Colorimetric Gas Detection Tubes: Limits of Detection and Evaluation Using Active Chemical Warfare Agents.

Chemical weapons continue to be an ongoing threat that necessitates the improvement of existing detection technologies where new technologies are absent. Lower limits of detection will facilitate early warning of exposure to chemical weapons and enable more rapid deployment of countermeasures. Here, we evaluate two colorimetric gas detection tubes, developed by Draeger Inc., for sarin and sulfur mustard chemical warfare agents and determine their limits of detection using active chemical agent. Being that commercial companies are only able to use chemical agent simulants during sensor development, it is imperative to determine limits of detection using active agent. The limit of detection was determined based on the absence of a reasonably perceptible color response at incrementally lower concentrations. A chemical vapor generator was constructed to produce stable and quantifiable concentrations of chemical agent vapor, with the presence of chemical agent verified and monitored by a secondary detector. The limits of detection of the colorimetric gas detection tubes were determined to be 0.0046 ± 0.0002 and 2.1 ± 0.3 mg/m3 for sarin and sulfur mustard, respectively. The response of the sarin detection tube was readily observable with little issue. The sulfur mustard detection tube exhibited a weaker response to active agent compared to the simulant that was used during development, which will affect their concept of operations in real-world detection scenarios.

Bleeding profile satisfaction and pain and ease of placement with levonorgestrel 19.5 mg IUD: findings from the Kyleena® Satisfaction study.

PURPOSE: To investigate bleeding profile satisfaction and pain and ease of placement with levonorgestrel 19.5 mg IUD in routine clinical practice. METHODS: Women who independently chose levonorgestrel 19.5 mg IUD during routine counselling were invited to participate in this prospective, multinational, observational study. Patient-reported pain and clinician-reported ease of placement were assessed. Bleeding profile satisfaction was evaluated at 12 months/premature end of observation. RESULTS: Most participants (77.8%, n = 878/1129) rated levonorgestrel 19.5 mg IUD placement pain as 'none' or 'mild' and most clinicians (91.1%, n = 1029/1129) rated placement as 'easy'. Pain was more often rated higher in nulliparous compared with parous (p < .0001) and younger (<26 years) compared with older participants (p < .0001), although 67.7% and 69.0% of nulliparous and younger participants respectively reported 'none' or 'mild' pain. Bleeding profile satisfaction at 12 months/end of observation was similar in parous (72.9%, n = 318/436) and nulliparous (69.6%, n = 314/451) participants. Most participants irrespective of age reported bleeding profile satisfaction, ranging from 67.8% (n = 206/304) for 18-25 years to 76.5% (n = 218/285) for >35 years. CONCLUSION: We observed high bleeding profile satisfaction regardless of age or parity with levonorgestrel 19.5 mg IUD and confirmed that device placement is easy and associated with no more than mild pain in most cases in routine clinical practice. Real-world evidence from the Kyleena® Satisfaction Study in routine clinical practice shows high bleeding profile satisfaction with levonorgestrel 19.5 mg IUD regardless of age or parity. IUD placement was easy and associated with little to no pain for most women.

Isoflurane as an Accurate Negative Mode Calibrant for Ion Mobility Spectrometry.

The search for suitable ion mobility spectrometry (IMS) calibrant compounds is ongoing and necessitates the use of highly accurate reduced ion mobility (K0) values across a range of instrumental conditions. Such values will be used in calibrating devices to shift the ion mobility scales and alarm windows for chemicals of interest to their proper locations based on the instrumental conditions present during calibration and sampling. Many positive ion mode calibrants have been investigated, whereas investigations for a negative ion detection mode calibrant have been more limited. Isoflurane (IsoF) is a strong candidate as a negative ion mode calibrant. This report documents the accurately measured K0 values for IsoF product ions as a function of multiple instrumental parameters. K0 values were measured in two instrumentation modes as a function of drift gas temperature, water concentration, and dopant concentration. This report culminates with our evaluation of the suitability of IsoF as a negative ion mode calibrant for IMS applications.

