Parkinson's disease patients are more likely to be hospitalized, have higher rates of hospital complications, and have an increased risk of deterioration during hospitalization. Length of stay is an ...important underlying factor for these increased risks. We aimed to investigate potential medication errors that may occur during hospitalization and its impact on length of hospital stay.
A cross-sectional chart review of 339 consecutive hospital encounters from 212 PD subjects was performed. Medication errors were defined as wrong timing or omission of administration for dopaminergic drugs and administration of contraindicated dopamine blockers. An analysis of covariance was applied to examine whether these medication errors were related to increased length of hospital stays.
A significant effect for dopaminergic administration (p<0.01) on length of hospital stay was observed. Subjects who had delayed administration or missed at least one dose stayed longer (M=8.2 days, SD=8.9 vs. M=3.6 days SD=3.4). Contraindicated dopamine blocking agents were administered in 23% (71/339) of cases, and this was also significantly related to an increased length of stay (M=8.2 days, SD=8.9 vs. M=3.6 days SD=3.4), p<0.05. Participants who received a contraindicated dopamine blocker stayed in the hospital longer (M=7.5 days, SD=9.1) compared to those who did not (M=5.9 days, SD=6.8). Neurologists were consulted in 24.5% of encounters. Specialty consultation had no effect on the medication related errors.
Missing dopaminergic dosages and administration of dopamine blockers occur frequently in hospitalized Parkinson's disease patients and this may impact length of stay. These potentially modifiable factors may reduce the risk of a longer stay related to hospitalization.
We have biologically characterized two new members of the IL-17 cytokine family: IL-17F and IL-25. In contrast to conventional in vitro screening approaches, we have characterized the activity of ...these new molecules by direct in vivo analysis and have compared their function to that of other IL-17 family members. Intranasal administration of adenovirus expressing IL-17, IL-17C, or IL-17F resulted in bronchoalveolar lavage neutrophilia and inflammatory gene expression in the lung. In contrast, intranasal administration of IL-25-expressing adenovirus or IL-25 protein resulted in the production of IL-4, IL-5, IL-13, and eotaxin mRNA in the lung and marked eosinophilia in the bronchoalveolar lavage and lung tissue. Mice given intranasal IL-25 also developed epithelial cell hyperplasia, increased mucus secretion, and airway hyperreactivity. IL-25 gene expression was detected following Aspergillus and Nippostrongylus infection in the lung and gut, respectively. IL-25-induced eosinophilia required IL-5 and IL-13, but not IL-4 or T cells. Following IL-25 administration, the IL-5(+) staining cells were CD45R/B220(+), Thy-1(+/-), but were NK1.1-, Ly-6G(GR-1)-, CD4-, CD3-, and c-kit-negative. gamma-common knockout mice did not develop eosinophilia in response to IL-25, nor were IL-5(+) cells detected. These findings suggest the existence of a previously unrecognized cell population that may initiate Th2-like responses by responding to IL-25 in vivo. Further, these data demonstrate the heterogeneity of function within the IL-17 cytokine family and suggest that IL-25 may be an important mediator of allergic disease via production of IL-4, IL-5, IL-13, and eotaxin.
Background
Children awaiting transplantation face a high risk of waitlist mortality due to a shortage of pediatric organ donors. Pediatric donation consent rates vary across Organ Procurement ...Organizations (OPOs), suggesting that some OPOs might utilize more effective pediatric‐focused donor recruitment techniques than others. An online survey of 193 donation requestor staff sheds light on the strategies that OPO staff utilize when approaching potential pediatric deceased organ donors.
Methods
In collaboration with the Association of Organ Procurement Organizations, the research team contacted the executive directors and medical directors of all 57 of the OPOs in the US. Of these, 51 OPOs agreed to participate, and 47 provided contact information for donation requestor staff. Of the 379 staff invited to participate in the survey, 193 provided complete responses.
