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Isbreer beveger seg og isdynamikken kontrolleres av mange prosesser. I dette arbeidet fokuserer vi spesielt på basalglidning, eller glidning mot underlaget. Basalglidning er interessant å studere fordi grønlandsisen mister masse til havet, og basalglidning står for opptil 90% av bevegelsen til isdekket. For å studere basalglidning, jobber vi med isbreer i sørvest-Grønland. De fleste isbreene her er landbaserte, slik at vi kan isolere glidningsprosesser og ikke trenger å tenke på prossesser mellom hav og is. En bedre forståelse av denne prosessen er viktig for å si noe om hvordan isbreer kommer til å respondere på fremtidig klima. På sommeren smelter snø på toppen av isbreene, smeltevannet renner ned gjennom sprekker i isen og påvirker hvordan isen glir på underlaget. For å forstå hvordan smeltevann påvirker hvordan breene beveger seg over lange tidsskalaer, produserte vi isbevegelseshastighetskart for alle breene i sørvest-Grønland for perioden 2000-2019. Tidligere studier har visst at gjennomsnittsbevegelsen i disse isbreene har bremset opp mellom 2000 og 2012, og hastighetskartene våre bekrefter dette resultatet. For perioden 2012-2019 viser noen studier at breene akselererer igjen. Dette resultatet støttes ikke av våre hastighetskart. Årsaken er at tidligere studier har brukt hele regionens gjennomsnittshastighet (et datapunkt per år), mens vi har sporet ishastigheten på individuelle 150-kvadratmeters piksler (millioner av datapunkter per år). Vi viser at denne mer detaljerte fremgangsmåten er nødvendig fordi isbevegelsen ikke er konstant innenfor isdekket. Vår studie viser at det er viktig å sørge for at bildene, som brukes til hastighetskartene, er tatt i samme periode hvert år for å ha tall som er sammenlignbare fra år til år. For å se på sammenhengen mellom produksjon av overflatesmeltevann og ishastigheter, kombinerer vi også hastighetskartene med klimareanalyser. Vi viser at ishastighet ikke varierer lineært med smeltevannsavrenning, men at ishastigheten først øker, så minker, og deretter øker igjen med økende avrenning. Det er ikke tidligere påvist at høy smeltevannsproduksjon kan føre til raskere ishastigheter. I vår studie analyserte vi bare en liten del av kartdatasettet i detalj. Ishastighetskartene for årene 1984 til 2020 for sørvest-Grønland er åpent tilgjengelige. Glaciers are flowing. While several processes take part in ice movement, this thesis focuses on one in particular: basal sliding. We are particularly interested in this last one as the Greenland Ice Sheet is losing mass through discharge of ice into ocean, and basal sliding accounts to up to 90% of the displacement of ice. In order to study this process, the study area was specifically chosen, Southwest Greenland, where most glaciers are land-terminating, so that ice-ocean interactions do not have to be taken into account. Recent studies also argued that, for the two other processes to consider (deformation of the ice, and deformation of the sediment underlying the ice), ice deformation is almost negligible, and hard-bed conditions were observed in our area. Being able to isolate basal sliding is an advantage to help understand how this single process works, and how it might be affected by climate. The first part of the scientific results reassesses the ice velocity trends over 2000-2019 using yearly optical feature-tracking, but goes beyond previous scientific work, as we derive here linear regressions for every single pixel in our area, while previous work derived velocity trends on area-wide yearly velocity averages. We used two time periods for our study, 2000-2012 and 2013-2019, and found a significant deceleration for the first period, but only find significant reacceleration for the second period in small part of the study area, namely low-lying glaciers tongues. We find inconsistent results for the rest of the study area, while another study did find a significant acceleration using area-wide yearly velocity averages. We display per-pixel linear regressions slopes maps and associated p-values maps in opposition to difference maps in previous papers, and proved that we cannot assume similar ice velocity trends for the entire area. Our second result in this first part is that the way data is averaged for yearly averages can affect the obtained velocity. Previous studies did use all data available, therefore aggregating yearly velocities derived from image pairs that start before, during and after summer. We show that doing so can affect yearly velocities by up to 15%, and argued for the selection of image pairs that start before summer, so that the period assessed is comparable for every year, encompassing a summer and the following winter. For this first part, we derived a dataset of yearly velocities for the years 1984 to 2020 for Southwest Greenland. Constituting such dataset for the whole Southwest of Greenland nearly took two years, and we rendered all the data publicly available on an open repository in December 2022. The second part of the scientific results is built from the same dataset containing yearly ice velocities in the same area, but combined with climate reanalysis. We focus on 5 basins in our study area, and for the period 2013-2021. The velocity variations in this land-terminating part of Greenland are relatively small, therefore we followed the recommendations from our first publication, and only selected image pairs starting before summer. This precise selection of data is only possible after the launch of Landsat 8, reducing our dataset to after 2013. We find that the impact of meltwater on velocities varies with altitude and location, and that positive melt anomalies do not necessarily lead to slower velocities, especially for the year 2019 were the melt was up to 40% above the 2013-2021 average, and where some basins show a faster than average velocities. Both parts underline the importance of local ice behaviors: ice velocity trends vary with basin and altitude, and subsequently the relationship with runoff was also observed to vary in location and altitude. We therefore urge further studies to not consider similar ice velocity behaviors for different parts of the Greenland Ice Sheet, especially when performing long-term ice loss estimations. Doktorgradsavhandling

