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In this article, a novel MPPT technique is proposed and experimentally tested. It is called “grid-connected photovoltaic (PV) systems maximum power point tracking (MPPT) technique driven by the power factor correction (PFC) controller” (CICERONE). It generates, for both single stage (SS) and double stage (DS) grid-connected PV systems, the bulk voltage reference by exploiting only the internal (not coming from sensors) PFC control signal. CICERONE leads to a piecewise ramp bulk voltage whose slope is updated to maximize the average power injected into the grid. Experimental results show that CICERONE exhibits better performance and robustness than the Perturb and Observe MPPT technique, especially in case of dynamic irradiance conditions. In addition, CICERONE can be applied without modifications to both SS and DS grid-connected PV systems. Hence, differently from a traditional DS system, in a CICERONE based DS system, the dc–dc converter can be operated with a fixed duty-cycle and can work in the highest efficiency conditions. Moreover, CICERONE operates without using external signals coming from sensors and affected by measuring noise (such as PV voltage, PV current, grid current, or their derivatives), but it performs the MPPT using only an internal signal already used for PFC purposes.

Mucopolysaccharidoses (MPSs) are childhood diseases caused by inherited deficiencies in glycosaminoglycan degradation. Most MPSs involve neurodegeneration, which to date is untreatable. Currently, most therapeutic strategies aim at correcting the primary genetic defect. Among these strategies, gene therapy has shown great potential, although its clinical application is challenging. We have shown previously in an MPS-IIIA mouse model that the molecular tweezer (MT) CLR01, a potent, broad-spectrum anti-amyloid small molecule, inhibits secondary amyloid storage, facilitates amyloid clearance, and protects against neurodegeneration. Here, we demonstrate that combining CLR01 with adeno-associated virus (AAV)-mediated gene therapy, targeting both the primary and secondary pathologic storage in MPS-IIIA mice, results in a synergistic effect that improves multiple therapeutic outcomes compared to each monotherapy. Moreover, we demonstrate that CLR01 is effective therapeutically in mouse models of other forms of neuronopathic MPS, MPS-I, and MPS-IIIC. These strongly support developing MTs as an effective treatment option for neuronopathic MPSs, both on their own and in combination with gene therapy, to improve therapeutic efficacy and translation into clinical application.

The experimental characteristics of a temperature sensor based on a 4H-SiC diode-connected lateral NMOSFET are shown in the range between 14K and 481K. The device is fully compatible with 4H-SiC CMOS technology. The analysis of the sensor characteristics reveals a main temperature dependence on the threshold voltage compared to the channel mobility. Due to the oxide/semiconductor interface traps, the sensor characteristic is divided in three temperature ranges to obtain a good linearity: in 14K $\leq $ T $\leq 200$ K, the sensitivity is 53.46mV/K, the rms error is 5.49K and the coefficient of determination is 0.9927 for a bias current of $1.59\mu $ A; instead, a current of $100\mu $ A permits to have a maximum coefficient of determination of 0.9708 with a sensitivity of 29.9mV/K for 200K < T $\leq 394$ K, and a linearity of 0.9926 with a sensitivity of 13.72mV/K at T >394K. Finally, for currents between 870nA and $9\mu $ A the linearity is higher than 0.95 in all temperature ranges.

Background Underrepresented minority groups (URMs) in surgery are not significantly increasing despite evidence suggesting that diversity in health care providers leads to excellent patient outcomes and care. Efforts to increase URM representation in surgical residency programs are essential for addressing disparities and improving health care delivery.Methods This retrospective study outlines a three-phase strategy implemented at a large academic-affiliated hospital to increase URM representation in its general surgery residency program. The strategy encompassed interview selection with a holistic review and implicit bias training for interviewers, modification of the interview scoring rubric, and post-interview recruitment efforts, including a virtual second look event for URM applicants.Results Following the implementation of these strategies, the URM match rate improved from 0 to 33.3% in the first year and was sustained at 33.3% in the subsequent year. Consequently, the representation of URMs in the residency program rose from 6.7% before our intervention to 13.3% afterwards.Discussion This structured approach successfully increased URM representation in a surgical residency program, affirming the success of targeted recruitment strategies. By promoting a diverse and inclusive environment, the program better reflects the community it serves, with aims at improved patient care and patient satisfaction.

This study aimed to evaluate epilepsy outcome and antiseizure medication (ASM) discontinuation after lesionectomies as first surgical approach in pediatric population diagnosed with low‐grade epilepsy‐associated neuroepithelial tumors (LEATs). We conducted a retrospective study. Thirty‐six consecutive patients with histological diagnoses of LEATs who underwent surgery between 2018 and 2021 at our institution were included. The clinical and surgical data were retrospectively analyzed. Thirty (83.3%) of 36 patients are free of disabling seizures (Engel class I) and 19 (63,4%) of them are classified as Engel Ia. In 17 (47.2%) patients, ASM could be discontinued. The mean age at surgery was 8.6 years (±4.04) and the mean age at onset of epilepsy was 7.2 years (±3.8), whereas the mean duration of epilepsy in months at the time of surgery was 21.3 months (±23.7). The epileptogenic tumor was in the temporal lobe in 20 (55.5%) patients. Because of seizure persistence, a second or a third surgery was necessary for six patients (16.7%) and four of them had residual lesions (three in temporal and one in extratemporal site). No perioperative complications were recorded, including acute seizures, with a median hospitalization time of 7 days. Shorter epilepsy duration at time of surgery as long as a single ASM was significantly correlated with an Engel class I outcome (p‐value = .01 and p‐value = .016, respectively). Focal seizure semeiology was associated with an increased probability of antiseizure medication discontinuation (p‐value = .042). Our findings confirm that shorter epilepsy disease duration, monotherapy before surgery, and seizure semeiology are determinant factors for a positive seizure outcome and medication discontinuation, also with less invasive surgical approaches such as lesionectomies. However, considering the intrinsic multifactorial epileptogenic nature of LEATs, a tailored surgical approach should be considered to optimize clinical and seizure outcome, especially for lesions located in the temporal lobe.

