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Background There is a lack of specific data about the efficacy and safety of medications administered via feeding tubes, although there is a general awareness that not all drug formulations are suitable. Aims and objectives To overview the current situation with solid medications administered through feeding tubes in the Tartu University Hospital intensive care units. To evaluate the availability of information on the suitability of drug formulations for administration via feeding tubes. Design This was a descriptive retrospective document analysis study. Methods During visits to the intensive care units, medication data for current patients were collected from paper medical charts and nurses. In addition, package information leaflets, summaries of product characteristics, and two practical handbooks were used for evaluating the medicines' suitability for administration via feeding tubes. A request for information was also sent to manufacturers or marketing authorization holders. Results In 3 months, data were collected from 113 intensive care patients' medical charts. A total of 306 medication administrations via feeding tubes were documented and analysed, 67% of which were solid oral dosage forms. Exactly 91.2% of these were conventional tablets. After the analysis of information availability, 88% of the medications were classified as suitable for administration via feeding tubes, but only 48% had the manufacturer-provided information. Conclusion This study showed that the information about the suitability of formulations administration through a feeding tube is not readily available for almost half of the medications. The manufacturers seem to have the relevant information, but it is not always added to their medications' official information, putting these patients at higher risk for errors. Relevance to clinical practice This study shows that if there is no clear statement about administration through feeding tubes on official manufacturers' information, this should be sought directly from manufacturers or marketing authorization holders, and the data could be incorporated into local guidelines.

PURPOSE Standard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy. PATIENTS AND METHODS One hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital. RESULTS Mean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed. CONCLUSION Subjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.

Salvage lymph node dissection is a rescue treatment for patients with nodal recurrence after radical prostatectomy. Very limited data are available on robotic salvage lymph node dissection. Our purpose was to investigate perioperative and oncological outcomes of robotic salvage lymph node dissection in a large monocentric series.Perioperative data, complications within 30 days after surgery and oncological outcomes as assessed by histology, prostate specific antigen changes, prostate specific antigen nadir after salvage lymph node dissection, and time to further therapy were analyzed. To identify predictive factors for oncological outcome, Kaplan-Meier and Cox-regression analyses were performed. For cases with a mismatch between preoperative positron emission tomography/computed tomography and the number of histologically positive lymph nodes, prostate specific membrane antigen immunohistochemistry was performed on removed lymph nodes.A total of 68 patients underwent robotic salvage lymph node dissection with a median operation time of 126 minutes, a blood loss of 50 ml, and a length of stay of 4 days. No major complications (Clavien 3) occurred. Median followup was 12.1 months. Median time to further therapy was 12.4 months, 37% of patients experienced complete biochemical response (prostate specific antigen0.2 ng/ml) and 11% reached an undetectable prostate specific antigen, which was maintained for1 year in 3 cases. Lower preoperative prostate specific antigen, longer time between radical prostatectomy and salvage lymph node dissection, preoperative prostate specific membrane antigen positron emission tomography/computed tomography and complete biochemical response after salvage lymph node dissection were significant predictors of longer therapy-free survival (all p0.005). Prostate specific membrane antigen immunohistochemistry revealed that prostate specific membrane antigen positron emission tomography/computed tomography tends to miss small lymph node metastases5 mm.Robotic salvage lymph node dissection is a feasible approach with low perioperative morbidity and delays further systemic therapy in most patients. Prostate specific membrane antigen positron emission tomography/computed tomography detection is mostly limited to tumor foci5 mm.

Objectives To investigate the effect of ACE inhibitors (ACEi) on the incidence of scleroderma renal crisis (SRC) when given prior to SRC in the prospectively collected cohort from the European Scleroderma Trial and Research Group (EUSTAR). Methods SSc patients without prior SRC and at least one follow-up visit were included and analyzed regarding SRC, arterial hypertension, and medication focusing on antihypertensive medication and glucocorticoids (GC). Results Out of 14,524 patients in the database, we identified 7648 patients with at least one follow-up. In 27,450 person-years (py), 102 patients developed SRC representing an incidence of 3.72 (3.06–4.51) per 1000 py. In a multivariable time-to-event analysis adjusted for age, sex, disease severity, and onset, 88 of 6521 patients developed SRC. The use of ACEi displayed an increased risk for the development of SRC with a hazard ratio (HR) of 2.55 (95% confidence interval (CI) 1.65–3.95). Adjusting for arterial hypertension resulted in a HR of 2.04 (95%CI 1.29–3.24). There was no evidence for an interaction of ACEi and arterial hypertension (HR 0.83, 95%CI 0.32–2.13, p = 0.69). Calcium channel blockers (CCB), angiotensin receptor blockers (ARB), endothelin receptor antagonists, and GC—mostly in daily dosages below 15 mg of prednisolone—did not influence the hazard for SRC. Conclusions ACEi in SSc patients with concomitant arterial hypertension display an independent risk factor for the development of SRC but are still first choice in SRC treatment. ARBs might be a safe alternative, yet the overall safety of alternative antihypertensive drugs in SSc patients needs to be further studied.

