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Sensors are integrated into collaborative robot systems to ensure the safety of human workers by allowing them to perceive their environments, detect human presence, and adjust their actions accordingly. This preferred reporting items for systematic reviews and meta-analyses extension for scoping review (PRISMA-ScR) focuses on current sensor-enabled safety systems for human–robot collaboration (HRC) in the manufacturing industry based on both scientific papers and patents. From the initial search of 6669 references, 281 underwent full-text review and segmentation based on the sensor technology, installation location, and safety operating mode according to the ISO/TS 15066 standard. In the last decade, there has been a clear trend of increasing sensor-enabled safety systems. The dominant sensors used are infrared (IR)-structured light, capacitive, light detection and ranging (LiDAR), resistive, stereo/depth camera, RaDAR, and laser scanners. The primary safety operating mode identified was speed and separation monitoring (SSM). Some systems integrate multiple sensor types, with the most common combinations being LiDAR with stereo cameras or LiDAR with capacitive sensors, and laser scanners with RaDAR. We suggest multisensor integration and standardized benchmarks for future development. This review is among the few that employ the PRISMA-P protocol to study sensor technologies and contribute to a more systematic understanding of the current state of the art in this area.

Upregulation of L-type calcium channels (LTCCs) is implicated in a range of cardiovascular and neurological disorders. Therefore, the development of toolboxes that unlock fast imaging protocols in live cells is coveted. Herein, we report a library of first-in-class far-red small-molecule-based fluorescent ligands (FluoDiPines), able to target LTCCs. All fluorescent ligands were evaluated in whole-cell patch-clamp and live-cell Ca2+imaging whereby FluoDiPine 6was found to be the best candidate for live-cell fluorescence imaging. Low concentration of FluoDiPine 6(50 nM) and a quick labeling protocol (5 min) are successfully applied to fixed and live cells to image LTCCs with good specificity.

This paper presents a compact and low-cost on-chip sensor and readout circuit. The sensor achieves high-resolution 5-degrees-of-freedom (DoF) tracking (x, y, z, yaw, and pitch). With the help of an external wire wound sensor, it can also achieve high-resolution 6-degrees-of-freedom (DoF) tracking (x, y, z, yaw, pitch, and roll angles). The sensor uses low-frequency magnetic fields to detect the position and orientation of instruments, providing a viable alternative to using X-rays in image-guided surgery. To measure the local magnetic field, a highly miniaturised on-chip magnetic sensor capable of sensing the magnetic field has been developed incorporating an on-chip magnetic sensor coil, analog-front end, continuous-time $\Delta\Sigma$ analog-to-digital converter (ADC), LVDS transmitter, bandgap reference, and voltage regulator. The microchip is fabricated using 65 nm CMOS technology and occupies an area of 1.06 mm${}^{2}$, the smallest reported among similar designs to the best of our knowledge. The 5-DoF system accurately navigates with a precision of 1.1 mm within the volume-of-interest (VOI) of 15$\times$15$\times$15 cm${}^{3}$. The 6-DoF system achieves a navigation accuracy of 0.8 mm and an angular error of 1.1 degrees in the same VOI. These results were obtained at a 20 Hz update rate in benchtop characterisation. The prototype sensor demonstrates accurate position tracking in real-life pre-clinical in-vivo settings within the porcine lung of a live swine, achieving a reported worst-case registration accuracy of 5.8 mm.

ABSTRACTIntroductionInhibition of the enzymatic function of HDAC6 is currently being explored in clinical trials ranging from peripheral neuropathies to cancers. Advances in selective HDAC6 inhibitor discovery allowed studying highly efficacious brain penetrant and peripheral restrictive compounds for treating PNS and CNS indications.Areas coveredThis review explores the multifactorial role of HDAC6 in cells, the common pathological hallmarks of PNS and CNS disorders, and how HDAC6 modulates these mechanisms. Pharmacological inhibition of HDAC6 and genetic knockout/knockdown studies as a therapeutic strategy in PNS and CNS indications were analyzed. Furthermore, we describe the recent developments in HDAC6 PET tracers and their utility in CNS indications. Finally, we explore the advancements and challenges with HDAC6 inhibitor compounds, such as hydroxamic acid, fluoromethyl oxadiazoles, HDAC6 degraders, and thiol-based inhibitors.Expert opinionBased on extensive preclinical evidence, pharmacological inhibition of HDAC6 is a promising approach for treating both PNS and CNS disorders, given its involvement in neurodegeneration and aging-related cellular processes. Despite the progress in the development of selective HDAC6 inhibitors, safety concerns remain regarding their chronic administration in PNS and CNS indications, and the development of novel compound classes and modalities inhibiting HDAC6 function offer a way to mitigate some of these safety concerns.

