The purpose of this study was to demonstrate the utility of combining a design of experiment (DOE) approach with high-throughput formulation screening to identify the main factors affecting protein ...thermostability and solution viscosity. The optimization of buffer compositions was guided by statistical analysis of the data to obtain the targeted combination of low viscosity and high thermostability. Different monoclonal antibody (mAb) formulation variables were evaluated in the study to achieve optimization of two parameters: (i) thermostability characterized by temperature of hydrophobic exposure and (ii) viscosity. High-throughput measurements were employed to characterize both parameters. The significance of each factor and the two-way interactions between them was studied by multivariable regression analysis. An experimental design was used to estimate the significance of all factors, including interaction effects. The range of optimal buffer compositions that maximized thermostability and minimized viscosity of a mAb formulation was determined. The described high-throughput methods are well suited for characterization of multiple protein formulation compositions with minimized resources such as time and material. The DOE approach can be successfully applied to the screening of mAb formulations early in the development lifecycle.
Designed experiments with binary responses Bower, Keith M.; Germansderfer, Abe; Kerwin, Bruce A. ...
Journal of pharmaceutical sciences,
November 2011, Letnik:
100, Številka:
11
Journal Article
Background Pancreatic fistula (PF) is one of the most common complications after pancreaticoduodenectomy. There have been no large prospective randomized trials evaluating PF rates comparing ...invagination versus duct to mucosa pancreaticojejunostomy. We tested the hypothesis that a duct to mucosa pancreaticojejunostomy would reduce the PF rate. Study Design Between August 2006 and May 2008, 197 patients at two institutions underwent pancreaticoduodenectomy by a total of 8 experienced pancreatic surgeons as part of this prospective randomized trial (clinical trial no. NCT00359320 ). All patients were stratified by pancreatic texture and randomized to either an invagination or a duct to mucosa pancreaticojejunal anastomosis. Recorded variables included pancreatic duct diameter, operative time, blood loss, complications, and pathology. Primary end point was PF rate, as defined by the International Study Group on Pancreatic Fistula. Secondary end points included PF grade, postoperative length of hospital stay, other morbidities, and mortality. Results Rate of PF for the entire cohort was 17.8%. There were 23 fistulas (24%) in the duct to mucosa cohort and 12 fistulas (12%) in the invagination cohort (p < 0.05). The greatest risk factor for a PF was pancreas texture: PF developed in only 8 patients (8%) with hard glands, and in 27 patients (27%) with a soft gland. There were two perioperative deaths (both in the duct to mucosa group), with the proximate causes of death being PF, followed by bleeding and sepsis. Conclusions This dual-institution prospective randomized trial reveals considerably fewer fistulas with invagination compared with duct to mucosa pancreaticojejunostomy after pancreaticoduodenectomy. Results confirm increased PF rates in soft as compared with hard glands. Additional studies are needed to define the optimal technique of pancreatic reconstruction after pancreaticoduodenectomy.
Many business and engineering courses stress the use of confidence interval and hypothesis testing procedures based on the Student t distribution. However, students are often unaware of the ...underlying assumptions that govern these procedures and of the consequences of misapplying them. In this exegetic account, we discuss the concept of robustness by exploring violations of the Student t assumptions and the effects of those violations on the resulting inferences. We also discuss the use of randomization methods as possible alternative methods. Our goal is to familiarize readers with the underpinnings of the t procedures, to summarize their use in practice, and to offer words of caution as to when they should not be used.
Residency training in refractive surgery Weber, Marissa L; Stutzman, Richard D; Mines, Michael J ...
Journal of cataract and refractive surgery,
11/2012, Letnik:
38, Številka:
11
Journal Article
Recenzirano
To evaluate resident refractive surgery caseload and surgical outcomes in an academic medical center.
Walter Reed Army Medical Center, Washington, DC, USA.
Comparative case study.
Keratorefractive ...procedures performed by residents at the Walter Reed Center for Refractive Surgery between 2002 and 2010 were reviewed. Outcomes of surgeries performed by the graduating classes of 2008 to 2010 were compared with those of cases performed by staff. The uncorrected distance visual acuity (UDVA), manifest refraction spherical equivalent, corrected distance visual acuity (CDVA), and complications were analyzed.
