Interdisciplinary perspectives on computed tomography in sepsis: survey among medical doctors at a large university medical center.

OBJECTIVES: This study aims to describe physicians' perspectives on the use of computed tomography (CT) in patients with sepsis. METHODS: In January 2022, physicians of a large European university medical center were surveyed using a web-based questionnaire asking about their views on the role of CT in sepsis. A total of 371 questionnaires met the inclusion criteria and were analyzed using work experience, workplace, and medical specialty of physicians as variables. Chi-square tests were performed. RESULTS: Physicians considered the ability to detect an unknown focus as the greatest benefit of CT scans in sepsis (70.9%, n = 263/371). Two clinical criteria - "signs of decreased vigilance" (89.2%, n = 331/371) and "increased catecholamine demand" (84.7%, n = 314/371) - were considered highly relevant for a CT request. Elevated procalcitonin (82.7%, n = 307/371) and lactate levels (83.6%, n = 310/371) were consistently found to be critical laboratory values to request a CT. As long as there is evidence of infection in one organ region, most physicians (42.6%, n = 158/371) would order a CT scan based on clinical assessment. Combined examination of the chest, abdomen, and pelvis was favored (34.8%, n = 129/371) in cases without clinical clues of an infection source. A time window of ≥ 1-6 h was preferred for both CT examinations (53.9%, n = 200/371) and CT-guided interventions (59.3%, n = 220/371) in patients with sepsis. CONCLUSION: Despite much consensus, there are significant differences in attitudes towards the use of CT in septic patients among physicians from different workplaces and medical specialties. Knowledge of these perspectives may improve patient management and interprofessional communication. KEY POINTS: Despite interdisciplinary consensus on the use of CT in sepsis, statistically significant differences in the responses are apparent among physicians from different workplaces and medical specialties. The detection of a previously unknown source of infection and the ability to plan interventions and/or surgery based on CT findings are considered key advantages of CT in septic patients. Timing of CT reflects the requirements of specific disciplines.

Droplet digital PCR allows vector copy number assessment and monitoring of experimental CAR T cells in murine xenograft models or approved CD19 CAR T cell-treated patients.

BACKGROUND: Genetically engineered chimeric antigen receptor (CAR) T lymphocytes are promising therapeutic tools for cancer. Four CAR T cell drugs, including tisagenlecleucel (tisa-cel) and axicabtagene-ciloleucel (axi-cel), all targeting CD19, are currently approved for treating B cell malignancies. Flow cytometry (FC) remains the standard for monitoring CAR T cells using a recombinant biotinylated target protein. Nevertheless, there is a need for additional tools, and the challenge is to develop an easy, relevant, highly sensitive, reproducible, and inexpensive detection method. Molecular tools can meet this need to specifically monitor long-term persistent CAR T cells. METHODS: Based on 2 experimental CAR T cell constructs, IL-1RAP and CS1, we designed 2 quantitative digital droplet (ddPCR) PCR assays. By targeting the 4.1BB/CD3z (28BBz) or 28/CD3z (28z) junction area, we demonstrated that PCR assays can be applied to approved CD19 CAR T drugs. Both 28z and 28BBz ddPCR assays allow determination of the average vector copy number (VCN) per cell. We confirmed that the VCN is dependent on the multiplicity of infection and verified that the VCN of our experimental or GMP-like IL-1RAP CAR T cells met the requirement (< 5 VCN/cell) for delivery to the clinical department, similar to approved axi-cel or tisa-cel drugs. RESULTS: 28BBz and 28z ddPCR assays applied to 2 tumoral (acute myeloid leukemia (AML) or multiple myeloma (MM) xenograft humanized NSG mouse models allowed us to quantify the early expansion (up to day 30) of CAR T cells after injection. Interestingly, following initial expansion, when circulating CAR T cells were challenged with the tumor, we noted a second expansion phase. Investigation of the bone marrow, spleen and lung showed that CAR T cells disseminated more within these tissues in mice previously injected with leukemic cell lines. Finally, circulating CAR T cell ddPCR monitoring of R/R acute lymphoid leukemia or diffuse large B cell lymphoma (n = 10 for tisa-cel and n = 7 for axi-cel) patients treated with both approved CAR T cells allowed detection of early expansion, which was highly correlated with FC, as well as long-term persistence (up to 450 days), while FC failed to detect these events. CONCLUSION: Overall, we designed and validated 2 ddPCR assays allowing routine or preclinical monitoring of early- and long-term circulating approved or experimental CAR T cells, including our own IL-1RAP CAR T cells, which will be evaluated in an upcoming phase I clinical trial.

