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The androgen receptor signaling inhibitor apalutamide is used successfully for the treatment of prostate cancer. An increased risk of hypothyroidism, mostly subclinical, has been reported in the SPARTAN and TITAN trials. We present three cases of subacute deterioration of previously known but well-controlled hypothyroidism treated with levothyroxine, occurring shortly after the initiation of treatment with apalutamide, resulting in severe hypothyroidism. These cases highlight the importance of awareness of thyroid dysfunction during treatment with apalutamide, particularly in patients with pre-existing thyroid disease, common in the general population. We provide practice recommendations for thyroid management prior to and during apalutamide treatment as well as after the interruption of this therapy.

International Society of Urological Pathology grade group 1 (GG 1) prostate cancer (PCa) is generally considered insignificant, with recent suggestions that it should even be considered as “noncancerous”. We evaluated outcomes for patients with GG 1 PCa on biopsy (bGG 1) and high-risk features (prostate-specific antigen [PSA] >20 ng/ml and/or cT3–4 stage) to challenge the hypothesis that every case of bGG 1 PCa has a benign disease course. We used the multi-institutional EMPaCT database, which includes data for 9508 patients with high-risk PCa undergoing surgery. We included patients with bGG 1 PCa (n = 848) in our analysis and divided them into three groups according to PSA >20 ng/ml, cT3–4 stage, or both. The estimated 10-yr cancer-specific survival (CSS) rate was 96% in the overall population, 88% in the group with both PSA >20 ng/ml and cT3–4 stage, 97% in the group with PSA >20 ng/ml alone, and 98% in the group with cT3–4 stage alone. Similar CSS outcomes were found in subgroups with GG 1 PCa on pathology (n = 502) and with GG 1 on biopsy diagnosed after 2005 (n = 253). Study limitations include the lack of magnetic resonance imaging (MRI) staging and MRI-targeted biopsies. In conclusion, patients with GG 1 and either PSA >20 ng/ml or cT3–4 stage have a low risk of dying from their cancer after surgery. However, patients with GG 1 PCa and both PSA >20 ng/ml and cT3–4 stage are at higher risk of cancer-specific mortality and active treatment should be discussed for this subgroup. Patient summary: We assessed outcomes for patients diagnosed with low-grade prostate cancer on biopsy who also had one or two factors associated with high risk disease. Men with both of those risk factors had a higher risk of dying from their prostate cancer. Active treatment should be discussed for this subgroup of patients.

Abstract Carbon nanotubes (CNTs) filled natural rubber (NR) composites with various CNT contents at 0, 1, 2, 3, 4 and 5 phr were prepared by latex mixing method using glutaraldehyde as curing agent. This work aims to improve the electrical and mechanical properties of CNT filled NR vulcanizates. The CNT dispersion of NR composites was clarified using dispersion grader, optical microscopy and scanning electron microscopy. The electrical properties of NR composites in the existing of CNT networks were studied by following the well-known percolation theory. It was observed that the NR composites exhibited low percolation threshold at 0.98 phr of CNT. Moreover, a three-dimensional network formation of CNT in the NR composites was observed and it is indicated by the t-value of 1.67. The mechanical properties of NR composites in terms of modulus, tensile strength and hardness properties were increased upon the addition of CNT to the optimum mechanical properties at 1 phr of CNT. Therefore, the present work is found the novelty of the study that the conductive rubber latex film can be produced using GA as low-temperature curing agent which enhanced good electrical properties. Moreover, this work is found to be beneficial in case of conductive rubber latex film that requires high modulus at low strain. The additional advantage of this system is the curing process occurs at low-temperature using GA and it can be easily processed. Graphical abstract

Abstract The androgen receptor (AR) is a crucial player in various aspects of male reproduction and has been associated with the development and progression of prostate cancer (PCa). Therefore, the protein is the linchpin of current PCa therapies. Despite great research efforts, the AR signaling pathway has still not been deciphered, and the emergence of resistance is still the biggest problem in PCa treatment. To discuss the latest developments in AR research, the “1st International Androgen Receptor Symposium” offered a forum for the exchange of clinical and scientific innovations around the role of the AR in prostate cancer (PCa) and to stimulate new collaborative interactions among leading scientists from basic, translational, and clinical research. The symposium included three sessions covering preclinical studies, prognostic and diagnostic biomarkers, and ongoing prostate cancer clinical trials. In addition, a panel discussion about the future direction of androgen deprivation therapy and anti-AR therapy in PCa was conducted. Therefore, the newest insights and developments in therapeutic strategies and biomarkers are discussed in this report.