Results
Respondents indicated more comfort approaching adult donors than pediatric donors, and they endorsed approach techniques that were interpersonal and emotional rather than professional and informative. Respondents were accurate in their perceptions about which donor characteristics are associated with consent. However, respondents from OPOs with high consent rates (according to data from the Scientific Registry of Transplant Recipients), and those from OPOs with low consent rates were very similar in terms of demographics, training, experience, and reported techniques.
Conclusions
Additional research is needed to better determine why some OPOs have higher consent rates than others and whether the factors that lead to high consent rates in high‐performing OPOs can be successful when implemented by lower‐performing OPOs.
The process of plant speciation often involves the evolution of divergent ecotypes in response to differences in soil water availability between habitats. While the same set of traits is frequently ...associated with xeric/mesic ecotype divergence, it is unknown whether those traits evolve independently or if they evolve in tandem as a result of genetic colocalization either by pleiotropy or genetic linkage.
The self-fertilizing C4 grass species Panicum hallii includes two major ecotypes found in xeric (var. hallii) or mesic (var. filipes) habitats. We constructed the first linkage map for P. hallii by genotyping a reduced representation genomic library of an F2 population derived from an intercross of var. hallii and filipes. We then evaluated the genetic architecture of divergence between these ecotypes through quantitative trait locus (QTL) mapping.
Overall, we mapped QTLs for nine morphological traits that are involved in the divergence between the ecotypes. QTLs for five key ecotype-differentiating traits all colocalized to the same region of linkage group five. Leaf physiological traits were less divergent between ecotypes, but we still mapped five physiological QTLs. We also discovered a two-locus Dobzhansky–Muller hybrid incompatibility.
Our study suggests that ecotype-differentiating traits may evolve in tandem as a result of genetic colocalization.
The Trypanosoma brucei cysteine protease cathepsin B (TbCatB), which is involved in host protein degradation, is a promising target to develop new treatments against sleeping sickness, a fatal ...disease caused by this protozoan parasite. The structure of the mature, active form of TbCatB has so far not provided sufficient information for the design of a safe and specific drug against T. brucei. By combining two recent innovations, in vivo crystallization and serial femtosecond crystallography, we obtained the room-temperature 2.1 angstrom resolution structure of the fully glycosylated precursor complex of TbCatB. The structure reveals the mechanism of native TbCatB inhibition and demonstrates that new biomolecular information can be obtained by the "diffraction-before-destruction" approach of x-ray free-electron lasers from hundreds of thousands of individual microcrystals.
Expression of hepcidin, the key hormone governing iron transport, is reduced by anemia in a manner which appears dependent on increased bone marrow activity. The temporal associations between plasma ...hepcidin and other iron parameters were examined in healthy humans after erythropoietin administration and venesection. Profound hepcidin suppression appeared abruptly 24 hours after subcutaneous erythropoietin (P=0.003), and was near maximal at onset, with peak (mid-afternoon) levels reduced by 73.2%, gradually recovering over the following two weeks. Minor changes in circulating iron, soluble transferrin receptor and growth differentiation factor-15 were observed after the reduction in hepcidin. Similar but more gradual changes in these parameters were observed after reducing hematocrit by removal of 250 mL blood. These human studies confirm the importance of a rapidly responsive marrow-hepcidin axis in regulating iron supply in vivo, and suggest that this axis is regulated by factors other than circulating iron, soluble transferrin receptor or growth differentiation factor-15.
Background:
Hip arthroscopic surgery for femoroacetabular impingement syndrome (FAIS) has proven to be an effective surgical intervention, with high rates of return to sport and work as well as ...favorable outcomes at short- and midterm follow-up. However, limited data exist on outcomes at long-term follow-up.
Purpose:
To evaluate patient-reported outcomes (PROs) at a minimum 10-year follow-up after primary hip arthroscopic surgery including labral repair, femoral osteochondroplasty, acetabular osteochondroplasty, and capsular closure for FAIS.
