Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671).

BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. The RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment-naïve advanced TC. They received ramucirumab, carboplatin and paclitaxel for six cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Centralized radiologic review was carried out. RESULTS: From November 2018 to June 2023, 52 patients were screened and 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. The Eastern Cooperative Oncology Group performance status was 0 in 68.5% and 1 in 31.4% of patients. At the present analysis carried out some months after the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95% confidence interval (CI) 63.1% to 91.6%]. At the centralized radiological review of 33/35 assessable patients, ORR was 57.6% (95% CI 39.2% to 74.5%). After a median follow-up of 31.6 months, median PFS was 18.1 months (95% CI 10.8-52.3 months) and median OS was 43.8 months (95% CI 31.9 months-not reached). Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE ≥ grade 3. CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.

Public Education Can Be Used to Increase Support for Equity in Cannabis Policy.

Objectives: States that are legalizing cannabis for adult use are increasingly focused on equity, with the goal of repairing some of the harm caused by the War on Drugs. This study explains and describes the emphasis states are placing on equity and assesses whether public education can be used to increase public support for equity-focused cannabis policies. Methods: We conducted an online survey of 893 New Jersey adults in August and September of 2021, just as state's Cannabis Regulatory Commission was publishing the first set of regulations for the legal sale and use of cannabis for adults age 21 and older. The study included an experimental design, in which half of respondents viewed an educational message about equity-focused cannabis policies before answering survey questions, and the other half did not. Results: Few participants (24.9%) were familiar with the concept of equity in cannabis policy, and a substantial proportion-from about 20% to 35%-provided a "neutral" or "don't know" response when asked about support for specific policies. Exposure to an educational message was associated with greater perceived importance of equity in cannabis policy (p < 0.05) and greater support for equity-focused policies. Specifically, participants who saw an educational message had greater agreement that New Jersey should provide priority licensing (p < 0.01) and grants (p < 0.001) to people who have been arrested for cannabis, and who now want to participate in the legal cannabis industry. Conclusions: Cannabis regulators, public health professionals, and people working to advance racial justice may be able to advance state equity goals and remedy some of the harm from the War on Drugs by expanding public education campaigns to include equity messages.

Functional neurological restoration of amputated peripheral nerve using biohybrid regenerative bioelectronics.

The development of neural interfaces with superior biocompatibility and improved tissue integration is vital for treating and restoring neurological functions in the nervous system. A critical factor is to increase the resolution for mapping neuronal inputs onto implants. For this purpose, we have developed a new category of neural interface comprising induced pluripotent stem cell (iPSC)-derived myocytes as biological targets for peripheral nerve inputs that are grafted onto a flexible electrode arrays. We show long-term survival and functional integration of a biohybrid device carrying human iPSC-derived cells with the forearm nerve bundle of freely moving rats, following 4 weeks of implantation. By improving the tissue-electronics interface with an intermediate cell layer, we have demonstrated enhanced resolution and electrical recording in vivo as a first step toward restorative therapies using regenerative bioelectronics.

A qualitative analysis of family support for adolescent HIV care in South Africa.

Compared to other age groups, South African adolescents living with HIV (ALWH) have the lowest rates of retention in HIV care and medication adherence. While previous research suggests that familial social support may improve treatment retention and adherence within this population, we know little about the influence of differential types of social support on HIV-related outcomes. Thus, the purpose of this study is to qualitatively characterize the influence of type of familial social support on treatment retention and adherence among ALWH. We interviewed adolescents living with perinatally-acquired HIV (n = 20), their caregivers (n = 19), and community stakeholders (n = 20) in Cape Town, South Africa. Data were coded using deductive and inductive approaches to content analysis. We identified four types of familial social support: instrumental, appraisal, emotional, and informational support. Families provided instrumental support through logistical assistance, including transportation to appointments and pill reminders. Families also provided both emotional support and appraisal support, encouraging ALWH to adhere to their medication regimens by reflecting upon its importance to their futures. For informational support, families often educated ALWH about their HIV status and strategies for disease self-management. In characterizing familial social support, our findings highlight potential targets of future interventions to improve HIV-related outcomes among ALWH.

Hybrid fabrication of multimodal intracranial implants for electrophysiology and local drug delivery.