Satisfaction and continuation with LNG-IUS 12: findings from the real-world kyleena® satisfaction study.

PURPOSE: The Kyleena® Satisfaction Study (KYSS) aimed to assess satisfaction and continuation with levonorgestrel-releasing intrauterine system (LNG-IUS) 12 (Kyleena®) in routine clinical practice and to evaluate factors that influence satisfaction. MATERIALS AND METHODS: This prospective, observational, multicentre, single-arm cohort study, with 1-year follow-up, was conducted in Belgium, Canada, Germany, Mexico, Norway, Sweden, Spain and the United States from 2017 to 2018. During routine counselling, women who independently selected to use LNG-IUS 12 were invited to participate in the study. KYSS assessed LNG-IUS 12 satisfaction, continuation and safety. RESULTS: Overall, there were 1126 successful LNG-IUS 12 placements, with insertion attempted in 1129 women. Most participants (833/968, 86.1%, 95% CI 83.7-88.2%, with satisfaction outcome data available) reported satisfaction with LNG-IUS 12 at 12 months (or at the final visit if the device was discontinued prematurely). Satisfaction was not associated with age, parity or motivation for choosing LNG-IUS 12. The majority of women (919/1129, 81.4%) chose to continue after 12 months. Discontinuation was not correlated with age or parity. Overall, 191 women (16.9%) reported a treatment-emergent adverse event. CONCLUSIONS: Results from KYSS provide the first real-world evidence assessing LNG-IUS 12, and demonstrate high satisfaction and continuation rates irrespective of age or parity. Clinical trial registration: NCT03182140.

Accurate Evaluation of Potential Calibration Standards for Ion Mobility Spectrometry.

Ion mobility spectrometry (IMS)-based instruments have historically been accurate to, at best, ±2% of the reduced ion mobility (K0) value of the chemical of interest. Fielded IMS-based detectors that are in use for hazardous and illicit substance detection are subject to false-positive alarms because of this inaccuracy and the resulting wide alarm windows, which are required to maintain a high rate of true-positive alarms. To reduce false-positive alarm rates and improve the accuracy of any IMS-based instrument, accurate K0 values of an ion mobility reference standard need to be used for ion mobility scale calibration. However, a suitable calibrant has yet to be accurately analyzed and agreed upon by the IMS community. In this study, we have chosen five potential IMS calibrants on the basis of their rating against seven criteria for suitable standards and analyzed them as a function of drift gas temperature and humidity using an accurate ion mobility instrument. Recommendations are made herein for each potential calibrant's suitability as a standard for the wider IMS community.

High Accuracy Ion Mobility Spectrometry for Instrument Calibration.

Ion mobility spectrometry (IMS) is widely used to characterize compounds of interest (COIs) based on their reduced mobility ( K0) values. In an attempt to increase the accuracy and agreement of studies, the most recommended method has been to use a reference compound with a known K0 value to calibrate the instrument and calculate COI K0 values from normalized spectra. Researchers are limited by the accuracy of previous K0 value reference measurements on which to base their calibrations. Any inaccuracy in these reference K0 values, typically ±2%, will propagate through to the calculated K0 value of the COI. For this reason, there is a need to standardize reference K0 values with improved accuracy. Through improvement of the accuracy of reference measurements, a lower degree of error will propagate through new K0 value calculations. The K0 values of the ammonium reactant ion, the potential reference standard dimethyl methylphosphonate (DMMP), and three explosive COIs were characterized at multiple drift gas temperatures, drift gas water contents, and electric field strengths on an accurate ion mobility spectrometry instrument. K0 values reported here are known to ±0.1% as a result of reducing the error of all instrumental parameters.

Determination of E/N Influence on K0 Values within the Low Field Region of Ion Mobility Spectrometry.