Random telegraph noise (RTN) measurements are performed on as-processed, programmed, erased, and irradiated 80 nm vertical charge-trapping nand memory transistors. Variations in current with time of up to ±20% are observed during the RTN testing interval. The RTN of these devices is relatively unaffected by irradiation of devices to 500 krad(SiO2). Root-mean-square (rms) magnitudes of measured RTN exceed predictions of number-fluctuation models (NFMs) by up to six-times. This result demonstrates that fluctuations in carrier scattering rates caused by motion and/or reconfiguration of traps at grain boundaries likely lead to a significant fraction of the low-frequency noise and/or RTN in poly-crystalline Si channel, charge-trapping memory devices. The magnitudes of these fluctuations may present significant challenges to the resolution of highly scaled 3-D memory devices.

Compared to Si, IGZO is a competitive choice for FeFET channel material, because of the interlayer-free structure, which can lead to a higher endurance. However, the ferroelectric switching mechanism of erasure remains unclear due to the lack of holes in IGZO. In this work, we present a quasi-static charge sheet model of Metal/Ferroelectric/IGZO stack, considering the charges supplied by IGZO Density of States and interface states. The modeling results suggest that shallow donors, by emitting electrons into the conduction band and thereby partially ionized, can become positively charged and thus support the erase operation. Cryogenic Negative Bias Illumination Stress measurement indicates the presence of shallow donors.

According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, has been shown to suppress intestinal stemness. Here, we used Paneth cells as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation in mice. Upon inflammation, Paneth cell-specific Apcmutations led to intestinal tumors reminiscent not only of those arising in patients with inflammatory bowel disease, but also of a larger fraction of human sporadic colon cancers. The latter is possibly because of the inflammatory consequences of western-style dietary habits, a major colon cancer risk factor. Machine learning methods designed to predict the cell-of-origin of cancer from patient-derived tumor samples confirmed that, in a substantial fraction of sporadic cases, the origins of colon cancer reside in secretory lineages and not in stem cells.

Kidney transplant (KTx) biopsies showing transplant glomerulopathy (TG) (glomerular basement membrane double contours (cg) > 0) and microvascular inflammation (MVI) in the absence of C4d staining and donor-specific antibodies (DSAs) do not fulfill the criteria for chronic active antibody–mediated rejection (CA-AMR) diagnosis and do not fit into any other Banff category. To investigate this, we initiated a multicenter intercontinental study encompassing 36 cases, comparing the immunomic and transcriptomic profiles of 14 KTx biopsies classified as cg+MVI DSA-/C4d-with 22 classified as CA-AMR DSA+/C4d+through novel transcriptomic analysis using the NanoString Banff-Human Organ Transplant (B-HOT) panel and subsequent orthogonal subset analysis using two innovative 5-marker multiplex immunofluorescent panels. Nineteen genes were differentially expressed between the two study groups. Samples diagnosed with CA-AMR DSA+/C4d+showed a higher glomerular abundance of natural killer cells and higher transcriptomic cell type scores for macrophages in an environment characterized by increased expression of complement-related genes (i.e., C5AR1) and higher activity of angiogenesis, interstitial fibrosis tubular atrophy, CA-AMR, and DSA-related pathways when compared to samples diagnosed with cg+MVI DSA-/C4d-. Samples diagnosed with cg+MVI DSA-/C4d-displayed a higher glomerular abundance and activity of T cells (CD3+, CD3+CD8+, and CD3+CD8-). Thus, we show that using novel multiomic techniques, KTx biopsies with cg+MVI DSA-/C4d-have a prominent T-cell presence and activity, putting forward the possibility that these represent a more T-cell dominant phenotype.

