Miracle-dz/UniFAR-FTUs huggingface dataset:
Categorical Risk Stratification for Neonatal Early Onset Sepsis using Suspected Intraamniotic Infection and the Newborn Exam

Objective: To determine test characteristics of categorical risk stratification for early onset sepsis (EOS) using maternal criteria for suspected intraamniotic infection (IAI) and/or newborn exam and compare them to the EOS calculator. Study Design: Retrospective 1:3 case-control study of late preterm/term infants with bacterial culture growth obtained <72 hours of life. For categorical approach, infants of mothers with suspected IAI or equivocal/ill appearing were presumed high-risk for EOS and blood culture obtained. For calculator, estimated probability of EOS and care recommendations were recorded from online calculator. Test characteristics were compared with McNemar’s test; recommendation for blood culture was considered a “positive” test. Result: 52 cases and 172 controls were included. Compared to the calculator, the categorical approach had higher sensitivity 90%(95%CI:79–96%) vs 67% (95%CI:54–79%) but lower specificity 85%(95%CI:78–89%) vs. 92%(95%CI:87–96%). 10% of cases were not identified by either. Conclusion: A categorical approach using suspected IAI/newborn exam offers good EOS discrimination and is comparable to the calculator.
Adenosine Receptor 2A Blockade Increases the Efficacy of Anti–PD-1 through Enhanced Antitumor T-cell Responses

Beavis, Milenkovski, and colleagues reveal that adenosine receptor blockade enhanced anti-PD-1 efficacy against CD73+ tumors in twomouse models via augmentation of tumor-infiltrating CD8+ T-cell effector function by increasing IFNγ and Granzyme B production and suggest CD73 expression as a biomarker for anti-PD-1 efficacy. Immunotherapy is rapidly emerging as a cancer treatment with high potential. Recent clinical trials with anti-CTLA-4 and anti–PD-1/PD-L1 antibodies (mAbs) suggest that targeting multiple immunosuppressive pathways may significantly improve patient survival. The generation of adenosine by CD73 also suppresses antitumor immune responses through the activation of A2A receptors on T cells and natural killer (NK) cells. We sought to determine whether blockade of A2A receptors could enhance the efficacy of anti–PD-1 mAb. The expression of CD73 by tumor cells limited the efficacy of anti–PD-1 mAb in two tumor models, and this was alleviated with concomitant treatment with an A2A adenosine receptor antagonist. The blockade of PD-1 enhanced A2A receptor expression on tumor-infiltrating CD8+ T cells, making them more susceptible to A2A-mediated suppression. Thus, dual blockade of PD-1 and A2A significantly enhanced the expression of IFNγ and Granzyme B by tumor-infiltrating CD8+ T cells and, accordingly, increased growth inhibition of CD73+ tumors and survival of mice. The results of our study indicate that CD73 expression may constitute a potential biomarker for the efficacy of anti–PD-1 mAb in patients with cancer and that the efficacy of anti–PD-1 mAb can be significantly enhanced by A2A antagonists. We have therefore revealed a potentially novel biomarker for the efficacy of anti–PD-1 that warrants further investigation in patients. Because our studies used SYN-115, a drug that has already undergone phase IIb testing in Parkinson disease, our findings have immediate translational relevance for patients with cancer. Cancer Immunol Res; 3(5); 506–17. ©2015 AACR.
Non-asymptotic Properties of Individualized Treatment Rules from Sequentially Rule-Adaptive Trials

