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The relationship between radiographic crestal alveolar bone mass and changes in clinical periodontal attachment level following guided tissue regeneration (GTR) was evaluated in this retrospective study. A total of 12 intrabony two- or three-walled defects and 12 adjacent nondiseased proximal sites in 10 nonsmoking adult subjects received subgingival debridement and GTR using resorbable (Resolut; five sites) or nonresorbable (Gore-Tex; seven sites) barrier membranes. At a mean of 48.8 months posttreatment, clinical periodontal attachment level alterations were measured, and crestal alveolar bone mass changes on digital subtraction radiographic images derived from serial periapical radiographs were analyzed to correct for between-film geometric and contrast density differences. Intrabony defects exhibited a mean clinical periodontal attachment level gain of 2.3 +/- 0.4 mm, in contrast to a mean loss of 0.5 +/- 0.2 mm in adjacent nondiseased interproximal sites. Digital subtraction radiography revealed an increase in crestal alveolar bone mass at all intrabony sites treated with GTR and a decrease in three of the adjacent nondiseased sites. Site-based analysis yielded an odds ratio of 36 (P < .001) for the association between radiographic increases in crestal alveolar bone mass and clinical periodontal attachment level gains of > or = 2 mm. These results suggest a strong concordance between digital subtraction radiographic assessments of crestal alveolar bone mass and clinical periodontal attachment level in evaluating the long-term effects of GTR at human interproximal intrabony defects. [ABSTRACT FROM AUTHOR]

Combining platelet-rich plasma (PRP) with autogenous bone graft materials has recently been advocated as a means of enhancing rate and quality of new bone formation in regenerative procedures. The aim of this case series was to evaluate the potential of PRP in combination with bone allograft to enhance bone regeneration in alveolar ridge defects exhibiting both vertical and horizontal loss prior to the placement of dental implants. Augmentation resulted in clinical and radiographic gains in both vertical and horizontal components of the osseous defects, thereby facilitating subsequent placement of dental implants. Histologic evaluation of the cases revealed the presence of residual allograft particles surrounded by connective tissue as well as newly formed bone within the grafted areas. However, the addition of PRP did not appear to enhance the quality or quantity of new bone formation over that reported in comparable guided bone regeneration (GBR) studies without PRP. [ABSTRACT FROM AUTHOR]

Background: Improving the health outcomes of populations of individuals through population health management requires the use of electronic health records that can exchange real-time digital information using an accurate and complete shared care record that is accessible to health care providers, services, and patients., Objective: The aims of this study were to understand end users' (health care providers) experiences, attitudes, and insights using current electronic health records; their expectations of what is required to establish a shared care record; and how they anticipate adapting to the use of a shared care record in daily practice. This work is the result of a quality improvement initiative deemed not to require ethics approval according to the Western research ethics board checklist., Methods: Clinicians were contacted using voluntary response sampling and interviewed via Zoom (Zoom Video Communications) between June 2022 and July 2022. The participants were from various health care sectors and at various stages of career development., Results: Overall, adaptation to the use of a shared care record was viewed positively by health care providers, highlighting the benefits of a centralized, shared, and accessible location for real-time data, promoting patient continuity of care. The main concerns included the privacy, confidentiality, and security of the record along with patients' ability to interpret their own medical information found in a patient portal. The resources requested by end users included multifaceted ongoing training on the use of a shared care record., Conclusions: This study provides practical findings that will help emphasize factors that facilitate clinicians' practical use and process of adaptation to the use of a shared care record., (©Marta Chmielewski, Matthew J Meyer. Originally published in the Online Journal of Public Health Informatics (https://ojphi.jmir.org/), 27.02.2024.)

KRM-II-81 (1) is an imidazodiazepine GABA A receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst. GABAAR binding occurred with a K i of 150 nM, and only 3 of 41 screened binding sites produced inhibition ≥50% at 10 μM, and the potency to induce cytotoxicity was ≥240 mM. DS-II-73 was selective for α2/3/5- over that of α1-containing GABAARs. Oral exposure of plasma and brain of rats was more than sufficient to functionally impact GABAARs. Tonic convulsions in mice and lethality induced by pentylenetetrazol were suppressed by DS-II-73 after oral administration and latencies to clonic and tonic seizures were prolonged. Cortical slice preparations from a patient with pharmacoresistant epilepsy (mesial temporal lobe) showed decreases in the frequency of local field potentials by DS-II-73. As with KRM-II-81, the motor-impairing effects of DS-II-73 were low compared to diazepam. Molecular docking studies of DS-II-73 with the α1β3γ2L-configured GABAAR showed low interaction with α1His102 that is suggested as a potential molecular mechanism for its low sedative side effects. These findings support the viability of DS-II-73 as a backup molecule for its ethynyl analogue, KRM-II-81, with the human tissue data providing translational credibility.

Background: The operating room (OR) is a major cost and revenue center for a hospital. One of the few modifiable costs in the OR is single-use, sterile surgical supplies (SUSSS). If SUSSS are opened on the scrub table and not used, then they are wasted. High-fidelity SUSSS usage data is important to strategically implement solutions to reduce waste of SUSSS in the OR. OR waste reduction may decrease health systems' carbon footprints and reduce spending., Methods: A convenience sample of general pediatric surgical cases was observed in summer 2021. HIPAA-free images of the surgical scrub table were acquired every 2 s with minimal impact on pediatric OR workflow. These images were asynchronously analyzed to obtain SUSSS usage data for each case., Results: Image data from three pediatric surgeons performing 41 pediatric surgeries was reviewed. The median cost of unused SUSSS was $13.10 (IQR = $2.73-$47.97) with a range of $0.07 to $489.08 wasted in a single surgery. The mean number of items wasted was 9.3 ± 6.4. The most frequently wasted items were sutures, syringes, towels, paper rulers, and specimen cups. The most expensive sources of waste were laparoscopic trocars, sutures, insufflation needles, drapes, and guidewires., Conclusions: SUSSS that were discarded without being used were successfully identified through the asynchronous analysis of HIPAA-free OR scrub table image data. This may be an opportunity to identify SUSSS waste efficiently without an observer in the OR., Competing Interests: We declare that this manuscript is original, has not been published before, and is not being considered for publication elsewhere. This study was presented in part at the 2022 Planetary Health Annual Meeting. Matthew J. Meyer, Pumoli Malapati, Tyler Chafitz, and Nafisa Alamgir have interest in University-owned intellectual property related to technology that assists in the identification of intraoperative sterile surgical waste. They have stock in a company that may one day license this technology. This study was supported by a grant from the integrated Translational Health Research Institute of Virginia (iThriv) which is funded through the National Center for Advancing Translational Science of the National Institutes of Health. Generative-AI has NOT been used in the creation of this manuscript. As corresponding author, I confirm that the manuscript has been read and approved for submission by all named authors., (© 2023 The Authors. Published by Elsevier Inc.)

Novel gamma-aminobutyric acid receptor (GABA A R) ligands structurally related to imidazobenzodiazepine MIDD0301 were synthesized using spiro-amino acid N-carboxyanhydrides (NCAs). These compounds demonstrated increased resistance to phase 2 metabolism and avoided the formation of a 6H isomer. Compound design was guided by molecular docking using the available crystal structure of the α 1 β 3 γ 2 GABA A R and correlated with in vitro binding data. The carboxylic acid containing GABA A R ligands have high aqueous solubility, low permeability, and low cell toxicity. The inability of GABA A R ligands to cross the blood-brain barrier was confirmed in vivo by the absence of sensorimotor inhibition. Pharmacological activities at lung GABA A Rs were demonstrated by ex vivo relaxation of guinea pig airway smooth muscle and reduction of methacholine-induced airway hyperresponsiveness (AHR) in conscious mice. We identified bronchodilator 5c with an affinity of 9 nM for GABA A Rs that was metabolically stable in the presence of human and mouse microsomes.