In the future, precision medicine with agents targeting specific genetic alterations will play an important role in bladder cancer. This includes both single genetic alterations (e.g. FGFR3) and gene panel analyses in patients with no further therapeutic options, rare cancer subtypes or unusual clinical courses. These molecular analyses can be carried out on formalin-fixed paraffin-embedded tumor samples and the results should be discussed in interdisciplinary molecular tumor boards in order to either recommend approved targeted therapies or suggest patients for molecular-based clinical trials, compassionate use programs or off-label use of drugs. The remuneration of molecular diagnostics is largely well-represented for the outpatient sector in Germany; however, the covering of treatment costs must currently be approved by the health insurances.

Introduction The COVID-19 pandemic and its associated preventive measures such as national and regional lockdowns have dramatically changed the epidemiology of pediatric admissions to the emergency department. Nevertheless, there are scant data on the epidemiology and injury patterns of major pediatric trauma injuries during these lockdown periods. Methods A single-center retrospective study of data obtained from a tertiary level 1 trauma hospital trauma registry. The data included demographics, injury mechanisms, injury severity and type, treatment, and resource utilization in children aged 0–18 years who required trauma team activation upon arrival. The analysis compares the data from the 5-week lockdown period from March to May 2020 in Jerusalem, Israel, to its parallel periods in 2018–2019. Results A total of 187 trauma visits that required trauma team activation (TTA) were analyzed: 48 visits during the lockdown period vs. 139 in 2018–2019, corresponding to a 40% drop in TTA. There was a significant decrease of 34% in MVA-related injuries ( p = 0.0001) but a significant increase of 14% in burns ( p = 0.01) and a 16% increase in bicycle-related injuries ( p = 0.001). No changes in ISS, injury patterns, admission rate, PICU utilization, or need for interventions were observed. Conclusion There was a significant decrease in the number of overall pediatric trauma visits during the 2020 lockdown, mainly in MVA-associated trauma, but an increase in burns and bicycle injuries. These findings can thus inform policy makers as to the need to formulate prevention awareness programs alerting the public to indoor hazards and the dangers of activities outside the home. Furthermore, it can inform hospital policy decision-making in future lockdowns. The fact that PICU admissions and the need for operating rooms stayed unchanged suggests that it is vital to maintain trauma team capabilities even during lockdowns.

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa., Cholesterol metabolism is involved in the progression of aggressive prostate cancer (PCa). Here the authors show that miR-205 downregulation promotes cholesterol synthesis and androgen receptor signalling in PCa through enhancing the expression of the rate-limiting enzyme of cholesterol synthesis, squalene epoxidase.

Summary Objectives To explore the rate, characteristics, risk factors, and prognosis of children presenting with seizures as the main symptom of acute COVID-19 (coronavirus disease 2019). Methods We conducted a systematic retrospective study to identify all children who presented to the emergency departments of a tertiary academic medical center between March 1st and December 31st 2020 and had a SARS-CoV-2 infection based on RT-PCR (reverse transcription-polymerase chain reaction) from nasopharyngeal swab. Clinical and demographic data were extracted from the electronic medical records and reviewed. Results Total of 175 children were diagnosed with acute SARS-CoV-2 infection in the emergency departments during the study period. Of those, 11 presented with seizures. Age ranged from six months to 17 years and 4 were girls. Five presented with status epilepticus and responded to loading doses of anti-seizure medications. Six had fever. Seven had prior history of neurological disorder. Full recovery was the rule. Significance Unlike in adults, seizures occur early and may be the main manifestation of acute COVID-19 in children. Seizures, including status epilepticus, may occur without fever even in children with no history of epilepsy and are not associated with severe disease. A high index of suspicion is required for early diagnosis thus infection control measures can be taken.

