Cooperative planning for physically interacting heterogeneous robots.

Heterogeneous multi-agent systems can be deployed to complete a variety of tasks, including some that are impossible using a single generic modality. This paper introduces an approach to solving the problem of cooperative behavior planning in small heterogeneous robot teams where members can both function independently as well as physically interact with each other in ways that give rise to additional functionality. This approach enables, for the first time, the cooperative completion of tasks that are infeasible when using any single modality from those agents comprising the team.

PAC Reinforcement Learning Algorithm for General-Sum Markov Games.

This paper presents a theoretical framework for probably approximately correct (PAC) multi-agent reinforcement learning (MARL) algorithms for Markov games. Using the idea of delayed Q-learning, the paper extends the well-known Nash Q-learning algorithm to build a new PAC MARL algorithm for general-sum Markov games. In addition to guiding the design of a provably PACMARL algorithm, the framework enables checking whether an arbitrary MARL algorithm is PAC. Comparative numerical results demonstrate the algorithm's performance and robustness.

CD38 regulates ovarian function and fecundity via NAD+ metabolism.

Mammalian female reproductive lifespan is typically significantly shorter than life expectancy and is associated with a decrease in ovarian NAD+ levels. However, the mechanisms underlying this loss of ovarian NAD+ are unclear. Here, we show that CD38, an NAD+ consuming enzyme, is expressed in the ovarian extrafollicular space, primarily in immune cells, and its levels increase with reproductive age. Reproductively young mice lacking CD38 exhibit larger primordial follicle pools, elevated ovarian NAD+ levels, and increased fecundity relative to wild type controls. This larger ovarian reserve results from a prolonged window of follicle formation during early development. However, the beneficial effect of CD38 loss on reproductive function is not maintained at advanced age. Our results demonstrate a novel role of CD38 in regulating ovarian NAD+ metabolism and establishing the ovarian reserve, a critical process that dictates a female's reproductive lifespan.

The effects of home-based progressive resistance training in chronic kidney disease patients.

INTRODUCTION: Faced with lockdowns, it was mandatory the development of supervised home-based RT protocols to keep patients with chronic kidney disease engaged in programs. Nonetheless, there is a lack of scientific literature regarding its effects on patients. PURPOSE: To investigate the effects of a supervised home-based progressive resistance training program on functional performance, bone mineral density, renal function, endothelial health, inflammation, glycemic homeostasis, metabolism, redox balance, and the modulation of exerkines in patients with CKD in stage 2. METHODS: Patients (n = 31) were randomized and allocated into the control group (CTL; n = 15; 58.07 ± 5.22 yrs) or resistance training group (RT; n = 16; 57.94 ± 2.74 yrs). RT group performed 22 weeks of supervised progressive home-based resistance exercises. Bone mineral density, anthropometric measurements, and functional performance were assessed. Venous blood samples were collected at baseline and after the intervention for the analysis of markers of renal function, endothelial health, inflammation, glycemic homeostasis, metabolism, and redox balance. RESULTS: Twenty-two weeks of home-based RT were effective in improving (P < 0.05) functional performance, bone mineral density, uremic profile, ADMA, inflammatory markers, the Klotho-FGF23 axis, glycemic homeostasis markers, and exerkines. These improvements were accompanied by higher concentrations of exerkines and anti-inflammatory cytokines. RT group displayed a decrease in cases of osteopenia after the intervention (RT: 50 % vs. CTL: 86.7 %; X2 = 4.763; P = 0.029). CONCLUSION: Results provide new evidence that supervised home-based progressive RT may be a relevant intervention to attenuate the progression of CKD and improve functional capacity, bone mineral density, and the immunometabolic profile. These improvements are associated with positive modulation of several exerkines.

A multiple sclerosis-protective coding variant reveals an essential role for HDAC7 in regulatory T cells.