Objective: To determine the proportion of hospitals that implemented 6 leading practices in their antimicrobial stewardship programs (ASPs). Design: Cross-sectional observational survey., Setting: Acute-care hospitals., Participants: ASP leaders., Methods: Advance letters and electronic questionnaires were initiated February 2020. Primary outcomes were percentage of hospitals that (1) implemented facility-specific treatment guidelines (FSTG); (2) performed interactive prospective audit and feedback (PAF) either face-to-face or by telephone; (3) optimized diagnostic testing; (4) measured antibiotic utilization; (5) measured C. difficile infection (CDI); and (6) measured adherence to FSTGs., Results: Of 948 hospitals invited, 288 (30.4%) completed the questionnaire. Among them, 82 (28.5%) had <99 beds, 162 (56.3%) had 100-399 beds, and 44 (15.2%) had ≥400+ beds. Also, 230 (79.9%) were healthcare system members. Moreover, 161 hospitals (54.8%) reported implementing FSTGs; 214 (72.4%) performed interactive PAF; 105 (34.9%) implemented procedures to optimize diagnostic testing; 235 (79.8%) measured antibiotic utilization; 258 (88.2%) measured CDI; and 110 (37.1%) measured FSTG adherence. Small hospitals performed less interactive PAF (61.0%; P = .0018). Small and nonsystem hospitals were less likely to optimize diagnostic testing: 25.2% (P = .030) and 21.0% (P = .0077), respectively. Small hospitals were less likely to measure antibiotic utilization (67.8%; P = .0010) and CDI (80.3%; P = .0038). Nonsystem hospitals were less likely to implement FSTGs (34.3%; P < .001)., Conclusions: Significant variation exists in the adoption of ASP leading practices. A minority of hospitals have taken action to optimize diagnostic testing and measure adherence to FSTGs. Additional efforts are needed to expand adoption of leading practices across all acute-care hospitals with the greatest need in smaller hospitals.

National laboratories are a fundamental capacity for public health, contributing to disease surveillance and outbreak response. The establishment of regional laboratory networks has been posited as a means of improving health security across multiple countries. Our study objective was to assess whether membership in regional laboratory networks in Africa has an effect on national health security capacities and outbreak response. We conducted a literature review to select regional laboratory networks in the Eastern and Western African regions. We examined data from the World Health Organization Joint External Evaluation (JEE) mission reports, the 2018 WHO States Parties Annual Report (SPAR), and the 2019 Global Health Security Index (GHS). We compared the average scores of countries that are members of a regional laboratory network to those that are not. We also assessed country-level diagnostic and testing indicators during the COVID-19 pandemic. We found no significant differences in any of the selected health security metrics for member versus non-member countries of the either the East Africa Public Health Laboratory Networking Project (EAPHLNP) in the Eastern Africa region, nor for the West African Network of Clinical Laboratories (RESAOLAB) in the Western Africa region. No statistically significant differences were observed in COVID-19 testing rates in either region. Small sample sizes and the inherent heterogeneities in governance, health, and other factors between countries within and between regions limited all analyses. These results suggest potential benefit in setting baseline capacity for network inclusion and developing regional metrics for measuring network impact, but also beyond national health security capacities, other effects that may be required to justify continued support for regional laboratory networks., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: DB, SJS, DW, and YKT are all affiliated with the Africa Centers for Disease Control (Africa CDC), an entity which has supported extensive laboratory capacity strengthening across the continent and may have a vested interest in the outcomes of other efforts to strengthen regional capacity. EMS and CJS have previously interacted with Fondation Merieux, a leader in establishing RESAOLAB, on laboratory capacity strengthening projects in Guinea as well as global biosecurity training and policy efforts., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Accurate interpretation of the martian sedimentary rock record-and by extension that planet's paleoenvironmental history and potential habitability-relies heavily on rover-based acquisition of textural and compositional data and researchers to properly interpret those data. However, the degree to which this type of remotely sensed information can be unambiguously resolved and accurately linked to geological processes in ancient sedimentary systems warrants further study. In this study, we characterize Mars-relevant siliciclastic-evaporite samples by traditional laboratory-based geological methods (thin section petrography, X-ray diffraction [XRD], backscattered electron imaging, microprobe chemical analyses) and remote sensing methods relevant to martian rover payloads (visible-near-mid infrared reflectance spectroscopy, X-ray fluorescence mapping, XRD). We assess each method's ability to resolve primary and secondary sedimentologic features necessary for the accurate interpretation of paleoenvironmental processes. While the most dominant textures and associated compositions ( i.e., bedded gypsum evaporite) of the sample suite are readily identified by a combination of remote sensing techniques, equally important, although more subtle, components ( i.e., interbedded windblown silt, meniscus cements) are not resolved unambiguously in bulk samples. However, rover-based techniques capable of coordinating spatially resolved compositional measurements with textural imaging reveal important features not readily detected using traditional assessments ( i.e., subtle clay-organic associations, microscale diagenetic nodules). Our findings demonstrate the improved generational capacity of rovers to explore ancient sedimentary environments on Mars while also highlighting the complexities in extracting comprehensive paleoenvironmental information when limited to currently available rover-based techniques. Complete and accurate interpretation of ancient martian sedimentary environments, and by extension the habitability of those environments, likely requires sample return or in situ human exploration. Plain Language Summary Only when correctly translated can the ancient martian sedimentary rock record reveal the environmental evolution of the planet's surface through time. In this case study, we characterize Mars-relevant sedimentary rocks and evaluate the degree to which a comprehensive geological picture can be resolved unambiguously when limited to microscale remote sensing methods relevant to rovers on Mars. While the most dominant textural features and associated compositions of the sample suite are readily identified by a combination of remote sensing techniques, equally important but more subtle components are not resolved unambiguously in bulk samples. However, rover-based techniques capable of coordinating spatially resolved compositional measurements with textural imaging, such as Perseverance Rover's Planetary Instrument for X-Ray Lithochemistry instrument, reveal important features not readily detected by more traditional methods. We demonstrate that rovers have, generationally, improved in their capacity to resolve a true geological picture in ancient sedimentary environments, likely owing to an improved ability to coordinate spatially resolved compositional measurements with textural imaging at the microscale. However, our work also highlights the complexities involved in extracting subtle environmental information when limited to currently available rover-based techniques and suggests that comprehensive interpretation of ancient martian sedimentary systems likely requires sample return or in situ human exploration. Key Points Mars-relevant samples are characterized using both traditional laboratory and microscale rover-based remote sensing techniques to assess each method's ability to recognize features necessary for accurate paleoenvironmental process interpretation. While some key paleoenvironmental processes can reasonably be inferred via remote sensing methods, others cannot be resolved unambiguously. Perseverance Rover's Planetary Instrument for X-Ray Lithochemistry instrument reveals diagenetic features that would otherwise remain unseen by traditional thin section petrography.

A series of imidazodiazepines has been developed that possess reduced sedative liabilities but retain efficacy in anticonvulsant screening models. The latest of these compounds, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole known as KRM-II-81) is currently awaiting advancement into the clinic. A deuterated structural analog (D5-KRM-II-81) was made as a potential backup compound and studied here in comparison to KRM-II-81. In the present study, both compounds significantly prevented seizures in mice induced by 6 Hz (44 mA) electrical stimulation without significantly altering motoric function on a rotarod after intraperitoneal administration. Both compounds also significantly prevented clonic seizures, tonic seizures, and lethality induced by pentylenetetrazol in mice when given orally. D5-KRM-II-81 had a slightly longer duration of action against clonic and tonic seizures than KRM-II-81. Oral administration of 100 mg/kg of either KRM-II-81 or D5-KRM-II-81 was significantly less disruptive of sensorimotor function in mice than diazepam (5 mg/kg, p.o.). The present report documents that D5-KRM-II-81 represents another in this series of imidazodiazepines with anticonvulsant activity at doses that do not impair sensorimotor function., (© 2023 Wiley Periodicals LLC.)

