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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.

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.

Background: The optimal definition and prognostic significance of persistently elevated prostate-specific antigen (PSA) after salvage lymph node dissection (sLND) for node-only recurrent prostate cancer (PCa) remain unknown. Objective: To assess the definition and clinical implications of persistently elevated PSA after sLND for node-only recurrent PCa after radical prostatectomy. Design, setting, and participants: The study included 579 patients treated with sLND at 11 high-volume centers between 2000 and 2016. Outcome measurements and statistical analysis: We assessed the linear relationship between the first PSA after sLND and death from PCa. Different definitions of PSA persistence were included in a multivariable model predicting cancer-specific mortality (CSM) after surgery to identify the best cutoff value. We investigated the association between PSA persistence and oncologic outcomes using multivariable regression models. Moreover, the effect of early androgen deprivation therapy (ADT) after sLND was tested according to PSA persistence status and estimated risk of CSM. Results and limitations: We found an inverse relationship between the first PSA after sLND and the probability of cancer-specific survival. PSA persistence defined as first postoperative PSA ≥0.3 ng/ml provided the best discrimination accuracy (C index 0.757). According to this cutoff, 331 patients (57%) experienced PSA persistence. The median follow-up for survivors was 48 mo (interquartile range 27-74). After adjusting for confounders, men with persistently elevated PSA had higher risk of clinical recurrence (hazard ratio [HR] 1.61), overall mortality (HR 2.20), and CSM (HR 2.59; all p 10%. Conclusions: PSA persistence after sLND independently predicts adverse prognosis, with the best discrimination accuracy for CSM provided by a definition of PSA ≥ 0.3 ng/ml. We showed that when stratifying patients by final pathology results and PSA persistence status, early ADT use after sLND was beneficial only for patients with PSA persistence or with a calculated 5-yr risk of CSM of >10%, which could be useful as we await results from ongoing prospective trials. Patient summary: We found that for patients with prostate cancer who had lymph nodes removed after their cancer recurred, persistently elevated prostate-specific antigen (PSA) levels predict poorer prognosis. We showed that a PSA level of ≥0.3 ng/ml provides the best accuracy in identifying patients with worse prognosis. This may help to improve risk stratification after lymph node removal and allow physicians to optimize treatment strategies after surgery.

Objective: To assess the relationship between the volume of the index lesion (IL) measured at multiparametric magnetic resonance imaging (mpMRI; MRIvol) and at radical prostatectomy (RPvol), stratifying it according to Prostate Imaging-Reporting and Data System (PI-RADS) score. Patients and Methods: We identified 332 men with a positive mpMRI (single lesion with PI-RADS ≥3) who underwent systematic plus targeted biopsy and subsequent RP at two tertiary referral centres between 2013 and 2018. All mpMRIs were reviewed by experienced radiologists using PI-RADS scores. The study outcome was to assess the relationship between MRIvol (based on planimetry from MRI sequence best showing tumour) and RPvol (based on tumour involved area of each RP pathology slice). To achieve this endpoint, we performed a multivariable linear regression analysis (LRA) to predict RPvol using PI-RADS, prostate-specific antigen level, prostate volume, age, digital rectal examination, Gleason score at MRI-targeted biopsy, biopsy history and time from mpMRI to RP as covariates. Non-parametric locally estimated scatterplot smoothing (LOESS) function was used to graphically explore the relationship between MRIvol and RPvol, stratifying for PI-RADS score. Results: Overall, 24%, 49% and 27% of men had visible PI-RADS 3, 4 and 5 lesions at mpMRI. The median (interquartile range [IQR]) MRIvol and RPvol were 0.67(0.29–1.76)mL and 1.39(0.58–4.23)mL. At LRA, MRIvol was significantly correlated with a RPvol underestimation (slope: 2.4, 95% confidence interval [CI] 0.1–46.3). The non-parametric LOESS analysis showed a non-linear relationship between MRIvol and RPvol. Significant underestimation was reported across all volumes with the highest differences between MRIvol and RPvol in the low volume range (

Anaplastic thyroid cancer is a rare but devastating malignancy. Anaplastic thyroid cancer cells exhibit the Warburg effect by preferentially undergoing glycolysis even in aerobic conditions, leading to high glucose use. Here we assess if targeted inhibition of glycolysis can diminish anaplastic thyroid cancer growth and improve outcomes.Human anaplastic thyroid cancer cell line 8505C was grown in medium containing high (25 mmol/L) or low (3 mmol/L) glucose concentration and hexokinase II inhibitor 3-bromopyruvate (200 μM). Cellular proliferation, migration, and invasion were measured. An orthotopic xenograft model of anaplastic thyroid cancer was generated in nude mice using 8505C cells. Animals were provided standard chow or a ketogenic diet and treated with 3-bromopyruvate (1.8 mg/kg). Overall survival time was monitored. Necropsies were performed to harvest tumors for analysis.Growth of 8505C in low-glucose medium with 3-bromopyruvate decreased cell proliferation by 89%, migration by 44%, and invasion by 73% (P.001 for all) compared with high glucose. Animals concomitantly receiving a ketogenic diet and 3-bromopyruvate exhibited smaller tumor volumes (P = .03), slower tumor growth rates (P = .01), and improved overall survival (P = .006) compared with standard-diet control subjects. Monotherapy with a ketogenic diet or 3-bromopyruvate alone did not reduce tumor size or increase survival over the standard-diet control group.Glycolytic inhibition with 3-bromopyruvate inhibits tumor growth and extends survival in a murine model of anaplastic thyroid cancer when combined with the ketogenic diet. Thus, targeted glycolytic inhibition of anaplastic thyroid cancer exhibits context-specific utility and may only be effective during ketosis induced by dietary restriction of glycolytic inputs.

Evaluate the effect of 12 wks of concurrent training (CT) in the extracellular matrix (ECM) of subcutaneous adipose tissue (SAT) in people living with HIV/AIDS (PLWHA). In the non-randomized clinical trial, 19 participants, 11 healthy (HIV–) and 18 PLWHA under the use of highly active antiretroviral therapy (HAART) for at least 1 year (HIV+). All participants engaged in a moderate-intensity CT program for 12 weeks, 3 times a week. Before and after CT, aerobic and strength performance were assessed, as well as anthropometric and biochemical blood profiles. In addition, SAT biopsies were performed for histologic and morphometric analyses. Statistical analysis was carried out with R Studio, using descriptive and inferential analysis, ANOVA test, and mixed-effect model (P < 0.05). HIV+ showed higher levels of very-low-density lipoproteins and triglycerides and lower levels of high-density lipoproteins at baseline than HIV– (P < 0.05). All groups showed improved aerobic and strength performances (P < 0.05). Both groups showed reduced adipocyte sizes after CT (P < 0.05). Lastly, HIV+ presented smaller adipocytes and higher elastic fiber deposition at baseline and decreased after training only in HIV+, similar to the HIV group. Thus, CT in PLWHA promoted a decrease in the size heterogeneity of adipocytes and elastic fiber deposition, remodeling the ECM, and improving the SAT fibrosis profile. Brazilian Clinical Trials Registry (ensaiosclinicos.gov.br – UTN: U1111-1214-3022).Novelty: Adipose tissue fibrosis is improved by training in people living with HIV. Concurrent training remodels adipose tissue extracellular matrix.

