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Some recent services use a sequencer to simplify ordering operations on sharded data. The sequencer assigns each operation a multi-sequence number which explicitly orders the operation on each shard it accesses. Existing sequencers have two shortcomings. First, failures can result in some multi-sequence numbers never being assigned, exposing a non-contiguous multi-sequence, which requires complex scaffolding to handle. Second, existing implementations use single-machine sequencers, limiting service throughput to the ordering throughput of one machine.We make two contributions. First, we posit that sequencers should expose our new contiguous multi-sequence abstraction. Contiguity guarantees every sequence number is assigned an operation, simplifying the abstraction. Second, we design and implement MASON , the first system to expose the contiguous multi-sequence abstraction and the first to provide a scalable multi-sequence. MASON is thus an ideal building block for consistent, scalable services. Our evaluation shows MASON unlocks scalable throughput for two strongly-consistent services built on it.

The aim of this study was to understand the factors that impact the recruitment and retention of scientists that identify as Black, Indigenous or as People of Color (BIPOC). A total of 47 BIPOC participants who are currently working or have worked in the field of marine science were recruited using a non-probability snowball sampling method to participate in semi-structured interviews which were analyzed using Astin's Input-Environment-Output framework and Social Cognitive Career Theory. Several interventions which have been put in place to address the systemic issues that have led to the exclusion of certain groups including BIPOC-focused programs, research experiences and mentorship were identified as having positive impacts on the cognitive-personal outcomes of sense of belonging (feeling of acceptance within a group), science identity (the self-categorization of one's self as a 'science person') and self-efficacy (belief in one's ability to succeed). Several factors including discrimination, lack of allyship and negative research or mentorship experiences were identified as factors that greatly reduce these cognitive-personal outcomes. In addition, all three interviewees who left the field of marine science mentioned research experiences where they felt unsupported as a contributing factor to them leaving the field. This study serves to exemplify that systemic issues that have been observed in other STEM fields exist in the ocean science field as well. The study uses a novel framework to present and analyze trends in the experiences of BIPOC ocean scientists around the world.

BackgroundPersistent walking impairment following a stroke is common. Although rehabilitative interventions exist, few exist for use at home in the chronic phase of stroke recovery. InTandem (MedRhythms, Inc) is a neurorehabilitation system intended to improve walking and community ambulation in adults with chronic stroke walking impairment. ObjectiveUsing design best practices and human factors engineering principles, the research presented here was conducted to validate the safe and effective use of InTandem. MethodsIn total, 15 participants in the chronic phase of stroke recovery (≥6 months after stroke) participated in this validation study. Participants were scored on 8 simulated use tasks, 4 knowledge assessments, and 7 comprehension assessments in a simulated home environment. The number and types of use errors, close calls, and operational difficulties were evaluated. Analyses of task performances, participant behaviors, and follow-up interviews were conducted to determine the root cause of use errors and difficulties. ResultsDuring this validation study, 93% (14/15) of participants were able to successfully complete the critical tasks associated with the simulated use of the InTandem system. Following simulated use task assessments, participants’ knowledge and comprehension of the instructions for use and key safety information were evaluated. Overall, participants were able to find and correctly interpret information in the materials in order to answer the knowledge assessment questions. During the comprehension assessment, participants understood warning statements associated with critical tasks presented in the instructions for use. Across the entire study, 3 “use errors” and 1 “success with difficulty” were recorded. No adverse events, including slips, trips, or falls, occurred in this study. ConclusionsIn this validation study, people in the chronic phase of stroke recovery were able to safely and effectively use InTandem in the intended use environment. This validation study contributes to the overall understanding of residual use–related risks of InTandem in consideration of the established benefits.

Abstract Background Individuals with obesity frequently present for anaesthesia and surgery. Good communication during the preoperative consultation can optimise the provision of relevant health information and guide improvement of health status preoperatively. Methods We planned a systematic literature review to assess existing guidelines and evidence of effectiveness for how anaesthetists should communicate with patients who have obesity in the preoperative period about perioperative risks and weight management. Database searches used keywords related to perioperative weight loss conversations. We found no papers that directly addressed our aim. The literature identified as most relevant was analysed in the form of a narrative review. Results The majority of suggestions for weight loss conversations came from primary care. Four primary themes potentially relevant to anaesthetists were identified: barriers to such conversations, communication tools, language and communication and specific recommendations. Identified barriers included lack of skills, training, poor remuneration, pessimism and time constraints for clinicians. Established discussion tools including the ‘5A’s’ approach (Assess, Advise, Agree, Assist, Arrange) and motivational interviewing may hold promise to improve preoperative conversations. The papers highlighted a need for empathetic language, including use of patient-specific language where possible. Conclusions There are currently no published guidelines for how anaesthetists could most effectively discuss weight in the perioperative period with patients who have obesity. Much of the literature for obesity communication is based on the primary care setting. The perioperative period may represent an increased time of receptiveness for patients. Guidelines for discussions about weight management and associated perioperative risk are suggested.