Genome-wide association studies identifying hundreds of susceptibility loci for autoimmune diseases indicate that genes active in immune cells predominantly mediate risk. However, identification and functional characterization of causal variants remain challenging. Here, we focused on the immunomodulatory role of a protective variant of histone deacetylase 7 (HDAC7). This variant (rs148755202, HDAC7.p.R166H) was identified in a study of low-frequency coding variation in multiple sclerosis (MS). Through transcriptomic analyses, we demonstrate that wild-type HDAC7 regulates genes essential for the function of Foxp3+ regulatory T cells (Tregs), an immunosuppressive subset of CD4 T cells that is generally dysfunctional in patients with MS. Moreover, Treg-specific conditional hemizygous deletion of HDAC7 increased the severity of experimental autoimmune encephalitis (EAE), a mouse model of neuroinflammation. In contrast, Tregs transduced with the protective HDAC7 R166H variant exhibited higher suppressive capacity in an in vitro functional assay, mirroring phenotypes previously observed in patient samples. In vivo modeling of the human HDAC7 R166H variant by generation of a knock-in mouse model bearing an orthologous R150H substitution demonstrated decreased EAE severity linked to transcriptomic alterations of brain-infiltrating Tregs, as assessed by single-cell RNA sequencing. Our data suggest that dysregulation of epigenetic modifiers, a distinct molecular class associated with disease risk, may influence disease onset. Last, our approach provides a template for the translation of genetic susceptibility loci to detailed functional characterization, using in vitro and in vivo modeling.

Challenges and Opportunities for Graduate Medical Education: Steps to Keep Physician Training in North Carolina Exceptional.

Changes in health care present many challenges and opportunities to North Carolina's exceptional graduate medical education programs. Steps to keep these programs exceptional include boosting leadership training, championing well-being, expanding rural training, and more described here.

Impact of Faculty Training in Health Systems Science on Scholarly Presentation of Resident Physician and Fellow Quality Improvement Projects.

The objective was to evaluate whether faculty participation in a Health Systems Science training program was associated with increased presentation and publication of quality improvement (QI) projects involving resident physicians and fellows at 1 institution. The authors evaluated annual, department-level counts of QI projects with resident physician or fellow involvement, presented locally or published, according to residency or fellowship program director and faculty participation in Teachers of Quality Academy. Ten clinical departments had 82 presentations and 2 publications. Each additional faculty member's participation in Teachers of Quality Academy increased the annual count of published or presented QI projects by 9% (P < 0.001). At this institution, participation in a Health Systems Science training program among clinical faculty improved engagement of resident physicians and fellows in local presentation of QI projects.

Design and Construction of Unmanned Ground Vehicles for Sub-canopy Plant Phenotyping.

Unmanned ground vehicles can capture a sub-canopy perspective for plant phenotyping, but their design and construction can be a challenge for scientists unfamiliar with robotics. Here we describe the necessary components and provide guidelines for designing and constructing an autonomous ground robot that can be used for plant phenotyping.

Non-Smooth Control Barrier Navigation Functions for STL Motion Planning.

This paper reports on a new approach to Signal Temporal Logic (STL) control synthesis, that 1) utilizes a navigation function as the basis to construct a Control Barrier Function (CBF), and 2) composes navigation function-based barrier functions using nonsmooth mappings to encode Boolean operations between the predicates that those barrier functions encode. Because of these two key features, the reported approach 1) covers a larger fragment of STL compared to existing approaches, 2) alleviates the computational cost associated with evaluation of the control law for the system in existing STL control barrier function methodologies, and 3) simultaneously relaxes some of the conservativeness of smooth combinations of barrier functions as a means of implementing Boolean operators. The paper demonstrates the efficacy of this new approach with three simulation case studies, one aiming at illustrating how complex STL motion planning specification can be realized, the second highlights the less-conservativeness of the approach in comparison to the existing methods, and another that shows how this technology can be brought to bear to push the envelope in the context of human-robot social interaction.

A Hybrid PAC Reinforcement Learning Algorithm for Human-Robot Interaction.

