Mark Anderson

The autonomous surface vehicle (ASV) Wave Adaptive Modular Vehicle (WAM-V) offers a versatile and cost-effective platform for oceanographic research in dynamic ocean environments. This paper presents a predictive power model of the WAM-V to be used as a mission planning tool in environments of varying wind and water current conditions. A mathematical formulation for describing the dynamics and propulsion of the WAM-V is derived, which is used to compute a steady state solution of the aerodynamic, hydrodynamic, and propulsive forces experienced by the vehicle. Data collected during recent field deployments in German Channel, Palau, are used to calibrate and validate the model. The model's predictions of power consumption are shown to agree closely with measured data during quasi-steady state transits, producing confidence in its ability to serve as a predictive mission planning tool for real world estimation of operational endurance. This tool will allow for more intelligent planning and coordination of mission timelines, helping to optimize the effectiveness of autonomous surveys.

<h3>Background</h3> Immune checkpoint inhibitors (CPI) are known to cause new-onset diabetes (CPI-DM). While rare, this adverse event can be challenging for clinicians and negatively impact patient quality of life. Therefore, it is important to identify risk factors and clinical characteristics of the immune related adverse event (irAE). We present an expanded comprehensive, multi-institutional study of CPI-DM across multiple agents and cancer types from clinical trials sponsored by the National Cancer Institute (NCI). <h3>Methods</h3> The NCI Cancer Therapy Program (CTEP) database of adverse events (AEs) was queried for AEs related to diabetes (grade 3 or 4 hyperglycemia, acidosis including diabetic ketoacidosis (DKA), glucose intolerance and diabetes mellitus) among all patients who had been treated with a PD-(L)1 inhibitor alone or in combination with CTLA-4 inhibitors or other agents from 6/2015 to 12/2022. Each AE report was reviewed and classified as due to CPI DM, new onset type 2 diabetes mellitus (T2DM), T2DM exacerbation without medication non-adherence, existing DM with medication non-compliance, or association with steroids (SDM). CPI-DM was diagnosed based on evidence of insulin deficiency either through presentation in DKA or low c-peptide with an ongoing insulin requirement and/or positive islet autoantibodies. <h3>Results</h3> In total, out of just over 14,400 patients treated with CPIs, there were 178 cases with at least one of these AEs; 73 (0.51%) had CPI-DM, 51 (0.35%) had SDM, 5 (0.03%) had new T2DM , 19 (0.13%) had T2DM exacerbation, 10 (0.07%) had medication non-adherence, and 20 (0.14%) had acidosis not attributable to diabetes or had insufficient data. Overall, 41% of these AEs were attributable to CPI-DM. The incidence of CPI-DM was 0.51%. Melanoma was the most frequent cancer (21/73) with an overall incidence of 1.13%. Among cancers with over 100 subjects exposed, the incidence was highest in renal cell cancer (1.41%). While PD1 inhibitor monotherapy was most frequent CPI type (40/73) among CPI-DM patients, its incidence was lower (0.38%) compared to combination CTLA-4 and PD-(L)1 inhibitors (0.96%) (chi-square p &lt;0.01), with many patients also exposed to additional agents. Hospitalization was required for 87.5% of CPI-DM cases with 74.3% of those requiring an inpatient endocrine consult. <h3>Conclusions</h3> Among NCI CTEP sponsored trials, CPI-DM was a rare but costly irAE. CPI-DM was significantly more common in patients exposed to combination PD-(L)1 and CTLA-4 immunotherapy. Given these findings, providers in cancer types like melanoma and renal cell cancer that frequently use combination immunotherapy may need increased vigilance. <h3>Ethics Approval</h3> Consent was obtained for each trial but de-identified, human subject exempt data was used for this analysis. <h3>Consent</h3> Consent was obtained for each trial but de-identified, human subject exempt data was used for this analysis.