Learning optimal individualized treatment rules (ITRs) has become increasingly important in the modern era of precision medicine. Many statistical and machine learning methods for learning optimal ITRs have been developed in the literature. However, most existing methods are based on data collected from traditional randomized controlled trials and thus cannot take advantage of the accumulative evidence when patients enter the trials sequentially. It is also ethically important that future patients should have a high probability to be treated optimally based on the updated knowledge so far. In this work, we propose a new design called sequentially rule-adaptive trials to learn optimal ITRs based on the contextual bandit framework, in contrast to the response-adaptive design in traditional adaptive trials. In our design, each entering patient will be allocated with a high probability to the current best treatment for this patient, which is estimated using the past data based on some machine learning algorithm (for example, outcome weighted learning in our implementation). We explore the tradeoff between training and test values of the estimated ITR in single-stage problems by proving theoretically that for a higher probability of following the estimated ITR, the training value converges to the optimal value at a faster rate, while the test value converges at a slower rate. This problem is different from traditional decision problems in the sense that the training data are generated sequentially and are dependent. We also develop a tool that combines martingale with empirical process to tackle the problem that cannot be solved by previous techniques for i.i. d. data. We show by numerical examples that without much loss of the test value, our proposed algorithm can improve the training value significantly as compared to existing methods. Finally, we use a real data study to illustrate the performance of the proposed method.
Characterization of the leading-edge vortex dynamics using cyber-physical systems

of “Characterization of the Leading-edge Vortex Dynamics Using Cyberphysical Systems,” by Kyohei Onoue, Ph.D., Brown University, May 2016 We present experimental investigations aimed at characterizing the flow physics associated with strong fluid-structure interactions that drive large-scale oscillations of an elastically-supported wing in a uniform airflow. All experiments are performed using a cyber-physical system in which the structural characteristics of the system are emulated using a digital controller that monitors the motion of the structure in real time. Provided that the formation of the leading-edge vortex (LEV) plays an important role in driving large-scale oscillations, much of our effort has been devoted into characterizing the dynamical properties of the LEV. Towards this end, we first analyzed the phase-plane representation of the aeroelastic instability to follow and deduce from the measured motion and aerodynamic torque the formation time and separation dynamics of the LEV. The insight gained from the phase portraits are subsequently confirmed and directly quantified using 2D Particle Image Velocimetry (PIV). We demonstrate that the LEV stability, formation time and circulation scale robustly with the characteristic velocity of the feeding shear layer emanating from the leading edge, and the connection between this scaling and the concept of optimal vortex formation number is discussed. We developed a quasi-steady potential flow model to elucidate a quantitative connection between the location and strength of the LEV core and the resulting aerodynamic torque on the elastic structure. In the final phase of this work, we implemented tomographic PIV to characterize the three-dimensionality of the LEV core on 2D and 3D wings, and to identify important vorticity transport mechanisms responsible for regulating the LEV growth. Through systematic assessments of vortex stability, three-dimensional vorticity dynamics and vortex energy, we found that the stability of the LEV can be improved by (i) increasing the reduced frequency, (ii) moderating the LEV circulation via the process of vorticity annihilation and (iii) suppressing the formation of an arch-shaped LEV. We conclude this study by presenting a unified scaling for vortex formation on 2D and 3D pitching
Rab44 negatively regulates myoblast differentiation by controlling fusogenic protein transport and mTORC1 signaling

Skeletal muscle is composed of multinucleated myotubes formed by the fusion of mononucleated myoblasts. Skeletal muscle differentiation, termed as myogenesis, have been investigated using the mouse skeletal myoblast cell line C2C12. It has been reported that several “small” Rab proteins, major membrane‐trafficking regulators, possibly regulate membrane protein transport in C2C12 cells; however, the role of Rab proteins in myogenesis remains unexplored. Rab44, a member of “large” Rab GTPases, has recently been identified as a negative regulator of osteoclast differentiation. In this study, using C2C12 cells, we found that Rab44 expression was upregulated during myoblast differentiation into myotubes. Knockdown of Rab44 enhanced myoblast differentiation and myotube formation. Consistent with these results, Rab44 knockdown in myoblasts increased expression levels of several myogenic marker genes. Rab44 knockdown increased the surface accumulation of myomaker and myomixer, two fusogenic proteins required for multinucleation, implying enhanced cell fusion. Conversely, Rab44 overexpression inhibited myoblast differentiation and tube formation, accompanied by decreased expression of some myogenic markers. Furthermore, Rab44 was found to be predominantly localized in lysosomes, and Rab44 overexpression altered the number and size of lysosomes. Considering the underlying molecular mechanism, Rab44 overexpression impaired the signaling pathway of the mechanistic target of rapamycin complex1 (mTORC1) in C2C12 cells. Namely, phosphorylation levels of mTORC1 and downstream mTORC1 substrates, such as S6 and P70‐S6K, were notably lower in Rab44 overexpressing cells than those in control cells. These results indicate that Rab44 negatively regulates myoblast differentiation into myotubes by controlling fusogenic protein transport and mTORC1 signaling.
The Influence of Dexmedetomidine as an Adjuvant in Intrathecal Labor Analgesia: A Multicenter Study on Efficacy and Maternal Satisfaction