This paper offers a new hybrid probably approximately correct (PAC) reinforcement learning (RL) algorithm for Markov decision processes (MDPs) that intelligently maintains favorable features of both model-based and model-free methodologies. The designed algorithm, referred to as the Dyna-Delayed Q-learning (DDQ) algorithm, combines model-free Delayed Q-learning and model-based R-max algorithms while outperforming both in most cases. The paper includes a PAC analysis of the DDQ algorithm and a derivation of its sample complexity. Numerical results are provided to support the claim regarding the new algorithm's sample efficiency compared to its parents as well as the best known PAC model-free and model-based algorithms in application. A real-world experimental implementation of DDQ in the context of pediatric motor rehabilitation facilitated by infant-robot interaction highlights the potential benefits of the reported method.

Are Physical Fitness and CRP Related to Framingham Risk Score in HIV+ Adults?

Background. People living with HIV (PLWH) have increased risk of cardiovascular disease (CVD). The Framingham Risk Score (FRS) predicts a 10-year CVD risk. Its relationships to physical fitness and C-reactive protein (CRP) are not well established. The current aim is to determine the links between FRS, physical fitness, and CRP in PLWH. Methods. Participants (n = 87) were assessed on multiple biomarkers. The FRS was calculated with the respective variables. Other variables that correlated significantly with FRS were entered into a regression equation to determine their relationship to FRS. Results. The FRS for men was more than twice that for women (12.8 vs 6.0, P < .001). Men were more fit than women, but most participants were not fit. Aerobic capacity was predictive of FRS in men, but not in women, and muscular strength was not predictive of FRS. Women had more than double the CRP compared with men (7.9 vs 3.5 mg/L, P < .01), and it was unrelated to FRS. Conclusions. In men, aerobic capacity was significantly predictive of FRS, but muscular strength and CRP were unrelated to FRS in both genders. These results do not conclusively demonstrate that physical fitness and CRP are related to FRS in PLWH.

Multiple brace root phenotypes promote anchorage and limit root lodging in maize.

Plant mechanical failure (lodging) causes global yield losses of 7%-66% in cereal crops. We have previously shown that the above-ground nodal roots (brace roots) in maize are critical for anchorage. However, it is unknown how brace root phenotypes vary across genotypes and the functional consequence of this variation. This study quantifies the contribution of brace roots to anchorage, brace root traits, plant height, and root lodging susceptibility in 52 maize inbred lines. We show that the contribution of brace roots to anchorage and root lodging susceptibility varies among genotypes and this contribution can be explained by plant architectural variation. Additionally, supervised machine learning models were developed and show that multiple plant architectural phenotypes can predict the contribution of brace roots to anchorage and root lodging susceptibility. Together these data define the plant architectures that are important in lodging resistance and show that the contribution of brace roots to anchorage is a good proxy for root lodging susceptibility.

Telomere Length, SIRT1, and Insulin in Male Master Athletes: The Path to Healthy Longevity?

Lower SIRT1 and insulin resistance are associated with accelerated telomere shortening. This study investigated whether the lifestyle of master athletes can attenuate these age-related changes and thereby slow aging. We compared insulin, SIRT1, and telomere length in highly trained male master athletes (n=52; aged 49.9±7.2 yrs) and age-matched non-athletes (n=19; aged 47.3±8.9 yrs). This is a cross-sectional study, in which all data were collected in one visit. Overnight fasted SIRT1 and insulin levels in whole blood were assessed using commercial kits. Relative telomere length was determined in leukocytes through qPCR analyses. Master athletes had higher SIRT1, lower insulin, and longer telomere length than age-matched non-athletes (p<0.05 for all). Insulin was inversely associated with SIRT1 (r=-0.38; p=0.001). Telomere length correlated positively with SIRT1 (r=0.65; p=0.001), whereas telomere length and insulin were not correlated (r=0.03; p=0.87). In conclusion, master athletes have higher SIRT1, lower insulin, and longer telomeres than age-matched non-athletes. Furthermore, SIRT1 was negatively associated with insulin and positively associated with telomere length. These findings suggest that in this sample of middle-aged participants reduced insulin, increased SIRT1 activity, and attenuation of biological aging are connected.