New fabrication approaches for mechanically flexible implants hold the key to advancing the applications of neuroengineering in fundamental neuroscience and clinic. By combining the high precision of thin film microfabrication with the versatility of additive manufacturing, we demonstrate a straight-forward approach for the prototyping of intracranial implants with electrode arrays and microfluidic channels. We show that the implant can modulate neuronal activity in the hippocampus through localized drug delivery, while simultaneously recording brain activity by its electrodes. Moreover, good implant stability and minimal tissue response are seen one-week post-implantation. Our work shows the potential of hybrid fabrication combining different manufacturing techniques in neurotechnology and paves the way for a new approach to the development of multimodal implants.

Psychological impact of abnormally invasive placenta: an underestimated and hidden morbidity.

OBJECTIVES: To evaluate anxiety and psychological impact of abnormally invasive placenta (AIP) diagnosis during pregnancy. METHODS: A cross-sectional survey study was performed to assess the psychological response of pregnant women with an antenatally AIP diagnosis. The psychological impact was measured through a visual analogue scale (VAS) for anxiety, which ranged from 0 (not at all anxious) to 100 (extremely anxious) and was referred to three questions: (1) How anxious were you the first time they counselled you about AIP?; (2) How anxious were you the day of the planned cesarean delivery in terms of morbidity/mortality?; (3) How anxious were you in terms of future sexual activities? RESULTS: 48 singleton pregnancies that underwent planned cesarean hysterectomy for AIP, met the inclusion criteria and were surveyed for the study. Mean VAS was 41.6 ± 25.6, with 47.9% of women with VAS >50 for question 1 (p=0.015). Mean VAS was 52.9 ± 19.1, with 75.0% of women with VAS >50 for question 2 (p=0.02). Mean VAS was 49.6 ± 20.4, with 83.3% of women with VAS >50 for question 3 (p=0.006). CONCLUSIONS: More than half of pregnant women with an antenatally AIP diagnosis reported a high VAS score regarding anxiety, in particular when morbidity/mortality and long-term consequences on sexual activities were analyzed. Our findings could be used to formulate timely psychological interventions to improve mental health and psychological resilience in women with AIP.

Does Type of Social Support Influence Medication Adherence Among South African Adolescents Living With HIV? A Quantitative Analysis of Pilot Data.

ABSTRACT: Adolescents living with HIV often experience worse medication adherence than older and younger individuals living with HIV. One factor that may mitigate poor adherence is social support. However, few studies have examined the influence of specific social support constructs on HIV outcomes like medication adherence. In response to this gap, we performed bivariate analyses using data from 104 adolescents living with HIV in Cape Town, South Africa to understand the relationship between three types of social support (emotional, informational, and instrumental support) and four HIV-related outcomes: adherence self-efficacy, last recorded CD4+ count, last recorded viral load, and adherence to clinic appointments in the past year. We found small positive associations between two social support types (emotional and informational support) and adherence self-efficacy, with no other statistically significant associations. In light of our small sample size, future studies should seek to understand the differential effects of specific types of social support on HIV-related outcomes to better inform interventions for adolescents living with HIV.

Sensitive and robust chemical detection using an olfactory brain-computer interface.

When it comes to detecting volatile chemicals, biological olfactory systems far outperform all artificial chemical detection devices in their versatility, speed, and specificity. Consequently, the use of trained animals for chemical detection in security, defense, healthcare, agriculture, and other applications has grown astronomically. However, the use of animals in this capacity requires extensive training and behavior-based communication. Here we propose an alternative strategy, a bio-electronic nose, that capitalizes on the superior capability of the mammalian olfactory system, but bypasses behavioral output by reading olfactory information directly from the brain. We engineered a brain-computer interface that captures neuronal signals from an early stage of olfactory processing in awake mice combined with machine learning techniques to form a sensitive and selective chemical detector. We chronically implanted a grid electrode array on the surface of the mouse olfactory bulb and systematically recorded responses to a large battery of odorants and odorant mixtures across a wide range of concentrations. The bio-electronic nose has a comparable sensitivity to the trained animal and can detect odors on a variable background. We also introduce a novel genetic engineering approach that modifies the relative abundance of particular olfactory receptors in order to improve the sensitivity of our bio-electronic nose for specific chemical targets. Our recordings were stable over months, providing evidence for robust and stable decoding over time. The system also works in freely moving animals, allowing chemical detection to occur in real-world environments. Our bio-electronic nose outperforms current methods in terms of its stability, specificity, and versatility, setting a new standard for chemical detection.