In this study, we examined the impact of dexmedetomidine (DEX) on the effectiveness of epidural analgesia and labor outcomes. We administered different doses of DEX combined with 0.1% ropivacaine for epidural analgesia to evaluate the clinical effects and safety. To assess the effects of different concentrations of DEX in parturient women receiving epidural analgesia, we conducted a randomized double‐blind trial. We selected 400 parturient women and randomly assigned them to 4 groups, with 100 parturient women in each group: S0.1 (0.1 µg/mL DEX), S0.2 (0.2 µg/mL DEX), S0.3 (0.3 µg/mL DEX), and a control group (0.3 µg/mL sufentanil). Post‐analgesia, we recorded the Bromage score, duration of labor, method of delivery, bleeding, neonatal Apgar score, adverse reactions, and maternal satisfaction. The number of patients with a Bromage score of ≥2 and the incidence of bradycardia were higher in the S0.3 group compared with the other 3 groups (P < .05), whereas the high satisfaction rate was lower in the S0.3 group (P < .05). Moreover, we found that the number of times that additional patient‐controlled analgesia was administered was higher in the S0.1 group compared with the remaining 3 groups (P < .05). The control group exhibited a higher incidence of pruritus than the other 3 groups (P < .05). In conclusion, when administering spinal anesthesia for the relief of labor pain, epidural analgesia with 0.1% ropivacaine combined with 0.2 µg/mL DEX provides relatively ideal analgesic effects, higher maternal satisfaction, and reduces the incidence of pruritus, compared with the combination of 0.1% ropivacaine and 0.3 µg/mL sufentanil.
Evaluation of high‐density lipoprotein‐bound long non‐coding RNAs in subjects with familial hypercholesterolaemia

Long non‐coding RNAs (lncRNAs) could be attractive circulating biomarkers for cardiovascular risk stratification in subjects at high atherosclerotic cardiovascular disease risk such as familial hypercholesterolaemia (FH). Our aim was to investigate the presence of lncRNAs carried by high‐density lipoprotein (HDL) in FH subjects and to evaluate the associations of HDL‐lncRNAs with lipoproteins and mechanical vascular impairment assessed by pulse wave velocity (PWV).
Nuclear Actin Polymerization Regulates Cell Epithelial‐Mesenchymal Transition

Current studies on actin function primarily rely on cytoplasmic actin due to the absence of cellular models specifically expressing nuclear actin. Here, cell models capable of expressing varying levels of nuclear F/G‐actin are generated and a significant role of nuclear actin in the regulation of epithelial‐mesenchymal transition (EMT) is uncovered. Through immunoprecipitation and mass spectrometry analyses, distinct binding partners for nuclear F‐actin (β‐catenin, SMAD2, and SMAD3) and nuclear G‐actin (MYBBP1A, NKRF, and MYPOP) are investigated, which respectively modulate EMT‐promoting and EMT‐repressing transcriptional events. While nuclear F‐actin promotes EMT with enhanced cell migration, survival, and elongated mesenchymal morphology, nuclear G‐actin represses EMT and related cell activities. Mechanistically, nuclear F‐actin enhances β‐catenin, SMAD2, and SMAD3 expression and stability in the nuclei, while nuclear G‐actin increases MYBBP1A, NKRF, and MYPOP expression and stability in the nuclei. The association between nuclear F/G‐actin and N‐cadherin/E‐cadherin in the cell lines (in vitro), and increased nuclear actin polymerization in the wound healing cells (in vivo) affirm a significant role of nuclear actin in EMT regulation. With evidence of nuclear actin polymerization and EMT during development, and irregularities in disease states such as cancer and fibrosis, targeting nuclear actin dynamics to trigger dysregulated EMT warrants ongoing study.
Provider-Related Predictors of Utilization of University Health Services in Nigeria