Background The prognostic role of multiparametric magnetic resonance imaging (mpMRI) and systematic biopsy in predicting biochemical recurrence (BCR) after radical prostatectomy (RP) in prostate cancer (PCa) patients has not been addressed yet. Objective To develop a risk tool predicting BCR after RP in patients diagnosed with magnetic resonance imaging (MRI)-targeted biopsy. Design, setting, and participants A total of 804 patients with a clinical suspicion of PCa and positive mpMRI diagnosed with MRI-targeted plus concomitant systematic biopsy treated with RP were identified. Outcome measurements and statistical analyses The outcome was represented by BCR defined as two prostate-specific antigen (PSA) values ≥0.2 ng/ml after surgery. Multivariable Cox regression analyses assessed the predictors of BCR. A risk tool model based on imaging and biopsy parameters was developed and validated internally. The c-index, calibration plot, and decision curve analyses were used to assess discrimination, calibration, and the net benefit associated with its use in predicting BCR at 36 mo. Results and limitations Median (interquartile range) follow-up was 28 (25–29) mo, and 89 patients experienced BCR. The 36-mo BCR-free survival rate was 89%. The maximum diameter of the index lesion and seminal vesicle invasion (SVI) at mpMRI as well as the presence of clinically significant PCa at systematic biopsy (defined as a grade group of >2) were associated with BCR (all p ≤ 0.03). A model based on PSA, Prostate Imaging Reporting and Data System score, SVI at mpMRI, diameter of the index lesion, grade group at MRI-targeted biopsy, and clinically significant PCa at systematic biopsy achieved the highest discrimination (77%) among all clinical models, as well as the European Association of Urology risk groups (62%) and the Cancer of the Prostate Risk Assessment (CAPRA) score (60%). This tool was characterized by excellent calibration at internal validation and the highest net benefit when predicting BCR for the threshold risk between 0% and 30%. Conclusions The adoption of predictive models accounting for mpMRI and MRI-targeted biopsy-derived variables and concomitant systematic biopsy would improve clinicians’ ability to identify patients at a higher risk of early recurrence after surgery. Patient summary The use of information obtained at multiparametric magnetic resonance imaging (mpMRI), and MRI-targeted and concomitant systematic biopsy would improve clinicians’ ability to identify prostate cancer patients at a higher risk of experiencing early biochemical recurrence after surgery.

The coronavirus disease 2019 (COVID-19) pandemic has changed the way most medical procedures are performed. Autonomic units, as well as other healthcare sectors, are required to undergo a thorough reorganization of the protocols in order to guarantee the safety of patients and healthcare staff. Cardiovascular autonomic function testing (CAFT) is necessary in certain situations; however, it poses several concerns which need to be addressed. Here, we provide some practical advice based on current national and international health authorities’ recommendations and our experience about how to perform CAFT during the COVID-19 emergency. We examine aspects regarding patients, healthcare staff, laboratory preparation, and test performance.

ObjectivesTo investigate (1) the prevalence of REM sleep behavior disorder (RBD) as mode of disease onset in a cohort of patients with multiple system atrophy (MSA) and (2) disease progression and prognosis in patients with MSA with RBD predating (pre-RBD) and following (post-RBD) disease onset.MethodsWe retrospectively identified all patients with a clinical diagnosis of MSA evaluated at least once a year during the disease course. Type of onset was defined by the first reported motor or autonomic symptom/sign related to MSA. The occurrence of symptoms/signs and milestone of disease progression, and their latency from disease onset, were collected. Survival data were calculated. RBD was confirmed by video-polysomnography.ResultsOf a total of 158 patients, pre-RBD represented the mode of disease onset in 27% of patients, preceding disease onset according to the international criteria with a median of 3 (2–5) years. Comparing pre-RBD and post-RBD patients, the first group showed an increased prevalence of autonomic onset of disease, a reduced prevalence of parkinsonism, an earlier onset of stridor, pyramidal signs, symptomatic orthostatic hypotension, urinary dysfunction, severe dysphagia, and wheelchair dependency. The risk of death was higher in patients with pre-RBD.ConclusionsIn our MSA cohort, RBD represented the most frequent mode of disease presentation. A more rapid progression of disease was observed in the pre-RBD group. These findings suggested a careful assessment of sleep disorders to early recognize RBD and a closer follow-up of autonomic dysfunction and stridor in patients with pre-RBD.

Ketorolac is an effective analgesic but the potential for acute kidney injury (AKI) is concerning, particularly in geriatric “G-60 trauma” patients. The objectives of this study are to report the incidence of AKI in patients who receive ketorolac, identify risk factors for AKI, and develop a risk factor-guided algorithm for safe utilization. This retrospective cohort study included trauma patients age 60 years and older who received intravenous ketorolac. The primary endpoint was the incidence of AKI. Among 316 patients evaluated, the incidence of AKI was 2.5%. Patients with AKI received more nephrotoxins, had more comorbidities, and higher use of loop diuretics or vasopressors. Loop diuretic therapy and number of comorbidities were independent predictors of AKI. Risk for AKI with ketorolac was low, being more prevalent with comorbidities or receipt of loop diuretics.

Introduction The COVID-19 outbreak has become the dominant issue throughout the world whilst the governments, nations and health services are trying to deal with its impact. The aim of our study is to assess the impact of COVID-19 on patients treated with radical prostatectomy (RP) for prostate cancer (PCa) at European referral centers in terms of surgical volume (SV), waiting list meant as time from biopsy to surgery (WL) and risk of adverse pathologic findings at RP due to the selection of men with more adverse disease characteristics at final pathology. Material and methods Consecutive patients with a diagnosis of histologically proven PCa treated with RP between March 2020 (WHO declaration of pandemic) and December 2020 were identified. Patients with metastatic disease not eligible to local treatment and recurrent prostate cancer after RP or RT were excluded. Patients treated at the same institutions between March 2019 and December 2019 were considered as the control group. Multivariable logistic regression analysis tested the impact of the COVID-19 outbreak on the risk of adverse pathologic findings at RP after adjusting for confounders. The percentage change of SV and WL was assessed comparing the months of pandemic with the equivalent timespan of the previous year. Results A total of 2,574 patients treated with RP (927 cases and 1647 controls) were identified in 8 European tertiary referral centers. At multivariable analysis patients who were treated during the pandemic had higher risk of extra prostatic disease (OR:1.35, p = 0.038) and lymph node invasion (LNI) (OR:1.72, p = 0.048). An average 23% reduction of the SV with the equivalent timespan of the previous year allowed an illusory reduction of the WL after the peak gained during the first wave of COVID-19. Conclusions Our results showed that the COVID-19 outbreak resulted in a delay in the administration of curative-intent therapies in patients with localized PCa. This, in turn, resulted in a stage migration phenomenon with a potential impact on oncologic control. Weitere Verfasser:innen aus Einrichtungen außerhalb der Universität Duisburg-Essen sind nicht aufgeführt.