Electronics with shape actuation for minimally invasive spinal cord stimulation.

Spinal cord stimulation is one of the oldest and most established neuromodulation therapies. However, today, clinicians need to choose between bulky paddle-type devices, requiring invasive surgery under general anesthetic, and percutaneous lead-type devices, which can be implanted via simple needle puncture under local anesthetic but offer clinical drawbacks when compared with paddle devices. By applying photo- and soft lithography fabrication, we have developed a device that features thin, flexible electronics and integrated fluidic channels. This device can be rolled up into the shape of a standard percutaneous needle then implanted on the site of interest before being expanded in situ, unfurling into its paddle-type conformation. The device and implantation procedure have been validated in vitro and on human cadaver models. This device paves the way for shape-changing bioelectronic devices that offer a large footprint for sensing or stimulation but are implanted in patients percutaneously in a minimally invasive fashion.

Fifty-one years with an aortic valve prosthesis despite suboptimal anticoagulation: half a century with the Smeloff-Cutter valve.

This case report describes an unusual case of a 69-year-old man who had an aortic valve replacement with the Smeloff-Cutter aortic mechanical prosthesis for aortic valve regurgitation at the age of 18 years. Echocardiography revealed a well-suited and well-functioning mechanical prosthesis. Even though the patient did not take any anticoagulant therapy or anti-platelets agent for 12 years, he was in surprisingly good health. To the best of our knowledge, this is the first time a mechanical 'ball-in-cage' valve prosthesis has lasted for such a long time without complications, although the patient has not been compliant with the anticoagulant therapy for 12 consecutive years.

Microelectrode Arrays for Simultaneous Electrophysiology and Advanced Optical Microscopy.

Advanced optical imaging techniques address important biological questions in neuroscience, where structures such as synapses are below the resolution limit of a conventional microscope. At the same time, microelectrode arrays (MEAs) are indispensable in understanding the language of neurons. Here, the authors show transparent MEAs capable of recording action potentials from neurons and compatible with advanced microscopy. The electrodes are made of the conducting polymer poly(3,4-ethylenedioxythiophene) doped with polystyrene sulfonate (PEDOT:PSS) and are patterned by optical lithography, ensuring scalable fabrication with good control over device parameters. A thickness of 380 nm ensures low enough impedance and >75% transparency throughout the visible part of the spectrum making them suitable for artefact-free recording in the presence of laser illumination. Using primary neuronal cells, the arrays record single units from multiple nearby sources with a signal-to-noise ratio of 7.7 (17.7 dB). Additionally, it is possible to perform calcium (Ca2+) imaging, a measure of neuronal activity, using the novel transparent electrodes. Different biomarkers are imaged through the electrodes using conventional and super-resolution microscopy (SRM), showing no qualitative differences compared to glass substrates. These transparent MEAs pave the way for harnessing the synergy between the superior temporal resolution of electrophysiology and the selectivity and high spatial resolution of optical imaging.

Ultrasound-guided venipuncture for implantation of cardiac implantable electronic devices: A single-center, retrospective study.

BACKGROUND: The venous access for the insertion of permanent leads of cardiac implantable electronic devices is often achieved by venous cutdown of the cephalic vein, or by "blind" puncture of the subclavian vein using anatomical landmarks, or by fluoroscopy-assisted methods. METHODS: We have retrospectively analyzed our clinical experience to verify the feasibility, the safety, and efficacy of the adoption of ultrasound-guided puncture/cannulation of the axillary vein for this purpose. RESULTS: Nine hundred eighty-seven leads were placed during 548 consecutive procedures, accessing the axillary vein in the infraclavicular area using real-time ultrasound guidance. Venipuncture was successful in 99.8% of cases. The access time was 11 seconds (range 4-580). We recorded three cases of pneumothorax (0.5%), but no hemothorax and no hemo-mediastinum. The incidence of local hematoma was 2.1% (12 cases). No injury to the brachial plexus or to the phrenic nerve was recorded. In a follow-up of 33 months (range 16-39), we observed no cases of "subclavian crush syndrome" (damage of the leads at the level of the thoracic inlet), and the rate of pocket infection/infective endocarditis was 0.7%. CONCLUSION: In our experience, ultrasound-guided puncture/cannulation of the axillary vein for implantation of permanent leads is feasible, effective, and safe. It might be considered as a first option for this procedure.