Amivantamab, an epidermal growth factor receptor (EGFR)-c-Met bispecific antibody, targets activating/resistance EGFR mutations and MET mutations/amplifications. In the ongoing CHRYSALIS study (ClinicalTrials.gov Identifier: NCT02609776), amivantamab demonstrated antitumor activity in patients with non-small cell lung cancer harboring EGFR exon 20 insertion mutations (ex20ins) that progressed on or after platinum-based chemotherapy, a population in which amivantamab use has been approved by the US Food and Drug Administration. This bridging study clinically validated two novel candidate companion diagnostics (CDx) for use in detecting EGFR ex20ins in plasma and tumor tissue, Guardant360 CDx and Oncomine Dx Target Test (ODxT), respectively. From the 81 patients in the CHRYSALIS efficacy population, 78 plasma and 51 tissue samples were tested. Guardant360 CDx identified 62 positive (16 negative), and ODxT identified 39 positive (3 negative), samples with EGFR ex20ins. Baseline demographic and clinical characteristics were similar between the CHRYSALIS-, Guardant360 CDx-, and ODxT-identified populations. Agreement with local PCR/next-generation sequencing tests used for enrollment into CHRYSALIS demonstrated high adjusted negative (99.6% and 99.9%) and positive (100% for both) predictive values with the Guardant360 CDx and ODxT tests, respectively. Overall response rates were comparable between the CHRYSALIS, Guardant360 CDx, and ODxT populations. Both the plasma- and tissue-based diagnostic tests provided accurate, comprehensive, and complementary approaches to identifying patients with EGFR ex20ins who could benefit from amivantamab therapy.

On March 13, 2020, the president of the United States declared a national emergency in response to the coronavirus disease 2019 (COVID-19) pandemic (1). With reports of laboratory-confirmed cases in all 50 states by that time (2), disruptions were anticipated in the U.S. health care system's ability to continue providing routine preventive and other nonemergency care. In addition, many states and localities issued shelter-in-place or stay-at-home orders to reduce the spread of COVID-19, limiting movement outside the home to essential activities (3). On March 24, CDC posted guidance emphasizing the importance of routine well child care and immunization, particularly for children aged ≤24 months, when many childhood vaccines are recommended.

