Dose rationale for gabapentin and tramadol in pediatric patients with chronic pain

Despite off-label use, the efficacy and safety of gabapentin and tramadol in pediatric patients (3 months to <18 years old) diagnosed with chronic pain has not been characterized. However, generating evidence based on randomized clinical trials in this population has been extremely challenging. The current investigation illustrates the use of clinical trial simulations (CTSs) as a tool for optimizing doses and protocol design for a prospective investigation in pediatric patients with chronic pain. Pharmacokinetic (PK) modeling and CTSs were used to describe the PKs of gabapentin and tramadol in the target population. In the absence of biomarkers of analgesia, systemic exposure (AUC, Css) was used to guide dose selection under the assumption of a comparable exposure-response (PKPD) relationship for either compound between adults and children. Two weight bands were identified for gabapentin, with doses titrated from 5 to 63 mg/kg. This yields gabapentin exposures (AUC0-8 ) of approximately 35 mg/L*h (1200 mg/day adult dose equivalent). For tramadol, median steady state concentrations between 200 and 300 ng/mL were achieved after doses of 2-5 mg/kg, but concentrations showed high interindividual variability. Simulation scenarios showed that titration steps are required to explore therapeutically relevant dose ranges taking into account the safety profile of both drugs. Gabapentin can be used t.i.d. at doses between 7-63 and 5-45 mg/kg for patients receiving gabapentin weighing <15 and ≥15 kg, respectively, whereas a t.i.d. regimen with doses between 1 and 5 mg/kg can be used for tramadol in patients who are not fast metabolisers

Abundances of trace constituents in Jupiter's atmosphere inferred from Herschel/PACS observations

$Context.$ On October 31, 2009, the Photodetector Array Camera and Spectrometer (PACS) on board the Herschel Space Observatory observed far-infrared spectra of Jupiter between 50 and 220$\,\mu$m as part of the program "Water and Related Chemistry in the Solar System". $Aims.$ We investigate the disk-averaged chemical composition of Jupiter's atmosphere as a function of height using these observations. $Methods.$ We used the Planetary Spectrum Generator (PSG) and the least-squares fitting technique to infer the abundances of trace constituents. $Results.$ The PACS data include numerous spectral lines attributable to ammonia (NH$_3$), methane (CH$_4$), phosphine (PH$_3$), water (H$_2$O), and deuterated hydrogen (HD) in the Jovian atmosphere. We infer an ammonia abundance profile that decreases from a mole fraction of $(1.7\pm 0.8)\times 10^{-4}$ at $p\sim 900\,$mbar to $(1.7\pm 0.9)\times 10^{-8}$ at $p\sim 275\,$mbar, following a fractional scale height of about 0.114. For phosphine, we find a mole fraction of $(7.2\pm 1.2)\times 10^{-7}$ at pressures higher than $(550\pm 100)\,$mbar and a decrease of its abundance at lower pressures following a fractional scale height of $(0.09\pm 0.02)$. Our analysis delivers a methane mole fraction of $(1.49\pm 0.09)\times 10^{-3}$. Analyzing the HD $R(0)$ line at $112.1\,\mu$m yields a new measurement of Jupiter's D/H ratio, $\text{D/H}=(1.5\pm 0.6)\times 10^{-5}$. Finally, the PACS data allow us to put the most stringent $3\sigma$ upper limits yet on the mole fractions of hydrogen halides in the Jovian troposphere. These new upper limits are $<1.1\times 10^{-11}$ for hydrogen fluoride (HF), $<6.0\times 10^{-11}$ for hydrogen chloride (HCl), $<2.3\times 10^{-10}$ for hydrogen bromide (HBr) and $<1.2\times 10^{-9}$ for hydrogen iodide (HI) and support the proposed condensation of hydrogen halides into ammonium halide salts in the Jovian troposphere.Comment: Accepted for publication in Astronomy and Astrophysics, 16 pages, 4 tables, 24 figures incl. Appendi

Receptor transfer between immune cells by autoantibody-enhanced, CD32-driven trogocytosis is hijacked by HIV-1 to infect resting CD4 T cells

Immune cell phenotyping frequently detects lineage-unrelated receptors. Here, we report that surface receptors can be transferred from primary macrophages to CD4 T cells and identify the Fcγ receptor CD32 as driver and cargo of this trogocytotic transfer. Filamentous CD32+ nanoprotrusions deposit distinct plasma membrane patches onto target T cells. Transferred receptors confer cell migration and adhesion properties, and macrophage-derived membrane patches render resting CD4 T cells susceptible to infection by serving as hotspots for HIV-1 binding. Antibodies that recognize T cell epitopes enhance CD32-mediated trogocytosis. Such autoreactive anti-HIV-1 envelope antibodies can be found in the blood of HIV-1 patients and, consistently, the percentage of CD32+ CD4 T cells is increased in their blood. This CD32-mediated, antigen-independent cell communication mode transiently expands the receptor repertoire and functionality of immune cells. HIV-1 hijacks this mechanism by triggering the generation of trogocytosis-promoting autoantibodies to gain access to immune cells critical to its persistence

Retrieval of Jupiter&amp;#8217;s atmospheric parameters using far infrared spectra measured with PACS onboard the Herschel Space Observatory