Between 2002 and June 2010, residents performed 1566 procedures (1414 photorefractive keratectomy PRK, 152 laser in situ keratomileusis), for a mean of 20.2 procedures from 2002 to 2004, 51.6 from 2005 to 2007, and 99.9 from 2008 to 2010. Outcomes analysis was performed on 333 resident eyes and 977 staff eyes treated between 2008 and June 2010. Six months postoperatively, 96.1% of resident-treated eyes and 94.6% of staff-treated eyes had a UDVA 20/20 or better (P=.312) and 61.3% and 64.3%, respectively, had a UDVA 20/15 or better (P=.324). The percentage of eyes within ±0.50 diopter of emmetropia at 6 months was 94.0% for residents and 91.1% for staff (P=.105). The postoperative CDVA was within 2 lines of preoperative baseline in all resident cases and 99.8% of staff cases (P=.999).
Resident experience grew steadily over the period studied. Overall safety and efficacy of resident-performed surgery, albeit mainly PRK based, matched that of fellowship-trained refractive surgeons.
No author has a financial or proprietary interest in any material or method mentioned.
To evaluate the safety and efficacy of photorefractive keratectomy (PRK) in patients with posterior polymorphous dystrophy (PPMD) with vesicular and band subtypes.
Walter Reed Center for Refractive ...Surgery, Washington, DC, USA.
Case series.
The records of patients with PPMD who had PRK between January 2002 and May 2009 were reviewed. Data for analysis included sex, age, ablation depth, residual stromal bed thickness, manifest spherical equivalent, uncorrected (UDVA) and corrected (CDVA) distance visual acuities, central corneal thickness (CCT), endothelial cell density (ECD), intraocular pressure (IOP), and complications. Preoperative and postoperative results were compared using the Wilcoxon signed-rank test, with P < .05 considered significant.
Fourteen eyes of 7 men (mean age 29.1 years ± 9.1 SD; range 21 to 42 years) with at least a 6-month follow-up were reviewed. At the final follow-up (mean 19.5 months; range 6.3 to 58.3 months), all eyes had a UDVA of 20/15 and all eyes were within ± 0.50 diopter of emmetropia. The CDVA was unchanged from preoperatively in 71.4% of eyes and improved by 1 line in 28.6%. There were no significant complications. The IOP did not change significantly over the follow-up (P = .272). At the final visit, the mean ECD (2795.3 ± 366.0 cells/mm(2)) was unchanged from baseline (2809.1 ± 338.3 cells/mm(2)) (P = .114).
Photorefractive keratectomy in PPMD patients with vesicular and band subtypes resulted in excellent visual outcomes and a low incidence of adverse effects. Endothelial cell densities did not change significantly in the early postoperative period.
No author has a financial or proprietary interest in any material or method mentioned.
During austral summer 2015, the Microphysics of Antarctic Clouds (MAC) field campaign collected unique and detailed airborne and ground-based in situ measurements of cloud and aerosol properties over ...coastal Antarctica and the Weddell Sea. This paper presents the first results from the experiment and discusses the key processes important in this region, which is critical to predicting future climate change. The sampling was predominantly of stratus clouds, at temperatures between −20 and 0 °C. These clouds were dominated by supercooled liquid water droplets, which had a median concentration of 113 cm−3 and an interquartile range of 86 cm−3. Both cloud liquid water content and effective radius increased closer to cloud top. The cloud droplet effective radius increased from 4 ± 2 µm near cloud base to 8 ± 3 µm near cloud top. Cloud ice particle concentrations were highly variable with the ice tending to occur in small, isolated patches. Below approximately 1000 m, glaciated cloud regions were more common at higher temperatures; however, the clouds were still predominantly liquid throughout. When ice was present at temperatures higher than −10 °C, secondary ice production most likely through the Hallett–Mossop mechanism led to ice concentrations 1 to 3 orders of magnitude higher than the number predicted by commonly used primary ice nucleation parameterisations. The drivers of the ice crystal variability are investigated. No clear dependence on the droplet size distribution was found. The source of first ice in the clouds remains uncertain but may include contributions from biogenic particles, blowing snow or other surface ice production mechanisms. The concentration of large aerosols (diameters 0.5 to 1.6 µm) decreased with altitude and were depleted in air masses that originated over the Antarctic continent compared to those more heavily influenced by the Southern Ocean and sea ice regions. The dominant aerosol in the region was hygroscopic in nature, with the hygroscopicity parameter κ having a median value for the campaign of 0.66 (interquartile range of 0.38). This is consistent with other remote marine locations that are dominated by sea salt/sulfate.
During the summertime, dust from the Sahara can be efficiently transported
westwards within the Saharan air layer (SAL). This can lead to high aerosol
loadings being observed above a relatively clean ...marine boundary layer (MBL)
in the tropical Atlantic Ocean. These dust layers can impart significant
radiative effects through strong visible and IR light absorption and
scattering, and can also have indirect impacts by altering cloud properties.