In this letter, a compact DC SPICE model for 4H-SiC lateral metal oxide semiconductor field effect transistors is shown both for PMOSFET and NMOSFET. It is validated through experimental comparisons by varying channel sizes, temperature in the range between ${298}{K}$ and ${573}{K}$ , and body voltage conditions. A new model of the threshold voltage is introduced in order to take into account the effects of the high interface defects density. Finally, an inverter logic gate is simulated at different temperatures and compared with experimental data and with BSIM4SiC simulation outcomes, where a maximum logic threshold voltage error of ${0}.{85}\%$ to the experimental data is shown compared to ${6}.{78}\%$ of BSIM4SiC.

Malaria-causing protozoa of the genus Plasmodiumhave exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular footprints that outline the historical reach of these species1. Nevertheless, debate persists over when and how malaria parasites emerged as human pathogens and spread around the globe1,2. To address these questions, we generated high-coverage ancient mitochondrial and nuclear genome-wide data from P. falciparum, P. vivaxand P. malariaefrom 16 countries spanning around 5,500 years of human history. We identified P. vivaxand P. falciparumacross geographically disparate regions of Eurasia from as early as the fourth and first millennia bce, respectively; for P. vivax, this evidence pre-dates textual references by several millennia3. Genomic analysis supports distinct disease histories for P. falciparumand P. vivaxin the Americas: similarities between now-eliminated European and peri-contact South American strains indicate that European colonizers were the source of American P. vivax, whereas the trans-Atlantic slave trade probably introduced P. falciparuminto the Americas. Our data underscore the role of cross-cultural contacts in the dissemination of malaria, laying the biomolecular foundation for future palaeo-epidemiological research into the impact of Plasmodiumparasites on human history. Finally, our unexpected discovery of P. falciparumin the high-altitude Himalayas provides a rare case study in which individual mobility can be inferred from infection status, adding to our knowledge of cross-cultural connectivity in the region nearly three millennia ago.

This study, conducted under the oversight of National Health Service Blood & Transplant, aimed to evaluate the current feasibility and implementation of both comprehensive and focused donor echocardiography in United Kingdom Intensive Care Units through a nationwide survey. Responses from 95 hospitals across all 4 UK nations showed each ICU had median 4 (IQR 2, 6) personal with 3 (IQR 2, 5) consultants and 1 (IQR 0, 2) registrar trained in focused echocardiography. A comprehensive echocardiogram can be acquired in 48% (n= 46) of hospitals within 6 h during regular working hours. This percentage drops to 11% (n= 10) outside of regular working hours, with 53% (n= 50) indicating this would require more than 24 h. In the case of focused echocardiogram acquisition, 60% (n= 57) of hospitals can obtain it within 6 h during normal working hours. This figure decreases to 20% (n= 19) outside of regular working hours, with 32% (n= 30) indicating that this would require more than 24 h to obtain. Overall, 98% of responding units (n= 93) have point-of-care ultrasound machines (median 2 (IQR 2, 3) machines per ICU) all equipped with echocardiographic capabilities. However, only 52% (n= 49) of respondents indicated have the ability for remote viewing of echocardiogram images.

Background: Malignant pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare tumors and available systemic therapies are limited. Aim: To explore the role of peptide receptor radionuclide therapy (PRRT) with Yttrium-90 (90Y) and Lutetium-177 (177Lu) peptides in pheochromocytomas (PCCs) and paragangliomas (PGLs). Methods: We retrospectively analyzed more than 1500 patients with histologically proven neuroendocrine tumors treated with 177Lu- or 90Y-DOTA-TATE or –TOC between 1999 to 2017 at our Institute. Overall, 30 patients with confirmed malignant PCCs and PGLs matched inclusion/exclusion criteria and were considered eligible for this analysis. Results: Thirty (n= 30) patients were treated: 22 with PGLs and 8 with PCCs (12 M and 18 F, median age 47 [IQR: 35–60 years]). Eighteen patients (n= 18) had head and neck PGLs, 3 patients thoracic PGLs and 1 patient abdominal PGL. Sixteen patients (53%) had locally advanced and fourteen (47%) had metastatic disease. Twenty-seven (90%) patients had disease progression at baseline. Four (13%) patients were treated with 90Y, sixteen (53%) with 177Lu and ten (33%) with 90Y + 177Lu respectively. The median total cumulative activity from treatment with 90Y- alone was 9.45 GBq (range 5.11–14.02 GBq), from 177Lu- alone was 21.9 GBq (7.55–32.12 GBq) and from the combination treatment was 4.94 GBq from 90Y- and 6.83 GBq from 177Lu- (ranges 1.04–10.1 and 2.66–20.13 GBq, respectively). Seven out of 30 (23%) patients had partial response and 19 (63%) stable disease. Median follow up was 8.9 years (IQR: 2.9–12). The 5-y and 10-y PFS was 68% (95% CI: 48–82) and 53% (95% CI: 33–69), respectively, whereas 5-y and 10-y OS was 75% (95% CI: 54–87) and 59% (95% CI: 38–75), respectively. Grade 3 or 4 acute hematological toxicity occurred in three patients, two with leucopenia and one with thrombocytopenia, respectively. Conclusion: PRRT with 177Lu- or 90Y-DOTA-TATE or –TOC is feasible and well tolerated in advanced PGLs and PCCs.

Introduction: This retrospective study investigates the efficacy of cemiplimab, a monoclonal antibody targeting the PD-1 receptor, in treating squamous cell carcinoma (SCC) of the skin. Methods: The study analyzes data from 50 patients with SCC, focusing on various clinical parameters, including patient demographics, tumor characteristics, treatment history, disease status at the beginning of therapy, and survival outcomes. Results: Of the patients who received at least one cycle of cemiplimab, 42% showed a clinical response. Adverse reactions were generally low, with the safety profile deemed excellent. During a median follow-up of 9.6 months, 17 patients experienced progression or death. Among these, 15 patients had died at the time of the analysis. The median progression-free survival (PFS) for the entire cohort was approximately 20.8 months, while median overall survival (OS) was not reached. Univariate Cox regression analysis for PFS showed that tumors in the arms and legs were associated with higher progression risk, while age above 65 years was not statistically significant. Distant metastasis exhibited a trend towards improved PFS. In terms of OS, distant metastasis was a significant predictor of reduced survival, while age above 65 years was not statistically significant. In a multivariate model, only the absence of distant metastasis remained significant, with an adjusted odds ratio (OR) of 12.3 (95% confidence interval 1.3–112.1). Conclusion: These findings provide valuable insights into the real-world effectiveness of cemiplimab in SCC management.