Informal care is often accompanied by a reduction or abandonment of professional activity by the caregiver. Therefore, caregiving may be associated with a lower pension for the former caregiver than for people without care obligations. There is a large gender difference in informal care responsibilities, and this may contribute to the gender pension gap. As the impact of care-related labour market decisions depends on the design of the pension system, we carry out a cross-country comparison, in which we analyse the impact of care obligations in countries with high (Luxembourg), middle (Liechtenstein, Belgium, Portugal) and low (Slovenia) gender pension gaps. Using typical-case simulation models, we examine how the impact of care-related events is mediated by pension rules, given women's labour market decisions. To what extent does working part time or interrupting one’s career at the age of 30 or 54 reduce the later pension benefit? How are these losses mitigated by pension credits that are conditional on caregiving? We find that the mitigating effects are generally strongest in Belgium, followed by Luxembourg and Slovenia. Such credits hardly exist in Portugal, while in Liechtenstein they have only a small impact. However, the consequences of either working part time or interrupting work can also be mitigated via general rules in the system that are unrelated to caregiving (such as in Portugal and Liechtenstein). They can, on the other hand, be aggravated by the existence of higher accrual rates for individuals who extend their careers, as in Luxembourg and Slovenia.

Familial hypercholesterolemia (FH) is one of the most common genetically inherited disorders in the world. Children with severe heterozygous FH (HeFH), i.e. untreated low-density lipoprotein cholesterol (LDL-C) levels above the 90th percentile for age and sex among FH mutation carriers, can have LDL-C levels that overlap levels of children with homozygous FH (HoFH), but treatment regimen and cardiovascular follow-up to prevent cardiovascular disease are less intensive in children with severe HeFH. In children with HoFH, subclinical atherosclerosis can already be present using computed tomography coronary angiography (CTCA). The question remains whether this is also the case in children with severe HeFH who have a high exposure to elevated LDL-C levels from birth onwards as well. We calculated the cumulative LDL-C exposure (CEtotal[mmol]) in four children with severe HeFH and performed computed tomography coronary angiography (CTCA). These children, aged 13, 14, 15 and 18 years, had CEtotalof 71.3, 97.8, 103.6 and 136.1 mmol, respectively. None of them showed abnormalities on cardiovascular imaging, despite high LDL-C exposure. The results of this study, do not give us an indication to recommend performing CTCA routinely in children with severe HeFH.

Purpose: Resection of pediatric osteosarcoma in the extremities with soft tissue involvement presents surgical challenges due to difficult visualization and palpation of the tumor. Therefore, an adequate image-guided surgery (IGS) system is required for more accurate tumor resection. The use of a 3D model in combination with intraoperative tracked ultrasound (iUS) may enhance surgical decision making. This study evaluates the clinical feasibility of iUS as a surgical tool using a porcine cadaver model. Methods: First, a 3D model of the porcine lower limb was created based on preoperative scans. Second, the bone surface of the tibia was automatically detected with an iUS by a sweep on the skin. The bone surface of the preoperative 3D model was then matched with the bone surface detected by the iUS. Ten artificial targets were used to calculate the target registration error (TRE). Intraoperative performance of iUS IGS was evaluated by six pediatric surgeons and two pediatric oncologic orthopedists. Finally, user experience was assessed with a post-procedural questionnaire. Results: Eight registration procedures were performed with a mean TRE of 6.78 ± 1.33 mm. The surgeons agreed about the willingness for clinical implementation in their current clinical practice. They mentioned the additional clinical value of iUS in combination with the 3D model for the localization of the soft tissue components of the tumor. The concept of the proposed IGS system is considered feasible by the clinical panel, but the large TRE and degree of automation need to be addressed in further work. Conclusion: The participating pediatric surgeons and orthopedists were convinced of the clinical value of the interaction between the iUS and the 3D model. Further research is required to improve the surgical accuracy and degree of automation of iUS-based registration systems for the surgical management of pediatric osteosarcoma.