Outcome of patients with relapsed or refractory acute myeloid leukemia treated with Mito-FLAG salvage chemotherapy.

PURPOSE: Curative intended treatment is challenging in patients with relapsed or refractory acute myeloid leukemia (r/r AML) and associated with a dismal prognosis for long-term survival. Despite novel treatment options, the majority of patients are treated with chemotherapy-based regimens. Although widely used, little data exist on the combination of fludarabine, cytarabine, granulocyte colony stimulating factor (FLAG) and mitoxantrone as salvage strategy for r/r AML. MATERIALS AND METHODS: Sixty-six patients receiving Mito-FLAG for r/r AML treated at a German tertiary care center between 2009 and 2019 were analyzed with regard to response rates, survival and safety profile. RESULTS: Overall response rate was 75.8% with 56.1% of patients achieving complete remission (CR) and 19.7% partial remission (PR). After a median follow-up of 54 months, median overall survival (OS) was 13 months. Patients transitioned to allogeneic hematopoietic stem cell transplantation (alloHSCT) (75.8%) showed a significant improvement in OS with a median OS of 17 (95% CI 8.5-25.4) months vs 3 (95% CI 1.7-4.3) months (p < 0.001). 30- and 60-day mortality rates for all patients after the initial cycle of Mito-FLAG were 4.5% and 7.6%, respectively. CONCLUSION: The Mito-FLAG salvage protocol represents an effective and feasible treatment regimen for r/r AML. Importantly, a high rate of transition to successful alloHSCT with the aim of long-term disease-free survival has been shown.

Impact of induction chemotherapy with intermediate-dosed cytarabine and subsequent allogeneic stem cell transplantation on the outcome of high-risk acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) with antecedent hematological disease (s-AML) and treatment-related AML (t-AML) predicts poor prognosis. Intensive treatment protocols of those high-risk patients should consider allogeneic stem cell transplantation (allo-HSCT) in first complete remission (CR). Despite allo-HSCT, relapse rate remains high. Induction chemotherapy with liposomal cytarabine and daunorubicin (CPX-351) has been approved for patients with AML with myeloid-related changes (AML-MRC) or t-AML based on improved survival and remission rates compared to standard 7 + 3 induction. PATIENTS AND METHODS: 110 patients with newly diagnosed s-AML or t-AML at a university hospital were analyzed retrospectively. Median age was 62 years (24-77 years). A total of 65 patients with s-AML after MDS (59%) and 23 patients (20.9%) with t-AML were included. Induction chemotherapy consisted of intermediate-dosed cytarabine (ID-AraC) in combination with idarubicin (patients up to 60 years) or mitoxantrone (patients over 60 years). In patients subsequently undergoing allo-HSCT, reduced conditioning regimens (RIC) were applied prior to transplantation in 47 of 62 patients (76%). RESULTS: Induction chemotherapy with ID-AraC resulted in an overall response rate of 83% including complete remission (CR/CRi) in 69 patients (63%) with a low rate of early death (2.7%). Most relevant non-hematologic toxicity consisted of infectious complications including sepsis with need of intensive care treatment in five patients (4.5%) and proven or probable invasive fungal disease in eight patients (7.2%). Relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS) of the whole cohort were 19 months (0-167), 10 months (0-234) and 15 months (0-234), respectively (p < 0.0001). A significant improvement of OS was observed in patients who underwent allo-HSCT compared to those without subsequent allo-HSCT: 9 vs. 46 months, p < 0.0001. Rate of transplantation-related mortality (TRM) in the early phase post allo-HSCT was low (0.9% at day 30 and 1.8% at day 90, respectively). RIC conditioning results in OS rate of 60% after 60 months post allo-HSCT (median OS not reached). CONCLUSION: S-AML and t-AML patients receiving induction chemotherapy with intermediate-dosed cytarabine showed satisfactory response rate and consolidation therapy with allo-HSCT after full or reduced-intensity conditioning further improved survival in these patients with similar outcome as reported for CPX-351.

