Large-scale data mining of four billion human antibody variable regions reveals convergence between therapeutic and natural antibodies that constrains search space for biologics drug discovery.

The naïve human antibody repertoire has theoretical access to an estimated > 1015 antibodies. Identifying subsets of this prohibitively large space where therapeutically relevant antibodies may be found is useful for development of these agents. It was previously demonstrated that, despite the immense sequence space, different individuals can produce the same antibodies. It was also shown that therapeutic antibodies, which typically follow seemingly unnatural development processes, can arise independently naturally. To check for biases in how the sequence space is explored, we data mined public repositories to identify 220 bioprojects with a combined seven billion reads. Of these, we created a subset of human bioprojects that we make available as the AbNGS database (https://naturalantibody.com/ngs/). AbNGS contains 135 bioprojects with four billion productive human heavy variable region sequences and 385 million unique complementarity-determining region (CDR)-H3s. We find that 270,000 (0.07% of 385 million) unique CDR-H3s are highly public in that they occur in at least five of 135 bioprojects. Of 700 unique therapeutic CDR-H3, a total of 6% has direct matches in the small set of 270,000. This observation extends to a match between CDR-H3 and V-gene call as well. Thus, the subspace of shared ('public') CDR-H3s shows utility for serving as a starting point for therapeutic antibody design.

Genome-wide association analysis of the resistance to infectious hematopoietic necrosis virus in two rainbow trout aquaculture lines confirms oligogenic architecture with several moderate effect quantitative trait loci.

Infectious hematopoietic necrosis (IHN) is a disease of salmonid fish that is caused by the IHN virus (IHNV), which can cause substantial mortality and economic losses in rainbow trout aquaculture and fisheries enhancement hatchery programs. In a previous study on a commercial rainbow trout breeding line that has undergone selection, we found that genetic resistance to IHNV is controlled by the oligogenic inheritance of several moderate and many small effect quantitative trait loci (QTL). Here we used genome wide association analyses in two different commercial aquaculture lines that were naïve to previous exposure to IHNV to determine whether QTL were shared across lines, and to investigate whether there were major effect loci that were still segregating in the naïve lines. A total of 1,859 and 1,768 offspring from two commercial aquaculture strains were phenotyped for resistance to IHNV and genotyped with the rainbow trout Axiom 57K SNP array. Moderate heritability values (0.15-0.25) were estimated. Two statistical methods were used for genome wide association analyses in the two populations. No major QTL were detected despite the naïve status of the two lines. Further, our analyses confirmed an oligogenic architecture for genetic resistance to IHNV in rainbow trout. Overall, 17 QTL with notable effect (≥1.9% of the additive genetic variance) were detected in at least one of the two rainbow trout lines with at least one of the two statistical methods. Five of those QTL were mapped to overlapping or adjacent chromosomal regions in both lines, suggesting that some loci may be shared across commercial lines. Although some of the loci detected in this GWAS merit further investigation to better understand the biological basis of IHNV disease resistance across populations, the overall genetic architecture of IHNV resistance in the two rainbow trout lines suggests that genomic selection may be a more effective strategy for genetic improvement in this trait.

Benchmarking antibody clustering methods using sequence, structural, and machine learning similarity measures for antibody discovery applications.

Antibodies are proteins produced by our immune system that have been harnessed as biotherapeutics. The discovery of antibody-based therapeutics relies on analyzing large volumes of diverse sequences coming from phage display or animal immunizations. Identification of suitable therapeutic candidates is achieved by grouping the sequences by their similarity and subsequent selection of a diverse set of antibodies for further tests. Such groupings are typically created using sequence-similarity measures alone. Maximizing diversity in selected candidates is crucial to reducing the number of tests of molecules with near-identical properties. With the advances in structural modeling and machine learning, antibodies can now be grouped across other diversity dimensions, such as predicted paratopes or three-dimensional structures. Here we benchmarked antibody grouping methods using clonotype, sequence, paratope prediction, structure prediction, and embedding information. The results were benchmarked on two tasks: binder detection and epitope mapping. We demonstrate that on binder detection no method appears to outperform the others, while on epitope mapping, clonotype, paratope, and embedding clusterings are top performers. Most importantly, all the methods propose orthogonal groupings, offering more diverse pools of candidates when using multiple methods than any single method alone. To facilitate exploring the diversity of antibodies using different methods, we have created an online tool-CLAP-available at (clap.naturalantibody.com) that allows users to group, contrast, and visualize antibodies using the different grouping methods.