The established theory of ion motion within weak electric fields predicts that reduced ion mobility (K0) remains constant as a function of the ratio of electric field strength to drift gas number density (E/N). However, upon increasing the accuracy and precision of K0 value measurements during a previous study, a new relationship was seen in which the K0 values of ions decreased as a function of increasing E/N at field strengths below 4 Td. Here the effect of E/N on the K0 value of an ion has been investigated in order to validate the reality of the phenomenon and determine its cause. The pertinent measurements of voltage and drift time were verified in order to ensure the authenticity of the trend and that it was not a result of a systematic error in parametric measurements. The trend was also replicated on a separate ion mobility spectrometer drift tube in order to further validate its authenticity. As a result, the theory of ion motion within weak electric fields should be revised to reflect the behavior seen here.

E/N effects on K0 values revealed by high precision measurements under low field conditions.

Ion mobility spectrometry (IMS) is used to detect chemical warfare agents, explosives, and narcotics. While IMS has a low rate of false positives, their occurrence causes the loss of time and money as the alarm is verified. Because numerous variables affect the reduced mobility (K0) of an ion, wide detection windows are required in order to ensure a low false negative response rate. Wide detection windows, however, reduce response selectivity, and interferents with similar K0 values may be mistaken for targeted compounds and trigger a false positive alarm. Detection windows could be narrowed if reference K0 values were accurately known for specific instrumental conditions. Unfortunately, there is a lack of confidence in the literature values due to discrepancies in the reported K0 values and their lack of reported error. This creates the need for the accurate control and measurement of each variable affecting ion mobility, as well as for a central accurate IMS database for reference and calibration. A new ion mobility spectrometer has been built that reduces the error of measurements affecting K0 by an order of magnitude less than ±0.2%. Precise measurements of ±0.002 cm(2) V(-1) s(-1) or better have been produced and, as a result, an unexpected relationship between K0 and the electric field to number density ratio (E/N) has been discovered in which the K0 values of ions decreased as a function of E/N along a second degree polynomial trend line towards an apparent asymptote at approximately 4 Td.

A primer on the hormone-free interval for combined oral contraceptives.

BACKGROUND: The dosing, schedules, and other aspects of combined oral contraceptive (COC) design have evolved in recent years to address a variety of issues including short- and long-term safety, bleeding profiles, and contraceptive efficacy. In particular, several newer formulations have altered the length of the hormone-free interval (HFI), in order to minimize two key undesired effects that occur during this time: hormone-withdrawal-associated symptoms (HWaS) and follicular development. OBJECTIVE: This primer reviews our current understanding of the key biological processes that occur during the HFI and how this understanding has led to changes in the dosing and schedule of newer COC formulations. MAIN MESSAGE: In brief, HWaS are common, underappreciated, and a likely contributor to COC discontinuation; because of this, shortening the HFI and/or supplementing with estrogen during the progestin-free interval may provide relief from these symptoms and improve adherence. A short HFI (with or without estrogen supplementation) may also help maintain effective follicular suppression and contraceptive efficacy, even when the overall dose of estrogen throughout the cycle is low. CONCLUSIONS: Taken together, the available data about HWaS and follicular activity during the HFI support the rationale for recent COC designs that use a low estrogen dose and a short HFI. The availability of a variety of COC regimens gives physicians a range of choices when selecting the most appropriate COC for each woman's particular priorities and needs.

The Effect of Age, Parity and Body Mass Index on the Efficacy, Safety, Placement and User Satisfaction Associated With Two Low-Dose Levonorgestrel Intrauterine Contraceptive Systems: Subgroup Analyses of Data From a Phase III Trial.