In this article, three different implementations of an Axon-Hillock circuit are presented, one of the basic building blocks of spiking neural networks. In this work, we explored the design of such circuits using a unipolar thin-film transistor technology based on amorphous InGaZnO, often used for large-area electronics. All the designed circuits are fabricated by direct material deposition and patterning on top of a flexible polyimide substrate. Axon-Hillock circuits presented in this article consistently show great adaptability of the basic properties of a spiking neuron such as output spike frequency adaptation and output spike width adaptation. Additional degrees of adaptability are demonstrated with each of the Axon-Hillock circuit varieties: neuron circuit threshold voltage adaptation, differentiation between input signal importance, and refractory period modulation. The proposed neuron can change its firing frequency up to three orders of magnitude by varying a single voltage brought to a circuit terminal. This allows the neuron to function, and potentially learn, at vastly different timescales that coincide with the biologically meaningful timescales, going from milliseconds to seconds, relevant for circuits meant for interaction with the environment. Thanks to careful design choices, the average measured power consumption is kept in the nW range, realistically allowing upscaling towards the spiking neural networks in the future. The spiking neuron with refractory period modulation presented in this work has an area of 607.3 μm × 492.2 μm, it experimentally demonstrated firing rates as low as 11.926 mHz, and its energy consumption per spike is &approx; 700 pJ at 30 Hz.

In recent decades, rare-isotope facilities have enabled the study of short-lived, neutron-rich nuclei. Their measured properties indicate that shell structure changes in the regime of unbalanced neutron-to-proton ratios compared with that of stable nuclei. In the so-called islands of inversion in the nuclear chart—around the neutron-rich nuclei 32Mg, 42Si and 64Cr, for example—the textbook shell model predicts spherical shapes due to the respective magic neutron numbers of 20, 28 and 40 of these nuclei. However, nuclei in these regions turn out to be deformed in their ground states. Another hallmark of these islands is shape coexistence, where a nucleus assumes different shapes with excitation energy. Here we present evidence for this phenomenon from the observation of an excited 0+state in 62Cr, two neutrons away from the heart of the island of inversion around neutron number N= 40. We use large-scale shell-model calculations to interpret the results, and we report extrapolations for the doubly magic nucleus 60Ca.

ObjectiveThis study aimed to explore the prognostic impact of cognitive impairment on the long-term risk of major adverse cardiovascular events (MACEs) in older patients with non-ST-elevation acute coronary syndrome (NSTEACS) undergoing invasive treatment.MethodsPatients aged ≥75 years with NSTEACS undergoing an invasive strategy were included in the multicentre prospective study (NCT01933581). Montreal Cognitive Assessment was used to evaluate cognitive status at baseline (scores ≥26 classified as normal, <26 as cognitive impairment). Long-term follow-up data were obtained from electronic patient care records. The primary endpoint was MACE as a composite of all-cause deaths, reinfarction, stroke/transient ischaemic attack, urgent revascularisation and significant bleeding.Results239 patients with baseline cognitive assessment completed long-term follow-up. Median age was 80.9 years (IQR 78.2–83.9 years) and 62.3% were male. On 5-year follow-up, there was no significant difference in the occurrence of MACE between the cognitively impaired group and the normal cognition group (p=0.155). Cognition status was not associated with MACE (HR 1.37 (95% CI 0.96 to 1.95); p=0.082). However, there was significantly more deaths (p=0.005) in those with cognitive impairment. Kaplan-Meier survival analysis (log-rank p=0.003) and Cox regression analysis (aHR 1.85 (95% CI 1.11 to 3.08); p=0.018) revealed increased risk of all-cause mortality, even after adjusting for frailty and GRACE (Global Registry of Acute Coronary Events) score.ConclusionCognitive impairment in older patients with NSTEACS undergoing an invasive strategy was associated with long-term all-cause mortality. Routine cognitive screening may aid risk stratification and further studies are needed to identify how this should influence management strategies and individual decision-making in this patient group.Trial registration numberNCT01933581.

Coronary physiology assessment, including epicardial and microvascular investigations, is a fundamental tool in the contemporary management of patients with coronary artery disease. Coronary revascularisation guided by functional evaluation has demonstrated superiority over angiography-only-guided treatment. In patients with chronic coronary syndrome, revascularisation did not demonstrate prognostic advantage in terms of mortality over optimal medical therapy (OMT). However, revascularisation of coronary stenosis, which induces myocardial ischaemia, has demonstrated better outcome than OMT alone. Pressure wire (PW) or angiography-based longitudinal coronary physiology provides a point-by-point analysis of the vessel to detect the atherosclerotic pattern of coronary disease. A careful evaluation of this disease pattern allows clinicians to choose the appropriate management strategy.Patients with diffuse disease showed a twofold risk of residual angina after percutaneous coronary intervention (PCI) than those with focal disease. Therefore, OMT alone or coronary artery bypass graft might be considered over PCI. In addition, the post-PCI physiological assessment aims to optimise the result revealing residual myocardial ischaemia. Improvement in post-PCI PW or angiography-based functional indices has been associated with better quality of life and reduced risk of cardiac events and residual angina. Therefore, the information obtained from coronary physiology allows for an optimised treatment strategy, which ultimately leads to improve patient’s prognosis and quality of life. This review provides an overview of the latest available evidence in the literature regarding the use of functional assessment of epicardial coronary stenosis in different settings in the contemporary patient-tailored management of coronary disease.