BackgroundIntraocular pressure (IOP) monitoring in glaucoma management is evolving with novel devices. We investigated the reproducibility of 24 hour profiles on two consecutive days and after 30 days of self-measurements via telemetric IOP monitoring.MethodsSeven primary patients with open-angle glaucoma previously implanted with a telemetric IOP sensor in one eye underwent automatic measurements throughout 24 hours on two consecutive days (‘day 1’ and ‘day 2’). Patients wore an antenna adjacent to the study eye connected to a reader device to record IOP every 5 min. Also, self-measurements in six of seven patients were collected for a period of 30 days. Analysis included calculation of hourly averages to correlate time-pairs of day 1 versus day 2 and the self-measurements vers day 2.ResultsThe number of IOP measurements per patient ranged between 151 and 268 on day 1, 175 and 268 on day 2 and 19 and 1236 during 30 days of self-measurements. IOP time-pairs of automatic measurements on day 1 and day 2 were significantly correlated at the group level (R=0.83, p<0.001) and in four individual patients (1, 2, 6 and 7). IOP time-pairs of self-measurements and day 2 were significantly correlated at the group level (R=0.4, p<0.001) and in four individual patients (2, 5, 6 and 7).ConclusionsTwenty-four hour automatic measurements of IOP are correlated on consecutive days and, though to a lesser degree, with self-measurements. Therefore a virtual 24-hour IOP curve might be constructed from self-measurements. Both options provide an alternative to frequent in-office IOP measurements.

BackgroundHigher resting heart rate has been described as a risk factor for adverse outcome in healthy individuals and cardiovascular patients. The aim of this study was to evaluate resting heart rate as risk factor in adult congenital heart disease (ACHD).MethodsIn this prospective observational cohort study, patients with moderate or complex ACHD were included at routine outpatient visit. Standard 12-lead ECGs were obtained in rest. Heart rate was obtained from the ECG automatically by the Modular ECG Analysis System (MEANS). The primary endpoint was all-cause mortality and the secondary endpoint was a composite of all-cause mortality and heart failure. Survival was derived using the Kaplan-Meier estimator. Subgroups based on heart rate tertiles were compared by the log-rank test. Cox proportional hazards models were adjusted for clinical factors including age, sex and diagnosis (moderate vs complex ACHD).ResultsA total of 556 patients were included (median age 32 years (IQR 24–41), 57.6% male). Mean heart rate was 69±13 bpm. Negative chronotropic medication was used by 74 (13.3%) patients. During a median follow-up of 10.1 (IQR 9.6–10.5) years, 36 patients (6.5%) died and 83 (14.9%) reached the secondary endpoint. Patients with higher heart rates had significantly lower survival and heart failure-free survival. After adjusting for clinical factors, heart rate remained associated with mortality (HR 1.57 per 10 bpm, 95% CI 1.26 to 1.96) and mortality or heart failure (HR 1.33 per 10 bpm, 95% CI 1.13 to 1.57).ConclusionHigher heart rate is associated with lower survival and heart failure-free survival in ACHD.

We present a novel approach to the modeling of carrier energy relaxation during high-field phases in semiconductor-oxide-nitride-oxide-semiconductor (SONOS) flash memory gate stacks. We show that this method integrates well with TCAD simulators and that taking the energy relaxation of carriers into consideration solves two of the most prominent problems of trapping layer dynamics modeling: The missing slope degradation in incremental step-pulse programming (ISPP) simulations and the incompatibility of the resulting charge distributions with long-term room temperature charge retention measurements. This article consists of two parts where this part discusses the physical/TCAD level. The second part derives a semianalytical model specifically for programming that reduces the numerical complexity while still retaining the main physical assumptions and the applicability to experimental data.

