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Background: Stroke is a leading cause of long-term disability. Greater rehabilitation therapy after stroke is known to improve functional outcomes. This study examined therapy doses during the first year of stroke recovery and identified factors that predict rehabilitation therapy dose. Methods: Adults with new radiologically confirmed stroke were enrolled 2 to 10 days after stroke onset at 28 acute care hospitals across the United States. Following an initial assessment during acute hospitalization, the number of physical therapy, occupational therapy, and speech therapy sessions were determined at visits occurring 3, 6, and 12 months following stroke. Negative binomial regression examined whether clinical and demographic factors were associated with therapy counts. False discovery rate was used to correct for multiple comparisons. Results: Of 763 patients enrolled during acute stroke admission, 510 were available for follow-up. Therapy counts were low overall, with most therapy delivered within the first 3 months; 35.0% of patients received no physical therapy; 48.8%, no occupational therapy, and 61.7%, no speech therapy. Discharge destination was significantly related to cumulative therapy; the percentage of patients discharged to an inpatient rehabilitation facility varied across sites, from 0% to 71%. Most demographic factors did not predict therapy dose, although Hispanic patients received a lower cumulative amount of physical therapy and occupational therapy. Acutely, the severity of clinical factors (grip strength and National Institutes of Health Stroke Scale score, as well as National Institutes of Health Stroke Scale subscores for aphasia and neglect) predicted higher subsequent therapy doses. Measures of impairment and function (Fugl-Meyer, modified Rankin Scale, and Stroke Impact Scale Activities of Daily Living) assessed 3 months after stroke also predicted subsequent cumulative therapy doses. Conclusions: Rehabilitative therapy doses during the first year poststroke are low in the United States. This is the first US-wide study to demonstrate that behavioral deficits predict therapy dose, with patients having more severe deficits receiving higher doses. Findings suggest directions for identifying groups at risk of receiving disproportionately low rehabilitation doses.

Background Acute endovascular revascularization for isolated internal carotid occlusion without tandem intracranial occlusion has been proposed to prevent early neurologic deterioration (END) and improve outcome, but has not been shown to be more effective than medical therapy. We aimed to evaluate prognosis with initial medical therapy alone, and also performed a systematic review to put these results in a broader context. Methods We performed a retrospective cohort study of patients admitted over a 2‐year period with acute stroke/transient ischemic attack due to isolated internal carotid artery occlusion. Subjects with tandem intracranial occlusion or Alberta Stroke Program Early CT Score (ASPECTS) ≤5 were excluded. The primary outcome was END within 48 hours (National Institute of Health Stroke Scale [NIHSS] increase ≥4 persisting for ≥24 hours). Secondary outcomes included discharge NIHSS and disposition. We also performed a systematic review and meta‐analysis of published studies along with the data from our cohort. Results Twenty‐three patients met our inclusion criteria. Median age was 69 years, initial Alberta Stroke Program Early CT Score 10, and NIHSS score 3. END attributed to recurrent ischemia occurred in 5/23 patients (22%, 95% CI: 7%–44%). At discharge, 78% had a favorable outcome with a median NIHSS of 2 (interquartile range 1–3). END appeared more frequent in those with higher baseline NIHSS. In our systematic review, 7 prior studies met our inclusion criteria. END occurred in 17% (95% CI: 12%–23%) of patients, 18% with medical therapy versus 13% with endovascular therapy, with substantial heterogeneity among studies. Conclusion In patients with acute stroke or transient ischemic attack due to isolated internal carotid occlusion, END is relatively common (occurring in about 1 out of 6 patients). Further research is needed to evaluate the roles of maximal medical management or acute endovascular thrombectomy in these patients.

Although multiparametric magnetic resonance imaging (MRI) has high sensitivity, its lower specificity leads to a high prevalence of false-positive lesions requiring biopsy.To develop and externally validate a scoring system for MRI-detected Prostate Imaging Reporting and Data System (PIRADS)/Likert ≥3 lesions containing clinically significant prostate cancer (csPCa).The multicentre Rapid Access to Prostate Imaging and Diagnosis (RAPID) pathway included 1189 patients referred to urology due to elevated age-specific prostate-specific antigen (PSA) and/or abnormal digital rectal examination (DRE); April 27, 2017 to October 25, 2019.Visual-registration or image-fusion targeted and systematic transperineal biopsies for an MRI score of ≥4 or 3 + PSA density ≥0.12 ng/ml/ml.Fourteen variables were used in multivariable logistic regression for Gleason ≥3 + 4 (primary) and Gleason ≥4 + 3, and PROMIS definition 1 (any ≥4 + 3 or ≥6 mm any grade; secondary). Nomograms were created and a decision curve analysis (DCA) was performed. Models with varying complexity were externally validated in 2374 patients from six international cohorts.The five-item Imperial RAPID risk score used age, PSA density, prior negative biopsy, prostate volume, and highest MRI score (corrected c-index for Gleason ≥3 + 4 of 0.82 and 0.80-0.86 externally). Incorporating family history, DRE, and Black ethnicity within the eight-item Imperial RAPID risk score provided similar outcomes. The DCA showed similar superiority of all models, with net benefit differences increasing in higher threshold probabilities. At 20%, 30%, and 40% of predicted Gleason ≥3 + 4 prostate cancer, the RAPID risk score was able to reduce, respectively, 11%, 21%, and 31% of biopsies against 1.8%, 6.2%, and 14% of missed csPCa (or 9.6%, 17%, and 26% of foregone biopsies, respectively).The Imperial RAPID risk score provides a standardised tool for the prediction of csPCa in patients with an MRI-detected PIRADS/Likert ≥3 lesion and can support the decision for prostate biopsy.In this multinational study, we developed a scoring system incorporating clinical and magnetic resonance imaging characteristics to predict which patients have prostate cancer requiring treatment and which patients can safely forego an invasive prostate biopsy. This model was validated in several other countries.