Abstract Magnetorheological elastomers (MREs) are a category of smart materials composed of a magnetic powder dispersed in an elastomeric matrix. They are characterized by the ability to change their mechanical properties when an external magnetic field is applied, called magnetorheological (MR) effect. When a conductive filler is added to a magnetorheological elastomer, the resulting hybrid filler composite showcases both MR and piezoresistive effects. For such a reason, these composites are referred to as self‐sensing magnetorheological elastomers. In this case, the synthesized self‐sensing magnetorheological elastomers are based on styrene‐based thermoplastic elastomers (TPS), carbonyl iron particles (CIP), and carbon black (CB). The hybrid filler concept using various coated CIP and constant CB content showed that above 25 vol.% CIP the resistivity increased rapidly. This work proposes the first case of a 3D printable self‐sensing magnetorheological elastomer and cyclic mechanical compression and tensile mode analysis at high deformation (up to 20% and 10%, respectively). The results showcase a magnetoresistive change of up to 68% and a piezoresistive change of up to 42% and 98% in compression and tension, respectively. In addition, the magnetostriction of the self‐sensing samples has been characterized to be 3.6% and 5.6% in the case of CIP 15 and 30 vol.%, respectively.

Summary: Background: Tumour-promoting inflammation is a “hallmark” of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. Findings: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10–1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20–1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53–0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88–0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48–4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Interpretation: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. Funding: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).

Poly-silsesquioxanes have been numerously used to produce SiO2 or SixOyCz ceramics through pyrolysis under different atmospheres. In this study, crosslinking and pyrolysis behavior of a commercial methyl-silsesquioxane, was examined using thermogravimetry analysis and a lower SiO2 yield was observed after pyrolysis at low heating rates of 0.3 and 0.6 K/min under air atmosphere, namely 69.1 and 75.0 wt%, respectively. Using ceramic thermoplastic shaping techniques, a low heating rate, below 2 K/min, is usually required to remove processing additive (e.g., binders) gradually and avoid failures like blisters, pores, and cracks. A mixture of SILRES® MK and γ-Al2O3 was prepared to produce a mullite ceramic with Al2O3/ SiO2 ratio of 60/40 wt%. As expected, the stoichiometric ratio of alumina to silica was altered using a heating rate of 0.6 K/min and mullite ceramic with 61.70/37.70 wt% of Al2O3/ SiO2 ratio was obtained. By mixing above the crosslinking temperature of SILRES® MK, a constant ratio of alumina to silica could be achieved successfully, even at low heating rates. In addition, microstructure indicated the growth of needle-like mullite crystals with some amount of SiO2-rich ternary amorphous phase (MgO–Al2O3–SiO2) between the needle grains. Elemental analysis revealed that MgO sintering additive was mainly in the amorphous SiO2-rich phase.

In recent years, conductive polymer nanocomposites have gained significant attention due to their promising thermoresistive and Joule heating properties across a range of versatile applications, such as heating elements, smart materials, and thermistors. This paper presents an investigation of semi-crystalline polyvinylidene fluoride (PVDF) nanocomposites with 6 wt.% carbon-based nanofillers, namely graphene nanoplatelets (GNPs), multi-walled carbon nanotubes (MWCNTs), and a combination of GNPs and MWCNTs (hybrid). The influence of the mono- and hybrid fillers on the crystalline structure was analyzed by X-ray diffraction (XRD) and differential scanning calorimetry (DSC). It was found that the nanocomposites had increased amorphous fraction compared to the neat PVDF. Furthermore, nanocomposites enhanced the β phase of the PVDF by up to 12% mainly due to the presence of MWCNTs. The resistive properties of the nanocompositions were weakly affected by the temperature in the analyzed temperature range of 25–100 °C; nevertheless, the hybrid filler composites were proven to be more sensitive than the monofiller ones. The Joule heating effect was observed when 8 and 10 V were applied, and the compositions reached a self-regulating effect at around 100–150 s. In general, the inclusion in PVDF of nanofillers such as GNPs and MWCNTs, and especially their hybrid combinations, may be successfully used for tuning the self-regulated Joule heating properties of the nanocomposites.

Abstract Tactility in biological organisms is a faculty that relies on a variety of specialized receptors. The bimodal sensorized skin, featured in this study, combines soft resistive composites that attribute the skin with mechano‐ and thermoreceptive capabilities. Mimicking the position of the different natural receptors in different depths of the skin layers, a multi‐layer arrangement of the soft resistive composites is achieved. However, the magnitude of the signal response and the localization ability of the stimulus change with lighter presses of the bimodal skin. Hence, a learning‐based approach is employed that can help achieve predictions about the stimulus using 4500 probes. Similar to the cognitive functions in the human brain, the cross‐talk of sensory information between the two types of sensory information allows the learning architecture to make more accurate predictions of localization, depth, and temperature of the stimulus contiguously. Localization accuracies of 1.8 mm, depth errors of 0.22 mm, and temperature errors of 8.2 °C using 8 mechanoreceptive and 8 thermoreceptive sensing elements are achieved for the smaller inter‐element distances. Combining the bimodal sensing multilayer skins with the neural network learning approach brings the artificial tactile interface one step closer to imitating the sensory capabilities of biological skin.

