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Objectives One of the main challenges posed by the surgical deep brain stimulation (DBS) procedure is the successful targeting of the structures of interest and avoidance of side effects, especially in asleep surgery. Here, intraoperative motor evoked potentials (MEPs) might serve as tool to identify the pyramidal tract. We hypothesized that intraoperative MEPs are useful to define the distance to the pyramidal tract and reduce the occurrence of postoperative capsular side effects. Materials and methods Motor potentials were evoked through both microelectrode and DBS-electrode stimulation during stereotactic DBS surgery on 25 subthalamic nuclei and 3 ventral intermediate thalamic nuclei. Internal capsule proximity was calculated for contacts on microelectrode trajectories, as well as for DBS-electrodes, and correlated with the corresponding MEP thresholds. Moreover, the predictivity of intraoperative MEP thresholds on the probability of postoperative capsular side effects was calculated. Results Intraoperative MEPs thresholds correlated significantly with internal capsule proximity, regardless of the stimulation source. Furthermore, MEPs thresholds were highly accurate to exclude the occurrence of postoperative capsular side effects. Conclusions Intraoperative MEPs provide additional targeting guidance, especially in asleep DBS surgery, where clinical value of microelectrode recordings and test stimulation may be limited. As this technique can exclude future capsular side effects, it can directly be translated into clinical practice.

Background Endoscopic and laparoscopic electrosurgical devices (ED) are of great importance in modern medicine but can cause adverse events such as tissue injuries and burns from residual heat. While laparoscopic tools are well investigated, detailed insights about the temperature profile of endoscopic knives are lacking. Our aim is to investigate the temperature and the residual heat of laparoscopic and endoscopic monopolar instruments to increase the safety in handling ED. Methods An infrared camera was used to measure the temperature of laparoscopic and endoscopic instruments during energy application and to determine the cooling time to below 50 °C at a porcine stomach. Different power levels and cutting intervals were studied to investigate their impact on the temperature profile. Results During activation, the laparoscopic hook exceeded 120 °C regularly for an up to 10 mm shaft length. With regards to endoknives, only the Dual Tip Knife showed a shaft temperature of above 50 °C. The residual heat of the laparoscopic hook remained above 50 °C for at least 15 s after activation. Endoknives cooled to below 50 °C in 4 s. A higher power level and longer cutting duration significantly increased the shaft temperature and prolonged the cooling time (p Conclusion Residual heat and maximum temperature during energy application depend strongly on the chosen effect and cutting duration. To avoid potential injuries, the user should not touch any tissue with the laparoscopic hook for at least 15 s and with the endoknives for at least 4 s after energy application. As the shaft also heats up to over 120 °C, the user should be careful to avoid tissue contact during activation with the shaft. These results should be strongly considered for safety reasons when handling monopolar ED.

Manifestation of malignant lymphoma in the spine is rare, there have only been a few cases reported in the literature. Due to its rarity, there is no gold standard for the management of patients suffering from spinal lymphoma manifestations. Methods: We retrospectively reviewed the data for 37 patients (14 female, 23 male) with malignant lymphoma in the spine receiving intervention in our center from March 2006 until June 2020. Neurological impairment, pain, diagnostics, and/or surgical instability were the criteria for surgery in this patient cohort. Otherwise, only CT-guided biopsies were conducted. Analysis of the patient cohort was based on the Karnofsky performance status scale (KPSS), location of the lesion, spinal levels involved, spinal instability neoplastic score (SINS), surgical treatment, histopathological workup, adjuvant therapy, and overall survival. The following surgical procedures were performed: posterior stabilization and decompression in nine patients, decompression and/or tumor debulking in 18 patients, a two-staged procedure with dorsal stabilization and vertebral body replacement in four patients, decompression and biopsy in one patient, a two-stage procedure with kyphoplasty and posterior stabilization for one patient, posterior stabilization without decompression for one patient, a vertebroplasty and cement-augmented posterior stabilization for one patient, and a CT-guided biopsy alone for two patients. Twenty-one patients (56.78%) had ≥1 lesion in the thoracic spine, 10 patients (27.03%) had lesions in the lumbar spine, two patients had lesions in the cervicothoracic junction, two patients had lesions in the thoracolumbar junction, one patient had a lesion in the lumbosacral junction, and one patient had a lesion in the sacrum. The diagnoses of the histopathological workup were diffuse large B-cell lymphoma in 23 (62.16%) cases, indolent lymphoma in 11 (29.74%) cases, anaplastic T-cell lymphoma in one case (2.70%), T-cell lymphoma in one case (2.70%), and Burkitt lymphoma in one (2.70%) case. The median overall survival was 7.2 months (range 0.1–266.7 months). Pre- and postoperative KPSS scores were 70% (IQR 60–80%). Manifestation of malignant lymphomas in the spine is rare. Similar to the approach taken for spine metastases, a surgical intervention in cases of neurological impairment or manifest or potential instability is indicated, followed by chemoimmunotherapy and radiotherapy.

PurposeHypereosinophilia represents a heterogenous group of severe medical conditions characterized by elevated numbers of eosinophil granulocytes in peripheral blood, bone marrow or tissue. Treatment options for hypereosinophilia remain limited despite recent approaches including IL-5-targeted monoclonal antibodies and tyrosine kinase inhibitors.MethodsTo understand aberrant survival patterns and options for pharmacologic intervention, we characterized BCL-2-regulated apoptosis signaling by testing for BCL-2 family expression levels as well as pharmacologic inhibition using primary patient samples from diverse subtypes of hypereosinophilia (hypereosinophilic syndromen = 18, chronic eosinophilic leukemia not otherwise specifiedn = 9, lymphocyte-variant hypereosinophilian = 2, myeloproliferative neoplasm with eosinophilian = 2, eosinophilic granulomatosis with polyangiitisn = 11, reactive eosinophilian = 3).ResultsContrary to published literature, we found no difference in the levels of the lncRNAMorrbidand its targetBIM. Yet, we identified a near complete loss of expression of pro-apoptoticPUMAas well as a reduction in anti-apoptoticBCL-2. Accordingly,BCL-2inhibition using venetoclax failed to achieve cell death induction in eosinophil granulocytes and bone marrow mononuclear cells from patients with hypereosinophilia. In contrast,MCL1inhibition using S63845 specifically decreased the viability of bone marrow progenitor cells in patients with hypereosinophilia. In patients diagnosed with Chronic Eosinophilic Leukemia (CEL-NOS) or Myeloid and Lymphatic Neoplasia with hypereosinophilia (MLN-Eo) repression of survival was specifically powerful.ConclusionOur study shows thatMCL1inhibition might be a promising therapeutic option for hypereosinophilia patients specifically for CEL-NOS and MLN-Eo.