Two-photon rubidium clock detecting 776 nm fluorescence.

The optical atomic clock based on the 5S1/2 → 5D5/2 two-photon transition in rubidium is a candidate for a next generation, manufacturable, portable clock that fits in a small size, weight, and power (SWaP) envelope. Here, we report the first two-photon rubidium clock stabilized by detecting 776 nm fluorescence. We also demonstrate the use of a multi-pixel photon counter as a low voltage substitute to a photomultiplier tube in the feedback loop to the clock laser.

Quantifying preferences for urea cycle disorder treatments using a discrete choice experiment.

AIMS: Urea cycle disorders (UCDs) can cause ammonia accumulation and central nervous system toxicity. Nitrogen-binding medications can be efficacious, but certain attributes may negatively impact adherence. This study sought to quantify the administration-related attributes influencing overall prescription selection and patient adherence. METHODS: A web-based, quantitative survey including discrete choice experiment (DCE) methodology captured responses from health care providers for patients with UCDs. A series of hypothetical treatment profile sets with attributes such as route of administration, taste/odor, preparation instructions, packaging, dose measurement, and weight use restrictions were presented. From 16 sets of 3 hypothetical product profiles, respondents evaluated attributes most preferred for prescription selection or patient adherence. Attributes assumed a higher overall preference if relative importance (RI) scores were >16.67% (the value if all attributes were of equal importance). Preference weight scores were assessed. A nine-point Likert scale assessed respondent attitudes, such as satisfaction. RESULTS: A total of 51 respondents completed the survey. Respondents reported dissatisfaction with current treatments (mean [SD] = 5.4 [1.7]). For prescription selection, four attributes achieved RI >16.67%: taste/odor (24%), weight restrictions (21%), preparation instructions (18%), and route of administration (17%). For adherence, three attributes related to administration achieved RI >16.67%: taste/odor (28%), preparation instructions (21%), and route of administration (17%). Preference weights for "taste/odor masked" were higher than "not taste/odor masked" for prescription selection (mean [SD]; 1.52 [1.10] vs -1.52 [1.10]) and treatment adherence (73.8 [55.2] vs -73.8 [55.2]). LIMITATIONS: This study contained a relatively small sample size. Survey respondent selection, the use of hypothetical product profiles, and exclusion of non-pharmacologic treatment options could have contributed to potential biases. CONCLUSIONS: Among attributes tested, taste/odor was the most important attribute influencing overall preference for both prescribing and patient adherence, with taste/odor masking preferred. Optimizing nitrogen-binding medications through masking taste/odor may support improved patient adherence and outcomes in UCDs.

Epidemiology and outcomes of geriatric trauma patients consulting at the center hospitalier universitaire de Kigali emergency department.

Background: Life expectancy in low- and middle-income countries (LMIC) continues to rise, resulting in a growing geriatric population. In Rwanda, a sub-Saharan LMIC, traumatic injuries are a common cause of mortality and morbidity. However, little is known about the frequency and type of traumatic injuries among geriatric populations in Rwanda. Objective: We explored the epidemiology and outcomes of trauma for geriatric patients presenting to the emergency department (ED) of the center Hospitalier Universitaire de Kigali (CHUK) in Rwanda. Methods: This prospective cross-sectional study was conducted from July 2019 to January 2020 at the ED of CHUK. Trauma patients aged 65 and above and alive at the time of evaluation were eligible for inclusion. Demographic characteristics were collected along with triage category, mechanism of injury, transfer status, transport method to CHUK, time spent at the ED, complications, and mortality predictors. Results: For the 100 patients enrolled, the most common injury mechanism was falls (63%), followed by road traffic accidents (28%). The majority of patients spent less than 48 h in the ED (63%). The mortality rate was 14%, with most deaths resulting from injury-related complications. Triage category, Kampala Trauma Score, and Glasgow Coma Scale were significant predictors of mortality, with p-values of 0.002, <0.001, and <0.001, respectively. Conclusions: The epidemiology of geriatric trauma found in this study can inform public health and clinical guidelines. Interventions targeting falls and road traffic accidents would target the most common geriatric trauma mechanisms, and clinical protocols that take into account predictors of mortality could improve outcomes and increase life expectancy for this population.