Flexible electronics have gained popularity because of their capability to combine softness and functionality. Soft resistive sensors are susceptible to mechanical stimuli and detecting temperature selectively remains a challenge. In this study, soft flexible thermistors are developed for detecting temperature changes based on the positive temperature coefficient (PTC) effect, selectively. By thermomechanical analysis and differential scanning calorimetry, it is observed that thermoplastic elastomers with higher thermal expansion and semicrystalline morphology result in a sensitive thermistor response. To achieve a high sensitivity in temperature and low sensitivity in the detection of mechanical stimulus, a low‐carbon filler content is required. The opposite trend is seen for the piezoresistive sensors for mechanical strain detection. Both sensory material types are compatible with thermoplastic material extrusion‐based additive manufacturing. The method is used for the fabrication of the sensing elements and an open‐source prosthetic hand. The strain sensor detects the bending of the fingers and the temperature sensor detects the temperature when in contact with a heated surface, successfully. In addition, the temperature sensor is used as a tactile sensor to detect contact with a non‐heated surface. Combining selective multisensory capabilities will significantly affect the future development of sensorized prosthetic devices and wearable electronics.

Prostate cancer (PCa) is the most common cancer in men worldwide. Despite better and more intensive treatment options in earlier disease stages, a large subset of patients still progress to metastatic castration-resistant PCa (mCRPC). Recently, poly-(ADP-ribose)-polymerase (PARP)-inhibitors have been introduced in this setting. The TALAPRO-2 and PROpel trials both showed a marked benefit of PARPi in combination with an androgen receptor signaling inhibitor (ARSI), compared with an ARSI alone in both the homologous recombination repair (HRR)-mutated, as well as in the HRR-non-mutated subgroup. In this review, we present a comprehensive overview of how maximal AR-blockade via an ARSI in combination with a PARPi has a synergistic effect at the molecular level, leading to synthetic lethality in both HRR-mutated and HRR-non-mutated PCa patients. PARP2 is known to be a cofactor of the AR complex, needed for decompacting the chromatin and start of transcription of AR target genes (including HRR genes). The inhibition of PARP thus reinforces the effect of an ARSI. The deep androgen deprivation caused by combining androgen deprivation therapy (ADT) with an ARSI, induces an HRR-like deficient state, often referred to as “BRCA-ness”. Further, PARPi will prevent the repair of single-strand DNA breaks, leading to the accumulation of DNA double-strand breaks (DSBs). Due to the induced HRR-deficient state, DSBs cannot be repaired, leading to apoptosis.

The strain sensors based on conductive natural rubber (NR) composite, filled with carbon nanotubes (CNT) and conductive carbon black (CCB), are developed due to their superior elasticity and sensitivity. To encourage electron tunneling, ionic pathway for electron moving was achieved by modified deep eutectic solvent (mDES) synthesized in-house. It was found that the incorporation of mDES impacts the curing, mechanical and electrical properties of the composites due to the interconnected CNT/CCB-mDES networks. It is demonstrated that the electrical signal sensation of conductive NR composite was improved by adding mDES, and the inconsistent sensor behavior under cyclic and quasi-static loadings was eliminated. The mDES not only improves the movement of electrons, but it also promotes the crosslinking of NR molecules without adding ZnO. In addition, for analyzing the object motion, the piezoresistive rubber sensors were tested on a soft printing structure through the cyclic motion analysis of a soft tendon-based actuator. The obtained electrical signals showed the smooth signal with noise and un-prediction electrical peaks after the combination of the mDES into the conductive NR composites. This clarifies the flexible movement of the CNT/CCB structure into the NR matrix following the specific designed objects’ motion. The present work indicates the different core novel technologies based on the use of mDES in the conductive composites matching with the acceptable electrical signal for applying as the promising motion sensor materials for soft structures.

Abstract Self-healing materials can increase the lifetime of products and improve their sustainability. However, the detection of damage in an early stage is essential to avoid damage progression and ensure a successful self-healing process. In this study, self-healing sensor composite strips were developed with the embedding of a thermoplastic styrene-based co-polymer (TPS) sensor in a self-healing matrix. Piezoresistive TPS sensor fibers composites (SFCs) and 3D printed sensor element composites (SECs) were fabricated and embedded in a self-healing matrix by lamination process to detect damage. In both cases, the value of the initial resistance was used to detect the presence of damage and monitor the efficiency of healing. A higher elongation at fracture could be achieved with the extruded sensor fibers. However, for the composite strips the SECs could achieve a higher elongation at fracture. Mechano-electrical analysis revealed that the strips maintained a monotonic, reproducible response after the healing of the matrix. The SFCs had significantly lower drift of the sensor signal during cyclic mechanical analysis. Nevertheless, on a tendon-based soft robotic actuator, the SECs obtained a drift below 1%. This was explained by the lower deformation (e.g.) strain in comparison to the tensile test experiments.