Study Design:
Case series; Level of evidence, 4.
Methods:
Patients who underwent primary hip arthroscopic surgery for FAIS between June 2012 and January 2013 were identified. PROs were collected preoperatively and at a minimum of 10 years postoperatively, including the Hip Outcome Score–Activities of Daily Living (HOS-ADL), Hip Outcome Score–Sports Subscale (HOS-SS), modified Harris Hip Score (mHHS), International Hip Outcome Tool–12 (iHOT-12), and visual analog scale (VAS) for pain and satisfaction. Unique minimal clinically important difference (MCID) and patient acceptable symptom state (PASS) thresholds were calculated, and their rates of achievement were analyzed. An alpha level of <.05 was used to determine statistical significance.
Results:
A total of 94 patients (55 female; mean age, 34.3 ± 12.4 years) were analyzed with a mean follow-up of 10.1 ± 0.3 years (range, 10.0-10.7 years). Patients demonstrated significant 10-year improvement across all PRO measures (P < .001). MCID and PASS thresholds were calculated as follows: HOS-ADL (10.4 and 85.3, respectively), HOS-SS (14.6 and 60.2, respectively), mHHS (8.8 and 76.0, respectively), VAS pain (14.6 and 27.5, respectively), and iHOT-12 (PASS: 71.4). The majority of patients achieved the MCID and PASS for each PRO measure: HOS-ADL (73.4% and 70.9%, respectively), HOS-SS (78.5% and 77.2%, respectively), mHHS (81.0% and 70.9%, respectively), VAS pain (88.6% and 70.9%, respectively), and iHOT-12 (PASS: 73.4%). Overall, 9 patients (9.6%) underwent subsequent revision hip arthroscopic surgery at a mean 4.9 ± 3.7 years (range, 1.1-10.1 years) postoperatively, and 6 patients (6.4%) underwent conversion to total hip arthroplasty at a mean 4.1 ± 3.1 years (range, 0.9-9.3 years) postoperatively.
Conclusion:
Patients who underwent primary hip arthroscopic surgery for FAIS utilizing contemporary methods of labral repair, acetabular and/or femoral osteochondroplasty, and capsular closure commonly experienced sustained clinical improvement and reported high levels of satisfaction at a minimum 10-year follow-up with low rates of reoperation.
•GPCR drug discovery is hindered by limited access to purified receptor reagents.•Polymer technology (PoLiPa) enables purification of GPCRs that remain in their lipid environment.•This vastly ...increases access to and simplifies GPCR purification.•PoLiPa are amenable to biophysical / structural experiments essential to modern drug discovery.•We anticipate that this will herald a revolution in GPCR drug discovery.
G-protein-coupled receptor (GPCR) drug research is presently hindered by the technical challenges associated with generating purified receptors. Consequently, the application of critical modern discovery technologies has been limited, and the vast untapped opportunity for new GPCR-directed medicines is not being realised. A simple but transformative solution is to purify receptors without removing them from their native phospholipid environment by using polymer lipid particle (PoLiPa) technology, with reagents such as styrene-maleic acid co-polymer (SMA). Compared with contemporary detergent-based and stabilising mutagenesis methods, the PoLiPa approach is simple and generic and, therefore, offers huge advantages, with the potential to revolutionise GPCR research by facilitating the availability of the purified receptors that are required for structural biology, biophysical, and panning technologies.
PoLiPa technology (a.k.a. SMALPs) enables purification of GPCRs while they remain in their natural lipid environment, thus avoiding many of the challenges associated with current techniques and, therefore, increasing access to modern drug discovery techniques.