Background and Purpose: Structural brain networks possess a few hubs, which are not only highly connected to the rest of the brain but are also highly connected to each other. These hubs, which form a rich-club, play a central role in global brain organization. To investigate whether the concept of rich-club sheds new light on poststroke recovery, we applied a novel network-theoretical quantification of lesions to patients with stroke and compared the outcomes with what lesion size alone would indicate. Methods: Whole-brain structural networks of 73 patients with ischemic stroke were reconstructed using diffusion-weighted imaging data. Disconnectomes, a new type of network analyses, were constructed using only those fibers that pass through the lesion. Fugl-Meyer upper extremity scores and their changes were used to determine whether the patients show natural recovery or not. Results: Cluster analysis revealed 3 patient clusters: small-lesion-good-recovery, midsized-lesion-poor-recovery (MLPR), and large-lesion-poor-recovery (LLPR). The small-lesion-good-recovery consisted of subjects whose lesions were small, and whose prospects for recovery were relatively good. To explain the nondifference in recovery between the MLPR and LLPR clusters despite the difference (LLPR>MLPR) in lesion volume, we defined the metric to be the sum of the entries in the disconnectome and, more importantly, the to be the sum of all entries in the disconnectome corresponding to edges with at least one node in the rich-club. Unlike lesion volume and corticospinal tract damage (MLPR , this relationship was reversed (MLPR>LLPR) or showed no difference for . Conclusions: Smaller lesions that focus on the rich-club can be just as devastating as much larger lesions that do not focus on the rich-club, pointing to the role of the rich-club as a backbone for functional communication within brain networks and for recovery from stroke.

BACKGROUND Proprotein convertase subtilisin/kexin type-9 (PCSK9) is an enzyme promoting the degradation of low-density lipoprotein receptors (LDL-R) in hepatocytes. Inhibition of PCSK9 has emerged as a novel target for lipid-lowering therapy. Monocytes are crucially involved in the pathogenesis of atherosclerosis and can be divided into three subsets. OBJECTIVE The aim of this study was to examine whether circulating levels of PCSK9 are associated with monocyte subsets. METHODS We included 69 patients with stable coronary artery disease. PCSK9 levels were measured and monocyte subsets were assessed by flow cytometry and divided into classical monocytes (CD14++CD16-; CM), intermediate monocytes (CD14++CD16+; IM) and non-classical monocytes (CD14+CD16++; NCM). RESULTS Mean age was 64 years and 80% of patients were male. Patients on statin treatment (n = 55) showed higher PCSK9-levels (245.4 (206.0-305.5) ng/mL) as opposed to those without statin treatment (186.1 (162.3-275.4) ng/mL; p = 0.05). In patients on statin treatment, CM correlated with circulating PCSK9 levels (R = 0.29; p = 0.04), while NCM showed an inverse correlation with PCSK9 levels (R = -0.33; p = 0.02). Patients with PCSK9 levels above the median showed a significantly higher proportion of CM as compared to patients with PCSK9 below the median (83.5 IQR 79.2-86.7 vs. 80.4, IQR 76.5-85.2%; p = 0.05). Conversely, PCSK9 levels >median were associated with a significantly lower proportion of NCM as compared to those with PCSK9

To assess the feasibility of sparing routine antibiotic prophylaxis in patients without preoperative urinary tract infection (UTI) undergoing a miniaturized percutaneous nephrolithotomy (mPCNL). A retrospective, monocentric study was conducted to evaluate the outcome of a modified perioperative antibiotic management strategy according to the principles of antibiotic stewardship (ABS). From December 2015 patients undergoing mPCNL for kidney stone with preoperative unremarkable urine culture no longer received an antibiotic prophylaxis (NoPAP). The NoPAP group was compared to mPCNL patients who received standard antibiotic prophylaxis (PAP) in the two years before. Analysis focused on postoperative complications. Logistic regression analysis was performed to identify potential risk factors. Postoperative fever occurred in 8% of the NoPAP and 9% of the PAP patients (p = 0.764). Clavien 1–3 complications did not differ between groups with 33% in the NoPAP and 41% in the PAP (p = 0.511). No Clavien 4–5 complications were seen. A (partial) staghorn stone (HR 5.587; p = 0.019) and an infectious stone component (HR 6.313; p = 0.003) were identified as significant risk factors for postoperative fever. By sparing routine antibiotic prophylaxis the overall antibiotic usage was reduced from 100% (PAP) to 9% (NoPAP). Patients with negative preoperative UC, a none-staghorn stone and no history of recurrent UTI or infectious stones may not need routine antibiotic prophylaxis prior to mPCNL. A prospective validation is warranted.

Objective The effect of anesthesia type in terms of asleep vs. awake deep brain stimulation (DBS) surgery on therapeutic window (TW) has not been investigated so far. The objective of the study was to investigate whether asleep DBS surgery of the subthalamic nucleus (STN) improves TW for both directional (dDBS) and omnidirectional (oDBS) stimulation in a large single-center population. Materials and methods A total of 104 consecutive patients with Parkinson's disease (PD) undergoing STN-DBS surgery (80 asleep and 24 awake) were compared regarding TW, therapeutic threshold, side effect threshold, improvement of Unified PD Rating Scale motor score (UPDRS-III) and degree of levodopa equivalent daily dose (LEDD) reduction. Results Asleep DBS surgery led to significantly wider TW compared to awake surgery for both dDBS and oDBS. However, dDBS further increased TW compared to oDBS in the asleep group only and not in the awake group. Clinical efficacy in terms of UPDRS-III improvement and LEDD reduction did not differ between groups. Conclusions Our study provides first evidence for improvement of therapeutic window by asleep surgery compared to awake surgery, which can be strengthened further by dDBS. These results support the notion of preferring asleep over awake surgery but needs to be confirmed by prospective trials.

OBJECTIVERechargeable neurostimulators for deep brain stimulation have been available since 2008, promising longer battery life and fewer replacement surgeries compared to non-rechargeable systems. Long-term data on how recharging affects movement disorder patients are sparse. This is the first multicenter, patient-focused, industry-independent study on rechargeable neurostimulators.METHODSFour neurosurgical centers sent a questionnaire to all adult movement disorder patients with a rechargeable neurostimulator implanted at the time of the trial. The primary endpoint was the convenience of the recharging process rated on an ordinal scale from “very hard” (1) to “very easy” (5). Secondary endpoints were charge burden (time spent per week on recharging), user confidence, and complication rates. Endpoints were compared for several subgroups.RESULTSDatasets of 195 movement disorder patients (66.1% of sent questionnaires) with Parkinson’s disease (PD), tremor, or dystonia were returned and included in the analysis. Patients had a mean age of 61.3 years and the device was implanted for a mean of 40.3 months. The overall convenience of recharging was rated as “easy” (4). The mean charge burden was 122 min/wk and showed a positive correlation with duration of therapy; 93.8% of users felt confident recharging the device. The rate of surgical revisions was 4.1%, and the infection rate was 2.1%. Failed recharges occurred in 8.7% of patients, and 3.6% of patients experienced an interruption of therapy because of a failed recharge. Convenience ratings by PD patients were significantly worse than ratings by dystonia patients. Caregivers recharged the device for the patient in 12.3% of cases. Patients who switched from a non-rechargeable to a rechargeable neurostimulator found recharging to be significantly less convenient at a higher charge burden than did patients whose primary implant was rechargeable. Age did not have a significant impact on any endpoint.CONCLUSIONSOverall, patients with movement disorders rated recharging as easy, with low complication rates and acceptable charge burden.