Introduction: Blood-based next-generation sequencing assays of circulating tumor DNA (ctDNA) have the ability to detect tumor-associated mutations in patients with SCLC. We sought to characterize the relationship between ctDNA mean variant allele frequency (VAF) and radiographic total-body tumor volume (TV) in patients with SCLC. Methods: We identified matched blood draws and computed tomography (CT) or positron emission tomography (PET) scans within a prospective SCLC blood banking cohort. We sequenced plasma using our previously developed 14-gene SCLC-specific ctDNA assay. Three-dimensional TV was determined from PET and CT scans using MIM software and reviewed by radiation oncologists. Univariate association and multivariate regression analyses were performed to evaluate the association between mean VAF and total-body TV. Results: We analyzed 75 matched blood draws and CT or PET scans from 25 unique patients with SCLC. Univariate analysis revealed a positive association between mean VAF and total-body TV (Spearman’s ρ = 0.292, p < 0.01), and when considering only treatment-naive and pretreatment patients (n = 11), there was an increase in the magnitude of association (ρ = 0.618, p = 0.048). The relationship remained significant when adjusting for treatment status and bone metastases (p = 0.046). In the subgroup of patients with TP53 variants, univariate analysis revealed a significant association (ρ = 0.762, p = 0.037) only when considering treatment-naive and pretreatment patients (n = 8). Conclusions: We observed a positive association between mean VAF and total-body TV in patients with SCLC, suggesting mean VAF may represent a dynamic biomarker of tumor burden that could be followed to monitor disease status.

CXCL12 activates CXCR4 and is involved in embryogenesis, hematopoiesis, and angiogenesis. It has pathological roles in HIV-1, WHIM disease, cancer, and autoimmune diseases. An antagonist, AMD3100, is used for the release of CD34+ hematopoietic stem cells from the bone marrow for autologous transplantation for lymphoma or multiple myeloma patients. Adverse effects are tolerated due to its short-term treatment, but AMD3100 is cardiotoxic in clinical studies for HIV-1. In an effort to determine whether Saccharomyces cerevisiae expressing a functional human CXCR4 could be used as a platform for identifying a ligand from a library of less ∼1,000 compounds, a high-throughput screening was developed. We report that 2-carboxyphenyl phosphate (fosfosal) up-regulates CXCR4 activation only in the presence of CXCL12. This is the first identification of a compound that increases CXCR4 activity by any mechanism. We mapped the fosfosal binding site on CXCL12, described its mechanism of action, and studied its chemical components, salicylate and phosphate, to conclude that they synergize to achieve the functional effect.

Background. In 2013, the US Advisory Committee on Immunization Practices (ACIP) opted against adding meningococcal vaccines to the infant schedule due to poor cost-effectiveness. This raises a policy question: if meningococcal disease is too rare to justify routine vaccination, are there other vaccine-preventable causes of US infant deaths that could be supported? Methods. We tabulated US infant deaths from 2009–2013 using the CDC WONDER database. These causes of death were then categorized into one of 3 categories: 1) vaccine-preventable using currently available interventions; 2) potentially vaccine-preventable within the next 10 years; and 3) not preventable. Results. From 19.8 million births (3.9 million/year), ∼122,000 infants died (0.62%). Of these, 181 (0.15% of all deaths) were preventable using currently available vaccines, while an additional 779 were categorized as potentially preventable in the next 10 y. By exclusion, 121,040 (99.2%) were judged ‘not vaccine-preventable’. Meningococcal deaths contributed at most 0.03% of all infant deaths, but accounted for 17–34% of current vaccine-preventable deaths. Conclusions. The low number of vaccine-preventable deaths in the US makes it increasingly difficult to justify the introduction of any new infant vaccines.

Context Antidrug antibodies (ADA) can potentially affect drug pharmacokinetics, safety, and efficacy. Objective This work aimed to evaluate treatment-emergent (TE) ADA in tirzepatide (TZP)-treated participants across 7 phase 3 trials and their potential effect on pharmacokinetics, efficacy, and safety. Methods ADA were assessed at baseline and throughout the study until end point, defined as week 40 (SURPASS-1, -2, and -5) or week 52 (SURPASS-3, -4, Japan-Mono, and Japan-Combo). Samples for ADA characterization were collected at SURPASS trial sites. Participants included ADA-evaluable TZP-treated patients with type 2 diabetes (N = 5025). Interventions included TZP 5, 10, or 15 mg. ADA were detected and characterized for their ability to cross-react with native glucose-dependent insulinotropic polypeptide (nGIP) and glucagon-like peptide-1 (nGLP-1), neutralize tirzepatide activity on GIP and GLP-1 receptors, and neutralize nGIP and nGLP-1. Results TE ADA developed in 51.1% of tirzepatide-treated patients. Proportions were similar across dose groups. Maximum ADA titers ranged from 1:20 to 1: 81 920 among TE ADA+ patients. Neutralizing antibodies (NAb) against TZP activity on GIP and GLP-1 receptors were observed in 1.9% and 2.1% of patients, respectively. Less than 1.0% of patients had cross-reactive NAb against nGIP or nGLP-1. TE ADA status, ADA titer, and NAb status had no effect on the pharmacokinetics or efficacy of TZP. More TE ADA+ patients experienced hypersensitivity reactions or injection site reactions than TE ADA– patients. The majority of hypersensitivity and injection site reactions were nonserious and nonsevere, and most events occurred and/or resolved irrespective of TE ADA status or titer. Conclusion Immunogenicity did not affect TZP pharmacokinetics or efficacy. The majority of hypersensitivity or injection site reactions experienced by TE ADA+ patients were mild to moderate in severity. [ABSTRACT FROM AUTHOR]