Patella alta and increased TT-TG distance do not adversely affect patient-reported outcomes following isolated MPFL reconstruction: A systematic review.

OBJECTIVES: To analyze the effect of patellofemoral anatomical variations (patella alta, increased tibial tubercle-trochlear groove [TT-TG] distance, and trochlear dysplasia) on clinical outcomes after isolated medial patellofemoral ligament (MPFL) reconstruction. METHODS: A comprehensive search from PubMed, Embase, and the Cochrane Library databases was conducted to identify studies that compared outcomes based on the presence or absence of patella alta, elevated tibial tubercle-trochlear groove (TT-TG) distance, and/or trochlear dysplasia. Exclusion criteria included reviews and meta-analyses, studies that included patients who underwent associated bony procedures, and those reporting outcomes after isolated MPFL reconstruction with no comparison between varying anatomical groups. RESULTS: After application of selection criteria, 19 studies were included. Patella alta was not predictive of failure or poorer outcomes among 13 studies; however, 2 studies demonstrated poorer patient-reported outcome scores and/or higher failure rates with increasing patellar height. Increasing TT-TG distance demonstrated a statistically significant correlation with poorer outcomes in only one study, whereas 12 other studies showed no association. Trochlear dysplasia resulted in worse outcomes and greater failure rates in 6 studies, while 10 studies showed no statistically significant correlation between trochlear dysplasia and postoperative outcomes. CONCLUSION: Patella alta and increased TT-TG distance did not adversely affect outcomes following isolated MPFL reconstruction in the preponderance of reviewed studies. Data are mixed regarding the impact of trochlear dysplasia on the outcomes of isolated MPFL reconstruction. LEVEL OF EVIDENCE: IV.

"EM Doc On Call:" A Pilot Study to Improve Interhospital Transfers in Rwanda.

INTRODUCTION: Treatment of seriously ill patients is often complicated by prolonged or complex transfers between hospitals in sub-Saharan Africa. Difficulties or inefficiency in these transfers can lead to poor outcomes for patients. "On-call" triage systems have been utilized to facilitate communication between facilities and to avoid poor outcomes associated with patient transfer. This study attempts to examine the effects of a pilot study to implement such a system in Rwanda. METHODS: Data collection occurred prospectively in two stages, pre-intervention and intervention, in the emergency department (ED) at Kigali University Teaching Hospital (CHUK). All patients transferred during the pre-determined timeframe were enrolled. Data were collected by ED research staff via a standardized form. Statistical analysis was performed using STATA version 15.0. Differences in characteristics were assessed using χ2 or Fisher's exact tests for categorical variables and independent sample t-tests for normally distributed continuous variables. RESULTS: During the "on call" physician intervention, the indication for transfer was significantly more likely to be for critical care (P <.001), transfer times were faster (P <.001), patients were more likely to be displaying emergency signs (P <.001), and vital signs were more likely to be collected prior to transport (P <.001) when compared to the pre-interventional phase. CONCLUSION: The "[Emergency Medicine] EM Doc On Call" intervention was associated with improved timely interhospital transfer and clinical documentation in Rwanda. While these data are not definitive due to multiple limitations, it is extremely promising and worthy of further study.

Trends in industrialization of biotherapeutics: a survey of product characteristics of 89 antibody-based biotherapeutics.