Background Although short-term outcomes for liver transplantation have improved, patient and graft survival are limited by infection, cancer, and other complications of immunosuppression. Rapid induction of tolerance after liver transplantation would decrease these complications, improving survival and quality of life. Tolerance to kidneys, but not thoracic organs or islets, has been achieved in nonhuman primates and humans through the induction of transient donor chimerism. Since the liver is considered to be tolerogenic, we tested the hypothesis that the renal transplant transient chimerism protocol would induce liver tolerance. Methods Seven cynomolgus macaques received immune conditioning followed by simultaneous donor bone marrow and liver transplantation. The more extensive liver surgery required minor adaptations of the kidney protocol to decrease complications. All immunosuppression was discontinued on postoperative day (POD) 28. Peripheral blood chimerism, recipient immune reconstitution, liver function tests, and graft survival were determined. Results The level and duration of chimerism in liver recipients were comparable to those previously reported in renal transplant recipients. However, unlike in the kidney model, the liver was rejected soon after immunosuppression withdrawal. Rejection was associated with proliferation of recipient CD8 T effector cells in the periphery and liver, increased serum interleukin (IL)-6 and IL-2, but peripheral regulatory T cell (Treg) numbers did not increase. Antidonor antibody was also detected. Conclusions These data show the transient chimerism protocol does not induce tolerance to livers, likely due to greater CD8 T cell responses than in the kidney model. Successful tolerance induction may depend on greater control or deletion of CD8 T cells in this model.

Background Postoperative atrial fibrillation (POAF) is assumed as a complex and multifactorial interaction of different pathogenic factors. Data suggests an inflammatory process as the main trigger of this specific type of atrial fibrillation. CD8+ T lymphocytes that lack the surface protein CD28 were found to be crucially involved in chronic inflammatory processes within the cardiovascular system. Of utmost interest, these so-called CD8+CD28null T cells are known to present with autoaggressive behavior and deleterious cytotoxic effects on human tissue. Methods A total of 129 patients undergoing elective cardiac valve and/or coronary artery bypass graft surgery were enrolled. Fluorescence-activated cell sorting was performed to investigate lymphocyte subsets. Patients were stratified in two subgroups according to patients developing POAF (n = 60) and individuals free of POAF (n = 69). Results Comparing patients developing POAF to individuals free of POAF, the fraction of CD8+ lymphocytes was significantly higher in individuals developing POAF (30.5% [POAF] vs. 25.7% [no-POAF]; p = 0.021). Interestingly, also the fraction of CD8+CD28null T lymphocytes was significantly higher in the POAF subgroup (66.7% [POAF] vs. 61.6% [non-POAF]; p = 0.043). Multivariate logistic regression proved that the fraction of CD8+CD28null cells is a strong and independent prognosticator for the development of POAF with an adjusted odds ratio per 1 standard deviation of 3.21 (95% confidence interval 1.01–10.18; p = 0.048). Conclusion We found that cytotoxic CD8+CD28null T lymphocytes proved to be a strong and independent predictor for the development of POAF after elective cardiac surgery. Our results potentially indicate an autoimmune impact of this preexisting, highly cytotoxic T cell subset in the pathogenesis of POAF.

We report on 18 patients with myeloid neoplasms and associated tyrosine kinase (TK) fusion genes on treatment with the TK inhibitors (TKI) ruxolitinib (PCM1-JAK2, n = 8; BCR-JAK2, n = 1) and imatinib, nilotinib or dasatinib (ETV6-ABL1, n = 9). On ruxolitinib (median 24 months, range 2-36 months), a complete hematologic response (CHR) and complete cytogenetic response (CCR) was achieved by five of nine and two of nine patients, respectively. However, ruxolitinib was stopped in eight of nine patients because of primary resistance (n = 3), progression (n = 3) or planned allogeneic stem cell transplantation (allo SCT, n = 2). At a median of 36 months (range 4-78 months) from diagnosis, five of nine patients are alive: four of six patients after allo SCT and one patient who remains on ruxolitinib. In ETV6-ABL1 positive patients, a durable CHR was achieved by four of nine patients (imatinib with one of five, nilotinib with two of three, dasatinib with one of one). Because of inadequate efficacy (lack of hematological and/or cytogenetic/molecular response), six of nine patients (imatinib, n = 5; nilotinib, n = 1) were switched to nilotinib or dasatinib. At a median of 23 months (range 3-60 months) from diagnosis, five of nine patients are in CCR or complete molecular response (nilotinib, n = 2; dasatinib, n = 2; allo SCT, n = 1) while two of nine patients have died. We conclude that (a) responses on ruxolitinib may only be transient in the majority of JAK2 fusion gene positive patients with allo SCT being an important early treatment option, and (b) nilotinib or dasatinib may be more effective than imatinib to induce durable complete remissions in ETV6-ABL1 positive patients.

Introduction Dorsal root ganglion stimulation is a meanwhile established but rather new technique of neuromodulation to treat chronic pain states of different origin. While being primarily used in the lumbar region, dorsal root ganglion (DRG) stimulation also can be used in the upper thoracic and cervical region with slight alterations of the surgical approach. This offers new therapeutic options especially in the treatment of neuropathic pain states of the upper extremities. Data on surgical technique, outcome and complications rates of DRG in this region are limited. Materials and methods We report a consecutive series of 20 patients treated with DRG stimulation in the upper thoracic and cervical region. All patients suffered from chronic neuropathic pain unresponsive to best medical treatment. Main pain etiologies were trauma, spine surgery, postherpetic neuralgia, and peripheral nerve surgery. All patients were trialed with externalized electrodes prior to permanent pulse generator implantation. Routine clinical follow-up was performed during reprogramming sessions. Results Out of all 20 patients trialed, 18 were successfully trialed and implanted with a permanent stimulation system. The average pain relief after three months compared to the baseline was of 60.9% (mean VAS 8.5 to VAS 3.2). 77.8% of the patients reported a pain relief of at least 50% after three months. One patient developed a transient paresis of the arm caused by the procedure. She completely recovered within three months. Conclusion Cervical and upper thoracic DRG stimulation resulted in good overall response rates to trialing and similar pain relief when compared to DRG stimulation for groin and lower limb pain. A modified surgical approach has to be used when compared with lumbar DRG electrode placement. Surgery itself in this region is more complication prone and challenging.

INTRODUCTION Dorsal root ganglion stimulation (DRG) is a new but well-established neuromodulation technique allowing new indications and superiority to pre-existing stimulation techniques such as spinal cord stimulation in selected pain etiologies. Previous surgical procedures in the implantation area pose a challenge for the percutaneous technique and are therefore considered contraindications for DRG stimulation surgery. We describe the successful open DRG electrode placement in two patients with previous surgeries suffering from severe radiculopathy due to foraminal stenosis. METHODS Percutaneous implantation attempts failed and an open laminotomy/foraminotomy followed by open lead placement was performed. Leads and loops were placed under the microscope, lead location was verified by x-ray during surgery. Leads and loops were kept in position with fibrin glue and fibrin sealant patches. No special tool was required for open lead placement. RESULTS In both patients, surgery resulted in lead and loop placement resembling the results seen in percutaneous technique. Programming and stimulation results are similar to observations made following percutaneous techniques in one patient significantly lower stimulation amplitudes were necessary. In 18 and 12 months follow-up, respectively, lead location and paresthesia coverage were stable. CONCLUSION The option of open electrode placement should be taken into account following unsuccessful percutaneous lead placement. A combination of fibrin sealant patch and fibrin glue may be a good option for stabilization of the lead and specially of the strain relief loops in open placement. Knowledge of basic spinal surgery techniques and experience in percutaneous DRG stimulation is necessary to perform this procedure.