Aim: The objective of this research was to perform a pilot study to develop an automatic analysis of periapical radiographs from patients with and without periodontitis for the percentage alveolar bone loss (ABL) on the approximal surfaces of teeth using a supervised machine learning model, that is, convolutional neural networks (CNN). Material and methods: A total of 1546 approximal sites from 54 participants on mandibular periapical radiographs were manually annotated (MA) for a training set (n = 1308 sites), a validation set (n = 98 sites), and a test set (n = 140 sites). The training and validation sets were used for the development of a CNN algorithm. The algorithm recognised the cemento-enamel junction, the most apical extent of the alveolar crest, the apex, and the surrounding alveolar bone. Results: For the total of 140 images in the test set, the CNN scored a mean of 23.1 ± 11.8 %ABL, whilst the corresponding value for MA was 27.8 ± 13.8 %ABL. The intraclass correlation (ICC) was 0.601 (P < .001), indicating moderate reliability. Further subanalyses for various tooth types and various bone loss patterns showed that ICCs remained significant, although the algorithm performed with excellent reliability for %ABL on nonmolar teeth (incisors, canines, premolars; ICC = 0.763). Conclusions: A CNN trained algorithm on radiographic images showed a diagnostic performance with moderate to good reliability to detect and quantify %ABL in periapical radiographs.

Abstract Background Cytochrome P450 4F3 (CYP4F3) is an ω‐hydroxylase that oxidizes leukotriene B4 (LTB4), prostaglandins, and fatty acid epoxides. LTB4 is synthesized by leukocytes and acts as a chemoattractant for neutrophils, making it an essential component of the innate immune system. Recently, involvement of the LTB4 pathway was reported in various immunological disorders such as asthma, arthritis, and inflammatory bowel disease. We report a 26‐year‐old female with a complex immune phenotype, mainly marked by exhaustion, muscle weakness, and inflammation‐related conditions. The molecular cause is unknown, and symptoms have been aggravating over the years. Methods Whole exome sequencing was performed and validated; flow cytometry and enzyme‐linked immunosorbent assay were used to describe patient's phenotype. Function and impact of the mutation were investigated using molecular analysis: co‐immunoprecipitation, western blot, and enzyme‐linked immunosorbent assay. Capillary electrophoresis with ultraviolet detection was used to detect LTB4 and its metabolite and in silico modelling provided structural information. Results We present the first report of a patient with a heterozygous de novo missense mutation c.C1123 > G;p.L375V in CYP4F3 that severely impairs its activity by 50% (P 0.9 for both co‐immunoprecipitation with POR and Cytb5). In silico modelling of CYP4F3 in complex with POR and Cytb5 suggests that the loss of catalytic activity of the mutant CYP4F3 is explained by a disruption of an α‐helix that is crucial for the electron shuffling between the electron carriers and CYP4F3. Interestingly, zileuton still inhibits ex vivo LTB4 production in patient's whole blood to 2% of control (P

The aim of this study was the electrospinning of zirconia nanofibers without sol-gel precursors. Low-cost Zr-oxide and Zr-carbonate inorganic materials, with high molecular Zr-content compared to sol-gel methods, were used for precursor formulation. Using a polyvinylpyrrolidone (PVP) polymeric binder, zirconia nanofibers could successfully be synthesised with both Zr-sources. The effects of different electrospinning parameters were investigated to stabilize the processing and reduce the deviation of nanofiber diameters. Fibres calcined at 1000 °C produced from the two different precursors displayed differing crystal phases of zirconia. The one based on nanoparticles revealed a significantly higher amount of tetragonal phase. Zirconia nanofibers with poly-granular microstructure across the diameter were successfully produced.

An inorganic solid electrolyte is the most favorable candidate for replacing flammable liquid electrolytes in lithium batteries. Lithium lanthanum zirconium oxide (LLZO) is considered a promising solid electrolyte due to its safe operating potential window (0–5 V) combined with its good electrochemical stability. In this work, 250 g batches of pre-sintered Ta-doped LLZO (Li7La3Zr1.6Ta0.4O12, Ta-LLZO) were synthesized for bulk production of a dense LLZO electrolyte. A simple two-step thermal treatment process was developed. The first thermal step at 950 °C initiates nucleation of LLZO, with carefully controlled process parameters such as heating atmosphere, temperature, and dopant concentration. In the second thermal step at 1150 °C, sintered discs were obtained as solid electrolytes, with relative densities of 96%. X-ray diffraction analysis confirmed the phase purity of the sintered Ta-LLZO disc, and refined data were used to calculate the lattice parameter (12.944 Å). Furthermore, the presence of the Ta dopant in the disc was confirmed through X-ray photoelectron spectroscopy (XPS) analysis. The ionic and electronic conductivity values of the Ta-LLZO disc were 10−4 S cm−1 and 10−10 S cm−1, respectively. These values confirm that the prepared (Ta-LLZO) discs exhibit ionic conductivity while being electronically insulating, being suitable for use as solid electrolytes with the requisite electrical properties.