OBJECTIVE: To evaluate the ability of different types of vaccine storage units to maintain appropriate temperatures for the storage of vaccines and to characterize deviations from recommended temperatures. DATA SOURCES: Continuous temperature monitoring devices, or digital data loggers, from vaccine providers who participated in a continuous temperature monitoring pilot project. STUDY DESIGN: We computed descriptive statistics on the percentage of runtime with an out-of-range temperature, or excursion, for different storage unit types (freezers and refrigerators) and for different storage unit grades (household-grade combination, household-grade stand alone, and purpose-built or pharmaceutical grade). We developed frequency histograms for the percentage of storage unit runtime outside of the normal range. We plotted the duration and temperature extrema for identified excursions. Analyses were stratified by storage unit type and grade. RESULTS: Household-grade combination units underperformed relative to household-grade stand-alone and purpose-built units. Among refrigerators, household-grade combination units operated in the normal temperature range an average of 98.9% of their observed runtime, which was lower than 99.4% (p value = 0.038) for household-grade stand-alone and 99.9% (p value < 0.001) for purpose-built units. Among freezers, household-grade combination units operated in the normal temperature range an average of 95.0% of their observed runtime, which was lower than 99.3% (p value < 0.001) for household-grade stand-alone units and 99.7% (p value < 0.001) for purpose-built units. CONCLUSION: These findings, in particular the underperformance of household-grade combination units relative to household-grade stand-alone and purpose-built units, support current CDC recommendations to avoid the use of household-grade combination storage units when possible.

Black men who have sex with men (MSM) have disproportionate HIV disease burden in the United States. Black MSM have been underrepresented in biomedical research, including HIV clinical trials, due to a myriad of socio-structural, socio-cultural, and psychosocial factors. The HIV Prevention Trials Network (HPTN) 061, a feasibility study of a multi-component HIV prevention intervention for Black MSM in six US cities, incorporated the development and implementation of a Black Caucus as a culturally grounded model for the integration of Black MSM in clinical trials and research in HPTN. Based on a qualitative methodological approach, we describe the formation and implementation of the Black Caucus from the perspective of Black MSM key community stakeholders. Three major themes emerged from the qualitative narratives: (1) the role of the Black Caucus in shaping the HPTN, (2) how the Black Caucus addresses the needs of Black MSM communities pertaining to the influence of race and sexual identity, and (3) socio-cultural needs of Black MSM. These findings have implications for the provision of culturally congruent expertise, community engagement, cultural mistrust, recruitment and retention of Black MSM in HIV clinical trials, culturally-relevant study design and implementation, and the role of developing Black MSM prevention researchers.

Afforestation is considered a cost-effective and readily available climate change mitigation option. In recent studies afforestation is presented as a major solution to limit climate change. However, estimates of afforestation potential vary widely. Moreover, the risks in global mitigation policy and the negative trade-offs with food security are often not considered. Here, we present a new approach to assess the economic potential of afforestation with the IMAGE 3.0 integrated assessment model framework (Doelman et al., 2019). In addition, we discuss the role of afforestation in mitigation pathways and the effects of afforestation on the food system under increasingly ambitious climate targets. We show that afforestation has a mitigation potential of 4.9 GtCO2/yr at 200 US$/tCO2 in 2050 leading to large-scale application in an SSP2 scenario aiming for 2°C (410 GtCO2 cumulative up to 2100). Afforestation reduces the overall costs of mitigation policy. However, it may lead to lower mitigation ambition and lock-in situations in other sectors. Moreover, it bears risks to implementation and permanence as the negative emissions are increasingly located in regions with high investment risks and weak governance, for example in Sub-Saharan Africa. Our results confirm that afforestation has substantial potential for mitigation. At the same time, we highlight that major risks and trade-offs are involved. Pathways aiming to limit climate change to 2°C or even 1.5°C need to minimize these risks and trade-offs in order to achieve mitigation sustainably.The afforestation study published as Doelman et al. (2019) excluded biophysical climate effects of land use and land cover change on climate, even though this is shown to have a substantial effect especially locally (Alkama & Cescatti, 2016). As a follow-up to this study we implement the grid-specific temperature effects as derived by Duveiller et al. (2020) to the mitigation scenarios with large-scale afforestation to assess the effectiveness of afforestation for climate change mitigation as increased or reduced effectiveness may change cost-optimal climate policy. Notably in the boreal regions this can have a major effect, as transitions from agricultural land to forest are shown to have a substantial warming effect due to reduced albedo limiting the mitigation potential in these regions. Conversely, in the tropical areas the already high mitigation potential of afforestation could be even more efficient, as increased evapotranspiration from forests leads to additional cooling. However, it is uncertain whether the high efficiency of afforestation in tropical regions can be utilized as these are also the regions with high risks to implementation and permanence. ReferencesAlkama, R., & Cescatti, A. (2016). Biophysical climate impacts of recent changes in global forest cover. Science, 351(6273), 600-604.Doelman, J. C., Stehfest, E., van Vuuren, D. P., Tabeau, A., Hof, A. F., Braakhekke, M. C., . . . Lucas, P. L. (2019). Afforestation for climate change mitigation: Potentials, risks and trade-offs. Global Change BiologyDuveiller, G., Caporaso, L., Abad-Viñas, R., Perugini, L., Grassi, G., Arneth, A., & Cescatti, A. (2020). Local biophysical effects of land use and land cover change: towards an assessment tool for policy makers. Land Use Policy, 91, 104382.