Background: Prospective data collection for perioperative outcomes might increase awareness of surgical results obtained for patients with prostate cancer (PCa) undergoing robot-assisted radical prostatectomy (RARP). This would prompt the implementation of measures aimed at reducing the risk of adverse outcomes. Objective: To assess the efficacy of an audit and feedback process aimed at identifying the most common complications after RARP and at implementing measures to improve outcomes. Design, setting, and participants: Overall, 415 patients treated with RARP by a high-volume surgeon were included. Perioperative outcomes for 187 patients treated between September 2016 and December 2017 were prospectively collected at 30 d according to the European Association of Urology guideline recommendations (group 1). An audit and feedback process was implemented in January 2018 whereby the most common complication (anastomotic leak) was identified and measures aimed at improving outcomes (changes in the anastomotic technique) were implemented. The outcomes for group 1 were then compared to 228 patients treated after implementation of the modified surgical technique (group 2). Surgical procedure: A novel technique for posterior reconstruction and urethrovesical anastomosis was introduced. Measurements: Perioperative outcomes included blood loss, operative time, length of stay, and 30-d postoperative complications. Logistic regression models tested the effect of the novel surgical technique on anastomotic leaks. Results and limitations: Overall, 97 patients (23%) experienced postoperative complications at 30 d. The rate of anastomotic leaks was significantly lower in group 2 compared to group 1 (3.1% vs 9.6%; p < 0.01). Similarly, overall and Clavien-Dindo grade ≥2 complication rates were lower in group 2 versus group 1 (17% vs 31%, and 6% vs 20%; both p ≤ 0.001). In multivariable analyses, treatment after implementation of changes in the anastomotic technique independently predicted a lower risk of complications (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.38–0.89) and of anastomotic leaks (OR 0.43, 95% CI 0.17–0.97). The lack of randomization represents the main limitation. Conclusions: Implementation of changes in the urethrovesical anastomosis technique arising from increased awareness of surgical outcomes reduced the risk of anastomotic leaks. These findings highlight the importance of audit and feedback processes using a standardized method for reporting surgical morbidity. Patient summary: Increased awareness of surgical outcomes prompted us to change our technique for connecting the bladder to the urethra during robot-assisted surgery to remove the prostate in patients with prostate cancer. These changes resulted in significant improvements in surgical outcomes.

Prostate cancer (PCa) accounts as the most common non-cutaneous disease affecting males, and as the first cancer, for incidence, in male. With the introduction of the concept of immunoscore, PCa has been classified as a cold tumor, thus driving the attention in the development of strategies aimed at blocking the infiltration/activation of immunosuppressive cells, while favoring the infiltration/activation of anti-tumor immune cells. Even if immunotherapy has revolutionized the approaches to cancer therapy, there is still a window failure, due to the immune cell plasticity within PCa, that can acquire pro-tumor features, subsequent to the tumor microenvironment (TME) capability to polarize them. This review discussed selected relevant soluble factors [transforming growth factor-beta (TGFβ), interleukin-6 (IL-6), IL-10, IL-23] and cellular components of the innate immunity, as drivers of tumor progression, immunosuppression, and angiogenesis within the PCa-TME.

Small cell lung cancer (SCLC) is an aggressive tumor, and despite its sensitivity to chemotherapy and radiotherapy, patients usually have a short survival. There are no clinically relevant predictive factors of responses to therapies, and therapeutic options are still limited.Clinical data and somatic mutations of genes included in the MSK-IMPACT panel were retrieved from cBioPortal for 108 SCLCs and analyzed to identify mutated gene networks. Results were validated in an independent cohort of 54 SCLCs, whose information was also available from cBioPortal.Different networks were observed in tumors of short and long survivors. Degree (K) and betweenness (B) are key features that characterize a gene in its network of related mutations. By comparing their B/K ratio, 2 signatures of mutated genes were identified, describing short (IL-7R, NTRK2, HNF-1A) and long survivors (NBN, PTPN-11, IRS-1, INPP-4A, PIK-3CG, HGF, LATS-2, SMARCA-4, FLT-3, EIF-4A2, SPEN, PAX-5, SH2-D1A, ARID-1A, HOXB-13, ERCC-4, FANCA, FH, FGFR-2, MST-1R, SMAD-4, DDR-2, IGF-1R, PIK-3CB). Patients with at least 1 mutated gene of the short signature had a worse median overall survival of 8 versus 28 months (P.001). Patients with at least 1 mutated gene of the long signature had a better median overall survival of 39 versus 20 months (P = .004). The value of the short signature was further confirmed in an independent cohort of SCLCs.The networks of mutated genes could help subclassify SCLCs based on their somatic mutations and aid in identifying a subset of tumors with poor prognosis.

