Shadows of quantum machine learning.

Quantum machine learning is often highlighted as one of the most promising practical applications for which quantum computers could provide a computational advantage. However, a major obstacle to the widespread use of quantum machine learning models in practice is that these models, even once trained, still require access to a quantum computer in order to be evaluated on new data. To solve this issue, we introduce a class of quantum models where quantum resources are only required during training, while the deployment of the trained model is classical. Specifically, the training phase of our models ends with the generation of a 'shadow model' from which the classical deployment becomes possible. We prove that: (i) this class of models is universal for classically-deployed quantum machine learning; (ii) it does have restricted learning capacities compared to 'fully quantum' models, but nonetheless (iii) it achieves a provable learning advantage over fully classical learners, contingent on widely believed assumptions in complexity theory. These results provide compelling evidence that quantum machine learning can confer learning advantages across a substantially broader range of scenarios, where quantum computers are exclusively employed during the training phase. By enabling classical deployment, our approach facilitates the implementation of quantum machine learning models in various practical contexts.

Correction: The Omega-3 Fatty Acid Eicosapentaenoic Acid Accelerates Disease Progression in a Model of Amyotrophic Lateral Sclerosis.

[This corrects the article DOI: 10.1371/journal.pone.0061626.].

Myocardial inflammation after elective percutaneous coronary intervention.

OBJECTIVE: It is well established that inflammation plays a central role in the sequelae of percutaneous coronary intervention (PCI). Most of the studies to date have focused on the inflammatory reaction affecting the vessel wall after angioplasty. However, there are data to suggest that the main foci of inflammation are in fact in the myocardium beyond the vessel wall. The main aim of our study was to investigate the myocardial inflammation after elective, uncomplicated angioplasty with cardiovascular magnetic resonance (CMR) enhanced by ultrasmall superparamagnetic particles of iron oxide (USPIO) and also blood biomarkers. This is the first study to report such findings after elective angioplasty. METHODS: We assessed patients undergoing elective angioplasty for stable angina with USPIO-enhanced CMR two weeks after the procedure and compared the results with those of healthy volunteers who constituted the control group. We excluded patients with previous myocardial infarction, previous PCI, or any significant inflammatory condition. All patients also underwent blood biomarker testing at baseline (pre-PCI), 4 h, and two weeks later. RESULTS: A total of five patients and three controls were scanned. There was a small absolute increase, although statistically insignificant, in R2∗ values in the PCI area compared with either remote myocardium from the same patient (PCI area [left anterior descending artery (LAD)] vs remote myocardium [circumflex area]: 19.3 ± 10.8 vs 9.2 ± 7.9, p = 0.1) or healthy myocardium from healthy volunteers (PCI area [LAD] vs healthy myocardium [LAD]: 19.3 ± 10.8 vs 12.2 ± 4.0, p = 0.2). PTX3 and IL-6 were the only biomarkers that changed significantly from baseline to 4 h and 2 weeks. Both biomarkers peaked at 4 h. CONCLUSION: We used USPIO-enhanced CMR for the first time to assess myocardial inflammation after elective, uncomplicated PCI. We have demonstrated a small numerical increase in inflammation, which was not statistically significant. This study opens the way for future studies to use this method as a means to target inflammation.

Blood transcriptomic signatures for symptomatic TB in an African multi-cohort study.