When Bio Meets Technology: Biohybrid Neural Interfaces.

The development of electronics capable of interfacing with the nervous system is a rapidly advancing field with applications in basic science and clinical translation. Devices containing arrays of electrodes can be used in the study of cells grown in culture or can be implanted into damaged or dysfunctional tissue to restore normal function. While devices are typically designed and used exclusively for one of these two purposes, there have been increasing efforts in developing implantable electrode arrays capable of housing cultured cells, referred to as biohybrid implants. Once implanted, the cells within these implants integrate into the tissue, serving as a mediator of the electrode-tissue interface. This biological component offers unique advantages to these implant designs, providing better tissue integration and potentially long-term stability. Herein, an overview of current research into biohybrid devices, as well as the historical background that led to their development are provided, based on the host anatomical location for which they are designed (CNS, PNS, or special senses). Finally, a summary of the key challenges of this technology and potential future research directions are presented.

A bilayered PVA/PLGA-bioresorbable shuttle to improve the implantation of flexible neural probes.

OBJECTIVE: Neural electrophysiology is often conducted with traditional, rigid depth probes. The mechanical mismatch between these probes and soft brain tissue is unfavorable for tissue interfacing. Making probes compliant can improve biocompatibility, but as a consequence, they become more difficult to insert into the brain. Therefore, new methods for inserting compliant neural probes must be developed. APPROACH: Here, we present a new bioresorbable shuttle based on the hydrolytically degradable poly(vinyl alcohol) (PVA) and poly(lactic-co-glycolic acid) (PLGA). We show how to fabricate the PVA/PLGA shuttles on flexible and thin parylene probes. The method consists of PDMS molding used to fabricate a PVA shuttle aligned with the probe and to also impart a sharp tip necessary for piercing brain tissue. The PVA shuttle is then dip-coated with PLGA to create a bi-layered shuttle. MAIN RESULTS: While single layered PVA shuttles are able to penetrate agarose brain models, only limited depths were achieved and repositioning was not possible due to the fast degradation. We demonstrate that a bilayered approach incorporating a slower dissolving PLGA layer prolongs degradation and enables facile insertion for at least several millimeters depth. Impedances of electrodes before and after shuttle preparation were characterized and showed that careful deposition of PLGA is required to maintain low impedance. Facilitated by the shuttles, compliant parylene probes were also successfully implanted into anaesthetized mice and enabled the recording of high quality local field potentials. SIGNIFICANCE: This work thereby presents a solution towards addressing a key challenge of implanting compliant neural probes using a two polymer system. PVA and PLGA are polymers with properties ideal for translation: commercially available, biocompatible with FDA-approved uses and bioresorbable. By presenting new ways to implant compliant neural probes, we can begin to fully evaluate their chronic biocompatibility and performance compared to traditional, rigid electronics.

Molecularly selective nanoporous membrane-based wearable organic electrochemical device for noninvasive cortisol sensing.

Wearable biosensors have emerged as an alternative evolutionary development in the field of healthcare technology due to their potential to change conventional medical diagnostics and health monitoring. However, a number of critical technological challenges including selectivity, stability of (bio)recognition, efficient sample handling, invasiveness, and mechanical compliance to increase user comfort must still be overcome to successfully bring devices closer to commercial applications. We introduce the integration of an electrochemical transistor and a tailor-made synthetic and biomimetic polymeric membrane, which acts as a molecular memory layer facilitating the stable and selective molecular recognition of the human stress hormone cortisol. The sensor and a laser-patterned microcapillary channel array are integrated in a wearable sweat diagnostics platform, providing accurate sweat acquisition and precise sample delivery to the sensor interface. The integrated devices were successfully used with both ex situ methods using skin-like microfluidics and on human subjects with on-body real-sample analysis using a wearable sensor assembly.

Unexpectedly rapid evolution of mandibular shape in hominins.