A novel hardware digital architecture for the space vector pulsewidth modulation (SVPWM) technique is proposed and based on a novel algorithm for the evaluation of the dwell times. Indeed, the complexity of the calculation of trigonometric functions is solved by introducing a Taylor series decomposition and using a convenient definition of the space vector $\alpha -\beta $ plane. Our architecture can modify the dwell times as a function of the fundamental and switching frequencies, of the phase and of the modulation index. Compared to other techniques, it avoids the use of external reference voltages as well as of the precalculated dwell times, like for the LUT-based architectures. Although it can be implemented in several logic devices, an Altera Cyclone V field programmable gate array (FPGA) is used as a digital controller of a three-phase power inverters and its resources are 16% and 2%, respectively, of the look-up tables and of the flip flops. Several cases are studied in order to show the goodness of the output waveforms during the real-time variations of the inputs.

The accuracy and computational complexity of keyword spotting (KWS) systems are heavily influenced by the choice of audio features in speech signals. This letter introduces a novel approach for audio feature extraction in KWS by leveraging a convolutional autoencoder, which has not been explored in the existing literature. Strengths of the proposed approach are in the ability to automate the extraction of the audio features, keep its computational complexity low, and allow accuracy values of the overall KWS systems comparable with the state of the art. To evaluate the effectiveness of our proposal, we compared it with the widely-used Mel Frequency Cepstrum (MFC) method in terms of classification metrics in noisy conditions and the number of required operators, using the public Google speech command dataset. Results demonstrate that the proposed audio feature extractor achieves an average classification accuracy on 12 classes ranging from 81.84% to 90.36% when the signal-to-noise ratio spans from 0 to 40 dB, outperforming the MFC up to 5.2%. Furthermore, the required number of operations is one order of magnitude lower than that of the MFC, resulting in a reduction in computational complexity and processing time, which makes it well-suited for integration with KWS systems in resource-constrained edge devices.

Ac motor drives are becoming increasingly popular in the field of industrial processes and transportation electrification. Currently, many industrial applications are based on induction machines supplied by inverters and controlled with field-oriented control techniques. Such techniques require the knowledge of the machine parameters to ensure the correctness of the torque control both in dynamic and steady-state conditions. In particular, an accurate determination of the induction motor rotor time constant is crucial. Therefore, this article analyses in detail the physical phenomena involved during the flux-decay test used for the rotor time constant determination. The reported analysis has been performed on a 15 kW induction motor. The transient of the machine's back-electromotive force (back-emf) has been critically analyzed during its evolution, finding a link between its evolution in time and the magnetic phenomena that occur both in the stator and the rotor. In particular, the effects due to the lamination saturation, the stator and rotor leakage inductances, and the stator iron losses have been associated with the transient evolution of the machine's back-emf.

Bladder cancer is considered a global health concern characterized by significant morbidity and mortality rates. The complex relationship between diet and bladder cancer is examined, with a specific focus on the role of diet in risk, outcomes, and treatment efficacy. Attention is drawn to the burgeoning field of immunotherapy in bladder cancer treatment, and the possible influence of diet on its outcomes is explored. While evidence remains limited, prior studies in other cancer types have suggested a potential connection between diet and immunotherapy response. To address this knowledge gap, the ongoing BLOSSOM study is presented, which aims to investigate the link between dietary factors, lifestyle, and the effectiveness of immunotherapy in patients with non-muscle-invasive bladder cancer. Ongoing efforts to decipher the intricate relationship between diet and bladder cancer care are highlighted, emphasizing the quest to unravel the dietary puzzle for the improvement of bladder cancer management.

The concept of a focused ultrasound study to identify sources of haemodynamic instability has revolutionized patient care. Point-of-care ultrasound (POCUS) using transthoracic scanning protocols, such as FUSIC Heart, has empowered non-cardiologists to rapidly identify and treat the major causes of haemodynamic instability. There are, however, circumstances when a transoesphageal, rather than transthoracic approach, may be preferrable. Due to the close anatomical proximity between the oesophagus, stomach and heart, a transoesphageal echocardiogram (TOE) can potentially overcome many of the limitations encountered in patients with poor transthoracic ultrasound windows. These are typically patients with severe obesity, chest wall injuries, inability to lie in the left lateral decubitus position and those receiving high levels of positive airway pressure. In 2022, to provide all acute care practitioners with the opportunity to acquire competency in focused TOE, the Intensive Care Society (ICS) and Association of Anaesthetists (AA) launched a new accreditation pathway, known as Focused Transoesophageal Echo (fTOE). The aim of fTOE is to provide the practitioner with the necessary information to identify the aetiology of haemodynamic instability. Focused TOE can be taught in a shorter period of time than comprehensive and teaching programmes are achievable with support from cardiothoracic anaesthetists, intensivists and cardiologists. Registration for fTOE accreditation requires registration via the ICS website. Learning material include theoretical modules, clinical cases and multiple-choice questions. Fifty fTOE examinations are required for the logbook, and these must cover a range of pathology, including ventricular dysfunction, pericardial effusion, tamponade, pleural effusion and low preload. The final practical assessment may be undertaken when the supervisors deem the candidate’s knowledge and skills consistent with that required for independent practice. After the practitioner has been accredited in fTOE, they must maintain knowledge and competence through relevant continuing medical education. Accreditation in fTOE represents a joint venture between the ICS and AA and is endorsed by Association of Cardiothoracic Anaesthesia and Critical care (ACTACC). The process is led by TOE experts, and represents a valuable expansion in the armamentarium of acute care practitioners to assess haemodynamically unstable patients.