BACKGROUND: Multiple host blood transcriptional signatures have been developed as non-sputum triage tests for tuberculosis (TB). We aimed to compare the diagnostic performance of 20 blood transcriptomic TB signatures for differentiating between symptomatic patients who have TB versus other respiratory diseases (ORD). METHODS: As part of a nested case-control study, individuals presenting with respiratory symptoms at primary health care clinics in Ethiopia, Malawi, Namibia, Uganda, South Africa, and The Gambia were enrolled. TB was diagnosed based on clinical, microbiological, and radiological findings. Transcriptomic signatures were measured in whole blood using microfluidic RT-qPCR. Diagnostic performance was benchmarked against the WHO Target Product Profile (TPP) for a non-sputum TB triage test. RESULTS: Among 541 participants, 158 had definite, microbiologically-confirmed TB, 32 had probable TB, while 389 participants had ORD. Nine signatures differentiated between ORD and TB with equivalent performance (Satproedprai7: area under the curve 0.83 [95% CI 0.79-0.87], Jacobsen3: 0.83 [0.79-0.86]; Suliman2: 0.82 [0.78-0.86]; Roe1: 0.82 [0.78-0.86]; Kaforou22: 0.82 [0.78-0.86]; Sambarey10: 0.81 [0.77-0.85]; Duffy9: 0.81 [0.76-0.86]; Gliddon3: 0.8 [0.75-0.85]; and Suliman4 0.79 [0.75-0.84]. Benchmarked against a 90% sensitivity, these signatures achieved specificities between 44% (95% CI 38-49) and 54% (49-59), not meeting the TPP criteria. Signature scores significantly varied by HIV status and country. In country-specific analyses several signatures, such as Satproedprai7 and Penn-Nicholson6, met the minimal TPP criteria for a triage test in Ethiopia, Malawi, and South Africa. CONCLUSION: No signatures met the TPP criteria in a pooled analysis of all countries, but several signatures met the minimum criteria for a non-sputum TB triage test in some countries.

Double vitrification and warming of blastocysts does not affect pregnancy, miscarriage or live birth rates.

RESEARCH QUESTION: Does double blastocyst vitrification and warming affect pregnancy, miscarriage or live birth rates, or birth outcomes, from embryos that have undergone preimplantation genetic testing for aneuploidies (PGT-A) testing? DESIGN: This retrospective observational analysis of embryo transfers was performed at a single centre between January 2017 and August 2022. The double-vitrification group included frozen blastocysts that were vitrified after 5-7 days of culture, warmed, biopsied (either once or twice) and re-vitrified. The single vitrification (SV) group included fresh blastocysts that were biopsied at 5-7 days and then vitrified. RESULTS: A comparison of the 84 double-vitrification blastocysts and 729 control single-vitrification blastocysts indicated that the double-vitrification embryos were frozen later in development and had expanded more than the single-vitrification embryos. Of the 813 embryo transfer procedures reported, 452 resulted in the successful delivery of healthy infants (56%). There were no significant differences between double-vitrification and single-vitrification embryos in the pregnancy, miscarriage or live birth rates achieved after single-embryo transfer (55% versus 56%). Logistic regression indicated that while reduced live birth rates were associated with increasing maternal age at oocyte collection, longer culture prior to freezing and lower embryo quality, double vitrification was not a significant predictor of live birth rate. CONCLUSIONS: Blastocyst double vitrification was not shown to impact pregnancy, miscarriage or live birth rates. Although caution is necessary due to the study size, no effects of double vitrification on miscarriage rates, birthweight or gestation period were noted. These data offer reassurance given the absence of the influence of double vitrification on all outcomes after PGT-A.

Pericapsular Nerve Group Block Did Not Reduce Post-Operative Pain or Opioid Use After Total Hip Arthroplasty.