The impact of Wilson disease on myocardial tissue and function: a cardiovascular magnetic resonance study.

BACKGROUND: Systemic effects of altered serum copper processing in Wilson Disease (WD) might induce myocardial copper deposition and consequently myocardial dysfunction and structural remodeling. This study sought to investigate the prevalence, manifestation and predictors of myocardial tissue abnormalities in WD patients. METHODS: We prospectively enrolled WD patients and an age-matched group of healthy individuals. We applied cardiovascular magnetic resonance (CMR) to analyze myocardial function, strain, and tissue characteristics. A subgroup analysis of WD patients with predominant neurological (WD-neuro+) or hepatic manifestation only (WD-neuro-) was performed. RESULTS: Seventy-six patients (37 years (27-49), 47% women) with known WD and 76 age-matched healthy control subjects were studied. The prevalence of atrial fibrillation in WD patients was 5% and the prevalence of symptomatic heart failure was 2.6%. Compared to healthy controls, patients with WD had a reduced left ventricular global circumferential strain (LV-GCS), and also showed abnormalities consistent with global and regional myocardial fibrosis. WD-neuro+ patients presented with more severe structural remodeling and functional impairment when compared to WD-neuro- patients. CONCLUSIONS: In a large cohort, WD was not linked to a distinct cardiac phenotype except CMR indexes of myocardial fibrosis. More research is warranted to assess the prognostic implications of these findings. TRIAL REGISTRATION: This trial is registered at the local institutional ethics committee (S-188/2018).

Composition of browses consumed by Matschie's tree kangaroo (Dendrolagus matschiei) sampled from home ranges in Papua New Guinea.

Twenty-six samples (n = 24 spp.) of foods eaten, including ferns, shrubs, vines, orchids, herbaceous plants, and tree leaves, were collected from the Yopno, Uruwa, and Som Conservation Area at approximately 1,800 m altitude on the Huon Peninsula, Papua New Guinea (PNG). Samples were weighed fresh in the field and transported to the Lae National Herbarium in PNG for drying and confirmed identification, before transporting to the US for analysis of primary nutrient composition and minerals. Water content averaged 76 ± 10% (mean ± standard deviation); on a dry matter (DM) basis, foods averaged moderate protein (11 ± 5%), and soluble carbohydrate (27 ± 8%) content, along with exceptionally low starch (1 ± 1%) and crude fat (3 ± 2%) values, and moderate to high values in fiber fractions (neutral detergent fiber 52 ± 13%, acid detergent fiber 39 ± 10%, lignin 15 ± 6%). Calculated metabolizable energy content of native forages averaged 1.9 ± 0.3 Mcal/kg DM (ruminant model). Macromineral concentrations (DM basis) were not exceptional (calcium 1.1 ± 1.0%, phosphorus 0.2 ± 0.1%, magnesium 0.3 ± 0.2%, potassium 1.8 ± 0.9%, sodium 0.02 ± 0.02%), and select trace minerals were within anticipated ranges for herbivores (copper 12 ± 13 mg/kg, iron 48 ± 26 mg/kg, zinc 34 ± 18 mg/kg) with the exception of manganese (268 ± 225 mg/kg), which could be considered on the high end of dietary adequacy for most herbivores. These data provide useful information that can be used to adjust nutrient targets for dietary development and feeding management of captive populations of tree kangaroos.

[Parental Resolution of the Child's Disability Diagnosis in the Reaction to Diagnosis Interview (RDI) and Effects on the Play Interaction with the Child]. / Diagnoseverarbeitung von Eltern behinderter Kinder im Reaction to Diagnosis Interview (RDI) und Auswirkungen auf das Spiel mit dem Kind.

Parental Resolution of the Child's Disability Diagnosis in the Reaction to Diagnosis Interview (RDI) and Effects on the Play Interaction with the Child Examining 37 qualitative interviews with mothers and fathers of a child with intellectual disability it was observed that the emotions and traumatic experiences, associated with the child's diagnosis, still burden the relationship with the child even after several years, so that many affected cannot come to resolution. On the other hand, resolution of the diagnosis was indicated for 65 % of the parents, enabling them to reclaim lost space for building a relationship with their child. While these parents significantly more often report purposeless and responsive play interaction with their children, non-resolved parents still seem to be driven to counteract the disability by playing educational games or playing games, which promote the development. In a parallel music therapeutic study, the effects of parental resolution also are monitored in children's free play interaction: Children of resolved parents interact more often in a dialogic relationship, whereas children of non-resolved parents are less able to balance dyadic turn-taking and interaction control in free music play.