Background Faecal biomarkers have emerged as important tools in managing of inflammatory bowel disease [IBD], which includes Crohn’s disease [CD] and ulcerative colitis [UC]. Aim To identify new biomarkers of gut inflammation in the stools of IBD patients using a proteomic approach. Methods Proteomic analysis of stools was performed in patients with both active CD and CD in remission and in controls by 2-DIGE and MALDI-TOF/TOF MS. An ELISA was used to confirm results in a second cohort of IBD patients and controls. Results 2-DIGE analysis detected 70 spots in the stools of patients with active CD or patients in remission CD and in controls. MALDI-TOF/TOF MS analysis identified 21 proteins with Chymotrypsin C, Gelsolin and Rho GDP-dissociation inhibitor 2 [RhoGDI2] best correlating with the levels of intestinal inflammation. Results were confirmed in a second cohort of IBD patients and controls [57 CD, 60 UC, 31 controls]. The identified faecal markers significantly correlated with the severity of intestinal inflammation in IBD patients [SES-CD in CD, Mayo endoscopic subscore in UC] [CD; Chymotrypsin-C: r = 0.64, p < 0.001; Gelsolin: r = 0.82, p < 0.001; RhoGDI2: r = 0.64, p < 0.001; UC; Chymotrypsin-C: r = 0.76, p < 0.001; Gelsolin: r = 0.75, p < 0.001; RhoGDI2: r = 0.63, p < 0.001]. Moreover, ROC analysis showed that Gelsolin [p < 0.0002] and RhoGDI2 [p < 0.0001] in CD, and RhoGDI2 [p = 0.0004] in UC, have higher sensitivity and specificity than faecal calprotectin in discriminating between patients and controls. Conclusions We show for the first time that 2-DIGE is a reliable method to detect proteins in human stools. Three novel faecal biomarkers of gut inflammation have been identified that display good specificity and sensitivity for identifying IBD and significantly correlate with IBD severity.

OBJECTIVE: To evaluate the relationship between pre-operative PSA value, 68Ga-prostate-specific-membrane-antigen (PSMA) PET performance and oncologic outcomes after salvage lymph node dissection (sLND) for biochemical recurrent prostate cancer (PCa). PATIENTS AND METHODS: The study included 164 patients diagnosed with ≤2 pelvic lymph-node recurrence(s) of PCa documented on 68Ga-PSMA PET scan and treated with pelvic ± retroperitoneal sLND at 11 high-volume centres between 2012 and 2019. Pathologic findings were correlated to PSA values at time of sLND, categorized in early (1.5 ng/ml). Clinical recurrence (CR)-free survival after sLND was calculated using multivariable analyses and plotted over pre-operative PSA value. RESULTS: Median [interquartile range (IQR)] PSA at sLND was 1.1 (0.6, 2.0) ng/ml, and 131 (80%) patients had one positive spot at PET scan. All patients received pelvic sLND, whereas 91 (55%) men received also retroperitoneal dissection. Median (IQR) number of node removed was 15 (6, 28). The rate of positive pathology increased as a function of pre-operative PSA value, with highest rates for patients with pre-operative PSA > 1.5 ng/ml (pelvic-only sLNDs: 84%; pelvic + retroperitoneal sLNDs: 90%). After sLND, PSA ≤ 0.3 ng/ml was detected in 67 (41%) men. On multivariable analyses, pre-operative PSA was associated with PSA response (p