INTRODUCTION: The pericapsular nerve group (PENG) block is a newly developed regional anesthesia technique designed to manage post-operative hip pain following a fracture or surgery while also maintaining quadriceps strength and mobility. The goal of our study was to compare post-operative pain scores and opioid usage during the post-operative period prior to discharge following total hip arthroplasty (THA) using the posterior approach between patients who received a PENG block and those who did not. METHODS: We conducted a retrospective study on patients undergoing elective, posterior approach THA at a single tertiary care academic center. The two groups included a study group (THA with PENG block in 2021; n = 66) and a control group (THA prior to PENG block implementation in 2019; n = 70). RESULTS: There were no significant differences in pain scores during post-operative minutes 0 to 59 (study group 6.8; control group 6.6; P = 0.81) or during post-operative minutes 60 to 119 (study group 6.2; control group 5.6; P = 0.40). There were no significant differences in total post-operative in-hospital morphine milliequivalent (MME) opioid consumption (study group 55.8 MMEs; control group 75.0 MMEs; P = 0.14). The study group was found to have a shorter length of stay (LOS) (study group 17.0 hours; control group 32.6 hours; P < 0.0001) and faster mobilization (study group 3.0 hours; control group 4.9 hours; P < 0.0001) than the control group. CONCLUSION: Our results show that use of the PENG block did not result in lower post-operative pain scores or opioid consumption after THA using the posterior surgical approach. The study group had a shorter LOS and time to mobilization than the control group, though this was likely due to standard hospital procedure shifting to same day discharge for THA between 2019 and 2021 due to COVID-19.

A genetically inducible endothelial niche enables vascularization of human kidney organoids with multilineage maturation and emergence of renin expressing cells.

Vascularization plays a critical role in organ maturation and cell-type development. Drug discovery, organ mimicry, and ultimately transplantation hinge on achieving robust vascularization of in vitro engineered organs. Here, focusing on human kidney organoids, we overcame this hurdle by combining a human induced pluripotent stem cell (iPSC) line containing an inducible ETS translocation variant 2 (ETV2) (a transcription factor playing a role in endothelial cell development) that directs endothelial differentiation in vitro, with a non-transgenic iPSC line in suspension organoid culture. The resulting human kidney organoids show extensive endothelialization with a cellular identity most closely related to human kidney endothelia. Endothelialized kidney organoids also show increased maturation of nephron structures, an associated fenestrated endothelium with de novo formation of glomerular and venous subtypes, and the emergence of drug-responsive renin expressing cells. The creation of an engineered vascular niche capable of improving kidney organoid maturation and cell type complexity is a significant step forward in the path to clinical translation. Thus, incorporation of an engineered endothelial niche into a previously published kidney organoid protocol allowed the orthogonal differentiation of endothelial and parenchymal cell types, demonstrating the potential for applicability to other basic and translational organoid studies.

Ribosome-Associated Vesicles promote activity-dependent local translation.

Local protein synthesis in axons and dendrites underpins synaptic plasticity. However, the composition of the protein synthesis machinery in distal neuronal processes and the mechanisms for its activity-driven deployment to local translation sites remain unclear. Here, we employed cryo-electron tomography, volume electron microscopy, and live-cell imaging to identify Ribosome-Associated Vesicles (RAVs) as a dynamic platform for moving ribosomes to distal processes. Stimulation via chemically-induced long-term potentiation causes RAV accumulation in distal sites to drive local translation. We also demonstrate activity-driven changes in RAV generation and dynamics in vivo, identifying tubular ER shaping proteins in RAV biogenesis. Together, our work identifies a mechanism for ribosomal delivery to distal sites in neurons to promote activity-dependent local translation.

Seismically detected cratering on Mars: Enhanced recent impact flux?

Seismic observations of impacts on Mars indicate a higher impact flux than previously measured. Using six confirmed seismic impact detections near the NASA InSight lander and two distant large impacts, we calculate appropriate scalings to compare these rates with lunar-based chronology models. We also update the impact rate from orbital observations using the most recent catalog of new craters on Mars. The snapshot of the current impact rate at Mars recorded seismically is higher than that found using orbital detections alone. The measured rates differ between a factor of 2 and 10, depending on the diameter, although the sample size of seismically detected impacts is small. The close timing of the two largest new impacts found on Mars in the past few decades indicates either a heightened impact rate or a low-probability temporal coincidence, perhaps representing recent fragmentation of a parent body. We conclude that seismic methods of detecting current impacts offer a more complete dataset than orbital imaging.