Background The benefit of alpelisib in hormone-receptor-positive (HR+) metastatic breast cancer patients provided clinical evidence for the increasing importance of PIK3CA testing. We performed a comparison of liquid biopsy and tissue-based detection of PIK3CA mutations. Materials and methods PIK3CA hotspot mutation analysis using a high-resolution SiMSen-Seq assay was performed in plasma from 93/99 eligible patients with HR+/HER2- breast cancer. Additionally, mFAST-SeqS was used to estimate the tumour fractions in plasma samples. In 72/93 patients, matched tissue was available and analysed using a customised Ion Torrent panel. Results PIK3CA mutations were detected in 48.6% of tissue samples and 47.3% of plasma samples, with identical PIK3CA mutation detected in 24/72 (33.3%) patients both in tissue and plasma. In 10 (13.9%) patients, mutations were only found in plasma, and in 6 (8.3%) patients, PIK3CA mutations found in tissue were not detectable in ctDNA. In 49/93 plasma samples without detectable PIK3CA mutations, 22 (44.9%) samples had elevated tumour fractions, implying true negative results. Conclusion SiMSen-Seq-based detection of PIK3CA mutations in plasma shows advantageous concordance with the tissue analyses. A combination with an untargeted approach for detecting ctDNA fractions may confirm a negative PIK3CA result and enhance the performance of the SiMSen-Seq test.

Apart from clinical data, mouse models for SARS have helped advance our knowledge in fighting against COVID-19. We emphasised on a physiological model of infection and host-compatibility and used the murine coronavirus mCoV-A59, which belongs to the same subgroup as SARS-CoV-2. Thus, we could mimic asymptomatic infections with an immune response that results in major virus clearance at day 10 post infection. Using histology, multi-colour flow cytometry and RNAseq of mCoV infected lungs, we were able to detect an intriguing temporal interplay of innate and adaptive immunity in virus resolution. Virus clearance was already evident after 4 days and RNAseq revealed the unexpectedly crucial role of innate immune cell regulation, being strongest regulated cellular pathway. Moreover, interferon type I signalling was also remarkably upregulated during this early phase; a hallmark of SARS-CoV infections and mainly produced by innate immune cells. Lung cell apoptosis was highest at day 10, at which we could also observe a distinct increase in cytotoxic CD8 T cells. This indicates that successful, rapid SARS-CoV clearance depends mainly on innate immunity rather than on adaptive responses, while at a later phase recruited CD8 T cells contribute to lung tissue damage. This early innate immune response might explain the observed decline of SARS-CoV-2 antibodies in asymptomatic or mild infections. Thus, we highlight the importance to strengthen the innate immune system at the beginning of a SARS-CoV infection with the requirement to dampen CD8 T cell function. Lastly, our model allows screening of compounds modulating the innate and adaptive immunity during disease.

We present a method for automated nucleus identification and tracking in time-lapse microscopy recordings of entire developing embryos. Our method combines deep learning and global optimization to enable complete lineage reconstruction from sparse point annotations, and uses parallelization to process multi-terabyte light-sheet recordings, which we demonstrate on three common model organisms: mouse, zebrafish,Drosophila. On the most difficult dataset (mouse), our method correctly reconstructs 75.8% of cell lineages spanning 1 hour, compared to 31.8% for the previous state of the art, thus enabling biologists to determine where and when cell fate decisions are made in developing embryos, tissues, and organs.

Introduction Recent advances in prophylactic anticoagulation and antineoplastic treatment for advanced pancreatic cancer (aPC) warrant an updated reassessment of thromboembolic risk in this population. This multicenter retrospective cohort study aims to comprehensively characterize incidence, risk factors, and outcomes of venous (VTE) and arterial thromboembolism (ATE) in homogenously treated patients with aPC. Methods Four hundred and fifty-five patients with aPC undergoing palliative first-line chemotherapy (Gemcitabine/nab-Paclitaxel (GN) or FOLIRINOX) were included. Primary outcomes were objectively confirmed VTE and/or ATE. Results Over a median follow-up of 26 months, 86 VTE (cumulative incidence: 20.0%; 95% confidence interval [CI]: 16.3–24.0) and 11 ATE events (cumulative incidence: 2.8%; 95% CI: 1.5–4.9) were observed. VTE diagnosis was associated with increased mortality (transition hazard ratio [THR]: 1.59 [95% CI: 1.21–2.09]) and increased risk of cancer progression (THR: 1.47 [95% CI: 1.08–2.01]), while the impact of ATE on mortality was numerically but not statistically significant (THR: 1.85 [95% CI: 0.87–3.94]). The strongest predictor of increased VTE risk was history of cancer-associated VTE (subdistribution hazard ratio [SHR]: 3.29 [95% CI: 2.09–5.18]), while the Khorana score (SHR: 0.78 [0.57–1.06]) failed to predict VTE risk. A history of cerebrovascular disease was associated with markedly increased ATE risk (SHR: 22.05 [95% CI: 6.83–71.22], p Conclusion Patients with aPC undergoing palliative first-line chemotherapy with FOLFIRINOX or GN face a high risk for VTE/ATE and its diagnosis is linked to worse clinical outcomes. VTE-risk prediction models have limited ability to sub-stratify thrombotic events in this high-risk scenario.

Background: Increasing life expectancy and demographic change result in a rising number of geriatric patients, but knowledge about geriatric treatment options and adapted diagnostic pathways is low. Simultaneously, urinary tract infections (UTIs) are common in older people and often difficult to treat. Methods: Patients with a UTI at a urological outpatient department between January 01, 2016, and December 31, 2017, were retrospectively identified in the data system. One thousand one hundred fifteen patients with “N30” and “N39” diagnosis were included in this study, 965 of which were under the age of 75 (group 1) and 150 of which 75 years or older (group 2). Results: Of 150 patients in group 2, 41.6% had nitrite-positive urine (vs. 20.9% in group 1, p < 0.05 in χ2 testing). Patients in group 2 often had indwelling devices (30.3 vs. 6.0%, p < 0.05) and presented a sterile urine culture in only 20.7% (vs. 40.1% in group 1). Regarding calculated antibiotic therapy, there were significant differences concerning prescription of ciprofloxacin (34.9 vs. 25%, p < 0.05) and fosfomycin (12.7 vs. 40.7%, p < 0.05). Conclusion: UTI in geriatric patients should be treated differently than in younger patients because antibiotic resistance is high. The group with indwelling devices is complex. Individual strategies for geriatric patients should be considered.

Objective With the introduction of the 5-aminolevulinic acid (5-ALA) technique, surgical neuro-oncology has made a major advance. 5-ALA fluorescence–guided resection of malignant glioma results in more complete surgical resections and subsequently prolonged survival. However, it remains uncertain how light intensities of the blue light source and 5-ALA–derived fluorescence intensities of the illuminated tissue are connected. The aim of the present study was to compare light intensities of different blue light sources and protoporphyrin (PpIX) fluorescence intensities of PpIX solutions with defined concentrations after illumination with different light sources. Material and Methods The light spectrum of 7 different blue light sources and the fluorescence intensity of 2 PpIX solutions (0.15 μg/mL and 5 μg/mL) were quantified after illumination. We compared the Zeiss OPMI Pentero microscope, the Zeiss OPMI Pentero 900 microscope, the Leica M530 OH6 microscope, an endoscope equipped with the 5-ALA technique, a mini-spectrometer equipped with a multi-channel light-emitting diode (LED) source emitting monochromatic light, a modified commercially available LED head lamp, and a commercially available unmodified UV-LED lamp. PpIX fluorescence was quantified in a standardized setup using a mini-spectrometer. Results Maximum light intensities of the evaluated light sources were reached at different wavelengths. All tested devices were able to detect PpIX-induced fluorescence. However, the intensity of PpIX fluorescence of the differently concentrated PpIX solutions (0.15 μg/mL and 5 μg/mL) was significantly dependent on the light source used. Conclusions Intensity of the 5-ALA–derived fluorescence is related to the light source used.