The utilization of preceramic polymers (PCPs) to produce both oxide and non-oxide ceramics has caught significant interest, owing to their exceptional characteristics. Diverse types of polymer-derived ceramics (PDCs) synthesized by using various PCPs have demonstrated remarkable characteristics such as exceptional thermal stability, resistance to corrosion and oxidation at elevated temperatures, biocompatibility, and notable dielectric properties, among others. The application of additive manufacturing techniques to produce PDCs opens up new opportunities for manufacturing complex and unconventional ceramic structures with complex designs that might be challenging or impossible to achieve using traditional manufacturing methods. This is particularly advantageous in industries like aerospace, automotive, and electronics. In this review, various categories of preceramic polymers employed in the synthesis of polymer-derived ceramics are discussed, with a particular focus on the utilization of polysiloxane and polysilsesquioxanes to generate silicate ceramics. Further, diverse additive manufacturing techniques adopted for the fabrication of polymer-derived silicate ceramics are described.

Integrated additive manufacturing of actuators based on active materials could potentially replace conventional motors in numerous applications across disciplines like biomedical engineering, robotics, or aerospace. In this work, extrusion-based additive manufacturing of functional NiTi shape memory alloys is demonstrated via 3D printing of filaments consisting of thermoplastic binder and metal powder. Two alloys are fabricated, one showing superelastic, the other showing shape memory properties at room temperature. The microstructures of both alloys are characterized and set into perspective with the measured thermo-mechanical properties. The 3D-printed NiTi showed a shape memory strain of 1.9 %, respectively a superelastic strain of 1.3 % for an applied strain of 4 %. To enlarge the shape memory strain actuator geometries are designed, fabricated, and tested. The results of this study may find application in the field of additive manufacturing of active structures, also referred to as 4D printing. Commonly, polymeric materials are used in such structures, which often suffer from poor mechanical properties and durability. The use of metallic materials as it is investigated in this work could help to overcome these limitations.

Multiferroic ceramic composites have been engineered to incorporate multiple desired physical properties within a single ceramic component. The objective of this study was to create such composites through pressure less sintering ferroelectric-doped PZT and nickel–zinc ferrite at a temperature of 1250 °C. The growth of ferrite grains was found to be influenced by the concentration of the ferroelectric PZT phase. Consequently, an increase in the ferrite content decreased the average particle size of nickel–zinc ferrite by a factor of 1.8. After impedance spectroscopy, the multiferroic ceramic composites can be categorized into two groups: those with low ferrite content (20%). Composites with a high ferrite content are suitable for dual-band filters or shield applications. The impedance spectroscopy analysis revealed that the resonance frequency can be shifted to higher frequency ranges. Therefore, it was demonstrated that modifying the composition of the multiferroic composite allows for tailoring the impedance behavior to shield living and working spaces against such radiation to meet the demands of the 21st century.

Piezoresistive sensors for monitoring human motions are essential for the prevention and treatment of injury. Natural rubber is a material of renewable origin that can be used for the development of soft wearable sensors. In this study, natural rubber was combined with acetylene black to develop a soft piezoresistive sensing composite for monitoring the motion of human joints. An additive manufacturing technique based on stereolithography was used, and it was seen that the sensors produced with the method could detect even small strains (

A polygenic hazard score (PHS1) improves prostate cancer screening accuracy in European patients. Here, the authors test the performance of a version compatible with OncoArray genotypes (PHS2) in a multi-ethnic dataset and find that it risk-stratifies men for any, aggressive, and fatal prostate cancer.

We explore the feasibility of Ag fiber meshes as electron transport layer for high-efficiency flexible Cu(In,Ga)Se2 (CIGS) solar cells. Woven meshes of Ag fibers after UV illumination and millisecond flash-lamp treatment results in a sheet resistance of 17 Ω/sq and a visible transmittance above 85%. Conductive Ag meshes are integrated into flexible CIGS cells as transparent conductive electrode (TCE) alone or together with layers of Al-doped ZnO (AZO) with various thickness of 0…900 nm. The Ag mesh alone is not able to function as a current collector. If used together with a thin AZO layer (50 nm), the Ag mesh markedly improves the fill factor and cell efficiency, in spite of the adverse mesh shadowing. When Ag mesh is combined with thicker (200 nm or 900 nm) AZO layers, no improvements in photovoltaic parameters are obtained. When comparing a hybrid TCE consisting of 50 nm AZO and Ag fiber mesh with a thick 900 nm reference AZO device, an improved charge carrier collection in the near-infrared range is observed. Regardless of the AZO thickness, the presence of Ag mesh slows down cell degradation upon mechanical tensile stress, which could be interesting for implementation into flexible thin film CIGS modules.

