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Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an IFN-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4(+) and CD8(+) T cells. LDRT elicited predominantly CD4(+) cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand RAE1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide, and immune checkpoint blockade to patients with immune-desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4(+) cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low T cell-infiltrated tumors. SIGNIFICANCE: Low-dose radiation reprogrammed the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induced simultaneous mobilization of innate and adaptive immunity, predominantly CD4(+) effector T cells, to achieve tumor control dependent on NKG2D. The combination induced important responses in patients with metastatic immune-cold tumors.

Although aniline is a relatively simple small molecule, the origin of its two peaks observed in ion mobility spectrometry (IMS) has remained under debate for at least 30 years. First hypothesized as a difference in protonation site (amine vs. benzene ring), each ion mobility peak differs by one Dalton when coupled with mass spectrometry where the faster mobility peak is the molecular ion peak, and the slower mobility peak is protonated. To complicate the deconvolution of structures, some previous literature shows the peaks as unresolved and thus proposes these species exist in equilibrium. In this work, we show that when measured with high kinetic energy ion mobility spectrometry (HiKE-IMS), the two peaks observed in spectra of both aniline and all n-fluoroanilines are fully separated (chromatographic resolution from 2-7, Rp > 110) and therefore not in equilibrium. The HiKE-IMS is capable of changing ionization conditions independently of drift region conditions, and our results agree with previous literature showing that ionization source settings (including possible fragmentation at this stage) are the only influence determining the speciation of the two aniline peaks. Finally, when the drift and reactant gas are changed to nitrogen, a third peak appears at high E/N for 2-fluoroaniline and 4-fluoroaniline for the first time in reported literature. As observed by HiKE-IMS-MS, the new third peak is also protonated showing that the para-protonated aniline and resulting fragment ion, molecular ion aniline, can be fully separated in the mobility domain for the first time. The appearance of the third peak is only possible due to the increased separation of the other two peaks within the HiKE-IMS.

A growing demand for low-cost gas sensors capable of detecting the smallest amounts of highly toxic substances in air, including chemical warfare agents (CWAs) and toxic industrial chemicals (TICs), has emerged in recent years. Ion mobility spectrometers (IMS) are particularly suitable for this application due to their high sensitivity and fast response times. In view of the preferred mobile use of such devices, miniaturized ion drift tubes are required as the core of IMS-based lightweight, low-cost, hand-held gas detectors. Thus, we evaluate the suitability of a miniaturized ion mobility spectrometer featuring an ion drift tube length of just 40 mm and a high resolving power of Rp= 60 for the detection of various CWAs, such as nerve agents sarin (GB), tabun (GA), soman (GD), and cyclosarin (GF), as well as the blister agent sulfur mustard (HD), the blood agent hydrogen cyanide (AC) and the choking agent chlorine (CL). We report on the limits of detection reaching minimum concentration levels of, for instance, 29 pptvfor sarin (GB) within an averaging time of only 1 s. Furthermore, we investigate the effects of precursors, simulants, and other common interfering substances on false positive alarms.

For various applications, such as gate drivers for transistors, wireless chargers for mobile devices and cars, and isolated measurement equipment, an isolated DC power supply for electronic components is required. In this work, a new concept for an isolated power supply with insulation strength of 50 kV and power transmission of up to 60 W to supply measurement equipment with 12 or 24 V is presented. Furthermore, high overall efficiency of 82.5% at 55 W is achieved. Feasibility is demonstrated in a real application powering data acquisition electronics at high reference potential. Our new concept uses a coreless printed circuit board (PCB) transformer (15 cm × 10 cm × 4 cm and a weight of 480 g) designed for maximum efficiency via a coil layout and close proximity of adjacent coils on one PCB while reaching high isolation strength via the PCB material and potted coils. To increase efficiency, we investigated different coil geometries at different frequencies. A low-cost design consisting of two Qi charging coils mounted on one PCB is compared with our integrated PCB transformers manufactured from a four-layer PCB with ferrites applied on the outside. With this new design, high isolation voltages are possible while reaching high transformer efficiency of up to 90%. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