Background: Severe secondary hyperparathyroidism (SHPT) is associated with mortality in end stage kidney disease (ESKD). Parathyroidectomy (PTX) becomes necessary when medical therapy fails, thus highlighting the interest to compare biochemical and clinical outcomes of patients receiving either medical treatment or surgery. Methods: We aimed to compare overall survival and biochemical control of hemodialysis patients with severe hyperparathyroidism, treated by surgery or medical therapy followed-up for 36 months. Inclusion criteria were age older than 18 years, renal failure requiring dialysis treatment (hemodialysis or peritoneal dialysis) and ability to sign the consent form. A control group of 418 patients treated in the same centers, who did not undergo parathyroidectomy was selected after matching for age, sex, and dialysis vintage. Results: From 82 Dialysis units in Italy, we prospectively collected data of 257 prevalent patients who underwent parathyroidectomy (age 58.2 ± 12.8 years; M/F: 44%/56%, dialysis vintage: 15.5 ± 8.4 years) and of 418 control patients who did not undergo parathyroidectomy (age 60.3 ± 14.4 years; M/F 44%/56%; dialysis vintage 11.2 ± 7.6 y). The survival rate was higher in the group that underwent parathyroidectomy (Kaplan–Meier log rank test = 0.002). Univariable analysis (HR 0.556, CI: 0.387–0.800, p= 0.002) and multivariable analysis (HR 0.671, CI:0.465–0.970, p= 0.034), identified parathyroidectomy as a protective factor of overall survival. The prevalence of patients at KDOQI targets for PTH was lower in patients who underwent parathyroidectomy compared to controls (PTX vs non-PTX: PTH &lt; 150 pg/ml: 59% vs 21%, p= 0.001; PTH at target: 18% vs 37% p= 0.001; PTH > 300 pg/ml 23% vs 42% p= 0.001). The control group received more intensive medical treatment with higher prevalence of vitamin D (65% vs 41%, p= 0.0001), calcimimetics (34% vs 14%, p= 0.0001) and phosphate binders (77% vs 66%, p= 0.002). Conclusions: Our data suggest that parathyroidectomy is associated with survival rate at 36 months, independently of biochemical control. Lower exposure to high PTH levels could represent an advantage in the long term. Graphical abstract:

We assessed the efficacy and safety of the oral glucagon-like peptide-1 analogue, semaglutide 50 mg, taken once per day versus placebo for the treatment of overweight or obesity in adults without type 2 diabetes.

Purpose To report a case of possible multi-district thromboembolic event involving the eye of a patient with several cardiovascular risk factors, following a second inoculation of SARS-CoV-2 m-RNA based vaccine.Case-report A 60-year-old man presented with blurred vision in the left eye lasting 1 month but started within 24 hours from the 2nddose of BNT162b2 vaccine inoculation. He also reported a long-lasting but self-limiting priapism which started about 4 h after the vaccination. Patient's medical history included: acute lymphoblastic leukemia, treated with chemotherapy and HLA-identical sibling donor transplant 18 months earlier; subsequent cytomegalovirus posterior outer retinal necrosis (PORN) resolved with antiviral treatment; type II diabetes and erectile dysfunction. Ocular examination of the affected eye revealed vitreous hemorrhage which limited the observation of details of the fundus. After a 2-week follow-up without any clinical improvement, parsplana vitrectomy (PPV) with cataract extraction was performed. Surgical aspiration of a large preretinal hemorrhage revealed intraretinal flame-shaped hemorrhages and some cotton wool spots. Further intraoperative examination and post-operative fluorescein angiography excluded the rhegmatogenaous and the neovascular origin of the intraocular bleeding.Conclusions Due to the several predisposing factors such as diabetes, aspirin assumption, history of blood dyscrasia and infectious retinitis, the relationship between the acute intraocular bleeding and the BNT162b2 inoculation remains difficult to ascertain in this patient. However, the occurrence of lasting priapism and vitreous hemorrhage within 24 h from the vaccination is a critical event which deserves to be mentioned.

ESB1609 is a small‐molecule sphingosine‐1‐phosphate‐5 receptor–selective agonist designed to restore lipid homeostasis by promoting cytosolic egress of sphingosine‐1‐phosphate to reduce abnormal levels of ceramide and cholesterol in disease. A phase 1 study was conducted in healthy volunteers to determine the safety, tolerability, and pharmacokinetics of ESB1609. Following single oral doses, ESB1609 demonstrated linear pharmacokinetics in plasma and cerebrospinal fluid (CSF) for formulations containing sodium laurel sulfate. Plasma and CSF median time to maximum drug concentration (tmax) were reached by 4–5 hours and 6–10 hours, respectively. The delay in achieving tmaxin CSF relative to plasma, likely due to the high protein binding of ESB1609, was also observed in 2 rat studies. Continuous CSF collection via indwelling catheters confirmed that a highly protein‐bound compound is measurable and established the kinetics of ESB1609 in human CSF. Mean plasma terminal elimination half‐lives ranged from 20.2 to 26.8 hours. The effect of either a high‐fat or standard meal increased maximum plasma concentration and area under the concentration‐time curve from time 0 to infinity compared to the fasted state by 2.42–4.34‐fold higher, but tmaxand half‐life remained the same irrespective of fed state. ESB1609 crosses the blood‐brain barrier with CSF:plasma ratios ranging between 0.04% and 0.07% across dose levels. ESB1609 demonstrated a favorable safety and tolerability profile at exposures expected to be efficacious.

ABSTRACTNickel-based coatings are widely used as thermal barriers in several sectors thanks to their remarkable corrosion and wear resistance and outstanding stability at high temperatures. Recently, Ni coatings, produced with thermal spraying and vacuum techniques, have been investigated for solar power energy applications. In the present manuscript, low-pressure cold spray (LPCS) was used to deposit pure Nickel onto a steel substrate. The influence of gas temperature, nozzle stand-off distance, and advancing speed on morphological and mechanical properties were studied. The optimal deposition conditions were derived by ANOVA analysis. The hardness and the adhesion strength were approximately 160 HV and 26 MPa, respectively. The highest thickness obtained under the optimised deposition with a single pass was around 900 µm.

Nickel-based coatings are widely used as thermal barriers in several sectors thanks to their remarkable corrosion and wear resistance and outstanding stability at high temperatures. Recently, Ni coatings, produced with thermal spraying and vacuum techniques, have been investigated for solar power energy applications. In the present manuscript, low-pressure cold spray (LPCS) was used to deposit pure Nickel onto a steel substrate. The influence of gas temperature, nozzle stand-off distance, and advancing speed on morphological and mechanical properties were studied. The optimal deposition conditions were derived by ANOVA analysis. The hardness and the adhesion strength were approximately 160 HV and 26 MPa, respectively. The highest thickness obtained under the optimised deposition with a single pass was around 900 µm.