To provide back-up compounds to support the development of the GABA A receptor (GABAAR) potentiator KRM-II-81, three novel analogs were designed: replacing the pyridinyl with 2'-Cl-phenyl (FR-II-60), changing the positions of the N and O atoms in the oxazole ring with addition of an ethyl group (KPP-III-34 and KPP-III-51), or substituting a Br atom for the ethynyl of KRM-II-81 (KPP-III-34). The compounds bound to brain GABAARs. Intraperitoneal administration of FR-II-60 and KPP-III-34 produced anticonvulsant activity in mice [maximal electroshock (MES)-induced seizures or 6 Hz-induced seizures], whereas KPP-III-51 did not. Although all compounds were orally bioavailable, structural changes reduced the plasma and brain (FR-II-60 and KPP-III-51) exposures relative to KRM-II-81. Oral administration of each compound produced dose-dependent increases in the latency for both clonic and tonic seizures and the lethality induced by pentylenetetrazol (PTZ) in mice. Since KPP-III-34 produced the highest brain area under the curve (AUC) exposures, it was selected for further profiling. Oral administration of KPP-III-34 suppressed seizures in corneal-kindled mice, hippocampal paroxysmal discharges in mesial temporal lobe epileptic mice, and PTZ-induced convulsions in rats. Only transient sensorimotor impairment was observed in mice, and doses of KPP-III-34 up to 500 mg/kg did not produce impairment in rats. Molecular docking studies demonstrated that all compounds displayed a reduced propensity for binding to α 1His102 compared with the sedating compound alprazolam; the bromine-substituted KPP-III-34 achieved the least interaction. Overall, these findings document the oral bioavailability and anticonvulsant efficacy of three novel analogs of KRM-II-81 with reduced sedative effects. SIGNIFICANCE STATEMENT: A new non-sedating compound, KRM-II-81, with reduced propensity for tolerance is moving into clinical development. Three new analogs were orally bioavailable, produced anticonvulsant effects in rodents, and displayed low sensorimotor impairment. KPP-III-34 demonstrated efficacy in models of pharmacoresistant epilepsy. Docking studies demonstrated a low propensity for compound binding to the α1His102 residue implicated in sedation. Thus, three additional structures have been added to the list of non-sedating imidazodiazepine anticonvulsants that could serve as backups in the clinical development of KRM-II-81., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Malignant tumors can evade destruction by the immune system by attracting immune-suppressive regulatory T cells (Treg) cells. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Treg cells, and IKZF2 deficiency reduces tumor growth in mice. Here we report the discovery of NVP-DKY709, a selective molecular glue degrader of IKZF2 that spares IKZF1/3. We describe the recruitment-guided medicinal chemistry campaign leading to NVP-DKY709 that redirected the degradation selectivity of cereblon (CRBN) binders from IKZF1 toward IKZF2. Selectivity of NVP-DKY709 for IKZF2 was rationalized by analyzing the DDB1:CRBN:NVP-DKY709:IKZF2(ZF2 or ZF2-3) ternary complex X-ray structures. Exposure to NVP-DKY709 reduced the suppressive activity of human Treg cells and rescued cytokine production in exhausted T-effector cells. In vivo, treatment with NVP-DKY709 delayed tumor growth in mice with a humanized immune system and enhanced immunization responses in cynomolgus monkeys. NVP-DKY709 is being investigated in the clinic as an immune-enhancing agent for cancer immunotherapy., Competing Interests: Declaration of interests All authors are past or current employees of Novartis Institutes for Biomedical Research. Some of the authors have patents related to this work: WO2019038717, 3-(1-oxoisoindolin-2-YL)Piperidine-2-6-Dione derivatives and uses thereof (R.E.J.B., S.B., A.C., A.F., and M.V.); and WO2020128972, Dosing regimen and pharmaceutical combinations comprising 3-(1-oxoisoindolin-2-YL)Piperidine-2-6-Dione derivatives (S.B., E.d’H., G.D., R.R.F., D.H., and J.K.-A.)., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Interviewer effects can have consequential impacts on survey data, particularly for reporting sensitive attitudes and behaviours such as sexual activity and drug use, yet these effects remain understudied in low- and middle-income countries. The Demographic and Health Surveys (DHS) present a unique opportunity to study interviewer effects on the self-report of sensitive topics in low- and middle-income countries by including interviewer characteristics data. This paper aims to narrow the gap in research on interviewer effects by studying the effects that age difference between interviewer and respondent and interviewer survey experience have on the reporting of ever having sexual intercourse., Methods: We used DHS data from 91 066 women and 56 336 men in 21 countries where the standard DHS was implemented among all women of reproductive age, and interviewer characteristics were included in the data set. Using a Bayesian cross-classified model with random intercepts for interviewer and cluster, we assessed whether the effect of an age difference of 10 years or greater was associated with a difference in self-report of ever having sexual intercourse, adjusting for respondent demographics., Results: There was a meaningful association between an age difference of greater than ten years and reporting of ever having had sexual intercourse in most countries for both genders after adjusting for interviewer age and experience, rural or urban cluster, and individual-level characteristics. Among women, the marginal posterior probability of reporting ever having sexual intercourse if the interviewer was ten years or more years older was lower for 17 of 19 countries (countries ranged from -12.50 to 3.90 percentage points). Among men, the marginal posterior probability was lower for 16 of 20 countries, ranging from -18.30 to 17.10 percentage points., Conclusions: In most countries, women and men were less likely to report ever having sexual activity if the interviewer was ten or more years older than them, adjusting for potential confounders. These findings have important implications for interpreting numerous sexual health indicators, such as unmet family planning needs and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) risk. Survey administrators may consider more careful interviewer-respondent characteristic matching or novel approaches like Audio Computer Assisted Self Interview to minimize interviewer-induced variance., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2023 by the Journal of Global Health. All rights reserved.)

Introduction: Peripheral artery disease and cardiac disease are often comorbid conditions. Echocardiography is a diagnostic tool that can be performed preoperatively to risk stratify patients by a functional cardiac test. We hypothesized that ventricular dysfunction and valvular lesions were associated with an increased incidence of expanded major adverse cardiac events (Expanded MACE)., Methods and Materials: Retrospective cohort study from 2011 to 2020 including all patients from a major academic center who had vascular surgery and an echocardiographic study within two years of the index procedure., Results: 813 patients were included in the study; a majority had a history of smoking (86%), an ASA score of 3 (65%), and were male (68%). Carotid endarterectomy was the most common surgery (24%) and the least common surgery was open abdominal aortic aneurysm repair (5%). We found no significant association between the echocardiographic findings of left ventricular dysfunction, right ventricular dysfunction, or valvular lesions and the postoperative development of Expanded MACE., Conclusions: The preoperative echocardiographic findings of left ventricular dysfunction, right ventricular dysfunction and moderate to severe valvular lesions were not predictive of an increased incidence of postoperative Expanded MACE. We identified a significant association between RV dysfunction and post-operative dialysis that should be interpreted carefully due to the small number of outcomes. The transition from open to endovascular surgery and advances in perioperative management may have led to improved cardiovascular outcomes., Trial Registration: Trial Registration: NCT04836702 (clinicaltrials.gov). https://www.google.com/search?client=firefox-b-d&q=NCT04836702., Competing Interests: The authors acknowledge no competing interest related to this manuscript. MJM has patent applications related to perioperative efficiency (wireless suture needles, scrub table item usage analysis), ownership of PeriOp Green Inc., consulted with Dialectica on viscoelastic monitoring of blood clotting, spoke at Takeda Pharmaceutical on sustainability in healthcare. RSB receives a royalty for publication in UpToDate from Wolters-Kluwer., (Copyright: © 2023 Meyer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Though billions of passengers and crew travel by air each year and are exposed to altitude equivalents of 7000-8000 feet, the health impact of cabin oxygenation levels has not been well studied. The hypoxic environment may produce ectopic heartbeats that may increase the risk of acute in-flight cardiac events. We enrolled forty older and at-risk participants under a block-randomized crossover design in a hypobaric chamber study to examine associations between flight oxygenation and both ventricular (VE) and supraventricular ectopy (SVE). We monitored participant VE and SVE every 5 min under both flight and control conditions to investigate the presence and rate of VE and SVE. While the presence of VE did not differ according to condition, the presence of SVE was higher during flight conditions (e.g. OR ratio = 1.77, 95% CI: 1.21, 2.59 for SVE couplets). Rates of VE and SVE were higher during flight conditions (e.g. RR ratio = 1.25, 95% CI: 1.03, 1.52 for VE couplets, RR ratio = 1.76, 95% CI: 1.39, 2.22 for SVE couplets). The observed higher presence and rate of ectopy tended to increase with duration of the flight condition. Further study of susceptible passengers and crew may elucidate the specific associations between intermittent or sustained ectopic heartbeats and hypoxic pathways., (© 2023. The Author(s).)