Alterations in exhausted and classical memory B cells in lupus nephritis - Relationship with disease relapse.

INTRODUCTION: B cell exhaustion is a functional abnormality of B lymphocytes observed in chronic infections and shows association with autoreactivity. The role of exhausted and classical memory B cells in maintaining disease stability of lupus nephritis (LN) remains unclear. METHODS: We measured classical memory (CD19+CD21+CD27+), exhausted B cells (CD19+CD21-CD27-), and related cytokines in LN patients with multiple relapses (MR) (n = 15) and no relapse (NR) (n = 15) during disease remission. The expression of inhibitory/adhesion molecules, cell proliferation and calcium mobilization in classical memory and exhausted B cells were also assessed. RESULTS: The MR group had higher proportion of circulating exhausted and classical memory B cells compared to the NR group and healthy controls (HC) (p all <0.05 for MR vs. NR or HC). Blood levels of IL-6, BAFF, IL-21, CD62L, CXCR3 and Siglec-6 were all higher in the MR group (p < 0.05, for all). Exhausted B cells from the MR group showed higher FcRL4, CD22, CD85j and CD183 but lower CD62L expression than NR and HC groups. Exhausted B cells from MR patients exhibited reduced proliferation compared to NR patients and HC, while classical memory B cell proliferation in MR group was higher than the other two groups. Exhausted B cells from both MR and NR patients showed impaired calcium mobilization. CONCLUSION: Alterations in exhausted and classical memory B cells are related to disease relapse in LN. These findings may help devise new strategies for monitoring disease activity and preventing relapse in LN.

Design of a Lead-Like Cysteine-Targeting Covalent Library and the Identification of Hits to Cys55 of Bfl-1.

Covalent hit identification is a viable approach to identify chemical starting points against difficult-to-drug targets. While most researchers screen libraries of <2k electrophilic fragments, focusing on lead-like compounds can be advantageous in terms of finding hits with improved affinity and with a better chance of identifying cryptic pockets. However, due to the increased molecular complexity, larger numbers of compounds (>10k) are desirable to ensure adequate coverage of chemical space. Herein, the approach taken to build a library of 12k covalent lead-like compounds is reported, utilizing legacy compounds, robust library chemistry, and acquisitions. The lead-like covalent library was screened against the antiapoptotic protein Bfl-1, and six promising hits that displaced the BIM peptide from the PPI interface were identified. Intriguingly, X-ray crystallography of lead-like compound 8 showed that it binds to a previously unobserved conformation of the Bfl-1 protein and is an ideal starting point for the optimization of Bfl-1 inhibitors.

Identification and Evaluation of Reversible Covalent Binders to Cys55 of Bfl-1 from a DNA-Encoded Chemical Library Screen.

Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound 13 was successfully cocrystallized in Bfl-1, revealing the binding mode and providing further evidence of a covalent interaction with Cys55.

TREATMENT OF HIP AND KNEE PERIPROSTHETIC JOINT INFECTION REQUIRES EXTENSIVE ADMINISTRATIVE WORK.

INTRODUCTION: Treatment of periprosthetic joint infections (PJI) typically requires more resource utilization than primary total joint arthroplasty (TJA). This study quantifies the amount of time spent in the electronic medical record (EMR) for patients who have PJI requiring surgical intervention. METHODS: A retrospective analysis of EMR activity for 165 hip and knee PJI was performed to capture work during the preoperative and postoperative time periods. Independent sample t tests were conducted to compare total time based on procedure, age, insurance, health literacy, sex, race, and ethnicity. RESULTS: The EMR work performed by the orthopaedic team was 338.4 minutes (min) (SD [standard deviation] 130.3), with 119.4 minutes (SD 62.8) occurring preoperatively and 219.0 minutes (SD 112.9) postoperatively. Preoperatively, the surgeon's work accounted for 35.7 minutes (SD 25.4), mid-level providers 21.3 minutes (SD 15.9), nurses 38.6 minutes (SD 36.8), and office staff 32.7 minutes (SD 29.9). Infectious Disease (ID) colleagues independently performed 158.9 minutes (SD 108.5) of postoperative work. Overall, PJI of the knees required more postoperative work. Secondary analysis revealed that patients who have hip PJI and a BMI < 30 and patients < 65 years required more work when compared to the PJI of heavier and older individuals. There was no difference in total work based on insurance, health literacy, race, or ethnicity. CONCLUSION: Over 8 hours of administrative work is required for surgical management of PJI. Surgeons alone performed 451% more work for PJI during the preoperative period (7.9 versus 35.7min) compared to primary TJA. In efforts to provide best care for our sickest patients, much work is required perioperatively. This work is necessary to consider when assigning value and physician reimbursement.