There is considerable interest in the pharmaceutical industry toward development of antibody-based biotherapeutics because they can selectively bind diverse receptors and often possess desirable pharmacology. Here, we studied product characteristics of 89 marketed antibody-based biotherapeutics that were approved from 1986 to mid-2020 by gathering publicly available information. Our analyses revealed major trends in their emergence as the best-selling class of pharmaceuticals. Early on, most therapeutic monoclonal antibodies were developed to treat cancer, with CD20 being the most common target. Thanks to industrialization of antibody manufacturing technologies, their use has now blossomed to include 15 different therapeutic areas and nearly 60 targets, and the field is still growing! Drug manufacturers are solidifying their choices regarding types of antibodies and their molecular formats. IgG1 kappa continues to be the most common molecular format among marketed antibody-based biotherapeutics. Most antibody-based biotherapeutics approved since 2015 are either humanized or fully human, but the data we collected do not show a direct correlation between humanness and reported incidence of anti-drug antibodies. Furthermore, there have also been improvements in terms of drug product stability and high concentration liquid formulations suitable for subcutaneous route of administration, which are being approved more often in recent years. These improvements, however, have not been uniformly adopted across all therapeutic areas, suggesting that multiple options for drug product development are being used to serve diverse therapeutic purposes. Insights gained from this analysis may help us devise better end-to-end antibody-based biotherapeutic drug discovery and development strategies.

Compound-Specific Behavioral and Enzymatic Resistance to Toxic Milkweed Cardenolides in a Generalist Bumblebee Pollinator.

Plant secondary metabolites that defend leaves from herbivores also occur in floral nectar. While specialist herbivores often have adaptations providing resistance to these compounds in leaves, many social insect pollinators are generalists, and therefore are not expected to be as resistant to such compounds. The milkweeds, Asclepias spp., contain toxic cardenolides in all tissues including floral nectar. We compared the concentrations and identities of cardenolides between tissues of the North American common milkweed Asclepias syriaca, and then studied the effect of the predominant cardenolide in nectar, glycosylated aspecioside, on an abundant pollinator. We show that a generalist bumblebee, Bombus impatiens, a common pollinator in eastern North America, consumes less nectar with experimental addition of ouabain (a standard cardenolide derived from Apocynacid plants native to east Africa) but not with addition of glycosylated aspecioside from milkweeds. At a concentration matching that of the maximum in the natural range, both cardenolides reduced activity levels of bees after four days of consumption, demonstrating toxicity despite variation in behavioral deterrence (i.e., consumption). In vitro enzymatic assays of Na+/K+-ATPase, the target site of cardenolides, showed lower toxicity of the milkweed cardenolide than ouabain for B. impatiens, indicating that the lower deterrence may be due to greater tolerance to glycosylated aspecioside. In contrast, there was no difference between the two cardenolides in toxicity to the Na+/K+-ATPase from a control insect, the fruit fly Drosophila melanogaster. Accordingly, this work reveals that even generalist pollinators such as B. impatiens may have adaptations to reduce the toxicity of specific plant secondary metabolites that occur in nectar, despite visiting flowers from a wide variety of plants over the colony's lifespan.

Embedding Dynamics in Intrinsic Physicochemical Profiles of Market-Stage Antibody-Based Biotherapeutics.

Adequate stability, manufacturability, and safety are crucial to bringing an antibody-based biotherapeutic to the market. Following the concept of holistic in silico developability, we introduce a physicochemical description of 91 market-stage antibody-based biotherapeutics based on orthogonal molecular properties of variable regions (Fvs) embedded in different simulation environments, mimicking conditions experienced by antibodies during manufacturing, formulation, and in vivo. In this work, the evaluation of molecular properties includes conformational flexibility of the Fvs using molecular dynamics (MD) simulations. The comparison between static homology models and simulations shows that MD significantly affects certain molecular descriptors like surface molecular patches. Moreover, the structural stability of a subset of Fv regions is linked to changes in their specific molecular interactions with ions in different experimental conditions. This is supported by the observation of differences in protein melting temperatures upon addition of NaCl. A DEvelopability Navigator In Silico (DENIS) is proposed to compare mAb candidates for their similarity with market-stage biotherapeutics in terms of physicochemical properties and conformational stability. Expanding on our previous developability guidelines (Ahmed et al. Proc. Natl. Acad. Sci. 2021, 118 (37), e2020577118), the hydrodynamic radius and the protein strand ratio are introduced as two additional descriptors that enable a more comprehensive in silico characterization of biotherapeutic drug candidates. Test cases show how this approach can facilitate identification and optimization of intrinsically developable lead candidates. DENIS represents an advanced computational tool to progress biotherapeutic drug candidates from discovery into early development by predicting drug properties in different aqueous environments.