With the purpose of making soft robotic structures with embedded sensors, additive manufacturing techniques like fused deposition modeling (FDM) are popular. Thermoplastic polyurethane (TPU) filaments, with and without conductive fillers, are now commercially available. However, conventional FDM still has some limitations because of the marginal compatibility with soft materials. Material selection criteria for the available material options for FDM have not been established. In this study, an open-source soft robotic gripper design has been used to evaluate the FDM printing of TPU structures with integrated strain sensing elements in order to provide some guidelines for the material selection when an elastomer and a soft piezoresistive sensor are combined. Such soft grippers, with integrated strain sensing elements, were successfully printed using a multi-material FDM 3D printer. Characterization of the integrated piezoresistive sensor function, using dynamic tensile testing, revealed that the sensors exhibited good linearity up to 30% strain, which was sufficient for the deformation range of the selected gripper structure. Grippers produced using four different TPU materials were used to investigate the effect of the Shore hardness of the TPU on the piezoresistive sensor properties. The results indicated that the in situ printed strain sensing elements on the soft gripper were able to detect the deformation of the structure when the tentacles of the gripper were open or closed. The sensor signal could differentiate between the picking of small or big objects and when an obstacle prevented the tentacles from opening. Interestingly, the sensors embedded in the tentacles exhibited good reproducibility and linearity, and the sensitivity of the sensor response changed with the Shore hardness of the gripper. Correlation between TPU Shore hardness, used for the gripper body and sensitivity of the integrated in situ strain sensing elements, showed that material selection affects the sensor signal significantly.

The human tactile system is composed of multi-functional mechanoreceptors distributed in an optimized manner. Having the ability to design and optimize multi-modal soft sensory systems can further enhance the capabilities of current soft robotic systems. This work presents a complete framework for the fabrication of soft sensory fiber networks for contact localization, using pellet-based 3D printing of piezoresistive elastomers to manufacture flexible sensory networks with precise and repeatable performances. Given a desirable soft sensor property, our methodology can design and fabricate optimized sensor morphologies without human intervention. Extensive simulation and experimental studies are performed on two printed networks, comparing a baseline network to one optimized via an existing information theory based approach. Machine learning is used for contact localization based on the sensor responses. The sensor responses match simulations with tunable performances and good localization accuracy, even in the presence of damage and nonlinear material properties. The potential of the networks to function as capacitive sensors is also demonstrated.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

AimsPreventive interventions for children of parents with mental illness are widely recommended. Mental health services entrust concern for patients’ children by referrals to child protection services. We investigated service coverage for children following referrals.MethodsData from referrals regarding 376 children of adult psychiatry patients over 2008–2012 was linked to information from municipal records and Danish national registers. We conducted Cox regression and used Kaplan–Meier curves to show time to intervention and cumulative incidence of any child and family support services with one-year follow-up from referral date.ResultsAt follow-up, 32% of children were provided with a child and family support service on average 73.4 days after referral. The most common services were family treatment (18%) and family counseling (11%). A statutory child assessment was conducted for 21% of children. Contents of the referrals suggested that 60% of children experienced adverse home environments and/or acute situations due to parents’ psychiatric illness. Predictors of initiation of support services included a child living alone with the patient, hazard ratio 2.09 (1.41–3.08), the patient being the mother, hazard ratio 1.72 (1.11–2.65), and an adverse home environment presenting an acute situation specified in referral, hazard ratio 1.89 (1.01–3.51).ConclusionOur finding that only one third of children receive support after referrals from psychiatry within an average of three months suggests an underserved population of at-risk children. These findings warrant reconsideration of resource allocation and creation of more efficient intervention strategies to protect at-risk children and prevent development of mental illness and adversity.

Background: Cancer-specific survival (CSS) within high-risk non-metastatic prostate cancer varies dramatically. It is likely that within this heterogenous population there are subgroup(s) at extraordinary risk, burdened with an exaptational poor prognosis. Establishing the characteristics of these group(s) would have significant clinical implications since high quality preoperative risk stratification remains the cornerstone of therapeutic decision making to date.Objective: To stratify high-risk prostate cancer based on preoperative characteristics and evaluate cancer specific survival after radical prostatectomy.Method: The EMPaCT multi-center database offers an international population of non-metastatic high-risk prostate cancer. Preoperative characteristics such as age, biopsy Gleason score, PSA and clinical stage were subcategorized. A multivariate analysis was performed using predictors showing significant survival heterogeneity after stratification, as observed by a univariate analysis. Based upon the hazard ratios of this multivariate analysis, a proportional score system was created. The most ideal group distribution was evaluated trough different score cut-off's. The predictive value was tested by the herald C index.Results: An overall 5-years CSS of 94% was noted within the entire high-risk cohort (n = 4,879). Except for age, all preoperative risk factors showed a significantly differing CSS. Multivariate analysis indicated, T4 stage as being the strongest predictor of CSS (HR: 3.31), followed by ISUP grade 5 group (HR 3,05). A score system was created by doubling the hazard ratios of this multivariate analysis and rounding off to the nearest complete number. Multivariate analysis suggested 0, 4, 8, and 12 pts as being the most optimal group distribution (p-value: 0.0015). Five-years CSS of these groups were 97, 93, 87, and 70%, respectively. The calculated Herald C-index of the model was 0.77.Conclusion: An easy-to-use pre-operative model for risk stratification of newly diagnosed high-risk prostate cancer is presented. The heterogeneous CSS of high-risk non-metastatic prostate cancer after radical prostatectomy is illustrated. The model is clinically accessible through an online calculator, presenting cancer specific survival based on individualized patient characteristics.