We present the development and testing of an onboard behavior designed to achieve energy efficient transits by an autonomous underwater vehicle (AUV). The behavior allows an AUV to measure a profile of ocean currents on its descent and choose a depth in real-time that minimizes its energy consumption per unit distance. The behavior is implemented onboard a REMUS 100 AUV using a back-seat driver and the Robot Operating System (ROS). Two new behavior specific processes are defined and integrated on top of a previously developed ROS/REMUS architecture. Finally we present results from a proof of concept field experiment conducted off the coast of San Diego, CA. The AUV demonstrates successful depth-seeking and saves energy by intelligent navigation of ocean currents with a strong vertical gradient.

Abstract Autoimmune polyglandular syndrome 1 (APS1) is an autosomal recessive disorder due to biallelic pathogenic variants in the autoimmune regulator (AIRE) gene that manifests with chronic mucocutaneous candidiasis, primary hypoparathyroidism, and adrenal insufficiency. We report a 39-year-old woman with APS1 who developed partial lipodystrophy during adulthood. She presented with diaper rashes, oral thrush, and tetany during infancy due to candidiasis and hypoparathyroidism. During childhood, she developed hypothyroidism, primary adrenal insufficiency, and ovarian insufficiency. At age 14, she received a sibling-matched allogenic bone marrow transplant due to multiple antibiotic-refractory fungal infections. At age 35, her serum triglycerides were 914 mg/dL (10.32 mmol/L) and she had loss of subcutaneous fat from the upper and lower extremities and hips. A whole-body dual-energy x-ray absorptiometry revealed lower-extremity fat at less than the first percentile. Whole-exome sequencing on DNA extracted from saliva revealed pathogenic variants, p.Leu28Pro and p.Arg257* in AIRE but none in the known lipodystrophy genes. Phage-immunoprecipitation-sequencing revealed the presence of autoantibodies to MAGEB1, MAGEB4, and RFX6, which have been previously reported in APS1. Our case suggests that patients with APS1 may develop partial lipodystrophy due to autoantibodies against novel adipocyte-expressed proteins. A causal relationship of high levels of autoantibodies in our patient to adipose tissue–expressed ODC1, NUCKS1, or FNBP1L and lipodystrophy remains uncertain.

An energy saving behavior is presented for autonomous underwater vehicles (AUVs) that uses greedy control decisions to take advantage of vertical gradients in ocean currents. The behavior relies on a dynamic vehicle model for motion and power consumption and environmental information that can be realistically obtained and processed onboard. Vehicle model parameters are consistent with a 12.75-in-diameter propeller-driven AUV. Simulation results are presented using a two-year tidally resolving ocean circulation model over three spatially distinct transits in the Southern California Bight. The energy saving behavior is compared to the common practice of transiting at fixed depth, as well as a “best case” scenario in which a vehicle has knowledge of the full-depth ocean current profile at its local position. The proposed behavior saves between 3% and 10% in energy expenditure depending on the vehicle's initial launch depth. On average, it is most efficient to initialize the vehicle at depths corresponding to the base of the surface oceanic mixed layer. Finally, a reduced order approximation of the optimal planning solution shows that the vehicle's depth choices oscillate with dominant tidal constituents for the region.

Immunomodulatory agents targeting immune checkpoints are now the state-of-the-art for the treatment of many cancers, but at the same time have led to autoimmune side effects, including autoimmune diabetes: immune checkpoint inhibitor-induced diabetes (CPI-DM). Emerging research shows the importance of preexisting autoimmune disease risk that has been identified through genetics, and autoantibodies. Key associated clinical findings also include increased levels of lipase before diagnosis suggesting that the inflammatory process in the pancreas extends beyond the islets of Langerhans. There is selectivity for the blockade of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) for this adverse event, consistent with the role of this checkpoint in maintaining tolerance to autoimmune diabetes.