Observational studies suggest that bariatric–metabolic surgery might greatly improve non-alcoholic steatohepatitis (NASH). However, the efficacy of surgery on NASH has not yet been compared with the effects of lifestyle interventions and medical therapy in a randomised trial.

Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated individuals with severe obesity (BMI > 40 kg/m2) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60–1.94). We also conducted a prospective longitudinal study of a cohort of 28 individuals with severe obesity compared to 41 control individuals with normal BMI (BMI 18.5–24.9 kg/m2). We found that 55% of individuals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of individuals with normal BMI (P= 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for individuals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of individuals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in individuals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies.

Long-term remission of type 2 diabetes following lifestyle intervention or pharmacotherapy, even in patients with mild disease, is rare. Long-term remission following metabolic surgery however, is common and occurs in 23% to 98% depending on disease severity and type of surgery. Remission after surgery is associated with excellent glycemic control without reliance on pharmacotherapy, improvements in quality of life, and major reductions in microvascular and macrovascular complications. For patients with type 2 diabetes, early intervention with metabolic surgery, when beta cell function still remains intact, provides the greatest probability of long-term remission as high as 90% or more.

This brief proposes a new approach based on a tiny neural network to convert Pulse Density Modulation (PDM) signals acquired from digital Micro-Electro-Mechanical System (MEMS) microphones into the standard Pulse Code Modulation (PCM) format for any further digital audio processing. The proposed approach allows for a compact and ultra-low-power hardware implementation of the conversion, suitable for ultra tinyML Key Word Spotting (KWS) applications, closely coupled with the sensor itself and tightly coupled with a neural network classifier. The converter achieves a signal-to-noise ratio value of 48 dB, which enables KWS accuracy of 89% over 12 classes. Implementation on a Xilinx Artix-7 FPGA results in 917 LUTs, 361 FFs, and 182 $\mu \text{W}$ Dynamic Power (DynP) consumption. By targeting the TSMC 0.13 $\mu \text{m}$ CMOS technology, the synthesis reports an area occupation of 0.086 mm2 and a DynP of 128.7 $\mu \text{W}$ /MHz. These results enable the integration of the proposed design into the CMOS circuitry closely coupled with the MEMS microphone.

The meshing technique represents the capability to discretize the domain of interest, to fit the real physical continuum in the best possible way. The most used approach is the finite-element method (FEM), a numerical method to solve partial differential equations. To overcome the classical issues presented by FEM, other models are investigated. The goal is to allow the problem domain to be discretized by elements represented by arbitrary polygons, which can be concave and convex. Moreover, different polynomial consistency is sought within these methods with the possibility to handle non-conforming discretizations, mainly for local refinement and so on. This work aims to present the new adaptive elements, which are finite elements based on Carrera unified formulation, to demonstrate that all the previous capabilities can be done with these new elements, with easy implementation of the relative model. First, a classical patch test is done to investigate the mesh distortion sensitivity. Then, different study cases are presented with more complex meshes combining very distorted concave and convex elements.

The gait patterns of stroke survivors become slow and metabolically inefficient as a result of muscle weakness and low weight-bearing capacity. Exoskeletons and assistive robots can improve gait kinematics and energetics. However, the use of these powered devices may cause a reliance on the device itself that results in limited lasting improvement of the paretic leg function. Specifically, there exists a need to strengthen and train the response of weak ankle muscles, such as the soleus muscle, in stroke survivors. Impaired activation of the soleus muscle induces unnatural gait kinematics and reduced propulsion. The mechanical modulation of the soleus muscle can improve its loading response and enhance gait performance after a stroke. This paper develops a closed-loop feedback controller to manipulate the ankle joint dynamics to mechanically control the soleus muscle response using a motorized ankle orthosis. The control method is inspired by backstepping control techniques and developed to connect the ankle joint angular velocity and the soleus muscle response during the stance phase of walking. The tracking objective is quantified using an integral-like muscle error between the desired soleus response and the actual muscle response, which is measurable using surface electromyography (EMG). The closed-loop electric motor controller is designed to apply ankle perturbations exploiting the backstepping error and an adaptive control term to cope with uncertain parameters that satisfy the linear-in-the-parameters property. A switching signal is developed using heel and toe ground reaction forces to strategically perturb the ankle and target the soleus muscle loading response in real-time during the mid-late stance phase of walking. A Lyapunov-based stability analysis is used to guarantee a globally uniformly ultimately bounded (GUUB) tracking result.

Despite its integral role in hunting industries, venison production, and safeguarding wildlife populations worldwide, captive cervid breeding creates challenges related chronic wasting disease (CWD) transmission. Thus, it is vital that wildlife managers understand stakeholders' perceptions of the relationship between captive deer and CWD, and its implications for CWD management. We used mail-based and online surveys to assess Texas hunter and landowner perceptions (n = 984) of risks associated with CWD in free-range and captive deer populations, as well as their willingness to participate in actions that help prevent the spread of CWD. Risk perceptions related to the seriousness and susceptibility of CWD among captive deer were higher than free-range deer, while concern was lower. Additionally, increased willingness to engage in preventative actions was more frequently predicted by risk perceptions related to free-range deer than captive deer. These results can be used to help agencies improve their decision-making regarding CWD recommendations and policies.