Tissue regeneration or healing both require efficient vascularization within a tissue-damaged area. Based on this concept, a remarkable number of strategies, aimed at developing new tools to support re-vascularization of damaged tissue have emerged. Among the strategies proposed, the use of pro-angiogenic soluble factors, as a cell-free tool, appears as a promising approach, able to overcome the issues concerning the direct use of cells for regenerative medicine therapy. Here, we compared the effectiveness of adipose mesenchymal stem cells (ASCs), use as cell suspension, ASC protein extract or ASC-conditioned-medium (i.e., soluble factors), combined with collagenic scaffold, in supporting in vivo angiogenesis. We also tested the capability of hypoxia in increasing the efficiency of ASC to promote angiogenesis, via soluble factors, both in vivo and in vitro. In vivo studies were performed using the Integra® Flowable Wound Matrix, and the Ultimatrix in sponge assay. Flow cytometry was used to characterize the scaffold- and sponge-infiltrating cells. Real-time PCR was used to evaluate the expression of pro-angiogenic factors by stimulating Human Umbilical-Vein Endothelial Cells with ASC-conditioned media, obtained in hypoxic and normoxic conditions. We found that, in vivo, ACS-conditioned media can support angiogenesis similar to ASCs and ASC protein extract. Also, we observed that hypoxia increases the pro-angiogenic activities of ASC-conditioned media, compared to normoxia, by generating a secretome enriched in pro-angiogenic soluble factors, with bFGF, Adiponectine, ENA78, GRO, GRO-a, and ICAM1-3, as most regulated factors. Finally, ASC-conditioned media, produced in hypoxic condition, induce the expression of pro-angiogenic molecules in HUVECs. Our results provide evidence that ASC-conditioned-medium can be proposed as a cell-free preparation able to support angiogenesis, thus providing a relevant tool to overcome the issues and restrictions associated with the use of cells.

Surgical site infections (SSIs) after spine surgery are a significant cause of morbidity. Surgeons often prescribe oral antibiotics in the postoperative setting for infected-appearing wounds to prevent reoperation for infection; however, the efficacy of this practice has not been well studied.Neurosurgical spine patients with clinical concerns for SSI at the University of Pennsylvania were retrospectively studied from 2014 to 2018. Clinical predictors of 90-day reoperation for infection despite antibiotic treatment and variables that influenced antibiotic prescription were analyzed.Three hundred and ninety-two patients were included in the study. Preoperative albumin level, days elapsed to antibiotic prescription from index surgery, preoperative hemoglobin level, surgical location, gender, discharge disposition, and level of wound concern were significant predictors of reoperation for infection on bivariate analysis. Days elapsed to antibiotic prescription, surgical location, and level of wound concern remained significant after multivariable logistic regression. Variables that significantly predicted prescription of an antibiotic include length of stay, cerebrospinal fluid leak, race, and level of wound concern. Length of stay, race, and level of wound concern remained significant after multivariable analysis.Wound infection remains a challenging problem in spine surgery and it is reasonable to perform early reoperation in patients with high clinical concerns for infection, because bacterial isolates are often resistant to common oral antibiotics. Patients with wounds with low clinical concerns for infection may undergo a trial of oral antibiotics; however, duration of treatment should not be prolonged.

Background: Nonstenotic carotid plaque and undetected atrial fibrillation are potential mechanisms of embolic stroke of undetermined source (ESUS), but it is unclear which is more likely to be the contributing stroke mechanism. We explored the relationship between left atrial enlargement (LAE) and nonstenotic carotid plaque across age ranges in an ESUS population. Methods: A retrospective multicenter cohort of consecutive patients with unilateral, anterior circulation ESUS was queried (2015 to 2021). LAE and plaque thickness were determined by transthoracic echocardiography and computed tomography angiography, respectively. Descriptive statistics were used to compare plaque features in relation to age and left atrial dimensions. Results: Among the 4155 patients screened, 273 (7%) met the inclusion criteria. The median age was 65 years (interquartile range [IQR] 54–74), 133 (48.7%) were female, and the median left atrial diameter was 3.5 cm (IQR 3.1–4.1). Patients with any LAE more frequently had hypertension (85.9% versus 67.2%, P P =0.01), dyslipidemia (56.4% versus 40.0%, P =0.01), and coronary artery disease (22.8% versus 11.3%, P =0.02). Carotid plaque thickness was greater ipsilateral versus contralateral to the stroke hemisphere in the overall cohort (median 1.9 mm [IQR 0–3] versus 1.5 mm [IQR 0–2.6], P P P =0.047) and less moderate-to-severe LAE (6.3% versus 15.3%, P =0.02). Conclusions: Younger patients with ESUS had greater prevalence of ipsilateral nonstenotic plaque, while the elderly had more LAE. The differential effect of age on the probability of specific mechanisms underlying ESUS should be considered in future studies.