Impact of Baseline and Newly Acquired Conduction Disorders on Need for Permanent Pacemakers With 3 Consecutive Generations of Self-Expanding Transcatheter Aortic Heart Valves.

INTRODUCTION: We aimed to compare conduction dynamics and need for permanent pacemaker implantation (PPI) after CoreValve, Evolut R and PRO (transcatheter aortic valve replacement (TAVR)). METHODS: Patients were stratified based on conduction at baseline; Cohort A had normal conduction, Cohort B had conduction abnormalities including atrioventricular (AV)-block, fascicular block or complete bundle branch block. Three different dynamic QRS-patterns were defined: stable QRS-duration, transient QRS-prolongation and persistent QRS-prolongation. We performed multivariable regression analysis to estimate the effect of the three separate transcatheter heart valves (THV's) on need for PPI at 30 days. RESULTS: TAVR was performed with CoreValve (N = 113), Evolut R (N = 157) or Evolut PRO (N = 92). Conduction dynamics were similar between the different THVs. Overall, Evolut R and PRO showed a tendency towards less PPI compared to CoreValve (17% vs. 19% vs. 27%, P = 0.08), which was driven by a lower PPI rate in Cohort A (6% vs. 11% vs. 25%, P = 0.002). Need for PPI was restricted to patients with persistent QRS-prolongation in Cohort A (26/106) but did not correlate with conduction dynamics in Cohort B. In multivariable logistic regression analysis the use of Evolut R (OR 0.38, 95% CI 0.19-0.78, P = 0.008) and PRO (OR 0.41, 95% CI 0.19-0.91, P-value = 0.028) were independently associated with less need for PPI. CONCLUSION: The newer generations Evolut R and PRO were associated with less PPI compared to CoreValve. Acquired persistent conduction abnormalities predicted PPI after TAVR only in patients with normal conduction at baseline. Our findings may help identify eligible patients for early discharge after Evolut R/PRO TAVR.

Resilient Supervisory Multi-Agent Systems.

Accidental or deliberate disruption of the coordination function in a multi-agent system has been discussed and referred to in the social sciences literature as leader decapitation; this paper outlines a methodology for making multi-agent networks resilient to this type of failure, enabling a timely restoration of operation normalcy by leveraging machine learning techniques. The approach involves endowing the agents with a cascade of independent learning modules that enable them to discover over time their role in the overall system coordinating strategy, so that they are able to autonomously implement it when central coordination seizes to function. Through these machine learning algorithms, the agents incrementally identify the overall system's task specification and simultaneously optimize their strategy to serve the common goal.

The ryanodine receptor stabilizer S107 ameliorates contractility of adult Rbm20 knockout rat cardiomyocytes.

RNA binding motif 20 (RBM20) cardiomyopathy has been detected in approximately 3% of populations afflicted with dilated cardiomyopathy (DCM). It is well conceived that RBM20 cardiomyopathy is provoked by titin isoform switching in combination with resting Ca2+ leaking. In this study, we characterized the cardiac function in Rbm20 knockout (KO) rats at 3-, 6-, 9-, and 12-months of age and examined the effect of the ryanodine receptor stabilizer S107 on resting intracellular levels and cardiomyocyte contractile properties. Our results revealed that even though Rbm20 depletion promoted expression of larger titin isoform and reduced myocardial stiffness in young rats (3 months of age), the established DCM phenotype required more time to embellish. S107 restored elevated intracellular Ca2+ to normal levels and ameliorated cardiomyocyte contractile properties in isolated cardiomyocytes from 6-month-old Rbm20 KO rats. However, S107 failed to preserve cardiac homeostasis in Rbm20 KO rats at 12 months of age, unexpectedly, likely due to the existence of multiple pathogenic mechanisms. Taken together, our data suggest the therapeutic promises of S107 in the management of RBM20 cardiomyopathy.