Transportation electrification is leading to an impressive development of electric drives (eDrives) using either synchronous- (SM) or induction- (IM) motors. However, these eDrive solutions need high-performance torque controllers that must be easy to tune and able to deal with saturated machines. Besides, the torque regulation must be linear for the entire operating speed range, including deep flux-weakening (FW) operation with maximum torque per volt (MTPV) limitation. According to the current state-of-the-art, the torque controllers for traction applications are mainly based on control schemes like current vector control (CVC), direct torque control (DTC), or the more recent direct flux vector control (DFVC). However, these solutions employ inner control loops whose performance depends on the machine's inductances, thus requiring the execution of demanding tuning procedures to adapt the control parameters to the machine's operating point. Moreover, CVC-based torque controllers sometimes rely on demanding multi-dimensional calibrated maps to linearize the torque regulation and simultaneously perform FW operation with MTPV. In contrast with the torque control solutions mentioned above, this article proposes a unified torque controller for ac motors based on inner flux- and load angle- control loops since their performance is independent of the machine's inductances, i.e., magnetic saturation phenomena. Also, the torque linearization relies on a simple calibrated map providing maximum torque production under inverter current- and voltage- constraints. Experimental results are presented for four different eDrives using both SMs and IM, validating the unifying feature and demonstrating the high dynamic performance of the proposed torque controller.

ObjectiveLittle is known about how lower respiratory tract infections (LRTIs) before chronic obstructive pulmonary disease (COPD) are associated with future exacerbations and mortality. We investigated this association in patients with COPD in England.MethodsClinical Practice Research Datalink Aurum, Hospital Episode Statistics and Office of National Statistics data were used. Start of follow-up was patient’s first ever COPD diagnosis date and a 1-year baseline period prior to start of follow-up was used to find mild LRTIs (general practice (GP) events/no antibiotics), moderate LRTIs (GP events+antibiotics) and severe LRTIs (hospitalised). Patients were categorised as having: none, 1 mild only, 2+ mild only, 1 moderate, 2+ moderate and 1+ severe. Negative binomial regression modelled the association between baseline LRTIs and subsequent COPD exacerbations and Cox proportional hazard regression was used to investigate mortality.ResultsIn 215 234 patients with COPD, increasing frequency and severity of mild and moderate LRTIs were associated with increased rates of subsequent exacerbations compared with no recorded LRTIs (1 mild adjusted IRR 1.16, 95% CI 1.14 to 1.18, 2+ mild IRR 1.51, 95% CI 1.46 to 1.55, 1 moderate IRR 1.81, 95% CI 1.78 to 1.85, 2+ moderate IRR 2.55, 95% CI 2.48 to 2.63). Patients with 1+ severe LRTI (vs no baseline LRTIs) also showed an increased rate of future exacerbations (adjusted IRR 1.75, 95% CI, 1.70 to 1.80). This pattern of association was similar for risk of all-cause and COPD-related mortality; however, patients with 1+ severe LRTIs had the highest risk of all-cause and COPD mortality.ConclusionIncreasing frequency and severity of LRTIs prior to COPD diagnosis were associated with increasing rates of subsequent exacerbations, and increasing risk of all-cause and COPD-related mortality.

The creation and the destruction processes (CPs and DPs) are the basis of many efficient Monte Carlo methods for estimating the unreliability of highly reliable networks on both, the static and the stochastic flow network models, for the case of independent components. Some of these methods are based on the splitting variance reduction techniques. Due to the splitting basic mechanism, they operate over CP. Here, we propose a splitting-based Monte Carlo method, using the Marshall–Olkin copula for the case of nonindependent components. This proposal operates on the DP, because the Marshall–Olkin copula model over networks is quite related—and somehow similar—to DP, which is unusual but here necessary. Before addressing the proposal, the article presents a review of the methods based on CP and DP. At the end, a comparative experimental analysis shows the efficiency of the proposed approach.

ObjectiveClinical diagnosis and approval of new medications for non-alcoholic steatohepatitis (NASH) require invasive liver biopsies. The aim of our study was to identify non-invasive biomarkers of NASH and/or liver fibrosis.DesignThis multicentre study includes 250 patients (discovery cohort, n=100 subjects (Bariatric Surgery Versus Non-alcoholic Steato-hepatitis - BRAVES trial); validation cohort, n=150 (Liquid Biopsy for NASH and Liver Fibrosis - LIBRA trial)) with histologically proven non-alcoholic fatty liver (NAFL) or NASH with or without fibrosis. Proteomics was performed in monocytes and hepatic stellate cells (HSCs) with iTRAQ-nano- Liquid Chromatography - Mass Spectrometry/Mass Spectrometry (LC-MS/MS), while flow cytometry measured perilipin-2 (PLIN2) and RAB14 in peripheral blood CD14+CD16−monocytes. Neural network classifiers were used to predict presence/absence of NASH and NASH stages. Logistic bootstrap-based regression was used to measure the accuracy of predicting liver fibrosis.ResultsThe algorithm for NASH using PLIN2 mean florescence intensity (MFI) combined with waist circumference, triglyceride, alanine aminotransferase (ALT) and presence/absence of diabetes as covariates had an accuracy of 93% in the discovery cohort and of 92% in the validation cohort. Sensitivity and specificity were 95% and 90% in the discovery cohort and 88% and 100% in the validation cohort, respectively.The area under the receiver operating characteristic (AUROC) for NAS level prediction ranged from 83.7% (CI 75.6% to 91.8%) in the discovery cohort to 97.8% (CI 95.8% to 99.8%) in the validation cohort.The algorithm including RAB14 MFI, age, waist circumference, high-density lipoprotein cholesterol, plasma glucose and ALT levels as covariates to predict the presence of liver fibrosis yielded an AUROC of 95.9% (CI 87.9% to 100%) in the discovery cohort and 99.3% (CI 98.1% to 100%) in the validation cohort, respectively. Accuracy was 99.25%, sensitivity 100% and specificity 95.8% in the discovery cohort and 97.6%, 99% and 89.6% in the validation cohort. This novel biomarker was superior to currently used FIB4, non-alcoholic fatty liver disease fibrosis score and aspartate aminotransferase (AST)-to-platelet ratio and was comparable to ultrasound two-dimensional shear wave elastography.ConclusionsThe proposed novel liquid biopsy is accurate, sensitive and specific in diagnosing the presence and severity of NASH or liver fibrosis and is more reliable than currently used biomarkers.Clinical trialsDiscovery multicentre cohort: Bariatric Surgery versus Non-Alcoholic Steatohepatitis, BRAVES, ClinicalTrials.gov identifier: NCT03524365.Validation multicentre cohort: Liquid Biopsy for NASH and Fibrosis, LIBRA, ClinicalTrials.gov identifier: NCT04677101.