Background The utilization of health services is an important policy concern in most developing countries. Many staff and students do not utilize the health services within the university system despite the availability of good quality services. This study investigated the provider-related factors related to utilization of university health service by staff and students in a privately owneduniversity in Nigeria. Methods The perception of the quality of a university health service was investigated among a cross-section of 600 university staff and students who were selected by a stratified random sampling scheme. A self-administered questionnaire-based study was conducted. The structure, process and output predictors of utilization of the university health facility were assessed. Data analysis was carried out using Stata I/C 15.0. Results The average age of the participants was 22.93±7.58 years. About two-thirds of them did not have opinion about the mortality and morbidity rates at the university health center. Significant proportions of the participants reported good perceptions about the structure and process quality of service indicators. Utilization of the university health center was predicted by some structure and process indicators namely; the availability/experience of staff (AOR 2.44; CI 1.67–3.58), the organization of healthcare (AOR 1.64; CI 1.11–2.41), the continuity of treatment (AOR 1.74; CI 1.12–2.70) and the waiting time (AOR 0.41; CI 0.28–0.61). Conclusion The utilization of university health services was predicted by availability/experience of staff, the organization of healthcare, the waiting time and the continuity of care. The structure-process-outcome approach discriminates between the students and staff who utilize the university health center and those who donot. It also suggests a complex interplay of factors in the prediction of choice of a health facility.
Sporozoite immunization: innovative translational science to support the fight against malaria

ABSTRACT Introduction Malaria, a devastating febrile illness caused by protozoan parasites, sickened 247,000,000 people in 2021 and killed 619,000, mostly children and pregnant women in sub-Saharan Africa. A highly effective vaccine is urgently needed, especially for Plasmodium falciparum (Pf), the deadliest human malaria parasite. Areas covered Sporozoites (SPZ), the parasite stage transmitted by Anopheles mosquitoes to humans, are the only vaccine immunogen achieving >90% efficacy against Pf infection. This review describes >30 clinical trials of PfSPZ vaccines in the U.S.A. , Europe, Africa, and Asia, based on first-hand knowledge of the trials and PubMed searches of ‘sporozoites,’ ‘malaria,’ and ‘vaccines. ’ Expert opinion First generation (radiation-attenuated) PfSPZ vaccines are safe, well tolerated, 80–100% efficacious against homologous controlled human malaria infection (CHMI) and provide 18–19 months protection without boosting in Africa. Second generation chemo-attenuated PfSPZ are more potent, 100% efficacious against stringent heterologous (variant strain) CHMI, but require a co-administered drug, raising safety concerns. Third generation, late liver stage-arresting, replication competent (LARC), genetically-attenuated PfSPZ are expected to be both safe and highly efficacious. Overall, PfSPZ vaccines meet safety, tolerability, and efficacy requirements for protecting pregnant women and travelers exposed to Pf in Africa, with licensure for these populations possible within 5 years. Protecting children and mass vaccination programs to block transmission and eliminate malaria are long-term objectives.
The role of the HORMA domain proteins ATG13 and ATG101 in initiating autophagosome biogenesis