Context The variability of the positive predictive value (PPV) represents a significant factor affecting the diagnostic performance of multiparametric magnetic resonance imaging (mpMRI). Objective To analyze published studies reporting mpMRI PPV and the reasons behind the variability of clinically significant prostate cancer (csPCa) detection rates on targeted biopsies (TBx) according to Prostate Imaging Reporting and Data System (PI-RADS) version 2 categories. Evidence acquisition A search of PubMed, Cochrane library’s Central, EMBASE, MEDLINE, and Scopus databases, from January 2015 to June 2020, was conducted. The primary and secondary outcomes were to evaluate the PPV of PI-RADS version 2 in detecting csPCa and any prostate cancer (PCa), respectively. Individual authors’ definitions for csPCa and PI-RADS thresholds for positive mpMRI were accepted. Detection rates, used as a surrogate of PPV, were pooled using random-effect models. Preplanned subgroup analyses tested PPV after stratification for PI-RADS scores, previous biopsy status, TBx technique, and number of sampled cores. PPV variation over cancer prevalence was evaluated. Evidence synthesis Fifty-six studies, with a total of 16 537 participants, were included in the quantitative synthesis. The PPV of suspicious mpMRI for csPCa was 40% (95% confidence interval 36–43%), with large heterogeneity between studies (I2 94%, p Conclusions Our meta-analysis underlines that the PPV of mpMRI is strongly dependent on the disease prevalence, and that the main factors affecting PPV are PI-RADS version 2 scores and prior biopsy status. A substantially low PPV for PI-RADS 3 lesions was reported, while it was still suboptimal in PI-RADS 4 and 5 lesions. Lastly, even if the added value of a systematic biopsy for csPCa is relatively low, this rate can improve patient risk assessment and staging. Patient summary Targeted biopsy of Prostate Imaging Reporting and Data System 3 lesions should be considered carefully in light of additional individual risk assessment corroborating the presence of clinically significant prostate cancer. On the contrary, the positive predictive value of highly suspicious lesions is not high enough to omit systematic prostate sampling.

INTRODUCTION Radiomics has been proven effective for the characterisation of primary prostate cancer (PCa).1,2 However, the limited interpretability of the proposed models represents one of the major limitations in this field.3,4 This study investigated 68Ga-prostate-specific membrane antigen (PSMA) PET radiomics for the prediction of post-surgical International Society of Urological Pathology (ISUP) grade in patients with primary PCa, ensuring model interpretability. MATERIALS AND METHODS Forty-seven patients with PCa were examined with 68Ga-PSMA PET at the authors’ institution. Those patients were enrolled in this study prior to radical prostatectomy. Images were acquired using either PET/MRI or PET/CT. ISUP grade was available at both biopsy and radical prostatectomy for all patients. A radiologist manually segmented the whole prostate on PET images using the co-registered CT or MRI for anatomical localisation on 3D Slicer software (Brigham and Women’s Hospital, Boston, Massachusetts, USA).5 The whole prostate was used as volume of interest (VOI) to avoid the limitations of radiomics for small volumes.6 VOIs were normalised, resampled, and discretised. A total of 103 image biomarker standardisation initiative-compliant, radiomic features (RF) were extracted using PyRadiomics (Python Software Foundation, Beaverton, Oregon, USA).7 RFs were harmonised with the ComBat method8 to control for the scanner effect, and selected using the minimum redundancy maximum relevance algorithm. Combinations of the four most relevant RFs were used to train 12 radiomics machine learning models for the prediction of post-surgical ISUP ≥4 versus ISUP 0.05). See Table 1 for a detailed report of all the generated models’ performance. CONCLUSION These findings support the role of 68Ga-PSMA PET radiomics for the accurate and non-invasive prediction of post-surgical ISUP grade. Future multicentre studies will be needed to establish with certainty the accuracy and reproducibility of the radiomic signature proposed here.

Hormone therapy is currently the mainstay in the management of locally advanced and metastatic prostate cancer. Degarelix (Firmagon), a gonadotropin-releasing hormone (GnRH) receptor antagonist differs from luteinizing hormone-releasing hormone (LHRH) agonists by avoiding “testosterone flare” and lower follicle-stimulating hormone (FSH) levels. The direct effect of degarelix and leuprolide on human prostate cancer cells was evaluated. In LNCaP, C4-2BMDVR, and CWR22Rv1 cells, degarelix significantly reduced cell viability compared with the controls (P ≤ 0.01). Leuprolide was stimulatory in the same cell lines. In C4-2B MDVR cells, degarelix alone or combined with abiraterone or enzalutamide reduced the AR-V7 protein expression compared with the control group. SCID mice bearing VCaP xenograft tumors were divided into 4 groups and treated with surgical castration, degarelix, leuprolide, or buffer alone for 4 weeks. Leuprolide slightly suppressed tumor growth compared with the vehicle control group (P > 0.05). Tumors in degarelix-treated mice were 67% of those in the leuprolide-treatment group but 170% larger than in surgically castrated ones. Measurements of intratumoral steroids in serum, tumor samples, or treated cell pellets by LC/MS confirmed that degarelix better decreased the levels of testosterone and steroidogenesis pathway intermediates, comparable to surgical castration, whereas leuprolide had no inhibitory effect. Collectively, our results suggested a selective mechanism of action of degarelix against androgen steroidogenesis and AR-variants. This study provides additional molecular insights regarding the mechanism of degarelix compared with GnRH agonist therapy, which may have clinical implications.

Supplemental Fig.1. Bicalutamide and AR-V7 knockdown combination suppressed PSA luciferase activity; Supplemental Fig.2. Niclosamide and bicalutamide combination treatment suppressed AR and AR-V7 target genes expression in C4-2B MDVR cells.

Suppl. Figure1. Western blots of AR-FL and AR-V7 of A. CWR22Rv1 B. VCaP cells treated with leuprolide or degarelix. Suppl. Figure 2. Western blots of AR-V7 in representative tumor lysates from control, castration, leuprolide and degarelix groups.