Background: Health security funding is intended to improve capacities for preventing, detecting, and responding to public health emergencies. Recent years have witnessed substantial increases in the amounts of donor financial assistance to health security from countries, philanthropies, and other development partners. To date, no work has examined the effects of assistance on health security capacity development over time. This paper presents an analysis of the time-lagged effects of assistance for health security (AHS) on levels of capacity., Methods: We collected publicly available health security assessment scores published between 2010 and 2019 and data relating to financial AHS. Using validated methods, we rescaled assessment scores on analogous scales to enable comparison and binned them in quartiles. We then used a distributed lag model (DLM) in a Bayesian ordinal regression framework to assess the effects of AHS on capacity development over time., Results: Strong evidence exists for associations between financial assistance and select capacities on a variety of lagged time intervals. Financial assistance had positive effects on zoonotic disease capacities in the year it was disbursed, and positive effects on legislation, laboratory, workforce, and risk communication capacities one year after disbursal. Financial assistance had negative effects on laboratory and emergency response capacities two years after it was disbursed. Financial assistance did not have measurable effects on coordination, antimicrobial resistance (AMR), food safety, biosafety, surveillance, or response preparedness capacities over the timeframe considered., Conclusion: Financial AHS is associated with positive effects for several core health security capacities. However, for the majority of capacities, levels of funding were not significantly associated with capacity level, though we cannot fully exclude endogeneity. Future work should continue to investigate these relationships in different contexts and examine other factors that may contribute to capacity development., (© 2022 The Author(s); Published by Kerman University of Medical Sciences This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Studies of the proteome would benefit greatly from methods to directly sequence and digitally quantify proteins and detect posttranslational modifications with single-molecule sensitivity. Here, we demonstrate single-molecule protein sequencing using a dynamic approach in which single peptides are probed in real time by a mixture of dye-labeled N-terminal amino acid recognizers and simultaneously cleaved by aminopeptidases. We annotate amino acids and identify the peptide sequence by measuring fluorescence intensity, lifetime, and binding kinetics on an integrated semiconductor chip. Our results demonstrate the kinetic principles that allow recognizers to identify multiple amino acids in an information-rich manner that enables discrimination of single amino acid substitutions and posttranslational modifications. With further development, we anticipate that this approach will offer a sensitive, scalable, and accessible platform for single-molecule proteomic studies and applications.

CD3-engaging bispecific antibodies (BsAbs) enable the formation of an immune synapse between T cells and tumor cells, resulting in robust target cell killing not dependent on a preexisting tumor specific T cell receptor. While recent studies have shed light on tumor cell-specific factors that modulate BsAb sensitivity, the T cell-intrinsic determinants of BsAb efficacy and response durability are poorly understood. To better clarify the genes that shape BsAb-induced T cell responses, we conducted targeted analyses and a large-scale unbiased in vitro CRISPR/Cas9-based screen to identify negative regulators of BsAb-induced T cell proliferation. These analyses revealed that CD8+ T cells are dependent on CD4+ T cell-derived signaling factors in order to achieve sustained killing in vitro . Moreover, the mammalian target of rapamycin (mTOR) pathway and several other candidate genes were identified as intrinsic regulators of BsAb-induced T cell proliferation and/or activation, highlighting promising approaches to enhancing the utility of these potent therapeutics., Competing Interests: Authors RM, TF, GT, EC, DR, MP, JL, HW, and HL are currently employed by the Novartis Institutes for Biomedical Research (NIBR). The following authors were previously employed by NIBR when they were involved with the work described herein: MV (currently employed by Arbor Biotechnologies), GE (currently employed by Foghorn Therapeutics), MM (currently employed by Bristol Myers Squibb), and SK (currently employed by 2seventy Bio)., (Copyright © 2022 Molony, Funk, Trabucco, Corcoran, Ruddy, Varadarajan, Elliot, Piquet, Lam, Meyer, Wang, Kurtulus and Lu.)

Organic cation transporter 1 (OCT1) is a membrane transporter that affects hepatic uptake of cationic and weakly basic drugs. OCT1 transports structurally highly diverse substrates. The mechanisms conferring this polyspecificity are unknown. Here, we analyzed differences in transport kinetics between human and mouse OCT1 orthologs to identify amino acids that contribute to the polyspecificity of OCT1. Following stable transfection of HEK293 cells, we observed more than twofold differences in the transport kinetics of 22 out of 28 tested substrates. We found that the β2-adrenergic drug fenoterol was transported with eightfold higher affinity but at ninefold lower capacity by human OCT1. In contrast, the anticholinergic drug trospium was transported with 11-fold higher affinity but at ninefold lower capacity by mouse Oct1. Using human-mouse chimeric constructs and site-directed mutagenesis, we identified nonconserved amino acids Cys36 and Phe32 as responsible for the species-specific differences in fenoterol and trospium uptake. Substitution of Cys36 (human) to Tyr36 (mouse) caused a reversal of the affinity and capacity of fenoterol but not trospium uptake. Substitution of Phe32 to Leu32 caused reversal of trospium but not fenoterol uptake kinetics. Comparison of the uptake of structurally similar β2-adrenergics and molecular docking analyses indicated the second phenol ring, 3.3 to 4.8 Å from the protonated amino group, as essential for the affinity for fenoterol conferred by Cys36. This is the first study to report single amino acids as determinants of OCT1 polyspecificity. Our findings suggest that structure-function data of OCT1 is not directly transferrable between substrates or species., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Statement of Problem: Computer-aided design (CAD) software can merge the intraoral digital scan with patient photographs or 3-dimensional (3D) facial reconstructions for treatment planning purposes. However, whether an individual perceives a 3D facial reconstruction as a better self-representation compared with a 2-dimensional (2D) photograph is unclear., Purpose: The purpose of this observational study was to compare self-perception ratings and self-representation preference of the 2D and 3D facial reconstructions among laypersons, dental students, and dentists., Material and Methods: Three populations participated in the study: laypersons, dental students, and dentists (n=20, N=60). Facial and intraoral features were digitized by using facial and intraoral scanners, and a complete-face smile photograph was obtained. Two simulations were performed for each participant: 2D (2D group) and 3D (3D group) reconstructions. In the 2D group, a maxillary digital veneer waxing from the left to the right second premolars was produced without altering the shape, position, or length of the involved teeth. A software program (Dental Systems; 3Shape A/S) was used to merge the maxillary digital waxing with the full-face smile photograph. One image was obtained for each participant. In the 3D group, a dental software program (Matera 2.4; exocad GmbH) was used to merge the intraoral and facial scans. Subsequently, 1 video of a 180-degree rotation of each 3D superimposition was obtained. Participants evaluated both superimpositions on a scale from 1 (least esthetically pleasing) to 6 (most esthetically pleasing). Finally, participants were asked which superimposition they preferred for a potential treatment outcome representation., Results: All the ratings were esthetically pleasing (median group rating 5 or 6). When analyzed solely for differences across occupation groups, ratings for the 2D representation varied significantly across populations (Kruskal-Wallis chi-squared=13.241, df=2, P=.001), but the ratings for the 3D representation did not exhibit statistically significant differences (Kruskal-Wallis chi-squared=4.3756, df=2, P=.112). Ordinal logistic regression revealed no significant main effects but a significant effect of the population×image-type interaction on the esthetic rating. All participants felt well-represented in both the 2D and 3D representations. Also, 40% of dentists, 55% of dental students, and 50% of laypersons preferred the 3D reconstructions. Sex and occupation in general had no effect on the ratings. However, students tended to give higher ratings to the 3D representations of themselves., Conclusions: There is no evidence based on the current study that 2D and 3D representations were perceived differently, but representation preferences may depend on a person's occupation. When individuals rated 3D visualization higher than 2D visualization, they strongly preferred the 3D visualization for representing the treatment outcome., (Copyright © 2020 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