ObjectiveTo report 5-year efficacy and safety of upadacitinib (UPA) in rheumatoid arthritis (RA) from the phase III long-term extension (LTE) of SELECT-NEXT.MethodsPatients on stable conventional synthetic disease-modifying antirheumatic drugs were randomized to UPA 15 mg once daily (QD), UPA 30 mg QD, or placebo for 12 weeks. Following this, placebo-randomized patients were switched to UPA 15 mg QD or UPA 30 mg QD in the LTE; UPA-randomized patients continued their original dose. Blinding remained until dose switching from UPA 30 mg QD to UPA 15 mg QD because of approval of UPA 15 mg QD; the earliest switch occurred at week 168. Efficacy (as observed) and treatment-emergent adverse events (TEAEs) are reported through 5 years.ResultsOverall, 611 (92%) randomized patients entered the LTE; 271 (44%) discontinued the study drug by 5 years, primarily because of adverse events (16%). Clinical outcomes improved or were maintained at 5 years; 51% and 43% of patients achieved Clinical Disease Activity Index remission and 75% and 66% achieved Disease Activity Score in 28 joints based on C-reactive protein < 2.6 among those initially randomized to UPA 15 mg QD and UPA 30 mg QD, respectively. Proportions of patients achieving ≥ 20%/50%/70% improvement in American College of Rheumatology criteria responses increased from week 60 through 5 years. Results were similar regardless of initial randomization to UPA or placebo. TEAEs, including TEAEs of special interest, were consistent with earlier analyses and other SELECT studies. Malignancies (excluding nonmelanoma skin cancer), major adverse cardiovascular events, and venous thromboembolic events were reported infrequently. No new safety signals were observed.ConclusionThe 5-year benefit-risk profile for UPA in RA remains favorable. (SELECT-NEXT; ClinicalTrials.gov: NCT02675426)

Risankizumab, a biologic disease-modifying antirheumatic drug, helps control the body’s immune system to reduce symptoms of psoriatic arthritis (a disease that inflames the joints of people who have the skin condition psoriasis). The ongoing KEEPsAKE 2 study is evaluating how well risankizumab works and how safe it is for treating adult patients with active psoriatic arthritis who previously experienced inadequate response to one or more specific types of disease-modifying anti-arthritis drugs. Patients were randomly assigned to receive either risankizumab or an inactive drug; after 24 weeks, all patients received risankizumab. At study week 100, 57% of patients who were assigned to receive continuous risankizumab since the start of the study experienced a 20% or more improvement in a measure of psoriatic arthritis symptoms using criteria established by the American College of Rheumatology (ACR20); a similar proportion of patients achieved a 20% improvement at both weeks 24 and 52. Similarly, 56% and 53% of patients who switched from inactive drug to risankizumab achieved ACR20 at weeks 52 and 100 (more than before switching to risankizumab at week 24). Minimal disease activity (MDA) was evaluated by assessing joint and skin symptoms, affected body surface area, pain, and physical function. At week 100, 33% of patients achieved MDA (both groups), which was similar to week 52. Most patients who achieved ACR20 or MDA at week 52 maintained responses at week 100. Improvements with risankizumab were seen in several other measures of treatment outcomes through week 100. Risankizumab was generally safe through 100 weeks.

Introduction: This study aimed to describe the long-term efficacy and safety of upadacitinib and adalimumab through 228 weeks following immediate switch to the alternate therapy with a different mechanism of action (MoA) in patients with rheumatoid arthritis (RA) not achieving treatment goals with their initial randomized therapy in the ongoing phase 3 SELECT-COMPARE study. Methods: Patients with non-response or incomplete response to initially prescribed upadacitinib 15 mg once daily or adalimumab 40 mg every other week were switched to the alternate therapy by week 26. Efficacy was evaluated through 228 weeks post-switch using validated outcome measures, including Clinical Disease Activity Index (CDAI) low disease activity (LDA; ≤ 10)/remission (≤ 2.8); 28-joint Disease Activity Score based on C-reactive protein ≤ 3.2/&lt; 2.6; ≥ 20%/50%/70% improvement in American College of Rheumatology (ACR) response criteria; and change from baseline in ACR core components. Data are reported as observed. Safety was assessed by treatment-emergent adverse events (TEAEs) through week 264. Results: Of patients initially randomized to upadacitinib and adalimumab, 38.7% and 48.6%, respectively, switched to the alternate therapy by week 26. Clinically relevant improvements in all efficacy measures were observed through 228 weeks post-switch and were generally similar between groups, with small numeric differences mostly in favor of switching to upadacitinib. CDAI remission was achieved by 32.7% and 28.6% of initial non-responders, and 27.5% and 27.3% of incomplete responders, while CDAI LDA was achieved by 76.9% and 72.9% of non-responders, and 72.5% and 72.7% of incomplete responders switching to upadacitinib and to adalimumab, respectively. TEAE rates were similar between groups, although herpes zoster infection, lymphopenia, and creatine phosphokinase elevation were more frequent when switching to upadacitinib. No new safety signals were identified. Conclusion: Switching to a different MoA may provide long-term benefit to patients with RA not achieving treatment goals with their initial therapy, with acceptable safety profiles. Trial Registration: NCT02629159.