There are limited data on the impact of COVID-19 in children with a kidney transplant (KT). We conducted a prospective cohort study through the Improving Renal Outcomes Collaborative (IROC) to collect clinical outcome data about COVID-19 in pediatric KT patients. Twenty-two IROC centers that care for 2732 patients submitted testing and outcomes data for 281 patients tested for SARS-CoV-2 by PCR. Testing indications included symptoms and/or potential exposures to COVID-19 (N = 134, 47.7%) and/or testing per hospital policy (N = 154, 54.8%). Overall, 24 (8.5%) patients tested positive, of which 15 (63%) were symptomatic. Of the COVID-19-positive patients, 16 were managed as outpatients, six received non-ICU inpatient care and two were admitted to the ICU. There were no episodes of respiratory failure, allograft loss, or death associated with COVID-19. To estimate incidence, subanalysis was performed for 13 centers that care for 1686 patients that submitted all negative and positive COVID-19 results. Of the 229 tested patients at these 13 centers, 10 (5 asymptomatic) patients tested positive, yielding an overall incidence of 0.6% and an incidence among tested patients of 4.4%. Pediatric KT patients in the United States had a low estimated incidence of COVID-19 disease and excellent short-term outcomes.

Made available in DSpace on 2022-04-29T08:45:35Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 Chudley-McCullough syndrome (CMS) is an autosomal recessive condition first described in 1997. The most striking features of this syndrome include sensorineural hearing loss, craniofacial disproportion, and brain abnormalities such as agenesis of the corpus callosum, polymicrogyria, ventriculomegaly, and changes in cerebellar architecture. We describe the case of a 2-year-old patient with CMS confirmed by genetic testing (GPSM2 gene mutation), who presented with global developmental delays and characteristic neuroimaging features including arachnoid cysts, agenesis of the corpus callosum, cerebellar dysplasia, and frontal heterotopia. Early recognition of this rare clinical syndrome may reduce the diagnostic odyssey and ultimately improve the quality of life for affected children. This report will focus on unique clinical and radiographic features of CMS. Neuroradiology Department Beneficência Portuguesa de São Paulo Hospital Pontifical Catholic University of Campinas São Paulo Neuroradiology Department Antônio Prudente Hospital Fortaleza Neurogenetic Department State University of São Paulo Pediatric Neurologist Department State University of São Paulo-Ribeirão Preto

BACKGROUND AND AIMS Columnar cell variant (CCV) is a rare papillary thyroid carcinoma subtype. The majority of CCV occur in older patients and are large, invasive tumours that pursue an aggressive clinical course. Rare well-circumscribed CCV occur in younger female patients and are comparatively indolent. METHODS AND RESULTS We retrospectively identified CCV with material available to perform targeted next-generation sequencing and correlated molecular results with clinicopathological features and outcome. Our cohort was comprised of nine CCV. Nearly all were aggressive tumours; however, one was predominantly well-circumscribed and arose in a thyroglossal duct cyst of a 26-year-old woman who had no evidence of disease at last follow-up. Seven (78%) cases demonstrated activating oncogenic driver alterations in BRAF, including BRAF V600E, an activating N486_P490del deletion, and BRAF-AGK fusions. Activating RAS mutations were seen in two (22%) cases. Additionally, three (33%) cases had TERT promoter mutations, four (44%) had loss of the tumour suppressor CDKN2A and one (11%) case had a loss of function TP53 mutation. Most cases (89%) also demonstrated copy number alterations, including recurrent gain of chromosome 1q (five cases) and losses of chromosome 9p (three cases) and 22q (four cases). The one case without secondary pathogenic mutations or copy number alterations was the tumour in the 26-year-old woman. CONCLUSIONS We found that CCV is primarily a BRAF-driven tumour, with most also harbouring secondary oncogenic mutations and multiple chromosomal gains and losses. Moreover, our findings suggest that molecular analysis could potentially be used to help risk stratify CCV.

Purpose: The extent to which routine genomic sequencing can identify relevant secondary genomic alterations among BRAFV600E-mutant papillary thyroid carcinoma (PTC) is unknown. Such markers would prove highly valuable for prognostic purposes. Experimental Design: We reviewed clinicopathologic data of 225 patients with BRAFV600E-mutant PTC and integrated them with genomic data derived from targeted next-generation sequencing (NGS) on tumor specimens. We defined patient subgroups based on bona fide secondary oncogenic events (separate from BRAFV600E) and compared their clinical features and outcomes with those without additional oncogenic alterations. Results: Additional oncogenic alterations were identified in 16% of tumors. Patients in the “BRAF+additional mutations” group were more likely to be at high American Thyroid Association (ATA) risk of recurrence (48.6% vs. 17.6%; P = 0.0009), had larger baseline tumor (2.7 vs. 1.9 cm; P = 0.0005) and more advanced stage at presentation (14.3% vs. 1.1% stage 4; P < 0.0001). Importantly, over a 65-month follow-up, disease-specific mortality (DSM) was increased when additional mutations were identified (13.8% vs. 1.4% in the BRAF-only group; P = 0.005). Separately, we identified a subcluster of patients harboring oncogenic mutations in key effectors of the PI3K/AKT/mTOR pathway, which were independently associated with DSM (OR = 47.9; 95% confidence interval, 3.5–1,246.5; P = 0.0043). Conclusions: Identification of additional PIK3/AKT/mTOR alterations in patients with BRAFV600E-mutant PTC provides important and actionable prognostic risk stratification. These data support genomic profiling of PTC tumors to inform prognosis and clinical strategy.

There is no consensus on which weight clinicians should use for weight-based dosing of neuromuscular blocking agents (NMBAs), as exemplified by differing or absent recommendations in clinical practice guidelines. The purpose of this paper is to review studies that evaluated various size descriptors for weight-based dosing of succinylcholine and non-depolarising NMBAs, and to provide recommendations for the descriptors of choice for the weight-based dosing of these agents in patients with obesity. All of the studies conducted to date involving depolarising and non-depolarising NMBAs in patients with obesity have assessed single doses or short-term infusions conducted in perioperative settings. Recognising that any final dosing regimen must take into account patient-specific considerations, the available evidence suggests that actual body weight is the size descriptor of choice for weight-based dosing of succinylcholine and that ideal body weight, or an adjusted (or lean) body weight, is the size descriptor of choice for weight-based dosing of non-depolarising NMBAs.

Objective To evaluate the best option among orthoses for carpometacarpal (CMC) osteoarthritis (OA) of the thumb, using a network meta-analysis. Data Sources Medline, Embase, Cochrane, and ClinicalTrials.gov registry databases were used. PubMed, Embase, Cochrane Controlled Trials Register, Cochrane, and other databases were used without language restrictions. Study Selection We searched randomized controlled trials (RCTs) on adults with OA of the thumb by studying any orthosis from the beginning to March 10, 2020. Data Extraction Data were extracted and checked for accuracy and completeness by pairs of reviewers. Outcomes were pain and function. Comparative treatment effects were analyzed by random-effects model for direct pairwise comparisons and Bayesian network meta-analyses to integrate direct and indirect evidence. Data Synthesis Eleven RCTs involving 619 patients were included. We evaluated 5 groups, for 4 different orthoses: short thermoplastic CMC splint (rigid CMC) (n=5), long thermoplastic carpometacarpal-metacarpophalangeal splint (rigid CMC-MCP) (n=7), short neoprene CMC splint (soft CMC) (n=1), long neoprene CMC-MCP splint (soft CMC-MCP) (n=5), and one as a control group (n=5). Our results show that all splints were superior to placebo to reduce pain intensity and the top-ranked intervention was the rigid CMC-MCP (surface under the cumulative ranking curve analysis [SUCRA], score: 65.4). In function evaluation, we report a 71.6 SUCRA for rigid CMC. Conclusions Although the current evidence is unclear on the use of the splint in OA of the thumb, it is not known which orthosis is more effective and whether the orthosis is more effective than other interventions. The network meta-analysis shows that a long thermoplastic splint it is the best choice for pain relief and the short thermoplastic CMC splint is the best treatment to increase function. These results may suggest initial treatment with a long rigid orthosis and then a short rigid orthosis.