&amp;lt;p&amp;gt;On October 31, 2009, the Photodetector Array Camera and Spectrometer (PACS) onboard the Herschel Space Observatory observed far infrared (FIR) spectra of Jupiter in the wavelength range between 55 and 210 &amp;amp;#181;m in the framework of the program &amp;amp;#8216;Water and Related Chemistry in the Solar System&amp;amp;#8217; [Hartogh et al., 2009]. We aim at inferring the abundances of the trace constituents and the atmospheric temperature profile using these data, a line-by-line radiative transfer tool [Villanueva et al. 2018] and the least-squares fitting technique. Early model preparations and an earlier presentation of the preliminary spectra are given in Sagawa et al. [2010a,b]. Now, we present a more comprehensive data analysis. The spectra&amp;amp;#8217;s spectral resolution (R=&amp;lt;span class=&amp;quot;st&amp;quot;&amp;gt;&amp;amp;#955;&amp;lt;/span&amp;gt;/&amp;lt;span class=&amp;quot;st&amp;quot;&amp;gt;&amp;amp;#916;&amp;lt;/span&amp;gt;&amp;lt;span class=&amp;quot;st&amp;quot;&amp;gt;&amp;amp;#955;&amp;lt;/span&amp;gt;) depends on wavelength and grating order of the measurements and ranges from 990 to 5500. However, the effective spectral resolution was determined using detected, but unresolved spectral lines of stratospheric water, and varies between 1000 and 3000. Strong spectral features of methane (CH&amp;lt;sub&amp;gt;4&amp;lt;/sub&amp;gt;), ammonia (NH&amp;lt;sub&amp;gt;3&amp;lt;/sub&amp;gt;) and phosphine (PH&amp;lt;sub&amp;gt;3&amp;lt;/sub&amp;gt;) are clearly visible in the data (see fig. 1). Features from other species, such as water, hydrogen deuteride (HD), hydrogen sulfide (H&amp;lt;sub&amp;gt;2&amp;lt;/sub&amp;gt;S) and some hydrogen halides, such as hydrogen chloride (HCl), are also present in the data and might be used to retrieve upper limits for the relative abundances of these species. We assume a constant CH&amp;lt;sub&amp;gt;4&amp;lt;/sub&amp;gt; abundance due to vertical mixing and the lack of methane cloud condensation. Inferring atmospheric parameters from compositional measurements will not only help to characterize the atmosphere of Jupiter but will also contribute to a better understanding of a plethora of physicochemical processes in the atmosphere.&amp;lt;/p&amp;gt; &amp;lt;p&amp;gt;&amp;lt;img src=&amp;quot;data:image/jpeg;base64, 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

Ossifying plexiform tumor

We report a rare case of ossifying plexiform tumor in a 64‐year‐old female. The patient had a 2‐year history of gradual hardening of the right thumb pad and pain that radiated up the forearm. Physical examination showed a tender, mobile 2‐cm subcutaneous nodule distending the tip of the right thumb. The biopsy specimen showed a well‐delineated tumor with multiple lobules of epithelioid and spindled cells arranged in a plexiform pattern separated by fibrous bands and having foci of bone formation. The neoplastic cells had scant‐to‐moderate amphophilic cytoplasm with mild nuclear pleomorphism in a myxocollagenous background. No necrosis, mitoses or cytological atypicia were seen. The osteocytes present in the bone islands were bland, with occasional rimming osteoblasts. X‐ray showed stippled calcification in the soft tissue of the distal thumb without involvement of the phalanx. The patient is tumor free for 1 year after complete local excision. Only three cases of ossifying plexiform tumor have been reported. All previous cases and the current case presented as subcutaneous nodules on hand digits of females, measuring 1–2 cm in greatest dimension. Ossifying plexiform tumor appears to be a benign neoplasm with no reports of progression or metastasis

Six Planets Orbiting HD 219134

We present new, high-precision Doppler radial velocity (RV) data sets for the nearby K3V star HD 219134. The data include 175 velocities obtained with the HIRES Spectrograph at the Keck I Telescope and 101 velocities obtained with the Levy Spectrograph at the Automated Planet Finder Telescope at Lick Observatory. Our observations reveal six new planetary candidates, with orbital periods of P = 3.1, 6.8, 22.8, 46.7, 94.2, and 2247 days, spanning masses of ${\mathcal{M}}\mathrm{sin}i=3.8,$ 3.5, 8.9, 21.3, 10.8, and $108\;{{\mathcal{M}}}_{\oplus }$, respectively. Our analysis indicates that the outermost signal is unlikely to be an artifact induced by stellar activity. In addition, several years of precision photometry with the T10 0.8 m automatic photometric telescope at Fairborn Observatory demonstrated a lack of brightness variability to a limit of ∼0.0002 mag, providing strong support for planetary-reflex motion as the source of the RV variations. The HD 219134 system with its bright (V = 5.6) primary provides an excellent opportunity to obtain detailed orbital characterization (and potentially follow-up observations) of a planetary system that resembles many of the multiple-planet systems detected by Kepler, which are expected to be detected by NASA\u27s forthcoming TESS Mission and by ESA\u27s forthcoming PLATO Mission