Epidemiology and outcomes of geriatric trauma patients consulting at the center hospitalier universitaire de Kigali emergency department

Background Life expectancy in low- and middle-income countries (LMIC) continues to rise, resulting in a growing geriatric population. In Rwanda, a sub-Saharan LMIC, traumatic injuries are a common cause of mortality and morbidity. However, little is known about the frequency and type of traumatic injuries among geriatric populations in Rwanda. Objective We explored the epidemiology and outcomes of trauma for geriatric patients presenting to the emergency department (ED) of the center Hospitalier Universitaire de Kigali (CHUK) in Rwanda. Methods This prospective cross-sectional study was conducted from July 2019 to January 2020 at the ED of CHUK. Trauma patients aged 65 and above and alive at the time of evaluation were eligible for inclusion. Demographic characteristics were collected along with triage category, mechanism of injury, transfer status, transport method to CHUK, time spent at the ED, complications, and mortality predictors. Results For the 100 patients enrolled, the most common injury mechanism was falls (63%), followed by road traffic accidents (28%). The majority of patients spent less than 48 h in the ED (63%). The mortality rate was 14%, with most deaths resulting from injury-related complications. Triage category, Kampala Trauma Score, and Glasgow Coma Scale were significant predictors of mortality, with p-values of 0.002, <0.001, and <0.001, respectively. Conclusions The epidemiology of geriatric trauma found in this study can inform public health and clinical guidelines. Interventions targeting falls and road traffic accidents would target the most common geriatric trauma mechanisms, and clinical protocols that take into account predictors of mortality could improve outcomes and increase life expectancy for this population.

A grassroots approach for greener education: An example of a medical student-driven planetary health curriculum.

Given the widespread impacts of climate change and environmental degradation on human health, medical schools have been under increasing pressure to provide comprehensive planetary health education to their students. However, the logistics of integrating such a wide-ranging and multi-faceted topic into existing medical curricula can be daunting. In this article, we present the Warren Alpert Medical School of Brown University as an example of a student-driven, bottom-up approach to the development of a planetary health education program. In 2020, student advocacy led to the creation of a Planetary Health Task Force composed of medical students, faculty, and administrators as well as Brown Environmental Sciences faculty. Since that time, the task force has orchestrated a wide range of planetary health initiatives, including interventions targeted to the entire student body as well as opportunities catering to a subset of highly interested students who wish to engage more deeply with planetary health. The success of the task force stems from several factors, including the framing of planetary health learning objectives as concordant with the established educational priorities of the Medical School's competency-based curriculum known as the Nine Abilities, respecting limitations on curricular space, and making planetary health education relevant to local environmental and hospital issues.

Identification of Haplotypes Associated With Resistance to Bacterial Cold Water Disease in Rainbow Trout Using Whole-Genome Resequencing.