OBJECTIVE: Two low-dose levonorgestrel intrauterine contraceptive systems (LNG-IUSs; total content 13.5 mg [average approx. 8 µg/24 hours over the first year; LNG-IUS 8] and total content 19.5 mg [average approx. 13 µg/24 hours over the first year; LNG-IUS 13]) have previously been shown to be highly effective (3-year Pearl Indices: 0.33 and 0.31, respectively), safe and well tolerated. The present subgroup analyses evaluated whether or not outcomes were affected by parity, age (18-25 vs 26-35 years), or body mass index (BMI, <30 vs ≥30 kg/m2). METHODS: Nulliparous and parous women aged 18‒35 years with regular menstrual cycles (21‒35 days) requesting contraception were randomized to 3 years of LNG-IUS 8 or LNG-IUS 13 use. RESULTS: In the LNG-IUS 8 and LNG-IUS 13 groups, 1432 and 1452 women, respectively, had a placement attempted and were included in the full analysis set; 39.2%, 39.2% and 17.1% were 18-25 years old, nulliparous and had a BMI ≥30 kg/m2, respectively. Both systems were similarly effective regardless of age, parity or BMI; the subgroup Pearl Indices had widely overlapping 95% confidence intervals. Placement of LNG-IUS 8 and LNG-IUS 13 was easier (p < 0.0001) and less painful (p < 0.0001) in women who had delivered vaginally than in women who had not. The complete/partial expulsion rate was 2.2-4.2% across all age and parity subgroups and higher in parous than in nulliparous women (p = 0.004). The incidence of pelvic inflammatory disease was 0.1-0.6% across all age and parity subgroups: nulliparous and younger women were not at higher risk than parous and older women, respectively. The ectopic pregnancy rate was 0.3-0.4% across all age and parity subgroups. Across all age and parity subgroups, the 3-year completion rate was 50.9-61.3% for LNG-IUS 8 and 57.9-61.1% for LNG-IUS 13, and was higher (p = 0.0001) among older than younger women in the LNG-IUS 8 group only. CONCLUSIONS: LNG-IUS 8 and LNG-IUS 13 were highly effective, safe and well tolerated regardless of age or parity. TRIAL REGISTRATION: Clinical trials.gov NCT00528112.

Barriers and Misperceptions Limiting Widespread Use of Intrauterine Contraception Among Canadian Women.

Unintended pregnancy is a major social and public health problem with adverse effects on neonatal and developmental outcomes, as well as maternal health and wellbeing. Traditionally, family planning policies have focused on increasing contraceptive uptake in non-users; however, rates of non-use are low in many developed nations. A high proportion of unintended pregnancies are attributable to contraceptive failure, particularly when using barrier and short-acting hormonal contraceptives. Intrauterine contraceptive devices (IUCDs) are highly effective and have been shown to reduce unintended pregnancy rates. Despite this, global utilization rates are low, and IUCD uptake in Canada has been particularly low. In this review we explore why IUCDs are not more widely used, and specifically focus on barriers and misperceptions that may influence IUCD uptake, particularly in Canada. We reviewed relevant articles published in English between 1990 and 2014, through searches of PubMed and Medline, including primary studies of any design containing information on the knowledge and attitudes of health care providers and women. Providing education to care providers, women, and policy makers may help overcome misperceptions about the use of IUCDs, and may facilitate greater use. Increased support from federal and provincial health programs may also encourage the use of IUCDs in Canadian women, and help to reduce unintended pregnancy rates.