A selective nonoperative management (SNOM) of penetrating abdominal injuries (PAI) is a standard of care in numerous established trauma centers. However, available evidence supporting SNOM of PAI in European settings remains scarce. Thus, we performed a multi-center study at selected Northern European trauma centers to investigate the management and outcomes of PAI. We hypothesized that despite a low number of penetrating injuries in included trauma centers, SNOM is successfully utilized with outcomes comparable with trauma centers with a high number of PAI. All adult patients admitted to participating trauma centers in the Northern European region with PAI between 1/2015 and 12/2016 were retrospectively reviewed. Primary outcomes were mortality and success rate of SNOM. Overall, 119 patients were included. Median age was 38 (28–47) years. SNOM was initiated in 55 patients (46.0%) with 94.5% success rate. Three patients (5.5%) failed SNOM and had a delayed laparotomy with one gastric injury, one small bowel injury and one patient with a bleeding from mesentery. Overall mortality of the cohort was 5.0%. However, all patients in the SNOM group survived. Higher median ISS, median Abbreviated Injury Scale score of the abdomen, rate of combined anterior and posterior wounds, rate of in-hospital complications and longer hospital length of stay were observed in the immediate laparotomy group compared to the SNOM group. SNOM of PAI is a safe practice even in regions with a low prevalence of penetrating injuries. The outcomes in our study are comparable with results from trauma centers treating larger numbers of patients with PAI.

Objective:One explanation for the relationship between TV viewing and obesity is that people may (over)eat while watching TV. The current study investigated associations between TV viewing and the time spent on (concurrent) eating in a naturalistic setting among a general population sample.Design:Preregistered secondary data analyses were performed of a diary survey in which respondents reported their time use in 10-min blocks for 7 d.Setting:Concurrent TV viewing and eating was operationalised as all blocks in which TV viewing and eating occurred simultaneously. Furthermore, the TV content respondents watched was coded as food-related (i.e. culinary content) or non-food related.Participants:The sample composed of 2292 adults (58·9 % female) in the Netherlands, aged ≥ 20 years, from all educational levels (18·1 % low, 29·8 % middle and 51·4 % high).Results:More than half of the respondents (51·3 %) reported concurrent TV viewing and eating at least once during the 7-d diary period. The average eating occasion was longer in duration while watching TV (v. without media use), and the total time spent on eating was longer on days of concurrent TV viewing and eating (v. days of eating without media use). The percentage of TV viewing time spent on concurrent eating did not differ between food-related and non-food-related TV content.Conclusions:Eating while watching TV was related to an increased time spent on eating. Even though energy intake was not assessed, these findings from a naturalistic setting provide further evidence that concurrent TV viewing and eating may contribute to overeating.

At the time of writing, five anti-CD19 CAR T-cell products are approved by the U.S. Food and Drug Administration for seven different indications in lymphoid malignancies, including B-cell non-Hodgkin lymphoma, pediatric B-cell acute lymphoblastic leukemia, and multiple myeloma. CAR T cells for chronic lymphocytic leukemia, acute myeloid leukemia, and less common malignancies such as T-cell lymphomas and Hodgkin lymphoma are being tested in early-phase clinical trials worldwide. The purpose of this overview is to describe the current landscape of CAR T cells in hematologic malignancies, outline their outcomes and toxicities, and explain the outstanding questions that remain to be addressed.