This study aimed to investigate at 7.0-T MRI a) the role of multiple sclerosis (MS) cortical lesions in cortical tissue loss b) their relation to neurological disability. In 76 relapsing remitting and 26 secondary progressive MS patients (N = 102) and 56 healthy subjects 7.0-T T2*-weighted images were acquired for lesion segmentation; 3.0-T T1-weighted structural scans for cortical surface reconstruction/cortical thickness estimation. Patients were dichotomized based on the median cortical lesion volume in low and high cortical lesion load groups that differed by age, MS phenotype and degree of neurological disability. Group differences in cortical thickness were tested on reconstructed cortical surface. Patients were evaluated clinically by means of the Expanded Disability Status Scale (EDSS). Cortical lesions were detected in 96% of patients. White matter lesion load was greater in the high than in the low cortical lesion load MS group (p = 0.01). Both MS groups disclosed clusters (prevalently parietal) of cortical thinning relative to healthy subjects, though these regions did not show the highest cortical lesion density, which predominantly involved frontal regions. Cortical thickness decreased on average by 0.37 mm, (p = 0.002) in MS patients for each unit standard deviation change in white matter lesion volume. The odds of having a higher EDSS were associated with cortical lesion volume (1.78, p = 0.01) and disease duration (1.15, p

Objectives The prevalence of neurogenic orthostatic hypotension (NOH, due to cardiovascular autonomic failure) at early stage of Parkinson's disease (PD) is unknown. The aims of this study are to prospectively evaluate in a cohort of PD patients recruited within 3 years from motor onset (1) cardiovascular autonomic functions by means of cardiovascular reflex tests (CRTs) and the occurrence of NOH; (2) the frequency of orthostatic symptoms with a validated questionnaire. Methods We included the first 105 PD patients of the prospective “BoProPark” study. Each patient underwent CRTs (head up tilt test; Valsalva manoeuvre; deep breathing; cold face test and handgrip test) under continuous blood pressure monitoring according to standardized procedures and SCOPA-Aut questionnaire at baseline (T0) and after 16 months (T1). A group of 50 age- and sex-matched controls was used for comparison. Results At T0 (mean age 61 ± 9 years, disease duration 19 ± 9 months) NOH was detected in 4/105 (3.8%) patients, whereas at T1 in 8/105 (7.6%). CRTs responses assessing sympathetic function were impaired at T0 in PD patients compared to controls and progressively worsened at T1. Only 1 patient at T0 and 3 at T1 with NOH reported orthostatic symptoms with low frequency, while the majority of patients reporting these symptoms did not have OH at testing. Conclusions Our prospective study shows that NOH is not common at early PD stage. Asymptomatic mild sympathetic impairment was observed at first evaluation and progressed with disease evolution. Secondary OH may account for the higher prevalence of OH in PD reported so far.

Omphalopagus twins are joined ventrally in the umbilical region. In omphalopagus twins, liver's fusion is very frequent, being present in about 80% of cases. Two conjoined twins born in our Hospital were evaluated using plain x-rays, ultrasound (US), gastrointestinal xrays, Tc-99 hepatobiliary scintigraphy (SC) and contrast enhanced computed tomography (CT). There was no bony connection on conventional xrays, neither bowel communication on GI x-rays study. US demonstrated the fusion of left hepatic lobes and a not-quantifiable vascular shunt. Normal biliary function was demonstrated by Tc-99 SC. The first CT scan (twin A) showed irregular lobules in the site of hepatic fusion, a portoportal shunt and a venous vessel to the inferior vena cava of twin B. Only the second CT scan (twin B) showed an arterio-arterial partiallyextrahepatic shunts. The double CT scan allows to increase the probability of a correct individuation and description of vascular shunts for an effective preoperatory assessment. The omphalopagus twins in our case underwent planned surgical separation at 5 months of age. The surgery lasted 5 h and was not affected by any intraoperative complications.

Graphical abstract, Tuberculosis (TB), one of the oldest and deadliest bacterial diseases, continues to cause serious global economic, health, and social problems. Current TB treatments are lengthy, expensive, and routinely ineffective against emerging drug resistant strains. Thus, there is an urgent need for the identification and development of novel TB drugs possessing comprehensive and specific mechanisms of action (MoAs). Metabolomics is a valuable approach to elucidating the MoA, toxicity, and potency of promising chemical leads, which is a critical step of the drug discovery process. Recent advances in metabolomics methodologies for deciphering MoAs include high-throughput screening techniques, the integration of multiple omics methods, mass spectrometry imaging, and software for automated analysis. This review describes recently introduced metabolomics methodologies and techniques for drug discovery, highlighting specific applications to the discovery of new antitubercular drugs and the elucidation of their MoAs.

Oral mucositis (OM) is one of the most frequent and painful problems caused by head and neck radiotherapy and/or chemotherapy. Because there is no gold standard therapy for this disruptive conditions management, the therapeutic approach promotes palliative action, which consists of the signs and symptoms relief, in addition to preventing further complications. The present study aims to identify the main natural agents that act in the prevention and treatment of MO, as well as to describe the pathophysiology and classification of this condition. This is a literature review of qualitative and exploratory nature through survey of scientific articles in the database SciELO, Lilacs, Medline and Pubmed. The results demonstrated that chamomile, propolis, aloe and honey have been widely used in dentistry, being pointed out in the scientific literature as promising strategies, as they present analgesic and anti-inflammatory effects, besides being well tolerated by the patients and have a low cost. It can be considered that the use of these agents for the prevention and treatment of OM provides a clinical lesions improvement, with consequent advance in the quality of life of these patients. However, more studies need to be carried out in an attempt to obtain more information about the most appropriate posology and presentation form, besides evaluating the toxicity of these natural agents. Keywords: Stomatitis. Chamomile. Propolis. Aloe. Honey. ResumoA mucosite oral (MO) consiste em um dos problemas mais frequentes e dolorosos provocados pela radioterapia em região de cabeça e pescoço e/ou quimioterapia. Por não existir terapia considerada padrão ouro para o manejo desta condição perturbadora, a abordagem terapêutica promove ação paliativa, que consiste no alívio de sinais e sintomas, além de prevenir maiores complicações. O presente estudo teve como objetivo identificar os principais agentes naturais que atuam na prevenção e tratamento da MO, bem como descrever a fisiopatologia e classificação desta afecção. Trata-se de uma revisão de literatura de natureza qualitativa e exploratória através de levantamento de artigos científicos na base de dados SciELO, Lilacs, Medline e Pubmed. Os resultados demonstraram que a camomila, a aloe vera, a própolis e o mel têm sido amplamente utilizados na Odontologia,sendo apontados na literatura científica como estratégias de tratamento promissoras, pois apresentam efeito analgésico e antiinflamatório, além de serem bem tolerados pelos pacientes e possuirem baixo custo.Pode-se considerar que a utilização desses agentes para a prevenção e o tratamento da MO proporciona uma melhora clínica das lesões, com conseqüente melhora na qualidade de vida desses pacientes. Todavia, mais estudos precisam ser realizados na tentativa de se obter maiores informações acerca da posologia e forma de apresentação mais indicadas, além de avaliar a toxicidade desses agentes naturais. Palavras-chave: Estomatite. Camomila. Própolis. Aloe. Mel.

