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The presence of N-nitrosamines in drug products are currently an area of high regulatory and industry scrutiny, having been detected above acceptable regulatory levels in several solid oral drug products. For over 20 years, there has been an expectation that N-nitrosamines be eliminated or controlled to acceptable levels in orally inhaled and nasal drug products (OINDP). As a result, the OINDP industry has developed and implemented risk management processes and considerations to address N-nitrosamines in final drug product, including management and understanding of upstream supply particularly for OINDP device and container closure systems. We provide an overview of N-nitrosamine formation, discuss key current regulatory expectations worldwide for N-nitrosamines in drug products, discuss risk management approaches relevant for drug device combination products, and share analytical “tips” with respect to handling N-nitrosamines chemical assessments.

This thesis illustrates how the Response Surface Method (RSM) can be coupled with simulation tools to design an air defense projectile. The PROjectile Design and Analysis Software (PRODAS) was used to compute trajectories and target miss distances for an Enhanced Counter Air Projectile. These results were compared to a 2-DOF simulation to verify that a higher fidelity model is required when the projectile is spinning. Two RSM equations were derived to describe miss distance as a function of three variables. The first described the effects of projectile mass, launch angle, and applied acceleration. The second described the effects of thruster force, duration, and start time. The resultant RSM equation coefficients indicate how the miss distance depends on each individual variable and their interactions. This allows the designer to identify the primary governing variables and to narrow the design space to regions where the optimum design is most likely to occur.

This chapter contains sections titled: Introduction Leachables/Extractables Characterization and Profiling Determination of the AET Analytical Sensitivity and the AET : What is Modern Analytical Chemistry Capable of? Special Case Compounds Summary and Conclusions References

This chapter contains sections titled: Introduction TOA Identification of Extractables/Leachables Quantitative Analysis of Extractables/Leachables Concluding Summary References

This chapter contains sections titled: Introduction Extractables Profiling (Qualitative CES) Results from Extractables Profiling by LC/MS Optimization of a Selected GC/MS Extractable Profiling Method Simulated Leachables Study (Qualitative Extractables/Leachables Correlation) Conclusions and Recommendations Appendix: Case Study 15.1 Development and Evaluation of a Routine Extractables Test Method for a Sulfur ‐ Cured Elastomer Appendix: Case Study 15.2 Analysis of 2 ‐ Mercaptobenzothiazole (2 ‐ MBT) from Sulfur ‐ Cured Rubber by Liquid Chromatography – Tandem Mass Spectrometry (LC/MS/MS) Method References

The Post-exposure Prophylaxis in Infants (PEPI)-Malawi trial evaluated infant antiretroviral regimens for prevention of post-natal HIV transmission. A multi-assay algorithm (MAA) that includes the BED capture immunoassay, an avidity assay, CD4 cell count, and viral load was used to identify women who were vs. were not recently infected at the time of enrollment (MAA recent, N = 73; MAA non-recent, N = 2,488); a subset of the women in the MAA non-recent group known to have been HIV infected for at least 2 years before enrollment (known non-recent, N = 54). Antibody maturation and viral diversification were examined in these women. Samples collected at enrollment (N = 2,561) and 12-24 months later (N = 1,306) were available for serologic analysis using the BED and avidity assays. A subset of those samples was used for analysis of viral diversity, which was performed using a high resolution melting (HRM) diversity assay. Viral diversity analysis was performed using all available samples from women in the MAA recent group (61 enrollment samples, 38 follow-up samples) and the known non-recent group (43 enrollment samples, 22 follow-up samples). Diversity data from PEPI-Malawi were also compared to similar data from 169 adults in the United States (US) with known recent infection (N = 102) and known non-recent infection (N = 67). In PEPI-Malawi, results from the BED and avidity assays increased over time in the MAA recent group, but did not change significantly in the MAA non-recent group. At enrollment, HIV diversity was lower in the MAA recent group than in the known non-recent group. HRM diversity assay results from women in PEPI-Malawi were similar to those from adults in the US with known duration of HIV infection. Antibody maturation and HIV diversification patterns in African women provide additional support for use of the MAA to identify populations with recent HIV infection.

We compare the sensitivity and specificity of clinician visual waveform analysis against an automated system’s waveform analysis in detecting ineffective triggering in mechanically ventilated intensive care unit patients when compared against a reference label set based upon analysis of respiratory muscle activity. Electrical activity of the diaphragm or esophageal/transdiaphragmatic pressure waveforms were available to a single clinician for the generation of a reference label set indicating the ground truth, that is, presence or absence of ineffective triggering, on a breath-by-breath basis. Pressure and flow versus time tracings were made available to (i) a group of three clinicians; and (ii) the automated Syncron-E™ system capable of detecting patient-ventilator asynchrony in real-time, in order to obtain breath-by-breath labels indicating the presence or absence of ineffective triggering. The clinicians and the automated system did not have access to other waveforms such as electrical activity of the diaphragm or esophageal/transdiaphragmatic pressure. In total, 926 breaths were analyzed across the seven patients. Specificity for clinicians and the automated system were high (99.3% for clinician and 98.5% for the automated system). The automated system had a significantly higher sensitivity (83.2%) compared to clinicians (41.1%). Ineffective triggering detected by the automated system, which has access only to airway pressure and flow versus time tracings, is in substantial agreement with a reference detection derived from analysis of invasively measured patient effort waveforms.