Bacterial cold water disease (BCWD) is an important disease in rainbow trout aquaculture. Previously, we have identified and validated two major QTL (quantitative trait loci) for BCWD resistance, located on chromosomes Omy08 and Omy25, in the odd-year Troutlodge May spawning population. We also demonstrated that marker-assisted selection (MAS) for BCWD resistance using the favorable haplotypes associated with the two major QTL is feasible. However, each favorable haplotype spans a large genomic region of 1.3-1.6 Mb. Recombination events within the haplotype regions will result in new haplotypes associated with BCWD resistance, which will reduce the accuracy of MAS for BCWD resistance over time. The objectives of this study were 1) to identify additional SNPs (single nucleotide polymorphisms) associated with BCWD resistance using whole-genome sequencing (WGS); 2) to validate the SNPs associated with BCWD resistance using family-based association mapping; 3) to refine the haplotypes associated with BCWD resistance; and 4) to evaluate MAS for BCWD resistance using the refined QTL haplotypes. Four consecutive generations of the Troutlodge May spawning population were evaluated for BCWD resistance. Parents and offspring were sequenced as individuals and in pools based on their BCWD phenotypes. Over 12 million SNPs were identified by mapping the sequences from the individuals and pools to the reference genome. SNPs with significantly different allele frequencies between the two BCWD phenotype groups were selected to develop SNP assays for family-based association mapping in three consecutive generations of the Troutlodge May spawning population. Among the 78 SNPs derived from WGS, 77 SNPs were associated with BCWD resistance in at least one of the three consecutive generations. The additional SNPs associated with BCWD resistance allowed us to reduce the physical sizes of haplotypes associated with BCWD resistance to less than 0.5 Mb. We also demonstrated that the refined QTL haplotypes can be used for MAS in the Troutlodge May spawning population. Therefore, the SNPs and haplotypes reported in this study provide additional resources for improvement of BCWD resistance in rainbow trout.

Arthroscopic-Assisted Toggle Rod Stabilization in Canine Coxofemoral Luxation: A Cadaveric Study.

OBJECTIVE: The aim of this study was to describe an arthroscopic-assisted technique for coxofemoral toggle rod placement, and to report on the feasibility, drill tunnel trajectory and accuracy of tunnel aperture location using this method. STUDY DESIGN: Cadaveric pilot study. SAMPLE POPULATION: Eight coxofemoral joints. METHODS: Craniodorsal coxofemoral joint luxations were artificially created. A simulated open hip reduction and stabilization with a toggle rod were performed through a limited arthrotomy under arthroscopic guidance. Computed tomography scans were performed to evaluate drill hole trajectory across the femoral neck, and joints were disarticulated and photographed. Digital imaging software was used to determine the percent overlap of the drill hole apertures relative to the origin and insertion of the round ligament on the acetabulum and fovea. RESULTS: The exit point of the tunnel was entirely within the fovea capitis in five of eight femurs, three of eight femoral drill apertures were only partially within the target area. Of the eight acetabular bone tunnels examined, all were centred occupying the acetabular fossa. CONCLUSIONS: Coxofemoral toggle rod placement can be performed under arthroscopic guidance through a limited arthrotomy. Comparable femoral tunnel accuracy with the standard open technique should be achieved with the current method prior to its clinical use.

Ability to Perform Laparoscopic Intra- and Extracorporeal Suture Ligations in a Live Canine Ovariectomy Model after Simulation Training.

Veterinary resident training in minimally invasive surgery is currently inconsistent and depends on innate psychomotor skills. Simulation training has been shown to effectively increase basic skills, but demonstration of simulation training effects on advanced skills in the operating room is sparse. We aimed to determine if simulation-trained novice surgeons were able to perform laparoscopic suture ligation in live dogs. Three novice laparoscopic surgeons underwent a 12-session simulation training program with subsequent laparoscopic skills testing to demonstrate competency. The median skills scores of trainees and of one experienced surgeon were 417 and 472, respectively. Eighteen healthy client-owned (shelter) dogs were operated on by four surgeons: one experienced American College of Veterinary Surgeons (ACVS) diplomate, two novice ACVS residents, and one novice ACVS diplomate. Laparoscopic ovariectomy was performed with suture ligation of the ovarian pedicles. Successful surgery was defined as no evidence of ovarian vessel bleeding after transection of the pedicles. Simulation-trained novices performed successful suture-ligated ovariectomies in 11/13 dogs (85%), and the experienced surgeon in 5/5 (100%) dogs. Median total ligation time was 30 minutes (range: 17-57), which was not different among surgeons (p = .118). Median total surgery time was 105 minutes (range: 69-156) for novices and 89 minutes (range: 65-99) for the experienced surgeon (p = .038). Extensive simulation training including suturing may contribute toward surgery residents being able to perform complex laparoscopic procedures. These results need to be confirmed in larger numbers of trainees.