High Kinetic Energy Ion Mobility Spectrometers (HiKE-IMS) chemically ionize gaseous samples via reactant ions and separate the generated ions by their motion in a neutral gas under the influence of an electric field. Operation at reduced pressures of 10–40 mbar allows for reaching high reduced electric field strengths (E/N) of up to 120 Td. At these high E/N, the generated ions gain the namesake high kinetic energies, leading to a decrease in cluster size of the reactant ions by increasing the reaction rate of collision-induced cluster dissociation of hydrates. In positive ion polarity and in purified air, H3O+(H2O)n, NO+(H2O)n, and O2+•(H2O)p are the most abundant reactant ions. In this work, we investigate the effect of varying sample gas humidity on product ion formation for several model substances. Results show that increasing the sample gas humidity at high E/N of 120 Td shifts product ion formation from a charge transfer dominated reaction system to a proton transfer dominated reaction system. For HiKE-IMS operated at high E/N, the reduction in cluster size of reactant ions allows ionization of analytes with low proton affinity even at high relative humidity in the sample gas of RH = 75% at 303.15 K and 1013.25 hPa. In contrast to conventional IMS, where increasing the sample gas humidity inhibits ionization for various analytes, increasing sample gas humidity in HiKE-IMS operated at 120 Td is actually beneficial for ionization yield of most analytes investigated in this work as it increases the number of H3O+(H2O)n.

Multidrug resistance is an emerging healthcare issue, especially concerning Pseudomonas aeruginosa. In this multicenter study, P. aeruginosa isolates with resistance against meropenem detected by routine methods were collected and tested for carbapenemase production and susceptibility against ceftazidime-avibactam. Meropenem-resistant isolates of P. aeruginosa from various clinical materials were collected at 11 tertiary care hospitals in Germany from 2017-2019. Minimum inhibitory concentrations (MICs) were determined via microdilution plates (MICRONAUT-S) of ceftazidime-avibactam and meropenem at each center. Detection of the presence of carbapenemases was performed by PCR or immunochromatography. For meropenem-resistant isolates (n = 448), the MIC range of ceftazidime-avibactam was 0.25-128 mg/L, MIC90 was 128 mg/L and MIC50 was 16 mg/L. According to EUCAST clinical breakpoints, 213 of all meropenem-resistant P. aeruginosa isolates were categorized as susceptible (47.5%) to ceftazidime-avibactam. Metallo-beta-lactamases (MBL) could be detected in 122 isolates (27.3%). The MIC range of ceftazidime-avibactam in MBL-positive isolates was 4-128 mg/L, MIC90 was >128 mg/L and MIC50 was 32 mg/L. There was strong variation in the prevalence of MBL-positive isolates among centers. Our in vitro results support ceftazidime-avibactam as a treatment option against infections caused by meropenem-resistant, MBL-negative P. aeruginosa.

BACKGROUND Since its first proposal, the concept of on- and off-track lesions in anterior shoulder instability has gained clinical relevance as a tool to predict the failure rate of arthroscopic Bankart repair. Current literature only reports either short-term follow-up or long-term results of small sample sizes. The aim of this study was to provide a long-term evaluation of recurrent instability following arthroscopic Bankart repair in a large cohort using the on-track vs. off-track concept as a predictor for failure. METHODS We retrospectively analyzed 271 patients who underwent primary arthroscopic Bankart repair for anterior shoulder instability between 1998 and 2007. All patients with a minimum follow-up of 78 months and a preoperative computed tomographic (CT) or magnetic resonance imaging (MRI) scan were included into the study. Preoperative CT and/or MRI scans were used to determine the glenoid track and width of Hill-Sachs lesion. Recurrence of instability was defined as presence of instability symptoms (dislocation, subluxation, and/or apprehension) or revision surgery (stabilization procedure) and was assessed as the primary outcome parameter. RESULTS The glenoid track of 163 shoulders was assessed (female n = 51, male n = 112) with a mean follow-up of 124 months (99.4-145.6, standard deviation = 2.5) and a mean age of 24 years (20-34.). An off-track Hill-Sachs lesion was found in 77 cases (47%), and in 86 cases (53 %) it was on-track. The rate of recurrent instability in the off-track group was 74% (n = 57) compared with 27% (n = 23) in the on-track group (P < .001). The overall rate of revision surgery due to instability was 29% (n = 48) after a mean time of 50.9 months (±42.8) following Bankart repair. The rate of revision surgery in the off-track group was 48% (n = 37) after a mean of 53.5 months (±42.0) vs. 13% (n = 11) after 42.3 months (±46.3) in the on-track group (P < .001). CONCLUSION This study shows that the on- and off-track concept helps to