The tumour micro-environment (TME) plays a crucial role in the onset and progression of prostate cancer (PCa). Here we studied the potential of a selected panel of TME-markers to predict clinical recurrence (CLR) in PCa. Patient cohorts were matched for the presence or absence of CLR 5 years post-prostatectomy. Tissue micro-arrays (TMA) were composed with both prostate non-tumour (PNT) and PCa tissue and subsequently processed for immunohistochemistry (IHC). The IHC panel included markers for cancer activated fibroblasts (CAFs), blood vessels and steroid hormone receptors ((SHR): androgen receptor (AR), progesterone receptor (PR) and estrogen receptor (ER)). Stained slides were digitalised, selectively annotated and analysed for percentage of marker expression with standardized and validated image analysis algorithms. A univariable analysis identified several TME markers with significant impact on CR: expression of CD31 (vascular marker) in PNT stroma, expression of alpha smooth muscle actin (αSMA) in PCa stroma, and PR expression ratio between PCa stroma and PNT stroma. A multivariable model, which included CD31 expression (vascular marker) in PNT stroma and PR expression ratio between PCa stroma and PNT stroma, could significantly stratify patients for CLR, with the identification of a low risk and high-risk subgroup. If validated and confirmed in an independent prospective series, this subgroup might have clinical potential for PCa patient stratification.

TBP is a natural product from Tamarindus indica L. seeds used as a natural remedy in India. This product is an antioxidant and may have beneficial effects on endocrine and metabolic functions. However, the regulatory mechanisms involved remain to be elucidated. In males, testosterone is synthesized by Leydig cells from the testis. With aging and obesity, testis function declines, leading to decreased testosterone synthesis. The aim of the current research is to determine how TBP improves testosterone production in male mice under a high fat diet leading to hypoandrogenic condition. Using C2C12 myoblast cells, we have found that TBP increased mitochondrial mass and oxygen respiration, as well as the production of the IGF-1 hormone. In addition, treatment of TM3 Leydig cells with TBP resulted in increased testosterone production. In mice under a high fat diet, TBP lowered blood glucose level and corticosterone production and improved total testosterone production after five weeks of treatment. In addition, testicular expressions of genes encoding the mitochondrial transporter of cholesterol (Star) and steroidogenic enzymes (Cyp11a1, Hsd3b1, Cyp17a1 and Hsd17b3) were increased by TBP. Hence, TBP may prevent the detrimental effects of long-term consumption of a high fat diet and may have health benefits on the endocrine function.

Several key functions of the androgen receptor (AR) such as hormone recognition and co-regulator recruitment converge in the ligand binding domain (LBD). Loss- or gain-of-function of the AR contributes to pathologies such as the androgen insensitivity syndrome and prostate cancer. Here, we describe a gain-of-function mutation of the surface-exposed threonine at position 850, located at the amino-terminus of Helix 10 (H10) in the AR LBD. Since T850 phosphorylation was reported to affect AR function, we created the phosphomimetic mutation T850D. The AR T850D variant has a 1.5- to 2-fold increased transcriptional activity with no effect on ligand affinity. In the androgen responsive LNCaP cell line grown in medium with low androgen levels, we observed a growth advantage for cells in which the endogenous AR was replaced by AR T850D. Despite the distance to the AF2 site, the AR T850D LBD displayed an increased affinity for coactivator peptides as well as the 23FQNLF27 motif of AR itself. Molecular Dynamics simulations confirm allosteric transmission of the T850D mutation towards the AF2 site via extended hydrogen bond formation between coactivator peptide and AF2 site. This mechanistic study thus confirms the gain-of-function character of T850D and T850 phosphorylation for AR activity and reveals details of the allosteric communications within the LBD.

Chromosome 8q24 is known to be a major susceptibility region for prostate cancer risk. Here the authors analyze genetic data across the 8q24 region from 71,535 prostate cancer patients identifying 12 risk loci, three previously unreported, highlighting the contribution of germline variation at this locus.