GPCRs regulate all aspects of human physiology, and biophysical studies have deepened our understanding of GPCR conformational regulation by different ligands. Yet there is no experimental evidence ...for how sidechain dynamics control allosteric transitions between GPCR conformations. To address this deficit, we generated samples of a wild-type GPCR (A
R) that are deuterated apart from
H/
C NMR probes at isoleucine δ1 methyl groups, which facilitated
H/
C methyl TROSY NMR measurements with opposing ligands. Our data indicate that low Na
is required to allow large agonist-induced structural changes in A
R, and that patterns of sidechain dynamics substantially differ between agonist (NECA) and inverse agonist (ZM241385) bound receptors, with the inverse agonist suppressing fast ps-ns timescale motions at the G protein binding site. Our approach to GPCR NMR creates a framework for exploring how different regions of a receptor respond to different ligands or signaling proteins through modulation of fast ps-ns sidechain dynamics.
The Izu‐Bonin‐Mariana (IBM) fore arc preserves igneous rock assemblages that formed during subduction initiation circa 52 Ma. International Ocean Discovery Program (IODP) Expedition 352 cored four ...sites in the fore arc near the Ogasawara Plateau in order to document the magmatic response to subduction initiation and the physical, petrologic, and chemical stratigraphy of a nascent subduction zone. Two of these sites (U1440 and U1441) are underlain by fore‐arc basalt (FAB). FABs have mid‐ocean ridge basalt (MORB)‐like compositions, however, FAB are consistently lower in the high‐field strength elements (TiO2, P2O5, Zr) and Ni compared to MORB, with Na2O at the low end of the MORB field and FeO* at the high end. Almost all FABs are light rare earth element depleted, with low total REE, and have low ratios of highly incompatible to less incompatible elements (Ti/V, Zr/Y, Ce/Yb, and Zr/Sm) relative to MORB. Chemostratigraphic trends in Hole U1440B are consistent with the uppermost lavas forming off axis, whereas the lower lavas formed beneath a spreading center axis. Axial magma of U1440B becomes more fractionated upsection; overlying off‐axis magmas return to more primitive compositions. Melt models require a two‐stage process, with early garnet field melts extracted prior to later spinel field melts, with up to 23% melting to form the most depleted compositions. Mantle equilibration temperatures are higher than normal MORB (1,400 °C–1,480 °C) at relatively low pressures (1–2 GPa), which may reflect an influence of the Manus plume during subduction initiation. Our data support previous models of FAB origin by decompression melting but imply a source more depleted than normal MORB source mantle.
Plain Language Summary
This projects looks at how subduction zones form and evolve before island arc volcanism becomes established. Subduction zones are important because they are the primary sites for recycling chemically enriched crustal materials and because they form some of Earth's most important ore deposits. We drilled two deep core holes on the inner trench wall of the Izu‐Bonin subduction zone to recover samples from its earliest history, before formation of Izu‐Bonin island arc volcanoes. Samples from these cores were analyzed chemically to establish how lava compositions varied through time and to understand the processes that control their chemistry. We found a diverse set of lavas, with chemical compositions that are low in elements that are normally enriched in arc lavas. Calculations also show that these lavas were hotter than normal mid‐ocean ridge lavas. We found that the first lavas in a new subduction zone form by the upwelling of hot material from deeper in the Earth, which partially melts as it rises toward the surface. Small amounts of melt formed in equilibrium with garnet deeper in the Earth, while later melts formed in equilibrium with spinel at shallower depths in the Earth. The high extent of melting required, and the high calculated temperatures of these lavas, suggests the involvement of the Manus hot spot, which was located above the newly formed subduction zone some 52 million years ago. The lavas found in these drill holes are similar to lavas found in ocean crust that has been emplaced into mountain belts throughout the world and supports the proposition that in most areas, on‐land ocean crust formed above subduction zones, not at mid‐ocean ridges.
Key Points
Fore‐arc basalts (FABs) formed by decompression melting in response to subduction initiation and differ from mid‐ocean ridge basalts
FABs form by two‐stage melting, with early garnet field melts extracted prior to spinel field melting, resulting in LREE/HREE depletion
Highly depleted FAB may reflect both an older depletion event and higher ambient temperatures related to the Manus plume
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