Introduction The reclassification of membranoproliferative glomerulonephritis (MPGN) into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G) has provided insights into 2 distinct diseases. Although outcomes in adults are poor in both diseases, the pediatric literature is scarce and limited to small, single-center cohorts. Methods We conducted a retrospective analysis of 165 pediatric patients across 17 hospitals to compare outcomes between children with IC-MPGN and C3G. Results Forty-two percent of patients initially diagnosed with MPGN were reclassified as C3G after a review of renal biopsy reports. There was a trend toward higher serum creatinine levels in patients with C3G compared with IC-MPGN both at diagnosis (mean 168.9 [range 45.4–292.4] vs. 93.7 [range 70.7–116.6] μmol/l, P = 0.25) and after a mean follow-up time of 4 years (mean 145.0 (range −8.1 to 298.1) vs 99.1 (range 46.3–151.9) μmol/l, P = 0.47), although the estimated glomerular filtration rate (eGFR) was not significantly different. Steroid treatment was associated with a significant improvement in eGFR versus no steroids in C3G (mean +43.0 (range 12.9–73.0) vs. −3.0 (range −23.1 to 17.2) ml/min per 1.73 m2, P = 0.02) but not in IC-MPGN. Overall kidney function was preserved in both groups although hypertension remained prevalent in 42.5% of the cohort at the last follow-up, and the urine protein/creatinine ratio remained elevated (mean 253.8 [range 91.9–415.7] mg/mmol). Conclusion This large pediatric IC-MPGN/C3G cohort revealed nearly half of the patients were misclassified, and there may be a trend toward worse renal prognosis in C3G although they may have greater steroid responsiveness. The overall prognosis appears to be more favorable than in adults; however, persistent hypertension and proteinuria suggest suboptimal disease control., Graphical abstract

Background: LADIES TRIAL is considered one of the most important trials related to diverticular peritonitis. Its protocol and results were published in 2010, 2015, 2017, and 2019. Despite this one and other published trials, the proper procedures for each diverticular peritonitis scenario are still being debated, a thorough review of the methodology used in this trial is necessary to validate or reject their conclusions.Aim: To analyze the methodology used in the design, application, analysis of results, and conclusions of all LADIES TRIAL publications. Secondly, to collaborate in the improvement of the research about diverticular peritonitis and to facilitate its analysis by the readers.Methods: The central parts of a research trial were analyzed, from the research question, hypothesis development, operationalization of variables and trial design, statistical analysis of results, to conclusions. Errors, biases and weaknesses were searched for to try and challenge the trial's findings.Results: LADIES was a randomized, open-label, superiority trial analyzed according to intention to treat modified in cases of non-compliance with the inclusion-exclusion criteria. Its design was generally correct, although errors, weaknesses, and biases were detected in its application. Regarding results, LOLA showed that, in Hinchey 3, laparoscopic lavage has a higher rate in early morbidity and mortality than sigmoidectomy, but with a shorter operative time. For its part, DIVA showed that, in Hinchey 3 and 4, the primary anastomosis has higher ostomy-free survival with less morbidity, combining the initial surgery and ostomy closure, compared to the Hartmann procedure.Conclusions: Not having reached the sample size calculated in its design implies that only large effect differences achieved statistical significance. The low frequencies of adverse events accentuated this methodological problem. The specialization of the intervening centers and surgeons, the exclusion of hemodynamically unstable patients or patients undergoing steroid therapy, compromised the external validation of their findings.

The incidence of bladder diverticula in the pediatric population is unknown as they are often asymptomatic. A minority of cases are a manifestation of a genetic syndrome. Primary diverticula have different features compared to secondary diverticula, which are generally caused by an obstructive or iatrogenic mechanism. This clinical case deals with a rare neonatal finding of bladder diverticulosis with alteration of the bladder, first detected with ultrasound. Voiding cystography and magnetic resonance allowed us to delineate their heterogeneity in size, their distribution in the bladder and to rule out other malformations of the urinary tract. The features of these diverticula focused the diagnosis of cutis laxa syndrome, a rare disease where bladder diverticulosis is only one sign of a more complex disease.

We describe sleep disturbances in patients with cystic fibrosis emphasizing treatment of abnormal breathing during sleep with noninvasive ventilation. Advances in treatment have transformed cystic fibrosis from a pediatric disorder to an adult condition. The increase in cystic fibrosis life expectancy renders these patients at high risk for nocturnal and diurnal respiratory failure. Hypoventilation during sleep precedes diurnal hypoventilation in cystic fibrosis. In advanced cases, noninvasive ventilation improves awake ABGs, respiratory muscle strength, dyspnea, subjective sleep quality, and level of daily activities and attenuates sleep hypoventilation. Noninvasive ventilation can ameliorate symptoms and improve gas exchange, particularly in cystic fibrosis with advanced lung dysfunction. There is insufficient literature describing the effect of noninvasive ventilation on survival in cystic fibrosis.

Background Idiopathic ventral spinal cord herniation (ISCH) is a rare disease; however, it is an important differential diagnosis. Its treatment presents some controversies. Case Description We report on a 55-year-old woman who had been presenting with relevant back pain and leg weakness for the past 3 years and urinary incontinence for the past 3 months. Clinical examination disclosed paresis on the right inferior limb and right foot, as well as a T6-level painful hypoesthesia. Magnetic resonance imaging disclosed a T4/T5 ISCH. The patient underwent surgical decompression. During the procedure, we opened the arachnoid and cut the dentate ligaments of the spine, which considerably improved the mobility and safety of the procedure. In the early follow-up, our patient presented a partial improvement regarding the paresis grades and hypoesthesia pain relief on the left side. A video showing the surgical procedure and case evolution is presented. We also assembled literature reviews to compare our case with others. ISCH is becoming a more recognized cause of progressive thoracic myelopathy. However, this condition is still frequently misdiagnosed. Magnetic resonance imaging is the key for diagnosis. The objective of surgical treatment is to prevent myelopathy progression. The technique presented in this report is an appropriate surgical option, once it is a safer way to identify and treat the defect. The neurologic condition usually improves greatly after surgical treatment, especially when the patient presents positive predictive factors. Conclusions ISCH is being more recognized. The technique presented is an appropriate surgical option.