Tissue fusion transcript panel gene coverage (55 genes)

Purpose:The clinical utility of plasma cell-free DNA (cfDNA) has not been assessed prospectively in patients with glioblastoma (GBM). We aimed to determine the prognostic impact of plasma cfDNA in GBM, as well as its role as a surrogate of tumor burden and substrate for next-generation sequencing (NGS).Experimental Design:We conducted a prospective cohort study of 42 patients with newly diagnosed GBM. Plasma cfDNA was quantified at baseline prior to initial tumor resection and longitudinally during chemoradiotherapy. Plasma cfDNA was assessed for its association with progression-free survival (PFS) and overall survival (OS), correlated with radiographic tumor burden, and subjected to a targeted NGS panel.Results:Prior to initial surgery, GBM patients had higher plasma cfDNA concentration than age-matched healthy controls (mean 13.4 vs. 6.7 ng/mL, P < 0.001). Plasma cfDNA concentration was correlated with radiographic tumor burden on patients' first post-radiation magnetic resonance imaging scan (ρ = 0.77, P = 0.003) and tended to rise prior to or concurrently with radiographic tumor progression. Preoperative plasma cfDNA concentration above the mean (>13.4 ng/mL) was associated with inferior PFS (median 4.9 vs. 9.5 months, P = 0.038). Detection of ≥1 somatic mutation in plasma cfDNA occurred in 55% of patients and was associated with nonstatistically significant decreases in PFS (median 6.0 vs. 8.7 months, P = 0.093) and OS (median 5.5 vs. 9.2 months, P = 0.053).Conclusions:Plasma cfDNA may be an effective prognostic tool and surrogate of tumor burden in newly diagnosed GBM. Detection of somatic alterations in plasma is feasible when samples are obtained prior to initial surgical resection.

Circulating tumor DNA next-generation sequencing gene coverage (74 genes)

Purpose:In search of novel strategies to improve the outcome of advanced prostate cancer, we considered that prostate cancer cells rearrange iron homeostasis, favoring iron uptake and proliferation. We exploited this adaptation by exposing prostate cancer preclinical models to high-dose iron to induce toxicity and disrupt adaptation to androgen starvation.Experimental Design:We analyzed markers of cell viability and mechanisms underlying iron toxicity in androgen receptor–positive VCaP and LNCaP, castration-resistant DU-145 and PC-3, and murine TRAMP-C2 cells treated with iron and/or the antiandrogen bicalutamide. We validated the results in vivo in VCaP and PC-3 xenografts and in TRAMP-C2 injected mice treated with iron and/or bicalutamide.Results:Iron was toxic for all prostate cancer cells. In particular, VCaP, LNCaP, and TRAMP-C2 were highly iron sensitive. Toxicity was mediated by oxidative stress, which primarily affected lipids, promoting ferroptosis. In highly sensitive cells, iron additionally caused protein damage. High-basal iron content and oxidative status defined high iron sensitivity. Bicalutamide–iron combination exacerbated oxidative damage and cell death, triggering protein oxidation also in poorly iron-sensitive DU-145 and PC-3 cells.In vivo, iron reduced tumor growth in TRAMP-C2 and VCaP mice. In PC-3 xenografts, bicalutamide–iron combination caused protein oxidation and successfully impaired tumor expansion while single compounds were ineffective. Macrophages influenced body iron distribution but did not limit the iron effect on tumor expansion.Conclusions:Our models allow us to dissect the direct iron effect on cancer cells. We demonstrate the proof of principle that iron toxicity inhibits prostate cancer cell proliferation, proposing a novel tool to strengthen antiandrogen treatment efficacy.

Tissue next-generation sequencing gene coverage (152 genes)

Plasma cell-free DNA (cfDNA) concentration (ng/mL) is correlated with (A), total radiographic tumor burden (contrast-enhancing tumor + T2/FLAIR non-enhancing tumor) and (B), contrast-enhancing tumor burden at the first post-radiation MRI scan in patients with newly diagnosed glioblastoma

Supplementary materials and methods and Supplementary Figures S1-S12

Complete list of variants detected in 20 subjects who had both tissue and plasma next generation sequencing

Background Early diagnosis is essential for effective stroke therapy. Strokes in hospitalized patients are associated with worse outcomes compared with strokes in the community. We derived and validated an algorithm to identify strokes by monitoring upper limb movements in hospitalized patients. Methods and Results A prospective case–control study in hospitalized patients evaluated bilateral arm accelerometry from patients with acute stroke with lateralized weakness and controls without stroke. We derived a stroke classifier algorithm from 123 controls and 77 acute stroke cases and then validated the performance in a separate cohort of 167 controls and 33 acute strokes, measuring false alarm rates in nonstroke controls and time to detection in stroke cases. Faster detection time was associated with more false alarms. With a median false alarm rate among nonstroke controls of 3.6 (interquartile range [IQR], 2.1–5.0) alarms per patient per day, the median time to detection was 15.0 (IQR, 8.0–73.5) minutes. A median false alarm rate of 1.1 (IQR. 0–2.2) per patient per day was associated with a median time to stroke detection of 29.0 (IQR, 11.0–58.0) minutes. There were no differences in algorithm performance for subgroups dichotomized by age, sex, race, handedness, nondominant hemisphere involvement, intensive care unit versus ward, or daytime versus nighttime. Conclusions Arm movement data can be used to detect asymmetry indicative of stroke in hospitalized patients with a low false alarm rate. Additional studies are needed to demonstrate clinical usefulness.