Microfluidic chip to interface porous microneedles for ISF collection.

Porous microneedles (MNs) are expected to be applied for diagnostic microfluidic devices such as blood glucose monitoring as they enable a pain-free penetration of human skin and the extraction of interstitial fluids. However, conventional microfluidic systems require additional steps to separate the liquid from a porous structure used for fluid extraction. In this study, we developed a microfluidic system with a hydrodynamically designed interface between a porous MN array and microchannels to enable a direct analysis of liquids extracted by the porous MN array. The microfluidic chip with an interface for the MN array was successfully realized by standard MEMS processes, enabling a liquid flow through the whole microfluidic structure. The porous MN array was fabricated by the salt leaching and molding method, which was integrated with the chip and demonstrated the successful extraction of liquids from an agarose gel-based skin phantom.

Hybrid intracerebral probe with integrated bare LED chips for optogenetic studies.

This article reports on the development, i.e., the design, fabrication, and validation of an implantable optical neural probes designed for in vivo experiments relying on optogenetics. The probes comprise an array of ten bare light-emitting diode (LED) chips emitting at a wavelength of 460 nm and integrated along a flexible polyimide-based substrate stiffened using a micromachined ladder-like silicon structure. The resulting mechanical stiffness of the slender, 250-µm-wide, 65-µm-thick, and 5- and 8-mm-long probe shank facilitates its implantation into neural tissue. The LEDs are encapsulated by a fluropolymer coating protecting the implant against the physiological conditions in the brain. The electrical interface to the external control unit is provided by 10-µm-thick, highly flexible polyimide cables making the probes suitable for both acute and chronic in vivo experiments. Optical and electrical properties of the probes are reported, as well as their in vivo validation in acute optogenetic studies in transgenic mice. The depth-dependent optical stimulation of both excitatory and inhibitory neurons is demonstrated by altering the brain activity in the cortex and the thalamus. Local network responses elicited by 20-ms-long light pulses of different optical power (20 µW and 1 mW), as well as local modulation of single unit neuronal activity to 1-s-long light pulses with low optical intensity (17 µW) are presented. The ability to modulate neural activity makes these devices suitable for a broad variety of optogenetic experiments.

Phosphor-based light conversion for miniaturized optical tools.

This paper describes the application of phosphor-based light conversion for its use in optogenetic experiments to tailor the wavelength of light emitted from implantable miniaturized light sources. Gallium-nitride-based blue light-emitting diodes are used in combination with orthosilicate phosphor immersed in an epoxy matrix and emitting in the yellow wavelength range. The miniaturization of the phosphor-containing polymer droplets toward diameters as small as 300 µm provides the compatibility with implantable optical probes. The parameter study applied here varied the concentration of the phosphor material in the polymer matrix as well as the droplet height in order to tailor the characteristics of blue-to-yellow light conversion.

[Comparison of hospital rating websites among each other and with data from hospital quality reports and quality assurance based on routine data]. / Vergleich von Patientenbewertungen auf Online-Portalen untereinander und mit Qualitätsberichten der Krankenhäuser und der Qualitätssicherung mit Routinedaten.

BACKGROUND: In addition to the objectifiable treatment quality, patients' perspectives are gaining relevance. OBJECTIVE: This study aimed to characterize available hospital rating websites (HRW) with regards to patient ratings and to compare them with data from hospital quality reports and quality assurance based on routine data (QSR) for urological departments. MATERIALS AND METHODS: After a structured online search for HRWs, websites were compared based on patient ratings from the 10 urologic departments with the largest intervention rates in 2021 using generalized estimated equations. For radical prostatectomy (RPE), quantitative comparison of patient ratings (klinikbewertungen.de) and QSR-based ratings was performed using Spearman's rank correlation. RESULTS: Of 1845 hits, 25 portals were analyzed. The department-wise comparison of HRWs resulted in significantly different patient ratings (p < 0.001). Patient ratings (klinikbewertungen.de) and QSR data (AOK-Gesundheitsnavigator) showed no significant correlation. An internal comparison of QSR data and patient ratings from the AOK-Gesundheitsnavigator on RPE showed a significant negative correlation between the overall rating and unplanned reoperations (r = -0.81) or other complications (r = -0.91). There was no significant correlation with the recommendation rate by patients. CONCLUSION: Hospital rating websites show considerable heterogeneity regarding patient ratings of the same urology department in different portals. Furthermore, based on the selected examples, there seems to be no correlation between subjective and objective evaluations between different websites or within one website.