Light-sheet imaging of cleared and expanded samples creates terabyte-sized datasets that consist of many unaligned three-dimensional image tiles, which must be reconstructed before analysis. We developed the BigStitcher software to address this challenge. BigStitcher enables interactive visualization, fast and precise alignment, spatially resolved quality estimation, real-time fusion and deconvolution of dual-illumination, multitile, multiview datasets. The software also compensates for optical effects, thereby improving accuracy and enabling subsequent biological analysis.

This prospective trial aimed to investigate whether tumor-specific cKIT and PDGFRA mutations can be detected and quantified in circulating tumor (ct)DNA in patients with active GIST, and whether detection indicates disease activity. We included 25 patients with active disease and cKIT or PDGFRA mutations detected in tissue. Mutant ctDNA was detected in the peripheral blood plasma using allele-specific ligation (L-)PCR and droplet digital (d)PCR. CtDNA harboring tumor-specific cKIT or PDGFRA mutations was detected at least once in 16 out of 25 patients using L-PCR (64%) and in 20 out of 25 patients with dPCR (80%). Using dPCR, the absolute numbers of ctDNA fragments (DNA copies/ml) and the mutant allele frequency (MAF; in percent of wild-type control) strongly correlated with tumor size expressed as RECIST1.1 sum of diameter (SOD) in mm (ρ = 0.3719 and 0.408, respectively, p < 0.0001) and response status (ρ = 0.3939 and 0.392, respectively, p < 0.0001 and p < 0.001). Specificity of dPCR for detection of progression was 79.2% with a sensitivity of 55.2% and dPCR discriminated CR from active disease with a specificity of 96% and s sensitivity of 44.7%. With L-PCR, correlations of MAF with tumor size and response status were less prominent. Serial ctDNA measurement reflected individual disease courses over time. Targeted panel sequencing of four patients detected additional driver mutations in all cases and secondary resistance mutations in two cases. Thus, ctDNA indicates disease activity in patients with GIST and should be incorporated as companion biomarker in future prospective trials.

Kinase inhibitors are now among the most important drugs in targeted therapy and are used in particular for the treatment of different tumor entities. Since many kinase inhibitors inhibit various tyrosine kinases efficiently but not specifically, they are often characterized by their versatile use in a wide variety of entities and diseases. The diverse use of this group of drugs, as well as the challenge of their side-effect profile, continues to make kinase inhibitors the subject of numerous clinical studies. The following article provides an overview of recent new approvals in the field of kinase inhibitors and shows their importance for oncological therapy.

Introduction The burst waveform, a recent innovation in spinal cord stimulation (SCS), can achieve better outcomes than conventional tonic SCS, both for de novo implants and as a salvage therapy. Burst stimulation delivers more energy per second than tonic stimulation, which is a consideration for battery consumption. The clinical effectiveness of an energy-conserving strategy was investigated. Methods Subjects were experienced users of BurstDR SCS for back and leg pain. Three 2-week stimulation paradigms were presented in blinded random order: standard (continuously delivered) BurstDR, microdosing A: 5 sec of BurstDR alternating with 5 sec of no stimulation, and microdosing B: 5 sec of BurstDR alternating with 10 sec of no stimulation. The primary outcome for each paradigm was change in pain ratings, and secondary outcomes included changes in scores for quality of life, satisfaction, and preference. Results Twenty-five subjects assessed all three stimulation paradigms. There were no significant differences in pain (visual analog scale) or quality of life (EQ-5D) when comparing standard burst outcomes with those of microdosing A and, separately, microdosing B. Microdosing paradigms were graded with slightly higher level of satisfaction and were generally preferred above standard burst stimulation. Discussion These results suggest that the use of energy-efficient burst microdosing stimulation paradigms with alternating stimulation-on and stimulation-off periods can provide clinically equivalent results to standard burst stimulation. This is important for extending SCS battery life. Further research is needed to comprehensively characterize the clinical utility of this approach and the neurophysiological mechanisms for the maintenance of pain relief during stimulation-off periods.

Although it is well-known that smoking can cause lung cancer, the relationship between smoking and urologic cancers seems not as obvious and awareness is not widespread in the general population. For the KRAUT (knowledge of the relation between smoking and urological tumors among patients with a urological tumor disease) study, 258 patients with the diagnosis of urological cancer were interviewed using a questionnaire. Most (72.1%) stated that they never had a conversation regarding this topic with any doctor. Educational work in this field should be intensified to reduce the development and progression of urologic cancer. Purpose: Our objective was to investigate whether patients with urologic tumors were aware of smoking as a risk factor for the development and progression of several urologic cancers and the extent of the medical education they had received. Another aim was to investigate whether gender or age influenced patients' willingness to change their smoking habits. Materials and Methods: Patients with histologically malignant urologic tumors were enrolled in our questionnaire-based study from September 2013 to December 2014 in 2 urology departments. Patients were asked about their smoking habits and their general understanding of the relationship between smoking and the onset of cancer (urologic cancer and lung cancer). Also, the extent of information they had acquired from a physician was assessed. The descriptive and oncologic data of the patients were recorded. Results: Of 258 enrolled patients, 186 (72.1%) had never had an informational discussion with a doctor about smoking and their urologic tumor disease. Of the 160 active and former smokers, only 45 (28.1%) were planning to stop or reduce smoking because of their tumor disease. The willingness to change smoking habits was greater for women, with a statistically significant difference (odds ratio, 5.59;P = .002). Younger patients aged

In Deutschland erkranken nach Angaben des Robert-Koch-Instituts jahrlich etwa 1.200 Menschen neu an einer chronischen myeloischen Leukamie (CML). Durch die Einfuhrung von Tyrosinkinaseinhibitoren, die sich gegen das Fusionsprotein BCR-ABL1, eine pathologische Tyrosinkinase mit konstitutiver Aktivitat richten, hat sich die Prognose der Betroffenen deutlich gebessert. Fur einen Teil der Patienten bietet sich moglicherweise sogar die Chance auf eine andauernde therapiefreie Remission. Wie steht es um die Therapie von CML-Patienten in Deutschland?

