances of having this complication.

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A 56-year-old man gave a 6-month history of progressive dyspnoea and orthopnoea. During breathing, his abdominal muscles showed paradoxical movement and he rapidly and reproducibly developed difficulty breathing when lying supine. The most likely explanation was severe weakness or paralysis of both hemidiaphragms. This was confirmed with electrophysiology and ultrasonography. Extensive investigation identified no underlying cause, suggesting this is a case of bilateral isolated phrenic neuropathy. We present a video showing how easily bilateral diaphragmatic palsy can be detected clinically through identifying paradoxical abdominal wall movement.

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The mitochondrial protein apoptosis-inducing factor (AIF) translocates to the nucleus and induces apoptosis. Recent studies, however, have indicated the importance of AIF for survival in mitochondria. In the absence of a means to dissociate these two functions, the precise roles of AIF remain unclear. Here, we dissociate these dual roles using mitochondrially anchored AIF that cannot be released during apoptosis. Forebrain-specific AIF null (tel. AifDelta) mice have defective cortical development and reduced neuronal survival due to defects in mitochondrial respiration. Mitochondria in AIF deficient neurons are fragmented with aberrant cristae, indicating a novel role of AIF in controlling mitochondrial structure. While tel. AifDelta Apaf1(-/-) neurons remain sensitive to DNA damage, mitochondrially anchored AIF expression in these cells significantly enhanced survival. AIF mutants that cannot translocate into nucleus failed to induce cell death. These results indicate that the proapoptotic role of AIF can be uncoupled from its physiological function. Cell death induced by AIF is through its proapoptotic activity once it is translocated to the nucleus, not due to the loss of AIF from the mitochondria.

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Here we show a novel function for Retinoblastoma family member, p107 in controlling stem cell expansion in the mammalian brain. Adult p107-null mice had elevated numbers of proliferating progenitor cells in their lateral ventricles. In vitro neurosphere assays revealed striking increases in the number of neurosphere forming cells from p107(-/-) brains that exhibited enhanced capacity for self-renewal. An expanded stem cell population in p107-deficient mice was shown in vivo by (a) increased numbers of slowly cycling cells in the lateral ventricles; and (b) accelerated rates of neural precursor repopulation after progenitor ablation. Notch1 was up-regulated in p107(-/-) neurospheres in vitro and brains in vivo. Chromatin immunoprecipitation and p107 overexpression suggest that p107 may modulate the Notch1 pathway. These results demonstrate a novel function for p107 that is distinct from Rb, which is to negatively regulate the number of neural stem cells in the developing and adult brain.

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