Covariant description of transformation optics in nonlinear media.

The technique of transformation optics (TO) is an elegant method for the design of electromagnetic media with tailored optical properties. In this paper, we focus on the formal structure of TO theory. By using a complete covariant formalism, we present a general transformation law that holds for arbitrary materials including bianisotropic, magneto-optical, nonlinear and moving media. Due to the principle of general covariance, the formalism is applicable to arbitrary space-time coordinate transformations and automatically accounts for magneto-electric coupling terms. The formalism is demonstrated for the calculation of the second harmonic wave generation in a twisted TO concentrator.

Microfluidic chip connected to porous microneedle array for continuous ISF sampling.

Minimally invasive biosensing using microneedles (MNs) is a desirable technology for continuous healthcare monitoring. Among a wide range of MNs, porous MNs are expected to be applied for sampling of interstitial fluids (ISF) by connecting the internal tissue to external measurement devices. In order to realize a continuous measurement of biomarkers in ISF through porous MNs, their integration with a microfluidic chip is a promising approach due to its applicability to micro-total analysis system (µTAS) technology. In this study, we developed a fluidic system to directly interface porous MNs to a microfluidic chip consisting of a capillary pump for the continuous sampling of ISF. The porous and flexible MNs made of PDMS are connected to the microfluidic chip fabricated by standard microelectro-mechanical system (MEMS) processes, showing a continuous flow of phosphate buffered saline (PBS). The developed device will lead to the minimally invasive and continuous biosampling for long-term healthcare monitoring.

Age and gender effects on non-suicidal self-injury, and their interplay with psychological distress.

INTRODUCTION: NSSI (non-suicidal self-injury) is an important public health issue, with high prevalence and associations with future mental illness and suicide. To date, no large single study has tested age and gender effects on NSSI and their interplay with psychological distress. METHOD: NSSI and psychological distress were ascertained by questionnaire in a community study of 2368 young people aged 14-25; proportions at each age and of each gender were approximately equal. RESULTS: There was a significant quadratic interaction between age and gender on last month NSSI prevalence (p = 0.025): NSSI was more common in females ages 16-19, but there were no significant gender differences at younger/older ages. General distress partially mediated the effects of age and gender on NSSI. The association between general distress and NSSI was not significantly moderated by age, gender nor their interactions. CONCLUSIONS: Gender difference in NSSI is not a static gap, but evolves across time, widening in mid-adolescence and disappearing by early adulthood. Part of the reason for that gender gap being present at those ages is the increase levels of distress in young women at those ages. There was no evidence that the effects of general distress on NSSI differed by age/gender.

The glycocalyx of the human umbilical vein endothelial cell: an impressive structure ex vivo but not in culture.

Potter and Damiano recently assessed the hydrodynamic dimensions of the endothelial glycocalyx in vivo (mouse cremaster muscle venules) and in vitro (human umbilical vein and bovine aorta endothelium cultured in perfused microchannels) using fluorescent microparticle image velocimetry (Circ Res. 2008;102:770-776). Great discrepancy was observed, the glycocalyx presenting a zone of interaction extending approximately 0.52 microm into the vessel lumen in vivo, but only 0.02 to 0.03 microm from cultured cells. In an accompanying editorial, Barakat cautioned that the difference in hydrodynamic interaction did not allow one to conclude that the cultured cells totally lack a physical cell surface layer capable of mechanotransduction (Circ Res. 2008;102:747-748). To stabilize the glycocalyx for electron microscopic investigation, we perfusion-fixed 6 human umbilical veins and confluent and nonconfluent cultures (5 each) of human umbilical vein endothelial cells (HUVECs) with lanthanum/glutaraldehyde solution. Ex vivo, the thickness of glycocalyx of umbilical vein endothelium averaged 878 nm. HUVECs in vitro presented a glycocalyx with a dense-zone thickness of only 29.4 nm, plus sparse filaments reaching out on average to 118 nm, there being no difference between the nonconfluent and confluent cells. Immunohistology demonstrated the presence of heparan sulfates and syndecan-1, main constituents of the glycocalyx, both ex vivo and in vitro. These results support the observed discrepancy between glycocalyx thickness in vivo and in vitro, now for one and the same type of human cell. The presence of heparan sulfates and syndecan-1 also on cultured cells may explain why mechanotransduction phenomena can be observed even with a nonmature glycocalyx.