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): FWF Background and aims Proprotein convertase subtilisin/kexin type-9 (PCSK9) is an enzyme promoting the degradation of low-density lipoprotein receptors (LDL-R) in hepatocytes. Inhibition of PCSK9 has emerged as a novel target for lipid-lowering therapy. Monocytes are crucially involved in the pathogenesis of atherosclerosis and can be divided into three subsets. The aim of this study was to examine whether circulating levels of PCSK9 are associated with monocyte subsets. Methods We included 69 patients with stable coronary artery disease. PCSK9 levels were measured and monocyte subsets were assessed by flow cytometry and divided into classical monocytes (CD14++CD16-; CM), intermediate monocytes (CD14++CD16+; IM) and non-classical monocytes (CD14 + CD16++; NCM). Results Mean age was 64 years and 80% of patients were male. Patients on statin treatment (n = 55) showed higher PCSK9-levels (245.4 (206.0-305.5) ng/mL) as opposed to those without statin treatment (186.1 (162.3-275.4) ng/mL; p = 0.05). In patients on statin treatment, CM correlated with circulating PCSK9 levels (R = 0.29; p = 0.04), while NCM showed an inverse correlation with PCSK9 levels (R=-0.33; p = 0.02). Patients with PCSK9 levels above the median showed a significantly higher proportion of CM as compared to patients with PCSK-9 below the median (83.5 IQR 79.2-86.7 vs. 80.4, IQR 76.5-85.2%; p = 0.05). Conversely, PCSK9 levels >median were associated with a significantly lower proportion of NCM as compared to those with PCSK9 Conclusions We hereby provide a novel link between PCSK9 regulation, innate immunity and atherosclerotic disease in statin-treated patients.

Numerical simulations are subject to uncertainties due to the imprecise knowledge of physical properties, model parameters, as well as initial and boundary conditions. The assessment of these uncertainties is required for some applications. In the field of Computational Fluid Dynamics (CFD), the reliable prediction of hydrogen distribution and pressure build-up in nuclear reactor containment after a severe reactor accident is a representative application where the assessment of these uncertainties is of essential importance. The inital and boundary conditions that significantly influence the present buoyancy-driven flow are subject to uncertainties. Therefore, the aim is to investigate the propagation of uncertainties in input parameters to the results variables. As a basis for the examination of a representative reactor test containment, the investigations are initially carried out using the Differentially Heated Cavity (DHC) of aspect ratio 4 with Ra=2e9 as a test case from the literature. This allows for gradual method development for guidelines to quantify the uncertainty of natural convection flows in large-scale industrial applications. A dual approach is applied, in which Large Eddy Simulation (LES) is used as reference for the Unsteady Reynolds-Averaged Navier–Stokes (URANS) computations. A methodology for the uncertainty quantification in engineering applications with a preceding mesh convergence study and sensitivity analysis is presented. By taking the LES as a reference, the results indicate that URANS is able to predict the underlying mixing process at Ra=2e9 and the variability of the result variables due to parameter uncertainties.

Background: The level of evidence for palliative second-line therapy in advanced esophageal squamous cell carcinoma (aESCC) is limited. This is the first study that reports efficacy data comparing second-line therapy + active symptom control (ASC) versus ASC alone in aESCC. Methods: We conducted a tri-center retrospective cohort study ( n = 166) including patients with aESCC who had experienced disease progression on palliative first-line therapy. A propensity score model using inverse probability of treatment weighting (IPTW) was implemented for comparative efficacy analysis of overall survival (OS) in patients with second-line + ASC ( n = 92, 55%) versus ASC alone ( n = 74, 45%). Results: The most frequent second-line regimens used were docetaxel (36%) and paclitaxel (18%). In unadjusted primary endpoint analysis, second-line + ASC was associated with significantly longer OS compared with ASC alone [hazard ratio (HR) = 0.49, 95% confidence interval (CI): 0.35–0.69, p Conclusion: This real-world study supports the concept that systemic second-line therapy prolongs survival in patients with aESCC.

Background: The prognostic performance of the residual cancer burden (RCB) score is a promising tool for breast cancer patients undergoing neoadjuvant therapy. We independently evaluated the prognostic value of RCB scores in an extended validation cohort. Additionally, we analyzed the association between chemotherapy dose reduction and RCB scores. Methods: In this extended validation study, 367 breast cancer patients with available RCB scores were followed up for recurrence-free survival (RFS), distant disease-free survival (DDFS), and overall survival (OS). We also computed standardized cumulative doses of anthracyclines and taxanes (A/Ts) to investigate a potential interaction between neoadjuvant chemotherapy dose reduction and RCB scores. Results: Higher RCB scores were consistently associated with adverse clinical outcomes across different molecular subtypes (HR for RFS = 1.60, 95% CI 1.33–1.93, p &lt, 0.0001, HR for DDFS = 1.70, 95% CI 1.39–2.05, p &lt, HR for OS = 1.67, 95% CI 1.34–2.08, p &lt, 0.0001). The adverse impact prevailed throughout 5 years of follow-up, with a peak for relapse risk between 1–2 years after surgery. Clinical outcomes of patients with RCB class 1 did not differ substantially at 5 years compared to RCB class 0. A total of 180 patients (49.1%) underwent dose reduction of neoadjuvant A/T chemotherapy. We observed a statistically significant interaction between dose reduction and higher RCB scores (interaction p-value = 0.042). Conclusion: Our results confirm RCB score as a prognostic marker for RFS, DDFS, and OS independent of the molecular subtype. Importantly, we show that lower doses of cumulative neoadjuvant A/T were associated with higher RCB scores in patients who required a dose reduction.

Osteoporosis is the most common bone disease and is conventionally classified as a decrease of total bone mass. Current diagnosis of osteoporosis is based on clinical risk factors and dual energy X‐ray absorptiometry (DEXA) scans, but changes in bone quantity (bone mass) and quality (trabecular structure, material properties, and tissue composition) are not distinguished. Yet, osteoporosis is known to cause a deterioration of the trabecular network, which might be related to changes at the tissue scale—the material properties. The goal of the current study was to use a previously established test method to perform a thorough characterization of the material properties of individual human trabeculae from femoral heads in cyclic tensile tests in a close to physiologic, wet environment. A previously developed rheological model was used to extract elastic, viscous, and plastic aspects of material behavior. Bone morphometry and tissue mineralization were determined with a density calibrated micro‐computed tomography (μCT) set‐up. Osteoporotic trabeculae neither showed a significantly changed material or mechanical behavior nor changes in tissue mineralization, compared with age‐matched healthy controls. However, donors with osteopenia indicated significantly reduced apparent yield strain and elastic work with respect to osteoporosis, suggesting possible initial differences at disease onset. Bone morphometry indicated a lower bone volume to total volume for osteoporotic donors, caused by a smaller trabecular number and a larger trabecular separation. A correlation of age with tissue properties and bone morphometry revealed a similar behavior as in osteoporotic bone. In the range studied, age does affect morphometry but not material properties, except for moderately increased tissue strength in healthy donors and moderately increased hardening exponent in osteoporotic donors. Taken together, the distinct changes of trabecular bone quality in the femoral head caused by osteoporosis and aging could not be linked to suspected relevant changes in material properties or tissue mineralization. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., Individual trabeculae of human femoral heads were tested cyclically in tensile mode. Tensile modulus was determined in each loading and unloading cycle and significantly larger in the unloading phase. Determination of material properties with a rheological model revealed no significant difference between control and osteoporotic trabeculae. In contrast, bone morphometry was significantly deteriorated in osteoporosis and with increased ageing.