Resume L’exposition des enfants au plomb a diminue au cours des 20 dernieres annees, grâce notamment a l’interdiction de l’essence au plomb. Reduire l’exposition demeure cependant un objectif de sante publique en l’absence de seuil de toxicite. Il est donc important d’actualiser les connaissances sur l’impregnation des enfants par le plomb et d’identifier les determinants environnementaux des plombemies afin de mettre a jour les strategies de prevention. Nous avons realise deux enquetes transversales en 2008–2009 : (1) une enquete d’impregnation, Saturn-Inf, qui a recrute 3831 enfants de 6 mois a 6 ans residant en France et (2) une sous-enquete Plomb-Habitat au domicile de 484 enfants issus de Saturn-Inf avec des mesures de plomb dans l’eau, les sols, les poussieres, les peintures, les cosmetiques traditionnels et ceramiques artisanales. Deux modeles statistiques ont ete construits : un modele multivarie additif generalise sur la moyenne geometrique (MG) des plombemies et un modele de regression par quantile sur les 10e, 25e, 50e, 75e et 90e quantiles des plombemies. La MG des plombemies etait de 14,9 μg/L (intervalle de confiance a 95 % [IC 95 %] = [14,5–15,4]) ; 0,09 % des enfants (IC 95 % = [0,03–0,15]) avaient des plombemies superieures a 100 μg/L et 1,5 % (IC 95 % = [0,9–2,1]) des plombemies etaient superieures a 50 μg/L. La poussiere du logement et des parties communes, l’eau du robinet, la peinture interieure, les ceramiques artisanales, les cosmetiques traditionnels, le sol des aires de jeu exterieures et le tabagisme passif etaient associes avec la MG des plombemies. La poussiere du logement et de l’eau du robinet ont le plus contribue a la fois a la MG et au quantile 90 des plombemies. La concentration de plomb dans la poussiere etait positivement correlee avec tous les quantiles des plombemies meme a de faibles concentrations. Les concentrations de plomb dans l’eau du robinet au-dessus de 5 μg/L etaient egalement correlees positivement avec la MG et les quantiles 75 et 90 chez les enfants buvant de l’eau du robinet. Des actions preventives doivent cibler les poussieres du logement et l’eau du robinet pour reduire les plombemies des enfants en France. L’utilisation de cosmetiques traditionnels devrait etre evitee et les ceramiques devraient etre reservees a des fins decoratives.