Background/Objectives Chronic pancreatitis (CP) is a complex disease with a high complications rate, poor quality of life and considerable mortality. Prospective investigations on long-term outcomes in chronic pancreatitis are scarce. Thus, we aimed to assess long-term survival, causes of death and impact of risk factors on survival in a cohort of surgically managed patients with chronic pancreatitis. Methods After IRB approval, a prospective longitudinal cohort study with long-term follow-up (up to 19.6 years) was conducted. All consecutive single center patients operated between 1997 and 2019 were included. Data on health and social status, risk behavior, history of CP, indications for surgery, comorbidities and causes of death were collected. Survival analysis was performed using Kaplan-Meier analysis. Cox proportional multivariate hazard regression was used to assess the impact of risk factors on mortality. The results are reported as the hazard ratio (HR) with the 95% confidence interval (CI). The log-rank test was used to test for differences in survival between groups. Results A total of 161 patients with CP were subjected to operative management due to chronic pain or local complications of CP. Forty-eight patients (29.8%) died during the follow-up period. Mortality rate was 32.8 per 1000 patient-years (PY) since the diagnosis of CP. Standardized mortality ratio (SMR) was 1.8 (2.7 for the subgroup of continuous alcohol users). Median survival after surgical treatment was 13.3 years. Univariate analysis revealed the following risk factors on survival: preoperative and postoperative continuous moderate or heavy alcohol consumption, heavy smoking, age ≥50 years, Charlson’s comorbidity index (CCI) ≥4 and 2–3, unemployment, disability, insulin-dependent diabetes, pancreatic exocrine insufficiency (PEI), and low body mass index (BMI). In multivariate regression analysis lower survival was associated with continuous moderate/heavy alcohol consumption (hazard ratio (HR) 2.27), history of heavy smoking (HR 4.40), unemployment (HR 2.49), CCI 2–3 and ≥4 (HR 2.53 and HR 3.16, respectively), and BMI Behavioral risk factors accounted for the vast majority of deaths due to chronic alcoholic liver disease (21 cases, 43.7%), smoking-related diseases (15 cases, 31.3%). CP-related mortality was 4.2%. Conclusions Long-term outcomes of surgically treated chronic pancreatitis was associated with low CP-related mortality. Alcohol-related and smoking-related diseases caused the vast majority of deaths. Thus, surgery provides the best results in patients, preventing postsurgical relapse of original behavioral risks. For achieving this, ongoing postoperative support would be highly beneficial.

Introduction We aimed to examine the impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic on diabetic ketoacidosis (DKA) rates in children with type 1 diabetes (T1D). Methods A retrospective cross-sectional study of 11 Israeli pediatric emergency departments (ED) was conducted. Children with T1D who attended the ED between March 1, 2020 and May 31, 2020 were compared with those who attended the ED between March 1, 2019 and May 31, 2019. Results Overall, 150 and 154 children with T1D attended the EDs during the 3-month study periods in 2020 and 2019, respectively. Among patients with established T1D, DKA rates significantly increased in 2020 compared to 2019 [38/64 (59.3%) vs 31/74 (41.9%); p

Aims Describe the characteristics, management and outcomes of hospitalized ST-segment elevation myocardial infarction (STEMI) patients according to national ongoing myocardial infarction registries in Estonia, Hungary, Norway, and Sweden. Methods and results Country-level aggregated data was used to study baseline characteristics, use of in-hospital procedures, medications at discharge, in-hospital complications, 30-day and 1-year mortality for all patients admitted with STEMI during 2014–2017 using data from EMIR (Estonia; n = 4584), HUMIR (Hungary; n = 23 685), NORMI (Norway; n = 12 414, data for 2013–2016), and SWEDEHEART (Sweden; n = 23 342). Estonia and Hungary had a higher proportion of women, patients with hypertension, diabetes, and peripheral artery disease compared to Norway and Sweden. Rates of reperfusion varied from 75.7% in Estonia to 84.0% in Sweden. Rates of recommendation of discharge medications were generally high and similar. However, Estonia demonstrated the lowest rates of dual antiplatelet therapy (78.1%) and statins (86.5%). Norway had the lowest rates of beta-blockers (80.5%) and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (61.5%). The 30-day mortality rates ranged between 9.9% and 13.4% remaining lowest in Sweden. One-year mortality rates ranged from 14.8% in Sweden and 16.0% in Norway to 20.6% in Hungary and 21.1% in Estonia. Age-adjusted lethality rates were highest for Hungary and lowest for Sweden. Conclusion This inter-country comparison of data from four national ongoing European registries provides new insights into the risk factors, management and outcomes of patients with STEMI. There are several possible reasons for the findings, including coverage of the registries and variability of baseline-characteristics’ definitions that need to be further explored.