Multifunctional optrode for opsin delivery, optical stimulation, and electrophysiological recordings in freely moving rats.

Objective. Optogenetics involves delivery of light-sensitive opsins to the target brain region, as well as introduction of optical and electrical devices to manipulate and record neural activity, respectively, from the targeted neural population. Combining these functionalities in a single implantable device is of great importance for a precise investigation of neural networks while minimizing tissue damage.Approach. We report on the development, characterization, andin vivovalidation of a multifunctional optrode that combines a silicon-based neural probe with an integrated microfluidic channel, and an optical glass fiber in a compact assembly. The silicon probe comprises an 11-µm-wide fluidic channel and 32 recording electrodes (diameter 30µm) on a tapered probe shank with a length, thickness, and maximum width of 7.5 mm, 50µm, and 150µm, respectively. The size and position of fluidic channels, electrodes, and optical fiber can be precisely tuned according to thein vivoapplication.Main results.With a total system weight of 0.97 g, our multifunctional optrode is suitable for chronicin vivoexperiments requiring simultaneous drug delivery, optical stimulation, and neural recording. We demonstrate the utility of our device in optogenetics by injecting a viral vector carrying a ChR2-construct in the prefrontal cortex and subsequent photostimulation of the transduced neurons while recording neural activity from both the target and adjacent regions in a freely moving rat for up to 9 weeks post-implantation. Additionally, we demonstrate a pharmacological application of our device by injecting GABA antagonist bicuculline in an anesthetized rat brain and simultaneously recording the electrophysiological response.Significance. Our triple-modality device enables a single-step optogenetic surgery. In comparison to conventional multi-step surgeries, our approach achieves higher spatial specificity while minimizing tissue damage.

Intracortical probe arrays with silicon backbone and microelectrodes on thin polyimide wings enable long-term stable recordingsin vivo.

Objective.Recording and stimulating neuronal activity across different brain regions requires interfacing at multiple sites using dedicated tools while tissue reactions at the recording sites often prevent their successful long-term application. This implies the technological challenge of developing complex probe geometries while keeping the overall footprint minimal, and of selecting materials compatible with neural tissue. While the potential of soft materials in reducing tissue response is uncontested, the implantation of these materials is often limited to reliably target neuronal structures across large brain volumes.Approach.We report on the development of a new multi-electrode array exploiting the advantages of soft and stiff materials by combining 7-µm-thin polyimide wings carrying platinum electrodes with a silicon backbone enabling a safe probe implantation. The probe fabrication applies microsystems technologies in combination with a temporal wafer fixation method for rear side processing, i.e. grinding and deep reactive ion etching, of slender probe shanks and electrode wings. The wing-type neural probes are chronically implanted into the entorhinal-hippocampal formation in the mouse forin vivorecordings of freely behaving animals.Main results.Probes comprising the novel wing-type electrodes have been realized and characterized in view of their electrical performance and insertion capability. Chronic electrophysiologicalin vivorecordings of the entorhinal-hippocampal network in the mouse of up to 104 days demonstrated a stable yield of channels containing identifiable multi-unit and single-unit activity outperforming probes with electrodes residing on a Si backbone.Significance.The innovative fabrication process using a process compatible, temporary wafer bonding allowed to realize new Michigan-style probe arrays. The wing-type probe design enables a precise probe insertion into brain tissue and long-term stable recordings of unit activity due to the application of a stable backbone and 7-µm-thin probe wings provoking locally a minimal tissue response and protruding from the glial scare of the backbone.

Associations between baseline cortisol and trajectory of symptom improvement in depressed adolescents receiving psychological therapy.

BACKGROUND: Cortisol hypersecretion in depressed adolescents and adults is associated with more persistent illness and may signal a lower response to psychological therapies. A meta-analysis of small and heterogenous studies demonstrated that higher pre-treatment basal cortisol levels were associated with poorer response specifically to psychological therapy for depression. The objective of this study was to investigate the relationship between both morning and evening salivary cortisol levels and response to psychological therapy in depressed adolescents participating in one large randomised controlled trial. METHODS: We tested the association between morning and evening salivary cortisol levels at baseline and improvement in depressive symptoms in response to psychological therapies in depressed adolescents at 6 time points: baseline, 6, 12, 36, 52- and 86-weeks post-randomisation, using the self-reported Mood and Feelings Questionnaire (MFQ). RESULTS: High evening cortisol was associated with a slower initial decline in depressive symptoms (cortisol x quadratic time p = .022); however it was not associated with total change in depressive symtoms over the whole course of the study. Morning cortisol was not associated with change in depressive symptoms. These effects were not significantly different across the three psychological therapies. LIMITATIONS: Results may not generalize to adolescents receiving other treatments (medication) or no treatment, and may not generalize to adults. Only a minority of eligible participants collected valid cortisol samples. CONCLUSIONS: Higher pretreatment evening cortisol may impair a depressed adolescent's ability to use psychological therapy.