Policy makers and resource managers in Hawai‘i often look to the ancient Hawaiian system of resource management, known as the ahupua‘a system, as a holistic and sustainable mountains-to-sea model for restoration of social-ecological system health and function. Many components of this ancient system, such as agriculture, aquaculture, and nearshore fishery management, have been documented, studied, and revived in the name of both sustainability and perpetuation of Hawai‘i's indigenous culture. One relatively glaring hole in the context of our understanding of this ancient system is management of forest resources on a system (i.e., large-scale plant community) level. Five terms for identified and managed social-ecological zones, wao kānaka, wao lā‘au, wao nāhele, wao kele, and wao akua, were used to delineate GIS layers in the model ahupua‘a of Hā‘ena. These were then extrapolated across the entire island of Kaua‘i. The resulting map indicates that not all ahupua‘a on Kaua‘i had all five social-ecological zones, which gives valuable insight into how upland regions of the various ahupua‘a may have been managed in the ali‘i era. This research has implications for contemporary approaches to large-scale biocultural conservation initiatives and other resource management plans that aim toward having broader community support for such efforts. Analysis shows that broad overlap between the ancient system and contemporary management zones exists, which implies that it may be feasible to adapt this ancient approach in the bureaucratic system of the contemporary era.

Through research, restoration of agro-ecological sites, and a renaissance of cultural awareness in Hawaiʻi, there has been a growing recognition of the ingenuity of the Hawaiian biocultural resource management system. The contemporary term for this system, &ldquo, the ahupuaʻa system&rdquo, does not accurately convey the nuances of system function, and it inhibits an understanding about the complexity of the system&rsquo, s management. We examined six aspects of the Hawaiian biocultural resource management system to understand its framework for systematic management. Based on a more holistic understanding of this system&rsquo, s structure and function, we introduce the term, &ldquo, the moku system&rdquo, to describe the Hawaiian biocultural resource management system, which divided large islands into social-ecological regions and further into interrelated social-ecological communities. This system had several social-ecological zones running horizontally across each region, which divided individual communities vertically while connecting them to adjacent communities horizontally, and, thus, created a mosaic that contained forested landscapes, cultural landscapes, and seascapes, which synergistically harnessed a diversity of ecosystem services to facilitate an abundance of biocultural resources. &ldquo, The moku system&rdquo, is a term that is more conducive to large-scale biocultural restoration in the contemporary period, while being inclusive of the smaller-scale divisions that allowed for a highly functional system.

The use of spark-ignited (SI) production-style vehicle engines in high-performance applications is a growing trend in the aftermarket performance industry. However, the use of economically designed components, specifically cylinder heads, presents challenges when used in this manner. The study of flow through a cylinder head is a topic of extensive research where complex flow patterns have made modelling and computer simulation challenging. A variety of approaches have been employed including simplifying model assumptions, different boundary conditions, different meshing strategies, and different turbulence models. The focus of this research is modification of the air intake port geometry of a VR38DETT engine in order to increase the volumetric flow rate past a current limit of 330.4 CFM at 0.700” valve lift, which has been achieved by porting methods alone. Using SolidWorks, a computational fluid dynamics model was developed, verified, validated, and analyzed. The modelling methodology was verified using a mesh convergence study of the pressure drop along a pipe with a bend. Also, the bend loss coefficient was compared to published values for different ratios of the centerline radius of the bend to the internal pipe diameter. The model was then validated using steady-state flow bench test data. Results of the analysis indicate that the cylinder head can achieve a flow rate 5.15% above the current limit when the port geometry is enlarged and the short-side radius is increased, only in support of a cooling passage geometry change.

This paper discusses the experimental results of a study comparing several aspects of the mechanical behaviour of two quasi-unidirectional non-crimp fabric composites based on non-crimp fabrics that differ only in stitching pattern. A NEW stitching pattern was compared to an industry common type (ICT). The properties studied include fabric and laminate thickness, fibre volume fraction, static tensile modulus and strength in longitudinal and transverse direction, high-speed tensile strength and tension–tension fatigue life. Statistically significant differences were observed for fabric and composite thickness, which was found to be higher for the ICT type composite. A higher fibre volume fraction was observed for the NEW stitching pattern material, as well as a higher longitudinal tensile strength at high and low speeds and a slightly higher fatigue life.