Purpose A number of observational clinical studies suggest that prior primary tumor treatment favorably influences the course of metastatic prostate cancer (PCa), but its mechanisms of action are still speculative. Here, we describe the long-lasting sensitivity to various forms of androgen deprivation in patients after radical prostatectomy (RP) for locally advanced PCa as one potential mechanism. Methods A consecutive series of 115 radical prostatectomies after inductive therapy for T4 prostate cancer was re-analyzed, and long-term survival, as well as recurrence patterns and responses to different forms of hormonal manipulation, were assessed. Results The estimated biochemical response-free, PCa-specific, and overall survival rates after 200 months were 20%, 65%, and 47% with a median overall survival of 156 months. The majority of patients, although not cured of locally advanced PCa (84/115), showed long-term survival after RP. PCa-specific and overall survival rates of these 84 patients with biochemical recurrence were 61% and 44% at 150 months. Long-term sensitivity to ADT was found to be the main reason for the favorable tumor-specific survival in spite of biochemical recurrence. Conclusions Sensitivity to primary or secondary hormonal manipulation was the main reason for the long-term survival of patients who had not been cured by surgery only. The results suggest that treatment of the primary tumor-bearing prostate delays castration-resistant PCa and enhances the effect of hormonal therapies in a previously unknown manner. The underlying cellular and molecular mechanisms need to be explored in more detailed analyses, which could profoundly impact treatment concepts of locally advanced and metastatic PCa.

To compare tickborne relapsing fever (TBRF) in children and adults in Jerusalem, Israel, we collected data from the medical records of all 92 patients with TBRF during 2004–2018. The 30 children with TBRF had more episodes of fever and lower inflammatory markers than adult patients.

Purpose of review To discuss the important advances in CAR T cell therapy over the past year, focusing on clinical results where available. Recent findings Approximately 30 years after they were first conceived of and 15 years after the first small-scale single-center clinical trials, the past 3 years represent a major milestone in the development of CAR T cells. In the United States, the Food and Drug Administration (FDA) approved Tisagenlecleucel for the treatment of relapsed/refractory B-ALL and Axicabtagene Ciloleucel, for adults with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) in 2017. Tisagenlecleucel received a second indication in adults with R/R DLBCL in 2018. Regulatory approval for CAR T cells was then granted in Europe, Canada, Australia, and Japan. Most recently, in July 2020 the FDA granted regulatory approval to a third CAR T cell product, Brexucabtagene Autoleucel for mantle cell lymphoma. All products target the CD19 antigen but differ in the costimulatory molecule within the CAR construct. Currently, it is unknown whether there are any differences in clinical activity or toxicity between these products. Summary The CAR T cell the platform is evolving at a rapid pace and is expected to further improve the therapeutic outcomes of hematological malignancies.

Head trauma is one of the most common reasons for pediatric emergency medicine department (PED) visits. Computerized tomography (CT) scan is considered the criterion standard for the diagnosis of traumatic brain injury but was shown to increases the risk of malignancies.We retrospectively analyzed collected data of all children (ages 0-16 years) experiencing mild head trauma who were admitted to a single center, from January 1, 2010, to December 31, 2015. Comparison between patients treated by pediatricians/pediatric emergency medicine physicians (PEMP) with those treated by surgeons regarding CT rates and prognosis was done.During the previously mentioned period, 4232 children presented to the PED after minor head trauma, the average age was 5.4 (±4) years and 67.1% were male. Head CT was done in 7.7%, of which 30.7% had positive findings. Younger children tended to have higher percentage of positive findings on CT scan (60%, 43.8%, 26.6%, P = 0.003, for children up to 5 months, 5-24 months, and older than 24 months, respectively). Pediatricians ordered less CT scans when compared with surgeons (5.4% vs 8.5%, P0.001). Moreover, they had higher rates of positive findings on CT scan (52.5% vs 25.8%, P0.001). When all other characteristics were similar, if the case manager was a pediatrician, the patient's chances to undergo a CT scan were 4.3 times lower than if the case manager was a surgeon (odds ratio, 4.277; confidence interval, 2.274-7.104). No difference in readmissions or other complications were found between the 2 groups.This study highlights that when the case manager of children with minor head trauma is a pediatrician/PEMP, CT scan rates and thus exposure to radiation are diminished without a failure to detect clinically important traumatic brain injury.In conclusion, our findings suggest that when possible, all children experiencing minor head trauma should be treated by a pediatrician/PEMP in the PED.