Precision material design directed by cell biological processes represents a frontier in developing clinically translatable regenerative technologies. While understanding cell‐material interactions on multipotent progenitor cells yields insights on target tissue differentiation, equally if not more important is the quantification of indirect multicellular interactions. In this work, the relationship of two material properties, phosphate content and stiffness, of a nanoparticulate mineralized collagen glycosaminoglycan scaffold (MC‐GAG) in the expression of an endogenous anti‐osteoclastogenic secreted protein, osteoprotegerin (OPG) by primary human mesenchymal stem cells (hMSCs) is evaluated. The phosphate content of MC‐GAG requires the type III sodium phosphate symporter PiT‐1/SLC20A1 for OPG expression, correlating with β‐catenin downregulation, but is independent of the effects of phosphate ion on osteogenic differentiation. Using three stiffness MC‐GAG variants that do not differ significantly by osteogenic differentiation, it is observed that the softest material elicited ≈1.6–2 times higher OPG expression than the stiffer materials. Knockdown of the mechanosensitive signaling axis of YAP, TAZ, β‐catenin and combinations thereof in hMSCs on MC‐GAG demonstrates that β‐catenin downregulation increases OPG expression by 1.5‐fold. Taken together, these data constitute a roadmap for material properties that can used to suppress osteoclast activation via osteoprotegerin expression separately from the anabolic processes of osteogenesis. The next generation in strategies for regenerative material design is one that evolves from stochastic to directed design via the integration of precision in modulating multicellular biological responses with precision in tuning of material properties. The current work defines the impact of two material properties in coordinating anabolic and catabolic aspects of bone homeostasis, providing a roadmap for future material modifications.

Obesity is a global pandemic that is causally linked to many life-threatening diseases. Apart from some rare genetic conditions, the biological drivers of overeating and reduced activity are unclear. Here, we show that neurotensin-expressing neurons in the mouse interstitial nucleus of the posterior limb of the anterior commissure (IPAC), a nucleus of the central extended amygdala, encode dietary preference for unhealthy energy-dense foods. Optogenetic activation of IPACNtsneurons promotes obesogenic behaviors, such as hedonic eating, and modulates food preference. Conversely, acute inhibition of IPACNtsneurons reduces feeding and decreases hedonic eating. Chronic inactivation of IPACNtsneurons recapitulates these effects, reduces preference for sweet, non-caloric tastants and, furthermore, enhances locomotion and energy expenditure; as a result, mice display long-term weight loss and improved metabolic health and are protected from obesity. Thus, the activity of a single neuronal population bidirectionally regulates energy homeostasis. Our findings could lead to new therapeutic strategies to prevent and treat obesity.

•EQIP is an innovative quality improvement project for surgical training programs.•Thirty-six surgical training programs with 1264 trainees and 1500 faculty members were included in the dataset.•The APDS has proved the concept that a highly secure database for the purpose of continuous risk-adjusted quality improvement in surgical education can be successfully deployed.•Risk-adjusted multivariable analysis suggests that increased time in a technical skills lab was associated with increased success on the ABS's Qualifying Examination, alone.•Increased time in a technical skills lab and the presence of a formal teaching curriculum were associated with increased success on both the ABS's Qualifying and Certifying Examination.•Program type may be of some consequence in predicting success on the Qualifying Examination.

FUSIC haemodynamics (HD) – the latest Focused Ultrasound in Intensive Care (FUSIC) module created by the Intensive Care Society (ICS) – describes a complete haemodynamic assessment with ultrasound based on ten key clinical questions: 1. Is stroke volume abnormal? 2. Is stroke volume responsive to fluid, vasopressors or inotropes? 3. Is the aorta abnormal? 4. Is the aortic valve, mitral valve or tricuspid valve severely abnormal? 5. Is there systolic anterior motion of the mitral valve? 6. Is there a regional wall motion abnormality? 7. Are there features of raised left atrial pressure? 8. Are there features of right ventricular impairment or raised pulmonary artery pressure? 9. Are there features of tamponade? 10. Is there venous congestion? FUSIC HD is the first system of its kind to interrogate major cardiac, arterial and venous structures to direct time-critical interventions in acutely unwell patients. This article explains the rationale for this accreditation, outlines the training pathway and summarises the ten clinical questions. Further details are included in an online supplementary appendix.

To prospectively describe the epidemiology and long‐term outcome of childhood‐acquired hepatitis C virus (HCV) infection in a large cohort of children followed at a single center. All children with chronic HCV infection followed at the Liver Unit of our tertiary Hospital in Florence (Italy) from January 1, 1988, to September 30, 2021, were included in the analysis. The final sample consisted of 163 children (median age at enrollment 4 years, interquartile range (IQR): 10; median age at last follow‐up 14 years, IQR: 7). The median duration of follow‐up was 86 months (IQR: 112). One hundred twenty‐five children were vertically infected and 26 acquired the infection horizontally. Twenty‐six of the 125 children who were vertically infected (20.8%) underwent spontaneous clearance of HCV RNA at a median age of 4 years (IQR: 2), whereas all the others remained persistently viremic. One patient was diagnosed with cirrhosis; 2 presented clinically detectable extrahepatic manifestations (chronic urticaria). Thirty‐two children (19.6%) received antiviral therapy: 8 out of 32 (25%) were treated with pegylated‐interferon alfa‐2b [sustained virological response (SVR) 24 weeks after the end of treatment in 7/8]; 24 out of 32 (75%) were treated with direct‐acting antivirals (SVR 12 weeks after the end of treatment in 23/24). The present study describes the largest cohort of children with chronic HCV infection prospectively evaluated with a long follow‐up at a single center. HCV infection in children is often a chronic infection that can be cured with modern antiviral therapy. Early treatment could prevent the development of advanced liver disease.