We previously reported two siblings with inherited PD-1 deficiency who died from autoimmune pneumonitis at 3 and 11 years of age after developing other autoimmune manifestations, including type 1 diabetes (T1D). We report here two siblings, aged 10 and 11 years, with neonatal-onset T1D (diagnosed at the ages of 1 day and 7 wk), who are homozygous for a splice-site variant of CD274 (encoding PD-L1). This variant results in the exclusive expression of an alternative, loss-of-function PD-L1 protein isoform in overexpression experiments and in the patients' primary leukocytes. Surprisingly, cytometric immunophenotyping and single-cell RNA sequencing analysis on blood leukocytes showed largely normal development and transcriptional profiles across lymphoid and myeloid subsets in the PD-L1-deficient siblings, contrasting with the extensive dysregulation of both lymphoid and myeloid leukocyte compartments in PD-1 deficiency. Our findings suggest that PD-1 and PD-L1 are essential for preventing early-onset T1D but that, unlike PD-1 deficiency, PD-L1 deficiency does not lead to fatal autoimmunity with extensive leukocytic dysregulation.

) is thought to be a key component of maintaining tolerance to insulin. In spite of this general working model, direct detection of this thymic selection on insulin-specific T cells has been somewhat elusive. Here, we used a combination of highly sensitive T cell receptor transgenic models for detecting thymic selection and sorting and sequencing of Insulin-specific CD4+ T cells from Aire-deficient mice as a strategy to further define their selection. This analysis revealed a number of unique t cell receptor (TCR) clones in Aire-deficient hosts with high affinity for insulin/major histocompatibility complex (MHC) ligands. We then modeled the thymic selection of one of these clones in Aire-deficient versus wild-type hosts and found that this model clone could escape thymic negative selection in the absence of thymic Aire. Together, these results suggest that thymic expression of insulin plays a key role in trimming and removing high-affinity insulin-specific T cells from the repertoire to help promote tolerance.

Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

We present a modular simulation framework, in which vehicle and environmental models are combined to develop and test environmentally-adaptive, onboard behaviors for Autonomous Underwater Vehicles (AUVs). This framework is applicable to problems associated with path planning, environmental monitoring, and adaptive search which take into account power consumption, vehicle speeds, and ocean currents which evolve in time and space. We outline this framework specifically for a propeller driven AUV, and demonstrate its use-case in two example problems. The first problem considers energy consumption on long-duration transits in the presence of currents while the second illustrates a comparison of two algorithms designed to search for an unknown target.

&lt;p&gt; &lt;/p&gt; &lt;p&gt;&lt;strong&gt;Objective&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;Previous studies showed that inhibiting lymphocyte costimulation reduces declining beta cell function in individuals newly-diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal (NGT) to abnormal (AGT) glucose tolerance or to diabetes and the effects of treatment on immune and metabolic responses. &lt;/p&gt; &lt;p&gt;&lt;strong&gt;Research Design and Methods&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;We conducted a phase-2, randomized, placebo-controlled, double-masked trial of abatacept&lt;/p&gt; &lt;p&gt;in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The endpoint was AGT or diabetes, assessed by oral glucose-tolerance tests. &lt;/p&gt; &lt;p&gt;&lt;strong&gt;Results&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;101 participants received abatacept and 111 placebo. Eighty-one (35 abatacept/46 placebo) met the endpoint of AGT or type 1 diabetes diagnosis (HR=0.702 (0.452, 1.09)(p=0.11) The C-peptide responses to OGTTs were higher in the abatacept arm (p&lt;.03) . Abatacept reduced the frequency of ICOS+PD1+ T-follicular helper (Tfh) cells during treatment (p&lt;0.0001), increased naïve CD4+ T cells, and also reduced the frequency of CD4+ Tregs from the baseline (p=0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naïve CD4+ T, and Treg cells returned to baseline. &lt;/p&gt; &lt;p&gt;&lt;strong&gt;Conclusions&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;Although abatacept treatment for one year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion suggesting that costimulation blockade may modify progression of type 1 diabetes.&lt;/p&gt;