Background Although pathological factors remain the main determinate of survival for patients with bladder cancer, quality of surgical care is crucial for satisfactory outcomes. Using a validated quality score, we investigated the impact of surgical factors on the overall survival (OS), recurrence-free survival (RFS) and disease-specific survival (DSS) in patients with locally advanced and organ-confined disease (OCD). Retrospective review of IRCC database includes 2460 patients from 29 institutions across 11 countries. The final cohort included 1343 patients who underwent RARCs between 2005 and 2016. Patients with locally advanced disease (LAD) (> pT2 and/or N +) were compared with OCD (≤ pT2/N0). Validated Quality Cystectomy Score (QCS) based on four sets of quality metrics was used to compare surgical performance. Kaplan–Meier method was used to compute RFS, CSS and OS rates. Multivariable stepwise logistic regression was used to evaluate variables associated with RFS, DSS and OS. Results 48% had LAD. When compared to patients with OCD, they received neobladders less frequently (17% vs. 28%, p p = 0.05). Postoperatively, more patients in the LAD group received adjuvant chemotherapy (24% vs. 4%, p p p Conclusion Quality of surgical care can affect disease control and OS in patients with bladder cancer treated with robot-assisted radical cystectomy.

See Ware et al. (doi:10.1093/brain/awaa166) for a scientific commentary on this article. Using a modified MRI-based method that can detect subtle, region-specific blood-brain barrier dysfunction, Veksler et al. reveal slow blood-to-brain transport in a subset of amateur American football players. MRI may allow early detection of microvascular pathology in patients at risk for chronic traumatic encephalopathy., Repetitive mild traumatic brain injury in American football players has garnered increasing public attention following reports of chronic traumatic encephalopathy, a progressive tauopathy. While the mechanisms underlying repetitive mild traumatic brain injury-induced neurodegeneration are unknown and antemortem diagnostic tests are not available, neuropathology studies suggest a pathogenic role for microvascular injury, specifically blood–brain barrier dysfunction. Thus, our main objective was to demonstrate the effectiveness of a modified dynamic contrast-enhanced MRI approach we have developed to detect impairments in brain microvascular function. To this end, we scanned 42 adult male amateur American football players and a control group comprising 27 athletes practicing a non-contact sport and 26 non-athletes. MRI scans were also performed in 51 patients with brain pathologies involving the blood–brain barrier, namely malignant brain tumours, ischaemic stroke and haemorrhagic traumatic contusion. Based on data from prolonged scans, we generated maps that visualized the permeability value for each brain voxel. Our permeability maps revealed an increase in slow blood-to-brain transport in a subset of amateur American football players, but not in sex- and age-matched controls. The increase in permeability was region specific (white matter, midbrain peduncles, red nucleus, temporal cortex) and correlated with changes in white matter, which were confirmed by diffusion tensor imaging. Additionally, increased permeability persisted for months, as seen in players who were scanned both on- and off-season. Examination of patients with brain pathologies revealed that slow tracer accumulation characterizes areas surrounding the core of injury, which frequently shows fast blood-to-brain transport. Next, we verified our method in two rodent models: rats and mice subjected to repeated mild closed-head impact injury, and rats with vascular injury inflicted by photothrombosis. In both models, slow blood-to-brain transport was observed, which correlated with neuropathological changes. Lastly, computational simulations and direct imaging of the transport of Evans blue-albumin complex in brains of rats subjected to recurrent seizures or focal cerebrovascular injury suggest that increased cellular transport underlies the observed slow blood-to-brain transport. Taken together, our findings suggest dynamic contrast-enhanced-MRI can be used to diagnose specific microvascular pathology after traumatic brain injury and other brain pathologies.

Graft versus host disease (GvHD) remains a limiting factor for successful hematopoietic stem cell transplantation (HSCT). T cells and antigen-presenting cells (APCs) are major components of the hematopoietic G-CSF mobilized peripheral blood cell (MPBC) graft. Here we show that a short incubation (2 h) of MPBCs with hexameric Fas ligand (FasL) selectively induces apoptosis of specific donor T cell subsets and APCs but not of CD34+ cells. FasL treatment preferentially induces apoptosis in mature T cell subsets which express high levels of Fas (CD95), such as T stem cell memory, T central memory, and T effector memory cells, as well as TH1 and TH17 cells. Anti-CD3/CD28 stimulated T cells derived from FasL-treated-MPBCs express lower levels of CD25 and secrete lower levels of IFN-γ as compared to control cells not treated with FasL. FasL treatment also induces apoptosis of transitional, naïve, memory and plasmablastoid B cells leading to a reduction in their numbers in the graft and following engraftment in transplanted mice. Most importantly, ex vivo treatment of MPBCs with FasL prior to transplant in conditioned NOD-scid IL2Rγnull (NSG) mice prevented GvHD while preserving graft versus leukemia (GvL) effects, and leading to robust stem cell engraftment.