Important problème social et de santé publique, les grossesses non souhaitées exercent des effets indésirables sur les issues néonatales et développementales, ainsi que sur la santé et le bien-être de la mère. Traditionnellement, les politiques de planification familiale ont eu pour objectif principal d'accroître la mesure dans laquelle la contraception en vient à être adoptée par les non-utilisatrices; cependant, les taux de non-utilisation sont faibles dans de nombreux pays développés. Les grossesses non souhaitées sont, dans une importante proportion, attribuables à l'échec de la contraception (particulièrement dans les cas où des méthodes de barrière et des contraceptifs hormonaux à action brève ont été utilisés). Les dispositifs intra-utérins (DIU) sont grandement efficaces et leur capacité de réduire les taux de grossesse non souhaitée a été démontrée. Les taux mondiaux d'utilisation des DIU demeurent néanmoins faibles et leur adoption par les Canadiennes s'est avérée particulièrement lente. Dans cette analyse, nous explorons les raisons pour lesquelles les DIU ne sont pas plus vastement utilisés, en nous centrant principalement sur les obstacles et les perceptions erronées qui pourraient influencer l'adoption des DIU, particulièrement au Canada. Nous avons passé en revue les articles pertinents qui ont été publiés en anglais entre 1990 et 2014 (identifiés par l'intermédiaire de recherches menées dans PubMed et Medline), y compris les études primaires (tous devis confondus) contenant des renseignements sur les connaissances et les attitudes des fournisseurs de soins de santé et des femmes. L'offre d'outils pédagogiques aux fournisseurs de soins, aux femmes et aux décideurs pourrait contribuer à l'élimination des perceptions erronées quant à l'utilisation des DIU et à en accroître l'adoption. L'obtention d'un soutien accru de la part des programmes fédéraux et provinciaux de santé pourrait également inciter les Canadiennes à avoir recours aux DIU et contribuer à la baisse des taux de grossesse non souhaitée.

Understanding the barriers and myths limiting the use of intrauterine contraception in nulliparous women: results of a survey of European/Canadian healthcare providers.

OBJECTIVES: To evaluate healthcare providers' (HCPs') knowledge, attitudes and beliefs regarding intrauterine contraception (IUC). STUDY DESIGN: HCPs in eight European countries and Canada who saw at least 20 women per month for contraception completed an online questionnaire. Responses were evaluated by country. RESULTS: In total, 1103 HCPs completed the survey: 633 obstetrician-gynecologists, 335 general practitioners and 135 family planning clinicians (physician, midwife or nurse). When respondents in different countries were asked to report their three main barriers to considering IUC, predominant concerns were nulliparity (34-69%) and pelvic inflammatory disease (PID; 14-83%) for women in general, and insertion difficulty (25-83%), PID (17-83%), insertion pain (7-60%) and infertility (6-55%) for nulliparous women. In addition, 4-59% of HCPs reported that they never proactively include IUC in contraceptive counseling for a nulliparous woman, regardless of her age. Furthermore, only 30-61% of respondents correctly identified that, in the World Health Organization medical eligibility criteria for IUC, nulliparity is category 2 (benefits outweigh risks). CONCLUSIONS: HCPs in Europe and Canada have clear gaps in their knowledge regarding IUC and misplaced concerns persist, particularly regarding use of IUC in nulliparous women; the predominant misconceptions are about PID, insertion difficulty and insertion pain. Further education on the evidence is needed so that IUC is recognized as being suitable for young and nulliparous women and is included in contraceptive counseling.

Pharmacokinetics of two low-dose levonorgestrel-releasing intrauterine systems and effects on ovulation rate and cervical function: pooled analyses of phase II and III studies.

OBJECTIVE: To assess the pharmacokinetics and pharmacodynamics of levonorgestrel intrauterine system (LNG-IUS) 13.5 mg and LNG-IUS 19.5 mg (total content). DESIGN: Pooled pharmacokinetic and pharmacodynamic analyses of phase II and III studies. SETTING: Randomized, open-label, multicenter studies. PATIENT(S): Nulliparous and parous women. INTERVENTION(S): Levonorgestrel intrauterine system 13.5 mg, LNG-IUS 19.5 mg, or LNG-IUS 20 µg/24 h (total content 52 mg). MAIN OUTCOME MEASURE(S): Pharmacokinetics of LNG, ovulation rate, cervical function, and endometrium effects. RESULT(S): The in vivo LNG release rate of LNG-IUS 13.5 mg was approximately 14 µg/24 h after 24 days, declining progressively to 5 µg/24 h after 3 years. The average LNG serum concentration over 3 years of use was 74.3 ng/L, 114 ng/L, and 218 ng/L for LNG-IUS 13.5 mg, LNG-IUS 19.5 mg, and LNG-IUS 20 µg/24 h, respectively. All treatments showed very similar progestogenic effects on cervical mucus, with low and similar cervical scores throughout treatment. Ovulation was observed in the majority of women in all groups where assessment was possible, although there was a lower incidence of anovulation with LNG-IUS 13.5 mg and LNG-IUS 19.5 mg compared with LNG-IUS 20 µg/24 h. The progestogenic effect on the endometrium was marked in all three LNG-IUS groups. CONCLUSION(S): Levonorgestrel intrauterine system 13.5 mg and LNG-IUS 19.5 mg result in alower systemic exposure to LNG, lower incidence of anovulation, and similar progestin impact on the endometrium and cervical function compared with LNG-IUS 20 µg/24 h.