CASE We report the case of a 35-year-old patient who presented with a septic residual synovial cavity infection 8 weeks after a through-the-knee amputation because of a parosteal sarcoma. An endoscopic evacuation of the turbid fluid and synovial debridement through parapatellar portals as in a standard knee arthroscopy was performed, in conjunction with appropriate antibiotic therapy. One year postoperatively, there were no signs of residual infection. CONCLUSION Endoscopic treatment of a septic stump infection of the residual synovial cavity after through-the-knee amputation is feasible. In our case, this approach resulted in rapid wound healing and early prosthesis mobility.

Renal tubular cells frequently lose differentiation markers and physiological properties when propagated in conventional cell culture conditions. Embedding cells in 3D microenvironments or controlling their 3D assembly by bioprinting can enhance their physiological properties, which is beneficial for modeling diseases in vitro. A potential cellular source for modeling renal tubular physiology and kidney diseases in vitro are directly reprogrammed induced renal tubular epithelial cells (iRECs). iRECs were cultured in various biomaterials and as bioprinted tubular structures. They showed high compatibility with the embedding substrates and dispensing methods. The morphology of multicellular aggregates was substantially influenced by the 3D microenvironment. Transcriptomic analyses revealed signatures of differentially expressed genes specific to each of the selected biomaterials. Using a new cellular model for autosomal-dominant polycystic kidney disease, Pkd1$^{-/-}$ iRECs showed disrupted morphology in bioprinted tubules and a marked upregulation of the Aldehyde dehydrogenase 1a1 (Aldh1a1). In conclusion, 3D microenvironments strongly influence the morphology and expression profiles of iRECs, help to unmask disease phenotypes, and can be adapted to experimental demands. Combining a direct reprogramming approach with appropriate biomaterials will facilitate construction of biomimetic kidney tubules and disease models at the microscale.

BACKGROUND The best treatment of degenerative hip abductor tendon lesions remains largely unknown, as the natural course of the disease has not yet been reported. The aim of the present study was to investigate the natural history of symptomatic degenerative hip abductor lesions. HYPOTHESIS Nonoperatively treated hip abductor lesions progress over time, resulting in refractory hip pain and low functional outcomes. STUDY DESIGN Case series (prognosis); Level of evidence, 4. METHODS Consecutive patients with greater trochanteric pain syndrome and degenerative changes on magnetic resonance imaging (MRI) of the symptomatic hip were included. Bilateral hip MRI scans and a clinical examination were performed at a minimum follow-up of 36 months to study the type and location of hip abductor lesion. Progression of a lesion was defined as a more severe lesion as compared with the initial MRI results or if the lesion extended to another, initially not involved, trochanteric facet. The muscle's fatty infiltration (FI) was also described. RESULTS From 106 patients identified, 58 patients (64 hips) aged 66 ± 14 years (mean ± SD) agreed to return to the clinic for follow-up MRI and met the inclusion criteria. At a mean 71-month follow-up, an overall 34% (22/64) of lesions had progressed over time: from trochanteric bursitis to tendinopathy (9/64, 14%) or partial tear (5/64, 8%), from tendinopathy to partial tear (4/64, 6%), from a partial to complete tear (3/64, 4.5%), and with 1 complete tear (1/64, 1.5%) extending to another trochanteric facet. Interestingly, 90% of partial tears remained stable or transformed into a scar. Although patients with a progressive lesion experienced more trochanteric pain (visual analog scale, 4.6 vs 2.8; P = .001), the functional outcomes were comparable with patients with a stable lesion. The majority of hips with a partial tear (64%) demonstrated a progression of gluteus minimus FI from a median grade of 1 to 2, whereas only 1 hip (3%) progressed