Structural Uncertainty Due to Fault Timing: A Multimodel Case Study from the Perth Basin.

Faults can fundamentally change a groundwater flow regime and represent a major source of uncertainty in groundwater studies. Much research has been devoted to uncertainty around their location and their barrier-conduit behavior. However, fault timing is one aspect of fault uncertainty that appears to be somewhat overlooked. Many faulted models feature consistent layer offsets, thereby presuming that block faulting has occurred recently and almost instantaneously. Additionally, barrier and/or conduit behavior is often shown to extend vertically through all layers when a fault may in fact terminate well below-ground surface. In this study, we create three plausible geological interpretations for a transect in the Perth Basin. Adjacent boreholes show stratigraphic offsets and thickening which indicate faulting; however, fault timing is unknown. Flow modeling demonstrates that the model with the most recent faulting shows profoundly different flow patterns due to aquifer juxtaposition. Additionally, multiple realizations with stochastically generated parameter sets for layer, fault core, and fault damage zone conductivity show that fault timing influences flow more than layer or fault zone conductivity. Finally, fault conduit behavior that penetrates aquitards has significant implications for transport, while fault barrier behavior has surprisingly little. This research advocates for adequate data collection where faults may cause breaches in aquitards due to layer offsets or conduit behavior in the damage zone. It also promotes the use of multiple geological models to address structural uncertainty, and highlights some of the hurdles in doing so such as computational expense and the availability of seamless geological-flow modeling workflows.

Dysfunction of proprioceptive sensory synapses is a pathogenic event and therapeutic target in mice and humans with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by a varying degree of severity that correlates with the reduction of SMN protein levels. Motor neuron degeneration and skeletal muscle atrophy are hallmarks of SMA, but it is unknown whether other mechanisms contribute to the spectrum of clinical phenotypes. Here, through a combination of physiological and morphological studies in mouse models and SMA patients, we identify dysfunction and loss of proprioceptive sensory synapses as key signatures of SMA pathology. We demonstrate that SMA patients exhibit impaired proprioception, and their proprioceptive sensory synapses are dysfunctional as measured by the neurophysiological test of the Hoffmann reflex (H-reflex). We further show that loss of excitatory afferent synapses and altered potassium channel expression in SMA motor neurons are conserved pathogenic events found in both severely affected patients and mouse models. Lastly, we report that improved motor function and fatigability in ambulatory SMA patients and mouse models treated with SMN-inducing drugs correlate with increased function of sensory-motor circuits that can be accurately captured by the H-reflex assay. Thus, sensory synaptic dysfunction is a clinically relevant event in SMA, and the H-reflex is a suitable assay to monitor disease progression and treatment efficacy of motor circuit pathology.

Quality of hospital labour and delivery care: A multilevel analysis in Southern Nations and Nationalities People's Region of Ethiopia.