Introduction: In patients with cryptogenic stroke (CS), complex aortic plaque may be a potential underlying etiology. We performed a systematic review to determine the prevalence of complex aortic plaque in CS patients. Methods: A systematic review and meta-analysis were performed according to PRISMA guidelines (PROSPERO: CRD42022300865). PubMed and EMBASE databases were searched from Jan 1980 to Nov 2021 for studies assessing aortic (ascending, arch, descending) plaque by transesophageal echocardiogram (TEE), CT/CTA, or MRI in at least 10 CS patients. Prevalence rates were pooled using a random-effects model. I 2 statistics assessed heterogeneity. An Egger’s test assessed publication bias. Results: From 2712 articles, 31 met inclusion criteria. Ascending, arch, and descending aorta were assessed in 65%, 100%, 55% of studies, respectively. Studies investigated aortic plaque by TEE (84%), CT/CTA (19%) and MRI (16%). The prevalence of complex aortic plaque in 4666 CS patients was heterogeneous across studies and yielded a summary prevalence of 30% (95% CI 23-38%, I 2 = 96%; Figure 1) contrasting with 11% (95% CI 5-20%, I 2 =83%) in 677 patients without stroke. Prevalence rates in women and men were 26% (95% CI 14%-43%, I 2 = 94%) and 35% (95% CI 21-52%, I 2 = 97%), respectively. To investigate geographic differences, 14 studies from Europe were pooled (32%, 95% CI 23-43%, I 2 =93%), 3 from the Middle East (34%, 95% CI 11-67%, I 2 =94%) and 3 from the US (28%, 95% CI 13-51%, I 2 =90%). No publication bias was detected (p=0.66). Sources of heterogeneity included patient selection, imaging technology (e.g, transducer frequency) and plaque measurement criteria. Conclusions: Studies suggest a prevalence rate of complex aortic plaque in approximately 30% of CS patients. However, significant heterogeneity in the results indicate a need for less variability in CS patient selection and more reproducible imaging methods/criteria for detecting complex aortic plaque.

Introduction: Hematoma volume predicts poor outcome after intracerebral hemorrhage (ICH), while outcome associations with perihematomal edema (PHE) remain controversial. Prior studies using non-standardized timing of serial CT imaging reported larger ICH and PHE volumes in men than women, but worse outcome in women. Leveraging data from a cohort with early admission and time-locked follow-up imaging, we investigated the role of sex on PHE and outcomes. Methods: We conducted a post hoc analysis of the randomized FAST (Factor VII for Acute-Hemorrhagic Stroke Treatment) trial. Participants underwent CT imaging within 3 hours of symptom onset, and at 24 and 72 hours. Lesion volumes were calculated using computerized planimetric techniques (AnalyzeDirect). Outcomes (modified Rankin Scale, mRS) were assessed at 90 days. Two-way repeated measures ANOVA tested whether changes in lesion volumes were driven by an interaction between sex and time. Multivariable logistic regression tested for associations between PHE and poor outcome (mRS 4-6). Results: Of 842 subjects, 781 with supratentorial ICH (mean age 65 years, 38% women) were included. Men (n=485) compared to women (n=296) had similar mean ICH and PHE volumes at baseline (p=0.063 and p=0.98) but larger ICH and PHE at 24 hours (p=0.002 and p=0.017) and 72 hours (p=0.002 and p=0.003). All volumes varied over CT time points according to sex (Figure 1 A-C, all three ANOVA: p Conclusions: Men had greater early lesion expansion than women. In both sexes, PHE expanded beyond 24 hours and was associated with poor outcome. While mechanisms explaining sex differences need further investigation, future ICH studies should be carefully adjusted for sex.