Approaches that use the pseudolikelihood to perform multilevel modelling on survey data have been presented in the literature. To avoid biased estimates due to unequal selection probabilities, conditional weights can be introduced at each level. Less-biased estimators can also be obtained in a two-level linear model if the level-1 weights are scaled. In this paper, we studied several level-2 weights that can be introduced into the pseudolikelihood when the sampling design and the hierarchical structure of the multilevel model do not match. Two-level and three-level models were studied. The present work was motivated by a study that aims to estimate the contributions of lead sources to polluting the interior floor dust of the rooms within dwellings. We performed a simulation study using the real data collected from a French survey to achieve our objective. We conclude that it is preferable to use unweighted analyses or, at the most, to use conditional level-2 weights in a two-level or a three-level model. We state some warnings and make some recommendations.

Quasi-unidirectional glass fibre non crimp fabric composites are routinely used in wind energy applications. An important factor to consider in this type of application is the fatigue behaviour of the materials. The present paper gives an overview of the current approach to material fatigue testing and design in the wind energy industry, as well as a review of available material data for the fatigue of unidirectional glass fibre composites. Both “pure” unidirectional and quasi-unidirectional (NCF-based) materials are considered. ispartof: Mechanics & Industry vol:14 issue:3 pages:175-189 status: published

Children are exposed to toxic metals and metalloids via their diet and environment. Our objective was to assess the aggregate chronic exposure of children aged 3–6 years, living in France, to As, Cd, Cr, Cu, Mn, Pb, Sb, Sr, and V present in diet, tap water, air, soil and floor dust in the years 2007–2009. Dietary data came from the French Total Diet Study, while concentrations in residential tap water, soil and indoor floor dust came from the ‘Plomb-Habitat’ nationwide representative survey on children's lead exposure at home. Indoor air concentrations were assumed to be equal to outdoor air concentrations, which were retrieved from regulatory measurements networks. Human exposure factors were retrieved from literature. Data were combined with Monte Carlo simulations. Median exposures were 1.7, 0.3, 10.2, 34.1, 60.3, 0.7, 0.1, 44.3, 1.5 and 95th percentiles were 4.4, 0.5, 15.8, 61.3, 98.3, 2.5, 0.1, 111.1, 2.9 μg/kg bw/d for As, Cd, Cr, Cu, Mn, Pb, Sb, Sr, and V respectively. Dietary exposures dominate aggregate exposures, with the notable exception of Pb - for which soils and indoor floor dust ingestion contribute most at the 95th percentile. The strengths of this study are that it aggregates exposures that are often estimated separately, and uses a large amount of representative data. This assessment is limited to main diet and residential exposure, and does not take into account the relative bioavailability of compounds. These results could be used to help target prevention strategies. Keywords: Aggregate exposure, Metal, Total diet study, Residential exposure, Public health

International audience; This research addresses the effects of quasi-UD non-crimp fabric (NCF) design parameters on the fabric architecture and on the permeability tensor. These fabrics are designed for the Liquid Resin Infusion (LRI) of large and thick composite parts. Three fabrics’ parameters intended to bring a flow enhancement to the NCF are investigated: the stitch spacing, the stitch pattern and the weft tow lineal weight. Image analysis is undertaken to characterize the morphology of non-crimp fabric composite. A new continuous permeability measurement method based on compressive tests is proposed to relate the permeability of the quasi-UD NCF to the design parameters during the infusion process. The latter are proven to influence significantly both the fabric architecture and the permeability tensor coefficients.