ObjectiveAlthough exercise therapy is safe, effective, and recommended as a nonpharmacological treatment for axial spondyloarthritis (axSpA), there is a lack of guidelines regarding type and dosage. Insufficient knowledge about physical and physiological variables makes designing effective exercise programs challenging. Therefore, the goal of this study was to simultaneously assess trunk strength, spinal mobility, and the cardiorespiratory fitness of patients with axSpA.MethodsIn a cross-sectional study, 58 patients with axSpA (mean age 40.8 yrs, 50% male, mean symptom duration 10.3 yrs) performed maximal cervical and trunk mobility and isometric strength tests in all planes (using David Back Concept devices) and a maximal cardiopulmonary bicycle exercise test (n = 25). Mobility and strength data were compared to healthy reference data. Cut-off values for clinical cardiopulmonary exercise testing interpretation were used to judge normality. Patients were compared based on radiographic involvement and symptom duration.ResultsBoth strength (P≤ 0.02) and mobility (P≤ 0.001) were significantly lower for the patients with axSpA compared to the reference. Strength deficits were comparable between the radiographic and nonradiographic groups (P> 0.05, except trunk extension [P= 0.03]), whereas mobility showed higher deficits in the radiographic group (cervical extension [P= 0.02] and rotation [P= 0.01], and trunk extension [P= 0.03] and rotation [P= 0.03]), regardless of symptom duration. Similarly, symptom duration positively affected oxygen pulse (P= 0.03), relative anaerobic threshold (P= 0.02), and aerobic capacity (P= 0.02).ConclusionIn patients with axSpA, strength is more affected than mobility when compared to healthy controls. Likewise, mainly the metabolic component of aerobic capacity is impaired, affecting cardiopulmonary fitness. These findings indicate that future personalized exercise programs in patients with axSpA should incorporate exercises for cardiopulmonary fitness next to strength and mobility training.

Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells2. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Ccomplex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system3.

Flash memory with a charge trap layer (CTL), also known as silicon-oxide-nitride-oxide-silicon (SONOS), is the most common type in production, yet there is a lack of consensus on the physical modeling of its operation. In Part I, we therefore proposed a full TCAD model based on an energy relaxation approach and showed that it captures experimentally observed memory operation. This numerical model, however, comes with considerable complexity and computational cost. In Part II, we therefore construct a semianalytical model based on similar physical assumptions, called Pheido, to be as simple as possible. We first derive the model equations based on a balance of current densities, detailing the approximations made. We then use Pheido to analyze the various regimes of an experimental incremental step pulse programming (ISPP) curve and compare it to the full TCAD model derived in Part I. Finally, we investigate the impact of material and structural cell parameters on the ISPP curve, illustrating how the Pheido model offers wide utility at low computational cost.

In this article, a planar on-silicon inductor design for electromagnetic tracking (EMT) is presented. The design process has been demonstrated for a planar sensing coil in a 65-nm on-silicon process. The designed multilayer planar inductor configuration achieves SNR of 23.6 dB and sensitivity of 202 $\mu \text{V}$ /T/Hz. The designed inductor satisfies system requirements for clinical use in EMT applications. The current design has been verified on the Taiwan Semiconductor Manufacturing Company (TSMC) 65-nm process and exhibits a close correlation with simulation results. Measured SNR of 22.1 dB and sensitivity of 198 $\mu \text{V}$ /T/Hz at a frequency of 20 kHz and magnetic flux density of 150 nT is achieved. An improved lumped element model to account for multilayer planar inductor designs is also proposed.