Two low-dose levonorgestrel intrauterine contraceptive systems: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of two low-dose levonorgestrel intrauterine contraceptive systems. METHODS: Nulliparous and parous women aged 18-35 years with regular menstrual cycles (21-35 days) requesting contraception were randomized to 3 years of treatment with one of two levonorgestrel intrauterine contraceptive systems: 13.5 mg total content or 19.5 mg total content. The primary outcome was the pregnancy rate, calculated as the Pearl Index. RESULTS: Overall, 1,432 and 1,452 women in the 13.5 mg intrauterine contraceptive system and 19.5 mg intrauterine contraceptive system groups, respectively, had a placement attempted and were included in the full analysis set to evaluate efficacy and safety. Mean (standard deviation) age was 27.1 (4.8) years; 39.2% were nulliparous. Over the 3-year study period, 0.33 pregnancies per 100 women-years (95% confidence interval [CI] 0.16-0.60) were observed with the 13.5 mg intrauterine contraceptive system compared with 0.31 per 100 women-years (95% CI 0.15-0.57) with the 19.5 mg intrauterine contraceptive system. Kaplan-Meier estimates for that period were 0.009 and 0.010, respectively. At least partial expulsions occurred in 4.56% and 3.58% and discontinuation rates resulting from a reported adverse event occurred in 21.9% and 19.1%, respectively. Ten of the 20 pregnancies were ectopic. Serious adverse events included six cases of pelvic inflammatory disease and one partial uterine perforation. CONCLUSIONS: Both lower-dose levonorgestrel intrauterine contraceptive systems were highly effective for 3 years of use and generally well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00528112. LEVEL OF EVIDENCE: : I.

An assessment of computational methods for obtaining structural information of moderately flexible biomolecules from ion mobility spectrometry.

When utilized in conjunction with modeling, the collision cross section (Ω) from ion mobility spectrometry can be used to deduce the gas phase structures of analyte ions. Gas phase conformations are determined computationally, and their Ω calculated using an approximate method, the results of which are compared with experimental data. Though prior work has focused upon rigid small molecules or large biomolecules, correlation of computational and experimental Ω has not been thoroughly examined for analytes with intermediate conformational flexibility, which constitute a large fraction of the molecules studied in the field. Here, the computational paradigm for calculating Ω has been tested for the tripeptides WGY, YGW, and YWG (Y = tyrosine, W = tryptophan, G = glycine). Experimental data indicate that Ω(exp) (YWG) > Ω(exp) (WGY) ≈ Ω(exp) (YGW). The energy distributions of conformations obtained from tiers of simulated annealing molecular dynamics (SAMD) were analyzed using a wide array of density functionals. These quantum mechanical energy distributions do not agree with the MD data, which leads to structural differences between the SAMD and DFT conformations. The latter structures are obtained by reoptimization of the SAMD geometries, and are the only suite of structures that reproduce the experimental trend in analyte separability. In the absence of fitting Lennard Jones potentials that reproduce experimental results for the Trajectory Method, the Exact Hard Sphere Scattering method produced numerical values that are in best agreement with the experimental cross sections obtained in He drift gas.