BACKGROUND: Ethiopia has one of the highest maternal mortality ratios in Africa. Few have examined the quality of labour and delivery (L&D) care in the country. This study evaluated the quality of routine L&D care and identified patient-level and hospital-level factors associated with the quality of care in a subset of government hospitals. MATERIALS AND METHODS: This was a facility-based, cross-sectional study using direct non-participant observation carried out in 2016. All mothers who received routine L&D care services at government hospitals (n = 20) in one of the populous regions of Ethiopia, Southern Nations Nationalities and People's Region (SNNPR), were included. Mixed effects multilevel linear regression modeling was employed in two stages using hospital as a random effect, with quality of L&D care as the outcome and selected patient and hospital characteristics as independent variables. Patient characteristics included woman's age, number of previous births, number of skilled attendants involved in care process, and presence of any danger sign in current pregnancy. Hospital characteristics included teaching hospital status, mean number of attended births in the previous year, number of fulltime skilled attendants in the L&D ward, whether the hospital had offered refresher training on L&D care in the previous 12 months, and the extent to which the hospital met the 2014 Ethiopian Ministry of Health standards regarding to resources available for providing quality of L&D care (measured on a 0-100% scale). These standards pertain to availability of human resource by category and training status, availability of essential drugs, supplies and equipment in L&D ward, availability of laboratory services and safe blood, and availability of essential guidelines for key L&D care processes. RESULTS: On average, the hospitals met two-thirds of the standards for L&D care quality, with substantial variation between hospitals (standard deviation 10.9 percentage points). While the highest performing hospital met 91.3% of standards, the lowest performing hospital met only 35.8% of the standards. Hospitals had the highest adherence to standards in the domain of immediate and essential newborn care practices (86.8%), followed by the domain of care during the second and third stages of labour (77.9%). Hospitals scored substantially lower in the domains of active management of third stage of labour (AMTSL) (42.2%), interpersonal communication (47.2%), and initial assessment of the woman in labour (59.6%). We found the quality of L&D care score was significantly higher for women who had a history of any danger sign (ß = 5.66; p-value = 0.001) and for women who were cared for at a teaching hospital (ß = 12.10; p-value = 0.005). Additionally, hospitals with lower volume and more resources available for L&D care (P-values < 0.01) had higher L&D quality scores. CONCLUSIONS: Overall, the quality of L&D care provided to labouring mothers at government hospitals in SNNPR was limited. Lack of adherence to standards in the areas of the critical tasks of initial assessment, AMTSL, interpersonal communication during L&D, and respect for women's preferences are especially concerning. Without greater attention to the quality of L&D care, regardless of how accessible hospital L&D care becomes, maternal and neonatal mortality rates are unlikely to decrease substantially.

Observational methods for human studies of transgenerational effects.

There are substantial challenges in studying human transgenerational epigenetic outcomes resulting from environmental conditions. The task requires specialized methods and tools that incorporate specific knowledge of multigenerational relationship combinations of probands and their ancestors, phenotype data for individuals, environmental information of ancestors and their descendants, which can span historical to present datasets, and informative environmental data that chronologically aligns with ancestors and descendants over space and time. As a result, there are few epidemiologic studies of potential transgenerational effects in human populations, thus limiting the knowledge of ancestral environmental conditions and the potential impacts we face with modern human health outcomes. In an effort to overcome some of the challenges in studying human transgenerational effects, we present two transgenerational study designs: transgenerational space-time cluster detection and transgenerational case-control study design. Like other epidemiological methods, these methods determine whether there are statistical associations between phenotypic outcomes (e.g., adverse health outcomes) among probands and the shared environments and environmental factors facing their ancestors. When the ancestor is a paternal grandparent, a statistically significant association provides some evidence that a transgenerational inheritable factor may be involved. Such results may generate useful hypotheses that can be explored using epigenomic data to establish conclusive evidence of transgenerational heritable effects. Both methods are proband-centric: They are designed around the phenotype of interest in the proband generation for case selection and family pedigree creation. In the examples provided, we incorporate at least three generations of paternal lineage in both methods to observe a potential transgenerational effect.