AIMS In heart failure (HF), the haemodynamic response to exercise in relation to left atrial (LA) dynamics is unexplored. We sought to define whether abnormal LA dynamics during exercise may play a role in cardiac output (CO) limitation and tested its ability to predict outcome. METHODS AND RESULTS A total of 195 HF patients with reduced (n = 105), mid-range (n = 48), and preserved (n = 42) left ventricular ejection fraction (LVEF) and 46 non-cardiac dyspnoea (NCD) subjects underwent cardiopulmonary imaging with assessment of LA strain and strain rate (sra). HF patients, irrespective of LVEF, exhibited a significantly impaired LA strain and LA sra at rest, during exercise and recovery compared to NCD subjects with a blunted response in CO and right ventricular to pulmonary circulation coupling. LA strain and LA sra during exertion were significantly correlated with peak stroke volume index, peak CO and peak cardiac power output (R = 0.33, 0.48, 0.50 and R = 0.36, 0.51, 0.52 for LA strain and LA sra, respectively; all P 2, peak LVEF and peak heart rate, a higher LA strain (1% increase) during exercise was associated with a higher peak stroke volume index (mL/m2 ), CO (L/min) and cardiac power output (mmHg L/min) at multivariable analyses (β-coefficients ± standard error = 0.23 ± 0.07, 0.046 ± 0.014 and 0.012 ± 0.004, respectively; P

Our objective was to compare success and complication rates following minimally invasive sacrocolpopexy (SCP) based on body mass index (BMI). This is a retrospective cohort study of women who underwent laparoscopic or robotic SCP at one academic center from 2006 to 2016. Women were included if they had a postoperative pelvic organ prolapse quantification (POPQ) exam and subjective success documented. For our primary outcome, we compared composite success (POPQ stage ≤ I and report of no bulge symptoms) amongst three groups: normal weight (BMI ≤ 25), overweight (BMI 25–30) and obese (BMI ≥ 30) women. Secondary outcomes included intraoperative complications, 6 week postoperative complications, and sacrocolpopexy mesh exposure. Of the 431 women who met inclusion criteria, 140 (32%) had normal BMI (23 kg/m2; IQR 22, 24), 177 (41%) were overweight (27 kg/m2; IQR 26, 28), and 114 (26%) were obese (32 kg/m2; IQR 31, 36). Mean age was 60 ± 11 years, and most were Caucasian, with no differences in demographics or Charlson Comorbidity Index (CCI). Median length of follow-up was 49 weeks (IQR 9, 104), with similar follow-up for all groups. For our primary outcome, composite success was 72% overall, with no significant differences in composite success rates between groups. For secondary outcomes, there were no differences in the rates of perioperative complications but obese women had a 2.8 increased risk of mesh exposure (p = 0.02). Obesity was not associated with differences in the success or peri-operative complication rates for SCP in our population, but was associated with mesh exposure.

OBJECTIVE Our aim was to compare perioperative complications between older (≥65 years), middle-age (55-64 years), and younger (

AIMS Hobnail variant of papillary thyroid carcinoma (PTC) is an aggressive PTC subtype characterised by a hobnail cytomorphology. However, some classic PTC have a 'hobnail-like' cytomorphology associated with thick, hyalinised, variably oedematous fibrovascular cores that appears to be a form of ischaemic/degenerative atypia. METHODS AND RESULTS We studied three cohorts to compare the histopathological characteristics and clinical outcome of 'hobnail-like' classic PTC and true hobnail variant of PTC: cohort 1, PTC consecutively resected between 2016 and 2017 (to assess frequency of 'hobnail-like' cytomorphology); cohort 2, 20 'hobnail-like' classic PTC resected between 2005 and 2007 (to assess clinical outcome); and cohort 3, seven true hobnail variant of PTC. A 'hobnail-like' cytomorphology was identified in 16% of consecutively resected PTC. Compared with true hobnail variant, 'hobnail-like' classic PTC occurred in younger patients (mean age 40 years versus 68 years, P

Background. Several studies demonstrated the prophylactic benefit of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors for anthracyclines-based chemotherapy-induced cardiotoxicity. However, there is no consensus on management strategies at the time being. We present the interim analysis of the SAFE trial. Methods. The SAFE trial is a 2 × 2 factorial design randomized phase 3 study evaluating the impact of bisoprolol (B) (5 mg), ramipril (R) (5 mg), or both drugs as compared to placebo (P) on subclinical heart damage evaluated by speckle-tracking cardiac ultrasound. Enrolled patients included non-metastatic histology-proven breast cancer, treated with primary systemic therapy or adjuvant regimens based on anthracyclines with or without trastuzumab. Primary endpoint is evaluation of reduction in both systolic and diastolic, early and late subclinical cardiotoxicity measured with traditional echocardiography, pulsed tissue doppler, global linear strain (GLS), and 3-dimesional left ventricular ejection fraction (3D-LVEF). CT registry ID: NCT2236806; EudraCT number: 2015-000914-23. Results. A total of 191 out of 480 patients have been enrolled; overall 123 patients were available for the analysis (P=34; R=28; B=31; R+B=30). 3D-LVEF decreased at 3-month (-3.3%; p Citation Format: Lorenzo Livi, Icro Meattini, Francesca Martella, Calogero Saieva, Carlotta Becherini, Francesca Terziani, Isacco Desideri, Vieri Scotti, Carlotta Bacci, Mario Airoldi, Giacomo Allegrini, Domenico Amoroso, Luisa Fioretto, Giuseppe Barletta. Interim analysis of the SAFE trial (NCT2236806): A randomized phase 3 study evaluating a cardiovascular disease prevention strategy using beta-blockers and/or ACE inhibitors in non-metastatic breast cancer patients treated with anthracyclines [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-24.

Background Cervical spine degenerative disease is one of the main causes of myelopathy. Anterior cervical discectomy and fusion (ACDF) is the most common surgical procedure used to treat cervical myelopathy. Therefore, it is important to study pseudarthrosis rates after ACDF and correlate them with the graft used. Methods We performed a systematic review to evaluate the relationship between pseudarthrosis after ACDF and the interbody graft used. Results A total of 3732 patients were evaluated in 46 studies. The mean age of the included patients was 51.5 ± 4.18 years (range, 42–59.6 years). ACDF is most often perforemd as single-level surgery and the level most impaired is C5-C6. The use of titanium cages, zero profile, recombinant human bone morphogenetic protein 2, and carbon cages was seen as a protective factor for pseudarthrosis compared with the autograft group (control group); with an odds ratio of 0.29, 0.51, 0.03, and 0.3, respectively; the results were statistically relevant. The use of polyetheretherketone, poly(methyl methacrylate), and trabecular metal was a risk factor for development of pseudarthrosis compared with the control group, with an odds ratio of 1.7, 8.7, and 6.8, respectively; the results were statistically relevant. Radiologic follow-up was an important factor for the pseudarthrosis rate; paradoxically, a short follow-up ( 2 years increased the chance of finding pseudarthrosis. Conclusions Different types of grafts lead to a significant difference in pseudarthrosis rates. Follow-up time is also an important factor that affects the rate of pseudarthrosis after ACDF.