Members of the hominins - namely the so-called 'australopiths' and the species of the genus Homo - are known to possess short and deep mandibles and relatively small incisors and canines. It is commonly assumed that this suite of traits evolved in early members of the clade in response to changing environmental conditions and increased consumption of though food items. With the emergence of Homo, the functional meaning of mandible shape variation is thought to have been weakened by technological advancements and (later) by the control over fire. In contrast to this expectation, we found that mandible shape evolution in hominins is exceptionally rapid as compared to any other primate clade, and that the direction and rate of shape change (from the ape ancestor) are no different between the australopiths and Homo. We deem several factors including the loss of honing complex, canine reduction, and the acquisition of different diets may have concurred in producing such surprisingly high evolutionary rates. This study reveals the evolution of mandibular shape in hominins has strong morpho-functional and ecological significance attached.

An update on anesthetics and impact on the brain.

INTRODUCTION: While anesthetics are indispensable clinical tools and generally considered safe and effective, a growing concern over the potential neurotoxicity of anesthesia or specific anesthetic agents has called into question the safety of general anesthetics, especially when administered at extremes of age. Areas covered: This article reviews and updates research findings on the safety of anesthesia and anesthetics in terms of long-term neurotoxicity, with particular focus on postoperative cognitive dysfunctions, Alzheimer's disease and dementias, developing brain, post-operative depression and autism spectrum disorder. Expert opinion: Exposure to general anesthetics is potentially harmful to the human brain, and the consequent long-term cognitive deficits should be classified as an iatrogenic pathology, and considered a public health problem. The fact that in laboratory and clinical research only certain anesthetic agents and techniques, but not others, appear to be involved, raises the problem on what is the safest and the least safe anesthetic to maximize anesthesia efficiency, avoid occurrence of adverse events, and ensure patient safety. New trends in research are moving toward the theory that neuroinflammation could be the hallmark of, or could have a pivotal role in, several neurological disorders.

A Microfluidic Ion Pump for In Vivo Drug Delivery.

Implantable devices offer an alternative to systemic delivery of drugs for the treatment of neurological disorders. A microfluidic ion pump (µFIP), capable of delivering a drug without the solvent through electrophoresis, is developed. The device is characterized in vitro by delivering γ-amino butyric acid to a target solution, and demonstrates low-voltage operation, high drug-delivery capacity, and high ON/OFF ratio. It is also demonstrated that the device is suitable for cortical delivery in vivo by manipulating the local ion concentration in an animal model and altering neural behavior. These results show that µFIPs represent a significant step forward toward the development of implantable drug-delivery systems.

Organic transistor platform with integrated microfluidics for in-line multi-parametric in vitro cell monitoring.

Future drug discovery and toxicology testing could benefit significantly from more predictive and multi-parametric readouts from in vitro models. Despite the recent advances in the field of microfluidics, and more recently organ-on-a-chip technology, there is still a high demand for real-time monitoring systems that can be readily embedded with microfluidics. In addition, multi-parametric monitoring is essential to improve the predictive quality of the data used to inform clinical studies that follow. Here we present a microfluidic platform integrated with in-line electronic sensors based on the organic electrochemical transistor. Our goals are two-fold, first to generate a platform to host cells in a more physiologically relevant environment (using physiologically relevant fluid shear stress (FSS)) and second to show efficient integration of multiple different methods for assessing cell morphology, differentiation, and integrity. These include optical imaging, impedance monitoring, metabolite sensing, and a wound-healing assay. We illustrate the versatility of this multi-parametric monitoring in giving us increased confidence to validate the improved differentiation of cells toward a physiological profile under FSS, thus yielding more accurate data when used to assess the effect of drugs or toxins. Overall, this platform will enable high-content screening for in vitro drug discovery and toxicology testing and bridges the existing gap in the integration of in-line sensors in microfluidic devices.

Organic Transistor Arrays Integrated with Finger-Powered Microfluidics for Multianalyte Saliva Testing.

A compact multianalyte biosensing platform is reported, composed of an organic electrochemical transistor (OECT) microarray integrated with a pumpless "finger-powered" microfluidic, for quantitative screening of glucose, lactate, and cholesterol levels. A biofunctionalization method is designed, which provides selectivity towards specific metabolites as well as minimization of any background interference. In addition, a simple method is developed to facilitate multi-analyte sensing and avoid electrical crosstalk between the different transistors by electrically isolating the individual devices. The resulting biosensing platform, verified using human samples, offers the possibility to be used in easy-to-obtain biofluids with low abundance metabolites, such as saliva. Based on our proposed method, other types of enzymatic biosensors can be integrated into the array to achieve multiplexed, noninvasive, personalized point-of-care diagnostics.