Prostate cancer (PrCa) involves a large heritable genetic component. Here, the authors perform multivariate fine-mapping of known PrCa GWAS loci, identifying variants enriched for biological function, explaining more familial relative risk, and with potential application in clinical risk profiling.

Abstract Background Recent retrospective data suggest that neoadjuvant androgen deprivation therapy can improve the prognosis of high-risk prostate cancer (PCa) patients. Novel androgen receptor pathway inhibitors are nowadays available for treatment of metastatic PCa and these compounds are promising for early stage disease. Apalutamide is a pure androgen antagonist with a very high affinity with the androgen receptor. The combination of apalutamide with degarelix, an LHRH antagonist, could increase the efficacy compared to degarelix alone. Objective The primary objective is to assess the difference in proportions of minimal residual disease at prostatectomy specimen between apalutamide + degarelix vs placebo + degarelix. Various secondary endpoints are assessed: variations of different biomarkers at the tumour level (tissue microarrays to evaluate DNA-PKs, PARP, AR and splice variants, PSMA, etc.), whole transcriptome sequencing, exome sequencing and clinical (PSA and testosterone kinetics, early biochemical recurrence free survival, quality of life, safety, etc.) and radiological endpoints. Methods ARNEO is a single centre, phase II, randomized, double blind, placebo-controlled trial. The plan is to include at least 42 patients per each of the two study arms. Patients with intermediate/high-risk PCa and who are amenable for radical prostatectomy with pelvic lymph node dissection can be included. After signing an informed consent, every patient will undergo a pelvic 68Ga -PSMA-11 PSMA PET/MR and receive degarelix at standard dosage and start assuming apalutamide/placebo (60 mg 4 tablets/day) for 12 weeks. Within thirty days from the last study medication intake the same imaging will be repeated. Every patient will undergo PSA and testosterone testing the day of randomization, before the first drug intake, and after the last dose. Formalin fixed paraffin embedded tumour samples will be collected and used for transcriptome analysis, exome sequencing and immunohistochemistry. Discussion ARNEO will allow us to answer, first, whether the combined treatment can result in an increased proportion of patients with minimal residual disease. Secondly, It will enable the study of the molecular consequences at the level of the tumour. Thirdly, what the consequences are of new generation androgen receptor pathway inhibitors on 68Ga -PSMA-11 PET/MR. Finally, various clinical, safety and quality of life data will be collected. Trial Registration EUDRaCT number: 2016–002854-19 (authorization date 3rd August 2017). clinicalTrial.gov: NCT03080116.

Piezoelectric composites with 3-3 connectivity gathered attraction due to their potential application as an acoustic transducer in medical imaging, non-destructive testing, etc. In this contribution, piezoelectric composites were fabricated with a material extrusion-based additive manufacturing process (MEX), also well-known under the names fused deposition modeling (FDM), fused filament fabrication (FFF) or fused deposition ceramics (FDC). Thermoplastic filaments were used to achieve open and offset printed piezoelectric scaffold structures. Both scaffold structures were printed, debinded and sintered successfully using commercial PZT and BaTiO3 powder. For the first time, it could be demonstrated, that using the MEX processing method, closed pore ferroelectric structure can be achieved without pore-former additive. After ceramic processing, the PZT scaffold structures were impregnated with epoxy resin to convert them into composites with 3-3 connectivity. A series of composites with varying ceramic content were achieved by changing the infill parameter during the 3D printing process systematically, and their electromechanical properties were investigated using the electromechanical aix PES device. Also, the Figure of merit (FOM) of these composites was calculated to assess the potential of this material as a candidate for transducer applications. A maximum for the FOM at 25 vol.% of PZT could be observed in this study.

Self-healing materials can prolong the lifetime of structures and products by enabling the repairing of damage. However, detecting the damage and the progress of the healing process remains an important issue. In this study, self-healing, piezoresistive strain sensor fibers (ShSFs) are used for detecting strain deformation and damage in a self-healing elastomeric matrix. The ShSFs were embedded in the self-healing matrix for the development of self-healing sensor fiber composites (ShSFC) with elongation at break values of up to 100%. A quadruple hydrogen-bonded supramolecular elastomer was used as a matrix material. The ShSFCs exhibited a reproducible and monotonic response. The ShSFCs were investigated for use as sensorized electronic skin on 3D-printed soft robotic modules, such as bending actuators. Depending on the bending actuator module, the electronic skin was loaded under either compression (pneumatic-based module) or tension (tendon-based module). In both configurations, the ShSFs could be successfully used as deformation sensors, and in addition, detect the presence of damage based on the sensor signal drift. The sensor under tension showed better recovery of the signal after healing, and smaller signal relaxation. Even with the complete severing of the fiber, the piezoresistive properties returned after the healing, but in that case, thermal heat treatment was required. With their resilient response and self-healing properties, the supramolecular fiber composites can be used for the next generation of soft robotic modules.