Background: Urine examination has relevance for treatment, and reliability of positive urine culture (UC) is of importance. The technique of urine sampling (US), storage, and transportation is important. The objective of this study was to investigate if detailed patient information for the technique of US and hygiene reduces rates of contaminated UC in screened male patients, as this group was not investigated yet. Methods: All patients independently of complaints were enrolled prospectively and consecutively in an outpatient setting in 2 groups – the first group did not receive detailed information and the second group did. We examined 372 consecutive patients in 2017, 190 not receiving (median age 69 years) and 182 receiving information (median age 70 years), with comparable numbers of patients and age. The result of UC and age was imposed. Results: In all,74.2% of preclarification UC showed a contamination (n = 95) and 75.5% after clarification (n = 83), without significant differences (p = 0.827). This study is limited by the fact that adherence could not be checked. Conclusions: Similar to studies with females, no difference occurred in rates of contaminated UC, so detailed information regarding the US technique does not decrease rates of contaminated UC and vice versa does not increase the quality of midstream-sampled UC in male patients.

The clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. On the basis of 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved overall response and disease control rates (23.9% and 55.3%) compared with previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients. These data demonstrate the benefit of molecular stratification in rare cancers and represent a resource that may promote clinical trial access and drug approvals in this underserved patient population. Significance: Rare cancers are difficult to treat; in particular, molecular pathogenesis–oriented medical therapies are often lacking. This study shows that whole-genome/exome and RNA sequencing enables molecularly informed treatments that lead to clinical benefit in a substantial proportion of patients with advanced rare cancers and paves the way for future clinical trials. See related commentary by Eggermont et al., p. 2677. This article is highlighted in the In This Issue feature, p. 2659

Nicorandil, a balanced vasodilator, is used in the second-line therapy of angina pectoris. In this study, we aimed to illuminate the effects of nicorandil on inflammation, apoptosis, and atherosclerotic plaque progression. Twenty-five LDL-R -/- mice were fed a high-fat diet for 14 weeks. After 6 weeks mice were randomly allocated to treatment with nicorandil (10 mg/kg/day) or tap water. Nicorandil treatment led to a more stable plaque phenotype, displaying an increased thickness of the fibrous cap (p = 0.014), a significant reduction in cholesterol clefts (p = 0.045), and enhanced smooth muscle cell content (p = 0.009). In endothelial cells nicorandil did not reduce the induction of adhesion molecules or proinflammatory cytokines. In H2O2 challenged endothelial cells, pretreatment with nicorandil significantly reduced the percentage of late apoptotic/necrotic cells (p = 0.016) and the ratio of apoptotic to living cells (p = 0.036). Atherosclerotic lesions of animals treated with nicorandil exhibited a significantly decreased content of cleaved caspase-3 (p = 0.034), lower numbers of apoptotic nuclei (p = 0.040), and reduced 8-oxogunanine staining (p = 0.039), demonstrating a stabilizing effect of nicorandil in established atherosclerotic lesions. We suggest that nicorandil has a positive effect on atherosclerotic plaque stabilization by reducing apoptosis.

Transcranial direct current stimulation (tDCS)-based interventions for augmenting motor learning are gaining interest in systems neuroscience and clinical research. Current approaches focus largely on monofocal motorcortical stimulation. Innovative stimulation protocols, accounting for motor learning related brain network interactions also, may further enhance effect sizes. Here, we tested different stimulation approaches targeting the cerebro-cerebellar loop. Forty young, healthy participants trained a fine motor skill with concurrent tDCS in four sessions over two days, testing the following conditions: (1) monofocal motorcortical, (2) sham, (3) monofocal cerebellar, or (4) sequential multifocal motorcortico-cerebellar stimulation in a double-blind, parallel design. Skill retention was assessed after circa 10 and 20 days. Furthermore, potential underlying mechanisms were studied, applying paired-pulse transcranial magnetic stimulation and multimodal magnetic resonance imaging-based techniques. Multisession motorcortical stimulation facilitated skill acquisition, when compared with sham. The data failed to reveal beneficial effects of monofocal cerebellar or additive effects of sequential multifocal motorcortico-cerebellar stimulation. Multimodal multiple linear regression modelling identified baseline task performance and structural integrity of the bilateral superior cerebellar peduncle as the most influential predictors for training success. Multisession application of motorcortical tDCS in several daily sessions may further boost motor training efficiency. This has potential implications for future rehabilitation trials.

A stop-flow sample delivery system for transient spectroscopy is presented, which is, in particular, suited for laser-based instruments (quantum-cascade lasers or amplified femtosecond lasers) with excitation pulse repetition rates in the range 10–100 Hz. Two pulsing micro-valves are mounted onto a flow cuvette designed for transient IR spectroscopy, which is integrated into a flow cycle driven by a peristaltic pump. The performance of the system is demonstrated with transient IR experiments of the trans-to-cis photoisomerization of a water-soluble azobenzene derivative. The sample stands still when the micro-valves are closed and is pushed out from the probe beam focus on a 1 ms timescale when opening the micro-valves. The setup is extremely sample efficient. It needs only small sample volumes, and at the same time, it enables excitation of a large fraction of molecules in solution.

Population protocols are a well established model of computation by anonymous, identical finite state agents. A protocol is well-specified if from every initial configuration, all fair executions reach a common consensus. The central verification question for population protocols is the well-specification problem: deciding if a given protocol is well-specified. Esparza et al. have recently shown that this problem is decidable, but with very high complexity: it is at least as hard as the Petri net reachability problem, which is EXPSPACE-hard, and for which only algorithms of non-primitive recursive complexity are currently known. In this paper we introduce the class WS3 of well-specified strongly-silent protocols and we prove that it is suitable for automatic verification. More precisely, we show that WS3 has the same computational power as general well-specified protocols, and captures standard protocols from the literature. Moreover, we show that the membership problem for WS3 reduces to solving boolean combinations of linear constraints over N. This allowed us to develop the first software able to automatically prove well-specification for all of the infinitely many possible inputs., 29 pages, 1 figure

Background End-of-life decisions, specifically the provision of euthanasia and assisted suicide services, challenge traditional medical and ethical principles. Austria and Germany have decided to liberalize their laws restricting assisted suicide, thus reigniting the debate about a meaningful framework in which the practice should be embedded. Evidence of the relevance of assisted suicide and euthanasia for the general population in Germany and Austria is limited. Objective The aim of this study is to examine whether the public awareness documented by search activities in the most frequently used search engine, Google, on the topics of palliative care, euthanasia, and advance health care directives changed with the implementation of palliative care services and new governmental regulations concerning end-of-life decisions. Methods We searched for policies, laws, and regulations promulgated or amended in Austria, Germany, and Switzerland between 2004 and 2020 and extracted data on the search volume for each search term topic from Google Trends as a surrogate of public awareness and interest. Annual averages were analyzed using the Joinpoint Regression Program. Results Important policy changes yielded significant changes in search trends for the investigated topics. The enactment of laws regulating advance health care directives coincided with a significant drop in the volume of searches for the topic of euthanasia in all 3 countries (Austria: −24.48%, P=.02; Germany: −14.95%, P Conclusions Our results demonstrate that legal measures securing patients’ autonomy at the end of life may lower the search activities for topics related to euthanasia and assisted suicide. Palliative care may be a meaningful way to raise awareness of the different options for end-of-life care and to guide patients in their decision-making process regarding the same.