MIDD0301 is being developed as an oral drug to relax airway smooth muscle (ASM) and reduce lung inflammation in asthma. We report a comparative study of MIDD0301 and its S isomer (MIDD0301S), and found that the compounds have equivalent affinity for γ-aminobutyric acid type A receptor (GABA A R) expressed in rat brain, with half maximal inhibitory concentration values of 25.1 and 26.3 nM for the S and R enantiomers, respectively. Both compounds relaxed substance P contracted ASM within 30 min and neither enantiomer revealed affinity to 48 receptors in an off-target screen. Both enantiomers reduced airway hyperresponsiveness (AHR) with nebulized and oral dosing in two mouse models of bronchoconstriction. In A/J mice, which are very sensitive to methacholine-induced bronchoconstriction, we observed reduction of AHR at 10.8 mg/kg MIDD0301 and 15 mg/kg MIDD0301S. Using oral administration, 100 mg/kg/day for 3 days of either enantiomer was sufficient to reduce AHR. In a model of severe airway inflammation induced by interferon-γ and lipopolysaccharide (LPS), we observed reduction of AHR at 7.2 mg/kg for both enantiomers using nebulized administration, and at 100 mg/kg for oral administration. MIDD0301 and MIDD0301S did not undergo Phase I metabolism. Glucuronidation was observed for both compounds, whereas only MIDD0301 formed the corresponding glucoside in the presence of kidney microsomes. Pharmacokinetic analysis identified glucuronides as the major metabolite with concentrations up to 20-fold more than the parent compound. MIDD0301 glucuronide and MIDD0301 taurine bind GABA A Rs, although 10-fold weaker than MIDD0301. In mouse blood, the taurine adduct was only observed for MIDD0301. Overall, both compounds exhibited similar receptor binding and pharmacodynamic properties with subtle differences in metabolism and greater oral availability and blood concentrations of MIDD0301S., (© 2022 Wiley Periodicals LLC.)

OCT1 and OCT2 are polyspecific membrane transporters that are involved in hepatic and renal drug clearance in humans and mice. In this study, we cloned dog OCT1 and OCT2 and compared their function to the human and mouse orthologs. We used liver and kidney RNA to clone dog OCT1 and OCT2. The cloned and the publicly available RNA-Seq sequences differed from the annotated exon-intron structure of OCT1 in the dog genome CanFam3.1. An additional exon between exons 2 and 3 was identified and confirmed by sequencing in six additional dog breeds. Next, dog OCT1 and OCT2 were stably overexpressed in HEK293 cells and the transport kinetics of five drugs were analyzed. We observed strong differences in the transport kinetics between dog and human orthologs. Dog OCT1 transported fenoterol with 12.9-fold higher capacity but 14.3-fold lower affinity (higher K M ) than human OCT1. Human OCT1 transported ipratropium with 5.2-fold higher capacity but 8.4-fold lower affinity than dog OCT1. Compared to human OCT2, dog OCT2 showed 10-fold lower transport of fenoterol and butylscopolamine. In conclusion, the functional characterization of dog OCT1 and OCT2 reported here may have implications when using dogs as pre-clinical models as well as for drug therapy in dogs.

Background: Waste is endemic in the U.S. health care system. Operating rooms are a source of significant solid waste. Surgeons are integral to many decisions in the operating room., Method: Online survey of surgeons at 2 major academic centers in the United States assessing perspectives on intraoperative waste and willingness to work to actively reduce intraoperative waste., Results: We received responses from 219 surgeons: 90% agreed or strongly agreed that waste of sterile surgical items is an issue, and 95% agreed or strongly agreed to a willingness to change the operating room workflow to reduce waste. Surgeons estimated 26% of single-use, sterile supplies opened for surgery were unused at the end of the case. The barriers to waste reduction cited most frequently were: (1) lack of awareness of waste, (2) lack of concern for waste, and (3) lack of time to address the waste., Conclusion: Surgeons understand there is significant waste in the operating room and are willing to change their workflow to reduce waste. Changes in operating room practices that reduce waste will be beneficial to health systems' finances and their efforts to improve population health through a reduction in consumption and pollution. Efforts should be directed toward reducing operating room waste with an initial focus on the elimination of unnecessary waste of sterile surgical supplies. Further work is needed to determine the precise sources of perioperative waste and what initiatives can be implemented to reduce this burden while maintaining high-value patient care., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Several brain areas have been shown to participate in thirst and control of fluid intake. An understanding of how these circuits interact, and their roles in the activation, maintenance, and termination of fluid intake remains incomplete. Central glucagon-like peptide-1 (GLP-1) receptor activation appears to be an important part of the termination of drinking, but the site(s) of action for this suppression has not yet been determined. In an attempt to use GLP-1 responsiveness as a means to screen targets of hindbrain cells that participate in the termination of thirst and the resultant water intake, we injected the GLP-1 receptor agonist exendin-4 (Ex-4) into three brain areas known to express GLP-1 receptors, and measured subsequent water intake. Ex-4 reduced water consumption when injected into the paraventricular hypothalamic nucleus (PVH) and nucleus of the solitary tract (NTS), but not when injected into the nucleus accumbens (NAc). Using the effective response after injection into the PVH as a guide, we examined the connection between the NTS - the site of endogenous central GLP-1 production - and the PVH. Retrograde tracing combined with Fos immunohistochemistry suggested intake-induced activity in PVH-projecting NTS cells. To test the hypothesis that this pathway is important in the termination of drinking, we chemogenetically activated PVH-projecting hindbrain cells. Interestingly, activation of this population of cells increased water intake, calling into question the heterogeneity of the pathway with respect to the control of fluid intake. Taken together, we conclude that the PVH is a site of action for GLP-1 receptor activation in the inhibition of water intake, but suspect that endogenous GLP-1 in NTS-to-PVH projections may be counterbalanced by a parallel pathway that either activates or maintains already activated water intake., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The imidazodiazepine, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo [f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a new α2/3-selective GABAkine (gamma aminobutyric acid A receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models. Reducing metabolism was utilized as a means of potentially extending the half-life of KRM-II-81. In vitro and in vivo studies were conducted to evaluate metabolic liabilities. Incubation of KRM-II-81 in hepatocytes revealed sites of potential metabolism on the oxazole and the diazepine rings. These sites were targeted in the design of a deuterated analog (D5-KRM-II-81) that could be evaluated as a potentially longer-acting analog. In contrast to computer predictions, peak plasma concentrations of D5-KRM-II-81 in rats were not significantly greater than those produced by KRM-II-81 after oral administration. Furthermore, brain disposition of KRM-II-81 was higher than that of D5-KRM-II-81. The half-life of the two compounds in either plasma or brain did not statistically differ from one another but the t max for D5-KRM-II-81 occurred slightly earlier than for KRM-II-81. Non-metabolic considerations might be relevant to the lack of increases in exposure by D5-KRM-II-81. Alternative sites of metabolism on KRM-II-81, not targeted by the current deuteration process, are also possible. Despite its lack of augmented exposure, D5-KRM-II-81, like KRM-II-81, significantly prevented seizures induced by pentylenetetrazol when given orally. The present findings introduce a new orally active anticonvulsant GABAkine, D5-KRM-II-81., (© 2022 John Wiley & Sons Ltd.)