Utilisation of peripheral vasopressor medications and extravasation events among critically ill patients in Rwanda: A prospective cohort study.

Introduction: In high-income settings, vasopressor administration to treat haemodynamic instability through a central venous catheter (CVC) is the preferred standard. However, due to lack of availability and potential for complications, CVCs are not widely used in low- and middle-income countries. This prospective cohort study evaluated the use of peripheral vasopressors and associated incidence of extravasation events in patients with haemodynamic instability at the Centre Hospitalier Universitaire Kigali, Rwanda. Methods: Patients ≥18 years of age receiving peripheral vasopressors in the emergency centre (EC) or intensive care unit (ICU) for >1 hour were eligible for inclusion. The primary outcome was extravasation events. Patients were followed hourly until extravasation, medication discontinuation, death, or CVC placement. Extravasation incidence with 95% confidence intervals (CI) were calculated using Poisson exact tests. Results: 64 patients were analysed. The median age was 49 (Interquartile Range [IQR]:33-65) and 55% were female. Distributive shock was the most frequent aetiology (47%). Intravenous (IV) location was most commonly antecubital fossa/upper arm (31%) and forearm/hand (43%). IV gauges ≤18 were used in 58% of locations. Most patients were treated with adrenaline (66%) and noradrenaline (41%), and 11% received multiple vasopressors. The median treatment duration was 19 hours (IQR:8.5-37). Treatment discontinuation was predominantly due to mortality (41%) or resolution of instability (36%). There were two extravasation events (2.9%), both limited to soft tissue swelling. Extravasation incidence was 0.8 events per 1000 patient-hours (95% CI:0.2-2.2). Conclusion: Extravasation incidence with peripheral vasopressors was low, even with long use durations, suggesting peripheral infusions may be an acceptable approach when barriers exist to CVC placement.

Measurement of Optical Rubidium Clock Frequency Spanning 65 Days.

Optical clocks are emerging as next-generation timekeeping devices with technological and scientific use cases. Simplified atomic sources such as vapor cells may offer a straightforward path to field use, but suffer from long-term frequency drifts and environmental sensitivities. Here, we measure a laboratory optical clock based on warm rubidium atoms and find low levels of drift on the month-long timescale. We observe and quantify helium contamination inside the glass vapor cell by gradually removing the helium via a vacuum apparatus. We quantify a drift rate of 4×10-15/day, a 10 day Allan deviation less than 5×10-15, and an absolute frequency of the Rb-87 two-photon clock transition of 385,284,566,371,190(1970) Hz. These results support the premise that optical vapor cell clocks will be able to meet future technology needs in navigation and communications as sensors of time and frequency.

Patients' and Providers' Views on Optimal Evidence-Based and Scalable Interventions for Individuals at High Risk of HIV Treatment Failure: Sequential Explorations Among Key Stakeholders in Cape Town, South Africa.

To support translation of evidence-based interventions into practice for HIV patients at high risk of treatment failure, we conducted qualitative research in Cape Town, South Africa. After local health officials vetted interventions as potentially scalable, we held 41 in-depth interviews with patients with elevated viral load or a 3-month treatment gap at community clinics, followed by focus group discussions (FGDs) with 20 providers (physicians/nurses, counselors, and community health care workers). Interviews queried treatment barriers, solutions, and specific intervention options, including motivational text messages, data-informed counseling, individual counseling, peer support groups, check-in texts, and treatment buddies. Based on patients' preferences, motivational texts and treatment buddies were removed from consideration in subsequent FGDs. Patients most preferred peer support groups and check-in texts while individual counseling garnered the broadest support among providers. Check-in texts, peer support groups, and data-informed counseling were also endorsed by provider sub-groups. These strategies warrant attention for scale-up in South Africa and other resource-constrained settings.