Objective: We aimed at optimizing the follow-up for patients with a positive multiparametric magnetic resonance of the prostate (mpMRI) and a subsequent negative targeted biopsy (TBx) plus systematic biopsy (SBx). Materials and methods: A total of 308 men with a clinical suspicion of PCa and a positive mpMRI (PI-RADS ≥ 3) with concomitant negative systematic and targeted Bx performed at a single tertiary referral center. All patients were then followed with serial PSA measurements, digital rectal examination and eventual follow-up mpMRI and/or repeat Bx. The primary outcome was to evaluate the overall clinically significant PCa (csPCa)-free survival. The secondary outcome was to assess the role of a repeat mpMRI (Fu-mpMRI) and PSA density as predictors of csPCa diagnosis (defined as Gleason score ≥ 3 + 4) during follow-up. Kaplan Meier analysis and univariable Cox regression were used for survival and predictive analyses. Results: Median follow-up was 31 months (IQR: 23–43). During the study period 116 (37.7%) and 68 (22.1%) of men received a Fu-mpMRI and a Fu-Bx, respectively. Overall, 51 (16.6%) and 15 (4.9%) patients had a positive mpMRI and clinically significant (csPCa) diagnosis during follow-up, respectively. Among 68 men who received a Fu-Bx, the 2- and 3-years csPCa diagnosis-free survival in men with negative vs. positive Fu-mpMRI was 97% vs. 65% and 92% vs. 65%, respectively. At univariate Cox-regression analysis the presence of a positive Fu-mpMRI resulted to be significantly associated with the presence of csPCa at Fu-Bx (HR: 5.8, 95% CI: 1.3–26.6, P = 0.008). The 2- and 3-years csPCa diagnosis-free survival in men with PSAd

Chordoma is a rare tumor, usually diagnosed when the disease is advanced. Despite its slow growth, it is locally aggressive and has a poor long-term prognosis. Surgery is the mainstay treatment. Although cardiac metastases are very rare, the heart is frequently involved in systemic neoplastic diseases. This report describes a typical case of metastatic chordoma: the age at first diagnosis, the site of the primary tumor, and the slow growth of the cardiac metastasis were all typical features. Surgical excision of the mass from the right ventricular outflow tract is described together with echocardiographic, radiologic, and histopathologic characteristics of the metastatic chordoma.

IntroductionAs part of the PIONEER (Prostate Cancer Diagnosis and Treatment Enhancement Through the Power of Big Data in Europe) Consortium, we will explore which diagnostic and prognostic factors (DPFs) are currently being researched to previously defined clinical and patient-reported outcomes for prostate cancer (PCa).Methods and analysisThis research project will follow the following four steps: (1) a broad systematic literature review of DPFs for all stages of PCa, covering evidence from 2014 onwards; (2) discussion of systematic review findings by a multidisciplinary expert panel; (3) risk of bias assessment and applicability with Prediction model Risk Of Bias Assessment Tool criteria, Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) and the Quality In Prognosis Studies tool (QUIPS) and (4) additional quantitative assessments if required.Ethics and disseminationWe aim to develop an online tool to present the DPFs identified in this research and make them available across all stakeholders. There are no ethical implications.

Native hosts for the bacterial agent that causes Johne's disease are ruminants, which include cattle, sheep and goats among others. These large animals are often too costly to be used in testing experimental vaccines. In this chapter, we provide detailed methods to use an inexpensive and more manageable animal host, the ferret, to test efficacy and immunogenicity of live-attenuated Mycobacterium avium subspecies paratuberculosis (MAP) mutant strains prior to consideration as vaccine candidates.

Prospective cohort study. To analyze the circadian rhythm and state-dependent modulation of core body temperature (Tcore) in individuals with spinal cord injury (SCI) under controlled environmental conditions. Institute of the Neurological Sciences of Bologna, Italy. We assessed 48-h rectal Tcore and sleep–wake cycle by means of video-polygraphic recording in five cervical SCI (cSCI), seven thoracic SCI (tSCI), and seven healthy controls under controlled environmental conditions. cSCI showed higher night-time Tcore values with reduced nocturnal decrease, higher MESOR and earlier acrophase compared with tSCI and controls (p

Introduction Several studies have invariably shown that the risk of Grade Group (GG) upgrading between biopsy and radical prostatectomy (RP) is higher in elderly men. Whether this is due to a real biological effect or to a diagnostic bias is still unknown. We hypothesized that the introduction of multiparametric magnetic resonance imaging (MRI) has improved the diagnostic accuracy of PCa detection in older men thus reducing the risk of GG upgrading at RP reported in the pre-MRI era. Materials and Methods We selected 424 men who received a systematic plus targeted biopsy for a positive MRI and subsequent RP at two referral centers between 2013 and 2019. Upgrading was defined as an increase in GG at final pathology as compared to biopsy. Multivariable logistic regressions tested the risk of upgrading over increasing age according to any upgrading definition and after stratifying definitions according to GG group and biopsy type. Non-parametric functions explored the relationship between age and upgrading rate. Results Median rate of upgrading was 17%. In multivariable models, while age was not associated with increased risk of GG upgrading (p=0.4). At non-parametric analyses, probability of upgrading slightly decreased with age, without reaching statistical significance. In subgroup analyses according to different upgrading definition and to biopsy type, age did not predict higher risk of upgrading regardless of outcome definitions (GG 1 to 2 P = 0.1; GG 2 to 3 P = 0.2; GG 3 to 4-5 P = 0.2) and in GG detected at TBx (OR 0.998, P = 0.8). Conclusions We showed that use of MRI has obliterated the association between older age and increased risk of upgrading mainly due to improved diagnostic approaches in this group of men. Therefore, it is likely that the effect of age and GG upgrading reported in previous studies in elderly men was due to misdiagnosis and lead-time bias in the pre-MRI era.

Introduction Advances in neoadjuvant therapy for patients with localized, nonmetastatic, upper tract urothelial carcinoma (UTUC) is needed. Patients and methods PURE-02 was a feasibility study enrolling individuals with UTUC, at clinical stage N0M0, with high-risk features according to the modified European Association of Urology definition, based on the presence of either: high-grade disease, multifocality, tumor size ≥2 cm, and/or hydronephrosis. The treatment consisted of 3 courses of 200 mg pembrolizumab, intravenously, every 3 weeks, followed by radical nephroureterectomy (RNU). The endpoints were to assess the safety, pathological responses, and biomarkers. Results Ten patients were enrolled between August 2018 and November 2020, 9 (90%) completed the neoadjuvant course. One treatment-related death occurred as a complication of severe myocarditis, myasthenia gravis, hepatitis and myositis. One (14.3%) patient achieved a clinical complete response and refused to undergo RNU. Two (20%) had disease progression and received subsequent chemotherapy, prior to RNU. Overall, 7 patients underwent RNU: one (14.3%) achieved an ypT1N0 response, although this patient was reported to have a cT1 tumor at baseline imaging. The remaining patients were nonresponders. Circulating tumor DNA assay did not identify patients likely to achieve a complete pathologic response. Conclusion Single-agent neoadjuvant pembrolizumab did not appear to be a promising treatment strategy for patients with biomarker-unselected, high-risk localized UTUC.