Population-based seroprevalence surveys can provide useful estimates of the number of individuals previously infected with serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and still susceptible, as well as contribute to better estimates of the case-fatality rate and other measures of coronavirus disease 2019 (COVID-19) severity. No serological test is 100% accurate, however, and the standard correction that epidemiologists use to adjust estimates relies on estimates of the test sensitivity and specificity often based on small validation studies. We have developed a fully Bayesian approach to adjust observed prevalence estimates for sensitivity and specificity. Application to a seroprevalence survey conducted in New York State in 2020 demonstrates that this approach results in more realistic-and narrower-credible intervals than the standard sensitivity analysis using confidence interval endpoints. In addition, the model permits incorporating data on the geographical distribution of reported case counts to create informative priors on the cumulative incidence to produce estimates and credible intervals for smaller geographic areas than often can be precisely estimated with seroprevalence surveys., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hospitals regularly seek to upgrade their antimicrobial stewardship program (ASP). Our aim was to evaluate the impact of simplified therapeutic guidelines (STGs) compared to various established tools for ASP on the rate of optimal antibiotic therapy (OAT) and antibiotic consumption. Audits of antibiotic prescriptions were carried out over a 24-month period. Feedback information led to STGs (e.g., ≤ 15 drugs). The impact of STGs was based on the rate of OAT, defined as a diagnosis of the infectious disease in the patient's medical records associated with the corresponding therapy indicated in the STGs or in other guidelines. STGs were compared to five other means of ASP: internal or national guidelines, audit, information regarding antibiotic consumption and bacterial resistance, and restricted access to targeted antibiotics. Antibiotic consumption was measured in defined daily doses/1000 days of hospital stay, focusing on third-generation cephalosporins (TGC) and fluoroquinolones (FQ). Twenty-six hospitals were audited from April 2017 to June 2019. A total of 1,028 antibiotic prescriptions were analyzed, including 204 (20%) after STG implementation in seven hospitals. In multivariate analysis, OAT (n = 176, 17%) was associated with STGs, AOR 2.21 [1.51-3.22], and with three tools in place, 1.75 [1.24-2.48]. The relative variations of consumption of TGC and FQ for hospitals with or without STGs were - 13.1 vs. + 9.4% and - 18.5 vs. - 2.7%, respectively, from 2018 to 2019. STGs were more likely than other ASP tools to improve the rate of OAT and to reduce the consumption of antibiotics., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Research in functional regression has made great strides in expanding to non-Gaussian functional outcomes, but exploration of ordinal functional outcomes remains limited. Motivated by a study of computer-use behavior in rhesus macaques ( Macaca mulatta ), we introduce the Ordinal Probit Functional Outcome Regression model (OPFOR). OPFOR models can be fit using one of several basis functions including penalized B-splines, wavelets, and O'Sullivan splines-the last of which typically performs best. Simulation using a variety of underlying covariance patterns shows that the model performs reasonably well in estimation under multiple basis functions with near nominal coverage for joint credible intervals. Finally, in application, we use Bayesian model selection criteria adapted to functional outcome regression to best characterize the relation between several demographic factors of interest and the monkeys' computer use over the course of a year. In comparison with a standard ordinal longitudinal analysis, OPFOR outperforms a cumulative-link mixed-effects model in simulation and provides additional and more nuanced information on the nature of the monkeys' computer-use behavior.

Background: The perception of a steep learning curve associated with transradial access has resulted in its limited adoption in neurointervention despite the demonstrated benefits, including decreased access-site complications., Objective: To compare learning curves of transradial versus transfemoral diagnostic cerebral angiograms obtained by five neurovascular fellows as primary operator., Methods: The first 100-150 consecutive transradial and transfemoral angiographic scans performed by each fellow between July 2017 and March 2020 were identified. Mean fluoroscopy time per artery injected (angiographic efficiency) was calculated as a marker of technical proficiency and compared for every 25 consecutive procedures performed (eg, 1-25, 26-50, 51-75)., Results: We identified 1242 diagnostic angiograms, 607 transradial and 635 transfemoral. The radial cohort was older (64.3 years vs 62.3 years, p=0.01) and demonstrated better angiographic efficiency (3.4 min/vessel vs 3.7 min/vessel, p=0.03). For three fellows without previous endovascular experience, proficiency was obtained between 25 and 50 transfemoral angiograms. One fellow achieved proficiency after performing 25-50 transradial angiograms; and the two other fellows, in <25 transradial angiograms. The two fellows with previous experience had flattened learning curves for both access types. Two patients experienced transient neurologic symptoms postprocedure. Transradial angiograms were associated with significantly fewer access-site complications (3/607, 0.5% vs 22/635, 3.5%, p<0.01). Radial-to-femoral conversion occurred in 1.2% (7/607); femoral-to-radial conversion occurred in 0.3% (2/635). Over time, the proportion of transradial angiographic procedures increased., Conclusion: Technical proficiency improved significantly over time for both access types, typically requiring between 25 and 50 diagnostic angiograms to achieve asymptomatic improvement in efficiency. Reduced access-site complications and decreased fluoroscopy time were benefits associated with transradial angiography., Competing Interests: Competing interests: EIL: shareholder/ownership interests: NeXtGen Biologics, RAPID Medical, Claret Medical, Cognition Medical, Imperative Care (formerly the Stroke Project), Rebound Therapeutics, StimMed, Three Rivers Medical; national principal investigator/steering committees: Medtronic (merged with Covidien Neurovascular) SWIFT Prime, and SWIFT Direct Trials; honoraria: Medtronic (training and lectures); consultant: Claret Medical, GLG Consulting, Guidepoint Global, Imperative Care, Medtronic, Rebound, StimMed; advisory board: Stryker (AIS clinical advisory board), NeXtGen Biologics, MEDX, Cognition Medical, Endostream Medical; site principal investigator: CONFIDENCE study (MicroVention), STRATIS Study—Sub I (Medtronic). AHS: financial interest/investor/stock options/ownership: Adona Medical, Inc, Amnis Therapeutics, (purchased by Boston Scientific October 2017), Blink TBI Inc., Buffalo Technology Partners Inc., Cerebrotech Medical Systems, Inc., Cognition Medical, Endostream Medical Ltd., Imperative Care, International Medical Distribution Partners, Neurovascular Diagnostics Inc., Q’Apel Medical Inc, Rebound Therapeutics Corp. (purchased 2019 by Integra Lifesciences, Corp), Rist Neurovascular Inc., Sense Diagnostics, Inc., Serenity Medical Inc., Silk Road Medical, Spinnaker Medical, Inc., StimMed, Synchron, Three Rivers Medical Inc., Vastrax, LLC, VICIS, Inc., Viseon Inc; consultant/advisory board: Amnis Therapeutics, Boston Scientific, Canon Medical Systems USA Inc., Cerebrotech Medical Systems Inc., Cerenovus, Corindus Inc., Endostream Medical Ltd., Imperative Care, Inc. Integra LifeSciences Corp., Medtronic, MicroVention, Minnetronix Neuro, Inc., Northwest University–DSMB chair for HEAT Trial, Penumbra, Q’Apel Medical Inc., Rapid Medical, Rebound Therapeutics Corp. (purchased by Integra LifeSciences Corp.), Serenity Medical Inc., Silk Road Medical, StimMed, Stryker, Three Rivers Medical, Inc., VasSol, W.L. Gore & Associates; principal investigator/steering committee for the following trials: Cerenovus NAPA and ARISE II; Medtronic SWIFT PRIME and SWIFT DIRECT; MicroVention FRED & CONFIDENCE; MUSC POSITIVE; and Penumbra 3D Separator, COMPASS, INVEST, TIGER. KVS: consulting and teaching for Canon Medical Systems Corporation, Penumbra Inc., Medtronic, and Jacobs Institute; co-founder: Neurovascular Diagnostics, Inc. JMD: research grant: National Center for Advancing Translational Sciences of the National Institutes of Health under award number KL2TR001413 to the University at Buffalo; consulting: Medtronic; honoraria: Neurotrauma Science, LLC; shareholder/ownership interests: Cerebrotech, RIST Neurovascular., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