International audience; Sixty-six semi-volatile organic compounds (SVOCs)—phthalates, polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), one pyrethroid, organochlorine and organophosphorous pesticides, alkylphenols, synthetic musks, tri-n-butylphosphate and triclosan—were measured on PM10 filters collected over 7 days during a nationwide survey of 285 French dwellings, representative of nearly 25 million housing units. Thirty-five compounds were detected in more than half of the dwellings. PAHs, phthalates and triclosan were the major particle-bound SVOCs, with a median concentration greater than 1 ng m−3 for butylbenzyl phthalate (BBP) (median: 1.6 ng m−3), di(2-ethylhexyl) phthalate (DEHP) (46 ng m−3) and di-iso-nonyl phthalate (DiNP) (7.9 ng m−3), and greater than 0.1 ng m−3 for triclosan (114 pg m−3), benzo(a)anthracene (44.4 pg m−3), benzo(a)pyrene (138 pg m−3), benzo(b)fluoranthene (306 pg m−3), benzo(g,h,i)perylene (229 pg m−3), and indeno(1,2,3-c,d)pyrene (178 pg m−3). For most of the SVOCs, higher concentrations were found in the dwellings of smokers and during the heating season. The concentrations of banned SVOCs—namely, PCBs and organochlorine pesticides—were correlated. Permethrin, 4-tert-butylphenol and bisphenol-A showed no correlation with the other SVOCs and seemed to have their own specific sources. Most SVOCs were positively associated with PM10 concentration, suggesting that any factor that raises the mass of indoor airborne particles also increases the exposure to SVOCs through inhalation

The ‘standard drink’ concept is widely used as a standardized measure of alcohol consumption. There is no equivalent measure of cannabis consumption, perhaps due to challenges such as varied joint size, tetrahydrocannabinol content, and means of delivery. This study introduces a new measure of cannabis quantity and examines whether it predicts cannabis-related social problems with and without controlling for frequency of use. Cannabis-related problems, measured by the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST), were predicted from cannabis use frequency (days in past month) and quantity (one joint = 0.5 g, five bong or pipe hits, 10 puffs), controlling for age and gender. The sample consisted of 665 participants aged 15–67 (mean = 28.2, SD = 11.8) from the British Columbia Alcohol and Other Drug Monitoring Project, High Risk Group Surveys, 2008 to 2009. Cannabis use frequency and quantity were positively associated with cannabis-related problems. Individuals who consumed cannabis d...

This March 2009 Workshop Summary Report was sponsored by Product Quality Research Institute (PQRI) based on a proposal by the Inhalation and Nasal Technology Focus Group (INTFG) of the American Association of Pharmaceutical Scientists (AAPS). Participants from the pharmaceutical industry, academia and regulatory bodies from the United States, Europe, India, and Brazil attended the workshop with the objective of presenting, reviewing, and discussing recommendations for demonstrating bioequivalence (BE) that may be considered in the development of orally inhaled drug products and regulatory guidances for new drug applications (NDAs), abbreviated NDAs (ANDAs), and postapproval changes. The workshop addressed areas related to in vitro approaches to demonstrating BE, biomarker strategies, imaging techniques, in vivo approaches to establishing local delivery equivalence and device design similarity. The workshop presented material that provided a baseline for the current understanding of orally inhaled drug products (OIPs) and identified gaps in knowledge and consensus that, if answered, might allow the design of a robust, streamlined method for the BE assessment of locally acting inhalation drugs. These included the following: (1) cascade impactor (CI) studies are not a good 2 predictor of the pulmonary dose; more detailed studies on in vitro/in vivo correlations (e.g., suitability of CI studies for assessing differences in the regional deposition) are needed; (2) there is a lack of consensus on the appropriate statistical methods for assessing in vitro results; (3) fully validated and standardized imaging methods, while capable of providing information on pulmonary dose and regional deposition, might not be applicable to the BE of inhaled products mainly due to the problems of having access to radiolabeled innovator product; (4) if alternatives to current methods for establishing local delivery BE of OIPs cannot be established, biomarkers (pharmacodynamic or clinical endpoints) with a sufficiently steep dose-response need to be identified and validated for all relevant drug classes; and (5) the utility of pharmacokinetic studies for evaluating "local pulmonary delivery" equivalence deserves more attention. A summary of action items for seminars and working groups to address these topics in the future is also presented.