Background. Reliable methods for estimating the incidence of human immunodeficiency virus (HIV) infection are needed to monitor the epidemic, identify at-risk populations, and evaluate HIV prevention strategies. We used a multifaceted approach to estimate HIV incidence in the HIV Prevention Trials Network (HPTN) 064 study. Methods. The HPTN 064 study enrolled 2067 HIV-seronegative women and 32 HIV-seropositive women with no prior HIV infection diagnosis. Women were followed for up to 12 months. HIV incidence estimates were based on (1) detection of acute HIV infection, (2) documentation of HIV seroconversion, and (3) detection of recent HIV infection, using a multiassay algorithm (MAA). Results. Two women had acute HIV infection at enrollment, 4 seroconverted, and 2 were identified as recently infected at enrollment using the MAA. The annual HIV incidence estimate based on acute infection at enrollment (2.52% [95% confidence interval {CI}, .17%-9.33%], using a 14-day window period) was higher than the estimate based on seroconversion (0.24% [95% CI, .07%-. 62%]; P= .027). Incidence estimates obtained using the MAA at enrollment and at the end of study were 0.25% (95% CI, .03%-. 93%) and 0.13% (95% CI, .006%-.76%), respectively. Conclusions. We detected a high frequency of acute infection at enrollment. Cross-sectional HIV incidence estimates obtained using the MAA were similar to the longitudinal estimate based on HIV seroconversion.

Despite interest among North American orthopaedic residents to pursue rotations in resource-limited settings, little is known regarding resident motivations and impact on host surgeons. Surveys were distributed to North American orthopaedic surgeons and trainees who participated in international rotations during residency to assess motivations for participation and to orthopaedic surgeons at partnering low- and middle-income country (LMIC) institutions to assess impact of visiting trainees. Responses were received from 136 North American resident rotators and 51 LMIC host surgeons and trainees. North American respondents were motivated by a desire to increase surgical capacity at the LMIC while host surgeons reported a greater impact from learning from residents than on surgical capacity. Negative aspects reported by hosts included selfishness, lack of reciprocity, racial discrimination, competition for surgical experience, and resource burdens. The motivations and impact of orthopaedic resident rotations in LMICs need to be aligned. Host perceptions and bidirectional educational exchange should be incorporated into partnership guidelines. •Resident rotations in low-income countries must consider needs of host surgeons.•Successful academic partnerships foster reciprocity and bidirectional exchange.•Resident motivations are not aligned with perceived impact on host surgeons.

ObjectivesTo understand the perspectives of stroke survivors, caregivers and general practitioners (GPs) on a polypill approach, consisting of blood pressure and cholesterol-lowering therapies, with or without aspirin, for the secondary prevention of stroke.MethodsA qualitative interview study was undertaken in 5 GP surgeries in the East of England. 28 survivors of stroke/transient ischaemic attack (TIA) were interviewed, 14 of them with a caregiver present, along with a convenience sample of 5 GPs, to assess attitudes towards a polypill and future use. Topic guides explored participants attitudes, potential uptake and long-term use, management of polypill medication and factors influencing the decision to prescribe. Data were analysed using a grounded theory approach. Key themes are presented and illustrated with verbatim quotes.ResultsThe analysis identified 3 key themes: polypill benefits, polypill concerns and polypill lessons for implementation. Stroke/TIA survivors were positive about the polypill concept and considered it acceptable in the secondary prevention of stroke. Perceived benefits of a polypill included convenience resulting in improved adherence and reduced burden of treatment. Caregivers felt that a polypill would improve medication-taking practices, and GPs were open to prescribing it to those at increased cardiovascular risk. However, concerns raised included whether a polypill provided equivalent therapeutic benefit, side effects through combining medications, consequences of non-adherence, lack of flexibility in regulating dosage, disruption to current treatment and suitability to the wider stroke population.ConclusionsParticipants acknowledged potential advantages in a polypill approach for secondary prevention of stroke; however, significant concerns remain. Further research on the efficacy of a polypill is needed to reassure practitioners whose concerns around inflexibility and treatment suitability are likely to influence the decision to prescribe a polypill for secondary prevention of stroke. Acceptability among survivors, caregivers and GPs is likely to determine the uptake and subsequent use of a polypill in the future.