Experimental and numerical studies of terahertz surface waves on a thin metamaterial film.

We present experimental and numerical studies of localized terahertz surface waves on a subwavelength-thick metamaterial film consisting of in-plane split-ring resonators. A simple and intuitive model is derived that describes the propagation of surface waves as guided modes in a waveguide filled with a Lorentz-like medium. The effective medium model allows us to deduce the dispersion relation of the surface waves, in excellent agreement with the numerical data obtained from 3D full-wave calculations. Both the accuracy of the analytical model and the numerical calculations are confirmed by spectroscopic terahertz time-domain measurements.

Mechanisms of fibroblast cell therapy for dystrophic epidermolysis bullosa: high stability of collagen VII favors long-term skin integrity.

Here, we report on the first systematic long-term study of fibroblast therapy in a mouse model for recessive dystrophic epidermolysis bullosa (RDEB), a severe skin-blistering disorder caused by loss-of-function of collagen VII. Intradermal injection of wild-type (WT) fibroblasts in >50 mice increased the collagen VII content at the dermal-epidermal junction 3.5- to 4.7-fold. Although the active biosynthesis lasted <28 days, collagen VII remained stable and dramatically improved skin integrity and resistance to mechanical forces for at least 100 days, as measured with a digital 3D-skin sensor for shear forces. Experiments using species-specific antibodies, collagen VII-deficient fibroblasts, gene expression analyses, and cytokine arrays demonstrated that the injected fibroblasts are the major source of newly deposited collagen VII. Apart from transitory mild inflammation, no adverse effects were observed. The cells remained within an area

Customized Thinning of Silicon-based Neural Probes Down to 2 µm.

This paper reports on the customized thinning of neural probes based on silicon (Si) using deep reactive ion etching (DRIE) as a post-processing step. The reduced probe dimensions are expected to minimize local tissue trauma, while guaranteeing probe integrity during implantation. For DRIE, the probes are partially masked by a micromachined Si cover chip comprising tailored cavities enabling any desired thinned length l and probe thickness t by a proper choice of cover chip design and DRIE parameters, respectively. A broad variety of probe designs were realized with shank tip thicknesses ranging from 35 µm down to 2 µm. All probes could successfully be implanted into a brain tissue phantom, demonstrating a pronounced reduction in insertion force from 0.55 mN for unprocessed probes to 0.08 mN for 2-µm-thin shanks. When the dura mater was mimicked by a polyethylene (PE) membrane, forces were reduced from 28.9 mN to 16.6 mN for 15-µm-thin shanks.

CMOS-Compatible, Flexible, Intracortical Neural Probes.

Flexible intracortical neural probes elicit a lower foreign body response when compared to rigid implants. However, by incorporating complementary metal-oxide-semiconductor (CMOS) circuitry, silicon-based neural probes can offer an improved scalability and more functionalities than any other currently available technology. OBJECTIVE: Our goal is the development of a novel neural probe that combines flexibility with the functionalities of active CMOS-based probes. METHODS: We interface CMOS-based probe tips of only a few millimeters in length with flexible polyimide cables, which enable the complete implantation of the tips into brain tissue. The multilayer platinum metallization of the cables is patterned using a novel combination of ion beam and plasma etching. Implantation of the flexible probes is verified in brain models using stiff insertion shuttles. RESULT: We assembled neural probes from passive and active tips as short as 1.5 mm and less than 180 µm in width. Active probes feature electrode arrays with 72 recording sites and multiplexing to 16 parallel output lines. We reliably patterned cables with signal lines of 2 µm in width and 3 µm in spacing. Ion beam etching deteriorated the composition of the polyimide substrate and its resistance to around 1 kΩ. An additional plasma treatment re-established high insulation resistances and recovered the chemical composition. Probes were successfully implanted to a depth of 7 mm using insertion shuttles and withstood forces of 63 mN. CONCLUSIONS: This study presents the methods required for the fabrication and application of a new generation of neural probes. SIGNIFICANCE: The synergetic approach surpasses the limitation of each individual probe technology and should be considered in future developments.