El presente artículo reflexiona sobre el impacto que produjo la irrupción de la pandemia COVID-19 en el desarrollo de un proyecto investigativo abocado a analizar practicas pre profesionales en salud a cargo de estudiantes avanzados de la Licenciatura en Trabajo Social de la Facultad de Ciencia Política y Relaciones Internacionales, Universidad Nacional de Rosario. La pandemia no solo interpela a las políticas públicas y a las capacidades estatales de reaccionar simultáneamente en diversos planos, sino también los modos de intervenir en situaciones prioritarias en contextos de aislamiento social preventivo y obligatorio, como de distanciamiento social preventivo y obligatorio. Como Trabajadores Sociales y docentes universitarios, nuestros procesos no quedaron al margen, y el desafío de sostener un vinculo pedagógico a distancia, con las insuficiencias que ello implica, puso en tensión la estrategia metodológica asumida, incorporando la idea de lo paradojal y lo absurdo. La producción de conocimientos se constituye como un imperativo ético no sólo para otorgar mayor jerarquía al quehacer profesional, sino porque las problemáticas de este momento histórico y los desgarramientos sociales a los que asistimos así lo exigen. En esa línea la formación para la práctica profesional se torna una cuestión inquietante e ineludible desde el punto de vista político-pedagógico.

In this article, we present an approach for retrieving similar faces between the artistic and the real domain. The application we refer to is an interactive exhibition inside a museum, in which a visitor can take a photo of himself and search for a lookalike in the collection of paintings. The task requires not only to identify faces but also to extract discriminative features from artistic and photo-realistic images, tackling a significant domain shift. Our method integrates feature extraction networks which account for the aesthetic similarity of two faces and their correspondences in terms of semantic attributes. Also, it addresses the domain shift between realistic images and paintings by translating photo-realistic images into the artistic domain. Noticeably, by exploiting the same technique, our model does not need to rely on annotated data in the artistic domain. Experimental results are conducted on different paired datasets to show the effectiveness of the proposed solution in terms of identity and attribute preservation. The approach is also evaluated on unpaired settings and in combination with an interactive relevance feedback strategy. Finally, we show how the proposed algorithm has been implemented in a real showcase at the Gallerie Estensi museum in Italy, with the participation of more than 1,100 visitors in just three days.

Andreas Holzinger acknowledges funding support from the Austrian Science Fund (FWF), Project: P-32554 explainable Artificial Intelligence and from the European Union's Horizon 2020 research and innovation program under grant agreement 826078 (Feature Cloud). This publication reflects only the authors' view and the European Commission is not responsible for any use that may be made of the information it contains; Natalia Diaz-Rodriguez is supported by the Spanish Government Juan de la Cierva Incorporacion contract (IJC2019-039152-I); Isabelle Augenstein's research is partially funded by a DFF Sapere Aude research leader grant; Javier Del Ser acknowledges funding support from the Basque Government through the ELKARTEK program (3KIA project, KK-2020/00049) and the consolidated research group MATHMODE (ref. T1294-19); Wojciech Samek acknowledges funding support from the European Union's Horizon 2020 research and innovation program under grant agreement No. 965221 (iToBoS), and the German Federal Ministry of Education and Research (ref. 01IS18025 A, ref. 01IS18037I and ref. 0310L0207C); Igor Jurisica acknowledges funding support from Ontario Research Fund (RDI 34876), Natural Sciences Research Council (NSERC 203475), CIHR Research Grant (93579), Canada Foundation for Innovation (CFI 29272, 225404, 33536), IBM, Ian Lawson van Toch Fund, the Schroeder Arthritis Institute via the Toronto General and Western Hospital Foundation., Medical artificial intelligence (AI) systems have been remarkably successful, even outperforming human performance at certain tasks. There is no doubt that AI is important to improve human health in many ways and will disrupt various medical workflows in the future. Using AI to solve problems in medicine beyond the lab, in routine environments, we need to do more than to just improve the performance of existing AI methods. Robust AI solutions must be able to cope with imprecision, missing and incorrect information, and explain both the result and the process of how it was obtained to a medical expert. Using conceptual knowledge as a guiding model of reality can help to develop more robust, explainable, and less biased machine learning models that can ideally learn from less data. Achieving these goals will require an orchestrated effort that combines three complementary Frontier Research Areas: (1) Complex Networks and their Inference, (2) Graph causal models and counterfactuals, and (3) Verification and Explainability methods. The goal of this paper is to describe these three areas from a unified view and to motivate how information fusion in a comprehensive and integrative manner can not only help bring these three areas together, but also have a transformative role by bridging the gap between research and practical applications in the context of future trustworthy medical AI. This makes it imperative to include ethical and legal aspects as a cross-cutting discipline, because all future solutions must not only be ethically responsible, but also legally compliant., Austrian Science Fund (FWF) P-32554, European Union's Horizon 2020 research and innovation program 826078 965221, Spanish Government Juan de la Cierva Incorporacion IJC2019-039152-I, DFF Sapere Aude research leader grant, Basque Government KK-2020/00049, consolidated research group MATHMODE T1294-19, Federal Ministry of Education & Research (BMBF) 01IS18025 A 01IS18037I 0310L0207C, Ontario Research Fund RDI 34876, Natural Sciences Research Council NSERC 203475, Canadian Institutes of Health Research (CIHR) 93579, Canada Foundation for Innovation CGIAR CFI 29272 225404 33536, International Business Machines (IBM), Ian Lawson van Toch Fund, Schroeder Arthritis Institute via the Toronto General and Western Hospital Foundation