The processing of the dust aerosol can result in changes in both direct and
indirect radiative effects, leading to significant uncertainty in climate
prediction in this region. During August 2015, measurements of aerosol and
cloud properties were conducted off the coast of west Africa as part of the
Ice in Cloud Experiment – Dust (ICE-D) and AERosol properties – Dust
(AER-D) campaigns. Observations were obtained over a 4-week period using the
UK Facility for Atmospheric Airborne Measurements (FAAM) BAe 146 aircraft
based on Santiago Island, Cabo Verde. Ground-based observations were
collected from Praia (14∘57′ N, 23∘29′ W;
100 m a.s.l.), also located on Santiago Island. The dust in the SAL was
mostly sampled in situ at altitudes of 2–4 km, and the potential dust age
was estimated by backward trajectory analysis. The particle mass
concentration (at diameter d = 0.1–20 µm) decreased with
transport time. Mean effective diameter (Deff) for supermicron
SAL dust (d = 1–20 µm) was found to be 5–6 µm
regardless of dust age, whereas submicron Deff
(d = 0.1–1 µm) showed a decreasing trend with longer
transport. For the first time, an airborne laser-induced incandescence instrument (the
single particle soot photometer – SP2) was deployed to measure the hematite
content of dust. For the Sahel-influenced dust in the SAL, the observed
hematite mass fraction of dust (FHm) was found to be
anti-correlated with the single scattering albedo (SSA,
λ = 550 nm, for particles d < 2.5 µm); as
potential dust age increased from 2 to 7 days, FHm increased from
2.5 to 4.5 %, SSA decreased from 0.97 to 0.93 and the derived imaginary
part (k) of the refractive index at 550 nm increased from 0.0015 to
0.0035. However, the optical properties of Sahara-influenced plumes (not
influenced by the Sahel) were independent of dust age and hematite content
with SSA ∼ 0.95 and k ∼ 0.0028. This indicates that the
absorbing component of dust may be source dependent, or that gravitational
settling of larger particles may lead to a higher fraction of more absorbing
clay–iron aggregates at smaller sizes. Mie calculation using the measured
size distribution and size-resolved refractive indices of the absorbing
components (black carbon and hematite) reproduces the measured SSA to within
±0.02 for SAL dust by assuming a goethite ∕ hematite mass ratio of 2.
Overall, hematite and goethite constituted 40–80 % of the absorption for
particles d < 2.5 µm, and black carbon (BC) contributed
10–37 %. This highlights the importance of size-dependent composition in
determining the optical properties of dust and also the contribution from BC
within dust plumes.
In situ airborne observations of cloud microphysics, aerosol properties, and thermodynamic structure over the transition from sea ice to ocean are presented from the Aerosol-Cloud Coupling And ...Climate Interactions in the Arctic (ACCACIA) campaign. A case study from 23 March 2013 provides a unique view of the cloud microphysical changes over this transition under cold-air outbreak conditions. Cloud base lifted and cloud depth increased over the transition from sea ice to ocean. Mean droplet number concentrations, Ndrop, also increased from 110 ± 36 cm−3 over the sea ice to 145 ± 54 cm−3 over the marginal ice zone (MIZ). Downstream over the ocean, Ndrop decreased to 63 ± 30 cm−3. This reduction was attributed to enhanced collision-coalescence of droplets within the deep ocean cloud layer. The liquid water content increased almost four fold over the transition and this, in conjunction with the deeper cloud layer, allowed rimed snowflakes to develop and precipitate out of cloud base downstream over the ocean. The ice properties of the cloud remained approximately constant over the transition. Observed ice crystal number concentrations averaged approximately 0.5–1.5 L−1, suggesting only primary ice nucleation was active; however, there was evidence of crystal fragmentation at cloud base over the ocean. Little variation in aerosol particle number concentrations was observed between the different surface conditions; however, some variability with altitude was observed, with notably greater concentrations measured at higher altitudes ( > 800 m) over the sea ice. Near-surface boundary layer temperatures increased by 13 °C from sea ice to ocean, with corresponding increases in surface heat fluxes and turbulent kinetic energy. These significant thermodynamic changes were concluded to be the primary driver of the microphysical evolution of the cloud. This study represents the first investigation, using in situ airborne observations, of cloud microphysical changes with changing sea ice cover and addresses the question of how the microphysics of Arctic stratiform clouds may change as the region warms and sea ice extent reduces.
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