We report the modification of MIDD0301, an imidazodiazepine GABA A receptor (GABA A R) ligand, using two alkyl substituents. We developed PI310 with a 6-(4-phenylbutoxy)hexyl chain as used in the long-acting β2-agonist salmeterol and PI320 with a poly(ethylene glycol) chain as used to improve the brain:plasma ratio of naloxegol, a naloxone analogue. Both imidazodiazepines showed affinity toward the GABA A R binding site of clonazepam, with IC 50 values of 576 and 242 nM, respectively. Molecular docking analysis, using the available α 1 β 3 γ 2 GABA A R structural data, suggests binding of the diazepine core between the α1+/γ2- interface, whereas alkyl substituents are located outside the binding site and thus interact with the protein surface and solvent molecules. The physicochemical properties of these compounds are very different. The solubility of PI310 is low in water. PEGylation of PI320 significantly improves aqueous solubility and cell permeability. Neither compound is toxic in HEK293 cells following exposure at >300 μM for 18 h. Ex vivo studies using guinea pig tracheal rings showed that PI310 was unable to relax the constricted airway smooth muscle. In contrast, PI320 induced muscle relaxation at organ bath concentrations as low as 5 μM, with rapid onset (15 min) at 25 μM. PI320 also reduced airway hyper-responsiveness in vivo in a mouse model of steroid-resistant lung inflammation induced by intratracheal challenge with INFγ and lipopolysaccharide (LPS). At nebulized doses of 7.2 mg/kg, PI320 and albuterol were equally effective in reducing airway hyper-responsiveness. Ten minutes after nebulization, the lung concentration of PI320 was 50-fold that of PI310, indicating superior availability of PI320 when nebulized as an aqueous solution. Overall, PI320 is a promising inhaled drug candidate to quickly relax airway smooth muscle in bronchoconstrictive disorders, such as asthma. Future studies will evaluate the pharmacokinetic/pharmacodynamic properties of PI320 when administered orally., Competing Interests: The authors declare the following competing financial interest(s): L.A.A. and D.C.S. are employees of Pantherics Incorporated. L.A.A. and D.C.S. have an ownership interest in Pantherics, which has acquired rights to the technology reported in this publication. Some of the research was funded by R41HL147658, which was awarded to Pantherics. Pantherics did not finance this research directly. The funders indicated in the acknowledgment section they had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (© 2022 American Chemical Society.)

Wellbeing, or how people think and feel about their lives, predicts important life outcomes from happiness to health to longevity. Montessori pedagogy has features that enhance wellbeing contemporaneously and predictively, including self-determination, meaningful activities, and social stability. Here, 1905 adults, ages 18-81 ( M = 36), filled out a large set of wellbeing scales followed by demographic information including type of school attended each year from 2 to 17. About half the sample had only attended conventional schools and the rest had attended Montessori for between 2 and 16 years ( M = 8 years). To reduce the variable set, we first developed a measurement model of wellbeing using the survey data with exploratory then confirmatory factor analyses, arriving at four factors: general wellbeing, engagement, social trust, and self-confidence. A structural equation model that accounted for age, gender, race, childhood SES, and years in private school revealed that attending Montessori for at least two childhood years was associated with significantly higher adult wellbeing on all four factors. A second analysis found that the difference in wellbeing between Montessori and conventional schools existed even among the subsample that had exclusively attended private schools. A third analysis found that the more years one attended Montessori, the higher one's wellbeing as an adult. Unmeasured selection effects could explain the results, in which case research should determine what third variable associated with Montessori schooling causes adult wellbeing. Several other limitations to the study are also discussed. Although some of these limitations need to be addressed, coupled with other research, including studies in which children were randomly assigned to Montessori schools, this study suggests that attending Montessori as a child might plausibly cause higher adult wellbeing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lillard, Meyer, Vasc and Fukuda.)

Introduction: Health systems are a complex web of interacting and interconnected parts; introducing an intervention, or the allocation of resources, in one sector can have effects across other sectors and impact the entire system. A prerequisite for effective health system reorganisation or transformation is a broad and common understanding of the current system amongst stakeholders and innovators. Chronic obstructive pulmonary disease (COPD) and heart failure (HF) are common chronic diseases with high health care costs that require an integrated health system to effectively treat., Study Description: This case study documents the first phase of system transformation at a regional level in Ontario, Canada. In this first phase, visual representations of the health system in its current state were developed using a collaborative co-creation approach, and a focus on COPD and HF. Multiple methods were used including focus groups, open-ended questionnaires, and document review, to develop a series of graphical and visual representations; a health care ecosystem map., Results: The ecosystem map identified key sectoral components, inter-component interactions, and care requirements for patients with COPD and HF and inventoried current programs and services available to deliver this care. Main findings identified that independent system-wide navigation for this vulnerable patient group is limited, primary care is central to the accessibility of nearly half of the identified care elements, and resources are not equitably distributed. The health care ecosystem mapping helped to identify care gaps and illustrates the need to resource the primary care provider and the patient with system navigation resources and interdisciplinary team care., Conclusion: The co-created health care ecosystem map brought a collective understanding of the health care system as it applies to COPD and HF. The map provides a blueprint that can be adapted to other disease states and health systems. Future transformation will build on this foundational work, continuing the robust interdisciplinary co-creation strategies, exploring predictive health system modelling and identifying areas for integration., (© 2021. The Author(s).)

The ability to identify time periods when individuals are most susceptible to exposures as well as the biological mechanisms through which these exposures act is of great public health interest. Growing evidence supports an association between prenatal exposure to air pollution and epigenetic marks, such as DNA methylation, but the timing and gene-specific effects of these epigenetic changes are not well understood. Here, we present the first study that aims to identify prenatal windows of susceptibility to air pollution exposures in cord blood DNA methylation. In particular, we propose a function-on-function regression model that leverages data from nearby DNA methylation probes to identify epigenetic regions that exhibit windows of susceptibility to ambient particulate matter less than 2.5 microns (PM 2.5 ). By incorporating the covariance structure among both the multivariate DNA methylation outcome and the time-varying exposure under study, this framework yields greater power to detect windows of susceptibility and greater control of false discoveries than methods that model probes independently. We compare our method to a distributed lag model approach that models DNA methylation in a probe-by-probe manner, both in simulation and by application to motivating data from the Project Viva birth cohort. We identify a window of susceptibility to PM 2.5 exposure in the middle of the third trimester of pregnancy in an epigenetic region selected based on prior studies of air pollution effects on epigenome-wide methylation.