Since metastatic colorectal cancer (CRC) is a leading cause of cancer-related death, therapeutic approaches overcoming primary and acquired therapy resistance are an urgent medical need. In this study, the efficacy and toxicity of high-affinity inhibitors targeting antiapoptotic BCL-2 proteins (BCL-2, BCL-XL, and MCL-1) were evaluated. By RNA sequencing analysis of a pan-cancer cohort comprising >1500 patients and subsequent prediction of protein activity, BCL-XL was identified as the only antiapoptotic BCL-2 protein that is overactivated in CRC. Consistently, pharmacologic and genetic inhibition of BCL-XL induced apoptosis in human CRC cell lines. In a combined treatment approach, targeting BCL-XL augmented the efficacy of chemotherapy in vitro, in a murine CRC model, and in human ex vivo derived CRC tissue cultures. Collectively, these data show that targeting of BCL-XL is efficient and safe in preclinical CRC models, observations that pave the way for clinical translation.

Purpose: The coronavirus disease 2019 (COVID-19) pandemic is disrupting urology health-care worldwide. Reduced emergency room visits resulting in adverse outcomes have most recently been reported in pediatrics and cardiology. We aimed to compare patients with emergency room visits for pyelonephritis in 2019 (pre-COVID-19 era) and within the first wave of pandemic in 2020 (COVID-19 era) with regard to the number of visits and severe adverse disease outcomes. Methods: We performed a retrospective multicentre study comparing characteristics and outcomes of patients with pyelonephritis, excluding patients with hydronephrosis due to stone disease, in 10 urology departments in Germany during a 1-month time frame in March and April in each 2019 and 2020. Results: The number of emergency room visits for pyelonephritis in the COVID-19 era was lower (44 patients, 37.0%) than in the pre-COVID-19 era (76 patients, 63.0%), reduction rate: 42.1% (p = 0.003). Severe adverse disease outcome was more frequent in the COVID-19 era (9/44 patients, 20.5%) than in the pre-COVID-19 era (5/76 patients, 6.6%, p = 0.046). In detail, 7 versus 3 patients needed monitoring (15.9 vs. 3.9%), 2 versus no patients needed intensive-care treatment (4.5 vs. 0%), 2 versus no patients needed drain placement (4.5 vs. 0%), 2 versus no patients had a nephrectomy (4.5 vs. 0%), and 2 versus 1 patient died (4.5 vs. 1.3%). Conclusion: This report of collateral damage during CO­VID-19 showed that emergency room visits were decreased, and severe adverse disease outcomes were increased for patients with pyelonephritis in the COVID-19 era. Health authorities should set up information campaign programs actively encouraging patients to utilize emergency room services in case of severe symptoms specifically during the actual second wave of pandemic.

Introduction Sphenopalatine ganglion (SPG) stimulation is an efficient treatment for cluster headache. The target for the SPG microstimulator in the pterygopalatine fossa lies between the vidian canal and foramen rotundum, ideally two contacts should be placed in this area. However, placement according to the manufacturers recommendations is frequently not possible. It is not known whether a suboptimal electrode placement interferes with postoperative outcomes. Materials and methods SPG stimulation was performed in 13 patients between 2015 and 2018 in a single center. Lead location was determined by intraoperative computed tomography scan and correlated with the planned lead position as well as clinical data and stimulation parameters. Patients with a reduction of 50% or more in pain intensity or frequency were considered responsive. Results Eleven patients (84.6%) responded to SPG stimulation with eight being frequency responders (61.5%). In seven cases, there were less than two electrodes between vidian canal and foramen rotundum, there was no significant correlation with negative stimulation results (p = 0.91). The mean distance of lead location between pre- and postoperative images did not correlate with clinical outcomes (p = 0.84) and was even bigger in responders (4.91 mm vs. 4.53 mm). The closest electrode contact to the vidian canal was in the stimulation area in all but one patient, regardless of its overall distance to canal. The distance of the closest electrode to the vidian canal was, however, not significantly correlated to the percentage of frequency (p = 0.68) or intensity reduction (p = 0.61). Conclusion There was no significant correlation regarding aberrations of lead position from the planned position with clinical outcome. However, this study might be underpowered to detect such a correlation. The closest electrode contact to the vidian canal was in the stimulation area in all but one patient in the final programming. This indicates that, overall, the lead location does play a crucial role in SPG stimulation for cluster headache.

Stroke patients vary considerably in terms of outcomes: some patients present ‘natural’ recovery proportional to their initial impairment (fitters), while others do not (non-fitters). Thus, a key challenge in stroke rehabilitation is to identify individual recovery potential to make personalized decisions for neuro-rehabilitation, obviating the ‘one-size-fits-all’ approach. This goal requires (i) the prediction of individual courses of recovery in the acute stage; and (ii) an understanding of underlying neuronal network mechanisms. ‘Natural’ recovery is especially variable in severely impaired patients, underscoring the special clinical importance of prediction for this subgroup. Fractional anisotropy connectomes based on individual tractography of 92 patients were analysed 2 weeks after stroke (TA) and their changes to 3 months after stroke (TC − TA). Motor impairment was assessed using the Fugl-Meyer Upper Extremity (FMUE) scale. Support vector machine classifiers were trained to separate patients with natural recovery from patients without natural recovery based on their whole-brain structural connectomes and to define their respective underlying network patterns, focusing on severely impaired patients (FMUE, Koch et al. apply computational approaches to the structural whole brain connectome in stroke to identify (i) features that predict in the acute phase whether individual patients, especially those with severe impairments, will show natural recovery; and (ii) the distributed networks relevant to such recovery.

The conceptual foundation of light-sheet microscopy dates back to 1902 when Siedentopf and Zsigmondy developed a microscope, which they termed the “ultramicroscope”, to study the scattering of visible light from sub-wavelength colloidal particles. The low energy load in light-sheet microscopy experiments enables optimal utilization of the photon budget and affords whole-animal imaging with high spatial resolution and high temporal resolution at the same time. First-generation laser light-sheet fluorescence microscopes acquired volumetric data by translating the sample sequentially across the stationary light-sheet and detection focal plane. A majority of functional imaging with light-sheet microscopy in the mammalian brain has thus far been performed on ex vivo tissues. Whole-brain functional imaging experiments stand out among other types of light-sheet microscopy experiments in particular with respect to their unique performance requirements. The primary speed bottleneck in state-of-the-art light-sheet microscopes is camera performance.

High-throughput sequencing describes multiple alterations in each tumor (1), but their functional relevance is often unclear. Clinic-close, individualized molecular model systems are required for functional validation and to identify therapeutic targets of high significance for each patient (2). Here, we established a Cre-ERT2-loxP based inducible RNAi-mediated gene silencing system in patient-derived xenograft (PDX) models of acute leukemias in vivo. Mimicking anti-cancer therapy in patients, gene inhibition was initiated in mice harboring orthotopic tumors. Fluorochrome guided, competitive in vivo trials identified a major tumor-maintaining potency of the MLL-AF4 fusion protein and validated MCL1 as vulnerability in some, but not all patients’ tumors. We could prove DUX4 to play an essential role in patients’ leukemias carrying the recently described DUX4-IGH translocation. By individualizing functional genomics in established tumors in vivo, our technique decisively complements the value chain of precision oncology. Being broadly applicable to tumors of all kinds, it will considerably reinforce personalizing anti-cancer treatment in the future.