Autophagy is a process of regulated degradation. It eliminates damaged and unnecessary cellular components by engulfing them with a de novo‐generated organelle: the double‐membrane autophagosome. The past three decades have provided us with a detailed parts list of the autophagy initiation machinery, have developed important insights into how these processes function and have identified regulatory proteins. It is now clear that autophagosome biogenesis requires the timely assembly of a complex machinery. However, it is unclear how a putative stable machine is assembled and disassembled and how the different parts cooperate to perform its overall function. Although they have long been somewhat enigmatic in their precise role, HORMA domain proteins (first identified in Hop1p, Rev7p and MAD2 proteins) autophagy‐related protein 13 (ATG13) and ATG101 of the ULK‐kinase complex have emerged as important coordinators of the autophagy‐initiating subcomplexes. Here, we will particularly focus on ATG13 and ATG101 and the role of their unusual metamorphosis in initiating autophagosome biogenesis. We will also explore how this metamorphosis could potentially be purposefully rate‐limiting and speculate on how it could regulate the spontaneous self‐assembly of the autophagy‐initiating machinery.
Error detection and correction in intracortical brain–machine interfaces controlling two finger groups

Objective. While brain–machine interfaces (BMIs) are promising technologies that could provide direct pathways for controlling the external world and thus regaining motor capabilities, their effectiveness is hampered by decoding errors. Previous research has demonstrated the detection and correction of BMI outcome errors, which occur at the end of trials. Here we focus on continuous detection and correction of BMI execution errors, which occur during real-time movements. Approach. Two adult male rhesus macaques were implanted with Utah arrays in the motor cortex. The monkeys performed single or two-finger group BMI tasks where a Kalman filter decoded binned spiking-band power into intended finger kinematics. Neural activity was analyzed to determine how it depends not only on the kinematics of the fingers, but also on the distance of each finger-group to its target. We developed a method to detect erroneous movements, i.e. consistent movements away from the target, from the same neural activity used by the Kalman filter. Detected errors were corrected by a simple stopping strategy, and the effect on performance was evaluated. Main results. First we show that including distance to target explains significantly more variance of the recorded neural activity. Then, for the first time, we demonstrate that neural activity in motor cortex can be used to detect execution errors during BMI controlled movements. Keeping false positive rate below 5% , it was possible to achieve mean true positive rate of 28.1% online. Despite requiring 200 ms to detect and react to suspected errors, we were able to achieve a significant improvement in task performance via reduced orbiting time of one finger group. Significance. Neural activity recorded in motor cortex for BMI control can be used to detect and correct BMI errors and thus to improve performance. Further improvements may be obtained by enhancing classification and correction strategies.
Circulating levels of tumor necrosis factor correlate with indexes of depressed heart rate variability: a study in patients with mild-to-moderate heart failure.

OBJECTIVES Patients with heart failure have increased circulating levels of tumor necrosis factor (TNF) and TNF receptors. It is not known whether TNF, which is known to blunt beta-adrenergic responsiveness in experimental models, contributes to the loss of heart rate variability in patients with heart failure. Therefore, we examined heart rate variability in relation to circulating levels of TNF, TNF receptors, and norepinephrine in patients with heart failure and in control subjects. METHODS Heart rate variability was obtained from 24-h ambulatory ECG recordings in age-matched control subjects (n = 10) and patients with mild (n = 15) to moderate (n = 14) heart failure. Plasma levels of TNF and soluble type 1 and 2 TNF receptors were measured by enzyme-linked immunoassay; plasma norepinephrine levels were measured by high-performance liquid chromatography. RESULTS There was a significant inverse linear correlation between increased circulating levels of TNF, TNF receptors, and norepinephrine for time-domain and frequency-domain indexes of heart rate variability among patients with heart failure and control subjects. Multiple stepwise linear regression analysis showed that TNF was a stronger independent predictor of frequency-domain indexes of heart rate variability than norepinephrine. CONCLUSIONS TNF is an independent predictor of depressed heart rate variability in patients with heart failure. Insofar as TNF blunts beta-adrenergic signaling, this study suggests the possibility that overexpression of TNF and subsequent loss of beta-adrenergic responsiveness contributes to the decrease in heart rate variability observed in heart failure.