Background The impact of positive surgical margins (PSMs) on the risk of metastases in prostate cancer (PCa) patients treated with radical prostatectomy (RP) is still debated. Objective To identify PSM features associated with recurrence in a stage-by-stage analysis. Design, setting, and participants A total of 1757 PCa patients treated with RP without neoadjuvant or adjuvant treatments between 2011 and 2017 were identified. Patients were stratified according to the presence of PSM and to margins characteristics in three groups: no versus favourable (single margin Outcome measurements and statistical analysis Predictors of biochemical recurrence (BCR) and clinical recurrence (CR) were assessed using semiparametric Cox proportional hazard models. Results and limitations Overall, 285 (16%) patients had PSMs; 146 (51%) had a unifocal PSM, while 139 (49%) had a multifocal PSM. The median length of a PSM was 1 mm. Overall, 120 (42%) versus 165 (58%) patients had favourable versus unfavourable PSMs. In patients with ≤pT3a and pathologic grade group ≤3 disease (n = 1351), favourable (hazard ratio [HR]: 2.24; 95% confidence interval [CI]: 1.19–4.22) and unfavourable (HR: 2.68; 95% CI: 1.49–4.84) PSMs significantly increased the risk of BCR (p 0.05). Conversely, in patients with pT3b/4 and/or pathologic grade group 4–5 and/or pN1 (n = 406), only an unfavourable PSM was associated with both BCR (HR: 2.96; 95% CI: 1.19–4.22) and CR (HR: 2.60; 95% CI: 1.07–6.30; all p ≤ 0.04). Conclusions Although the presence of PSMs was associated with an increased risk of BCR in all stages, only men with adverse pathologic characteristics and an unfavourable PSM were at an increased risk of experiencing metastases as compared with their counterparts with no or a single margin shorter than 3 mm. Patient summary In this study, we defined a new category of unfavourable positive surgical margins (namely, ≥3 mm and/or multifocal), which confers a higher risk of developing metastasis in men with more aggressive pathologic features.

Background The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design.

From February 2020, the progressive adoption of measures to contain coronavirus’s contagion has resulted in a sudden change in anthropogenic activities in Italy, especially in Lombardy. From a scientific point of view, this situation represents a unique laboratory for understanding and predicting the consequences of specific measures aimed at improving air quality. In this work, the lockdown effect on Milan’s (Italy) air quality was analyzed. The PM10 and PM2.5 values were measured by the ARPA Lombardia, and the real-time on-road (ROM) air quality monitoring network indicates the seasonality of these pollutants, which typically record the highest values in the coldest months of the year. The 10-year particulate matter concentrations analysis shows a PM10 reduction of 35% from 2010 to 2020. March 2020 data analysis shows an alternation of days with higher and lower particulate matter concentrations, values decrease in pollutants concentrations of 16%, respective to 2018. The complexity of the phenomena related to the atmospheric particulates formation, transport, and accumulation is highlighted by some circumstances, such as the Sahara dust events. The study showed that the trend of a general pollutant concentration reduction should be attributed to the decrease in emissions (specifically, from the transport sector) from the variation of meteorological and environmental conditions.

Background: To assess the diagnostic added value of sampling secondary lesions at prostate mpMRI (SL) in addition to index lesion (IL) in detecting significant prostate cancer (csPCa) when also systematic biopsy (SBx) is performed. Methods: We relied on a cohort of 312 men with two suspicious lesions at prostate mpMRI who underwent subsequent targeted biopsy of each lesion (TBx) and concomitant SBx at two tertiary-referral centers between 2013 and 2019. The study outcome was the added value of targeting SL (i.e., the one with a lower PI-RADS score and/or the smaller size compared to IL) in the detection of csPCa. To this aim, we compared different biopsy strategies (SBx + overall TBx vs SBx + IL-targeted biopsy vs SBx + SL-targeted biopsy) and assessed whether SL features could be correlated with detection of csPCa at overall TBx in a multivariable logistic regression model (MVA). Results: Overall, 44% of men had csPCa at TBx of all lesions while 39% and 23% of men had csPCa found in IL and SL, respectively. The rate of csPCa found at SBx, IL-TBx, and SL-TBx only was 5%, 6%, and 2%, respectively. The detection rate of csPCa for SBx + IL-TBx was 47%. The addition of SL-TBx increased csPCa detection by only 2% (p = 0.12). At MVA, neither PI-RADS of SL nor the number of cores targeting SL was associated with an increased detection of csPCa (all p > 0.3). Conversely, age (OR: 1.07), PSA (OR: 1.07), prostate volume (OR: 0.98), and PI-RADS of the IL (OR: 2.36) were independently associated with csPCa detection at TBx (all p < 0.01). Conclusions: There is no significant benefit in terms of csPCa detection when an adequate SBx is performed in combination with IL-TBx in patients with multiple mpMRI lesions. In these men target biopsy of secondary lesions can be safely omitted.

Background: Although an increasing number of prostate cancer (PCa) patients received holmium laser enucleation of the prostate (HoLEP) previously for benign prostatic obstruction (BPO), there is still no evidence regarding the outcomes of radical prostatectomy (RP) in this setting. Objective: To assess functional and oncological results of RP in PCa patients who received HoLEP for BPO previously in a contemporary multi-institutional cohort. Design, setting, and participants: A total of 95 patients who underwent RP between 2011 and 2019 and had a history of HoLEP were identified in two institutions. Functional as well as oncological follow-up was prospectively assessed and retrospectively analyzed. Intervention: RP following HoLEP compared with RP without previous transurethral surgery. Outcome measurements and statistical analysis: Patients with complete follow-up data were matched with individuals with no history of BPO surgery using propensity score matching. Complications were assessed using the Clavien-Dindo scale. Results and limitations: The median follow-up was 50.5 mo. We found no significant impact of previous HoLEP on positive surgical margin rate (14.0% [HoLEP] vs 18.8% [no HoLEP], p = 0.06) and biochemical recurrence-free survival (hazard ratio 0.74, 95% confidence interval [CI] 0.32–1.70, p = 0.4). Patients with a history of HoLEP had increased 1-yr urinary incontinence rates after RP. After adjusting for confounders, no significant impact of previous HoLEP was found (odds ratio [OR] 0.87, 95% CI 0.74–1.01; p = 0.07). Previous HoLEP did not hamper 1-yr erectile function recovery (OR 1.22, 95% CI 1.05–1.43; p = 0.01). Limitations include retrospective design and small sample size. Conclusions: RP after previous HoLEP is surgically feasible, with low complication rates and no negative impact on biochemical recurrence–free survival. However, in a multivariable analysis, we observed significantly worse 1-yr continence rates in patients after previous HoLEP. Patient summary: In the current study, we assessed the oncological and functional outcomes of radical prostatectomy in patients who underwent holmium laser enucleation of the prostate (HoLEP) previously due to prostatic bladder outlet obstruction. A history of HoLEP did not hamper oncological results, 1-yr continence, and erectile function recovery. We provide data from a propensity score–matched population of patients who underwent radical prostatectomy with or without previous holmium laser enucleation of the prostate (HoLEP). In multivariable analyses, no differences were found in biochemical recurrence–free survival, positive surgical margin rates, and 1-yr continence recovery. Patients with previous HoLEP had similar rates of bilateral nerve sparing and increased 1-yrerectile function recovery compared with those without previous HoLEP.

The Coronavirus Disease 2019 (COVID-19) pandemic required a thorough re-organization of every sector of the healthcare system. Sleep laboratories need to renew protocols in order to guarantee the safety of patients and healthcare staff while providing exams. Polysomnography (PSG) examinations are essential for the diagnosis and treatment management of several sleep disorders, which may constitute a public or personal safety issue such as obstructive sleep apnea syndrome. Here we provide some practical advice on how to perform sleep studies after the COVID-19 outbreak based on our experience, the review of the existing literature and current national and international recommendations by Health Authorities. We believe that with appropriate precautions it is possible to guarantee a safe restart of PSG and other sleep studies.