The present study assessed target engagement, preliminary efficacy, and feasibility as primary outcomes of a free multi-session online cognitive bias modification of interpretation (CBM-I) intervention for anxiety in a large community sample. High trait anxious participants (N = 807) were randomly assigned to a CBM-I condition: 1) Positive training (90% positive-10% negative); 2) 50% positive-50% negative training; or 3) no-training control. Further, half of each CBM-I condition was randomized to either an anxious imagery prime or a neutral imagery prime. Due to attrition, results from six out of eight sessions were analyzed using structural equation modeling of latent growth curves. Results for the intent-to-treat sample indicate that for target engagement, consistent with predictions, decreases in negative interpretations over time were significantly greater among those receiving positive CBM-I training compared to no-training or 50-50 training, and vice-versa for increases in positive interpretations. For intervention efficacy, the decrease in anxiety symptoms over time was significantly greater among those receiving positive CBM-I training compared to no-training. Interaction effects with imagery prime were more variable with a general pattern of stronger results for those completing the anxious imagery prime. Findings indicate that online CBM-I positive training is feasible and shows some promising results, although attrition rates were very high for later training sessions., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Genome-wide association studies have identified an association between isobutyrylcarnitine (IBC) and organic cation transporter 1 (OCT1) genotypes. Higher IBC blood concentrations in humans with active OCT1 genotypes and experimental studies with mouse OCT1 suggested an OCT1-mediated efflux of IBC. In this study, we wanted to confirm the suggested use of IBC as an endogenous biomarker of OCT1 activity and contribute to a better understanding of the mechanisms behind the association between blood concentrations of carnitine derivatives and OCT1 genotype. Blood and urine IBC concentrations were quantified in healthy volunteers regarding intra- and interindividual variation and correlation with OCT1 genotype and with pharmacokinetics of known OCT1 substrates. Furthermore, IBC formation and transport were studied in cell lines overexpressing OCT1 and its naturally occurring variants. Carriers of high-activity OCT1 genotypes had about 3-fold higher IBC blood concentrations and 2-fold higher amounts of IBC excreted in urine compared to deficient OCT1. This was likely due to OCT1 function, as indicated by the fact that IBC correlated with the pharmacokinetics of known OCT1 substrates, like fenoterol, and blood IBC concentrations declined with a 1 h time delay following peak concentrations of the OCT1 substrate sumatriptan. Thus, IBC is a suitable endogenous biomarker reflecting both, human OCT1 (hOCT1) genotype and activity. While murine OCT1 (mOCT1) was an efflux transporter of IBC, hOCT1 exhibited no IBC efflux activity. Inhibition experiments confirmed this data showing that IBC and other acylcarnitines, like butyrylcarnitine, 2-methylbutyrylcarnitine, and hexanoylcarnitine, showed reduced efflux upon inhibition of mOCT1 but not of hOCT1. IBC and other carnitine derivatives are endogenous biomarkers of hOCT1 genotype and phenotype. However, in contrast to mice, the mechanisms underlying the IBC-OCT1 correlation in humans is apparently not directly the OCT1-mediated efflux of IBC. A plausible explanation could be that hOCT1 mediates cellular concentrations of specific regulators or co-substrates in lipid and energy metabolism, which is supported by our in vitro finding that at baseline intracellular IBC concentration is about 6-fold lower alone by OCT1 overexpression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jensen, Matthaei, Klemp, Meyer, Brockmöller and Tzvetkov.)

Organic cation transporter 1 (OCT1, SLC22A1) is localized in the sinusoidal membrane of human hepatocytes and mediates hepatic uptake of weakly basic or cationic drugs and endogenous compounds. Common amino acid substitutions in OCT1 were associated with altered pharmacokinetics and efficacy of drugs like sumatriptan and fenoterol. Recently, the common splice variant rs35854239 has also been suggested to affect OCT1 function. rs35854239 represents an 8 bp duplication of the donor splice site at the exon 7-intron 7 junction. Here we quantified the extent to which this duplication affects OCT1 splicing and, as a consequence, the expression and the function of OCT1. We used pyrosequencing and deep RNA-sequencing to quantify the effect of rs35854239 on splicing after minigene expression of this variant in HepG2 and Huh7 cells and directly in human liver samples. Further, we analyzed the effects of rs35854239 on OCT1 mRNA expression in total, localization and activity of the resulting OCT1 protein, and on the pharmacokinetics of sumatriptan and fenoterol. The 8 bp duplication caused alternative splicing in 38% (deep RNA-sequencing) to 52% (pyrosequencing) of the minigene transcripts when analyzed in HepG2 and Huh7 cells. The alternatively spliced transcript encodes for a truncated protein that after transient transfection in HEK293 cells was not localized in the plasma membrane and was not able to transport the OCT1 model substrate ASP + . In human liver, however, the alternatively spliced OCT1 transcript was detectable only at very low levels (0.3% in heterozygous and 0.6% in homozygous carriers of the 8 bp duplication, deep RNA-sequencing). The 8 bp duplication was associated with a significant reduction of OCT1 expression in the human liver, but explained only 9% of the general variability in OCT1 expression and was not associated with significant changes in the pharmacokinetics of sumatriptan and fenoterol. Therefore, the rs35854239 variant only partially changes splicing, causing moderate changes in OCT1 expression and may be of only limited therapeutic relevance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Römer, Meyer, Klein, Schneider, Matthaei, Tzvetkova, Łapczuk-Romańska, Gaedcke, Droździk, Brockmöller, Nies and Tzvetkov.)

Historical Functional Linear Models (HFLM) quantify associations between a functional predictor and functional outcome where the predictor is an exposure variable that occurs before, or at least concurrently with, the outcome. Prior work on the HFLM has largely focused on estimation of a surface that represents a time-varying association between the functional outcome and the functional exposure. This existing work has employed frequentist and spline-based estimation methods, with little attention paid to formal inference or adjustment for multiple testing and no approaches that implement wavelet-bases. In this work, we propose a new functional regression model that estimates the time-varying, lagged association between a functional outcome and a functional exposure. Building off of recently developed function-on-function regression methods, the model employs a novel use the wavelet-packet decomposition of the exposure and outcome functions that allows us to strictly enforce the temporal ordering of exposure and outcome, which is not possible with existing wavelet-based functional models. Using a fully Bayesian approach, we conduct formal inference on the time-varying lagged association, while adjusting for multiple testing. We investigate the operating characteristics of our wavelet-packet HFLM and compare them to those of two existing estimation procedures in simulation. We also assess several inference techniques and use the model to analyze data on the impact of lagged exposure to particulate matter finer than 2.5 μ g, or PM 2.5 , on heart rate variability in a cohort of journeyman boilermakers during the morning of a typical day's shift.

Background: High-quality shared decision-making for patients undergoing elective surgical procedures includes eliciting patient goals and treatment preferences. This is particularly important, should complications occur and life-sustaining therapies be considered. Our objective was to determine the preoperative care preferences of older higher-risk patients undergoing elective procedures and to determine any factors associated with a preference for limitations to life-sustaining treatments., Methods: Cross-sectional survey conducted between May and December 2018. Patients ≥55 years of age presenting for a preprocedural evaluation in a high-risk anesthesia clinic were queried on their desire for life-sustaining treatments (cardiopulmonary resuscitation, mechanical ventilation, dialysis, and artificial nutrition) as well as tolerance for declines in health states (physical disability, cognitive disability, and daily severe pain)., Results: One hundred patients completed the survey. The median patient age was 68. Most patients were Caucasian (87%) and had an American Society of Anesthesiologists (ASA) score of III (88%). The majority of patients (89%) desired cardiopulmonary resuscitation. However, most patients would not accept mechanical ventilation, dialysis, or artificial nutrition for an indefinite period of time. Similarly, most patients (67%-81%) indicated they would not desire treatments to sustain life in the event of permanent physical disability, cognitive disability, or daily severe pain., Conclusions: Among older, higher-risk patients presenting for elective procedures, most patients chose limitations to life-sustaining treatments. This work highlights the need for an in-depth goals of care discussion and establishment of advance care preferences before a procedure or operative intervention.