Little is known about the efficacy of prostate-specific membrane antigen (PSMA)–targeted radioligand therapy (RLT) against liver metastases of metastatic castration-resistant prostate cancer (mCRPC). We retrospectively analyzed efficacy-related outcomes of 177Lu-PSMA-617 RLT in this setting and potential predictors of those outcomes. Twenty-eight consecutive mCRPC patients with liver metastases given 177Lu-PSMA-617 RLT were analyzed retrospectively. Their planned regimen was 4–6 cycles at 6 ± 2-week intervals; the mean activity/cycle was 6.5 ± 0.5 GBq. Hepatic response was determined by modified positron emission tomography response criteria in solid tumors; association of such response with overall survival (OS) was tested, as were relationships of the selected patient, disease, and treatment characteristics with hepatic progression-free survival (PFShep) and OS. Survival analyses used Kaplan–Meier curves, log-rank test at p 25% of liver volume) had no apparent relationship with hepatic tumor response, PFShep, or OS. 177Lu-PSMA-617 RLT frequently controlled liver metastases, resulting in long PFShep and significantly improved OS. Hepatic tumor burden appeared to lack any relationship with treatment efficacy, supporting 177Lu-PSMA-617 RLT of late-stage/end-stage mCRPC with liver metastases.

Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy (CART19) occurs in 10% to 20% of patients with acute lymphoblastic leukemia (ALL); however, the mechanisms of this resistance remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T-cell cytotoxicity that permitted antigen persistence and was subsequently magnified by the induction of CAR T-cell functional impairment. These findings were validated using samples from two CAR T-cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T-cell fitness. Our findings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T-cell failure by impairing T-cell cytotoxicity and promoting progressive CAR T-cell dysfunction. Significance: Resistance to CART19 is a significant barrier to efficacy in the treatment of B-cell malignancies. This work demonstrates that impaired death receptor signaling in tumor cells causes failed CART19 cytotoxicity and drives CART19 dysfunction, identifying a novel mechanism of antigen-independent resistance to CAR therapy. See related commentary by Green and Neelapu, p. 492.

Background Evaluation of a child with POC/OC is complicated due difficulties in physical examination and risks of imaging by computed tomography. Method Retrospective review of children 0-16 years admitted to the pediatric emergency department for POC/OC from 2009 to 2019. Results Ten years study period, 243 children younger than 16 years presented to the pediatric emergency department with a diagnosis of POC/OC. OC was documented in 51 (20.6%) patients. The mean age was 7.8 years (±4.3 years). Fever (80.4%), upper respiratory tract infection (43%), swelling of both eyelids (96%), proptosis (33.3%), and tenderness on percussion (24.5%) were more common in comparison to POC (P = 0.0001, 0.03, 0.0001, 0.0001, 0.0001 respectively). All children with suspected diagnosis of OC underwent computed tomography scan. POC accounted for 196 patients. Mean age was 4.6 (±4.3) years. Twenty percent of the cases were recorded as local trauma or insect bite in the infected eye.Mean leukocyte count in the OC group had higher mean of 15.2 (10/L) versus 13.4(10/L) (P = 0.05), absolute neutrophil count was significantly higher in the OC 11.3(10/L) versus 7.2(10/L) (P = 0.0001) whereas the lymphocyte count was higher in the POC 4.5(10/L) versus 2.4(10/L) (P = 0.0001), NLR of 0.318 correlates with orbital cellulitis with sensitivity of 75.5% and specificity of 77.4%.Patients with OC had mean C-reactive protein levels of 11.7 (mg/dL) versus 4.9(mg/dL) (P = 0.0001), erythrocyte sedimentation rate was elevated in the OC 53.6 (cm/h) versus 36.4 (cm/h) (P = 0.02).Based on the aforementioned study a risk calculator for OC was formulated with 6 major variables. Conclusions Differentiation between POC/OC is cardinal. This study highlights the importance of ancillary laboratory tests especially C-reactive protein in the assessment of infections of the eye.

Introduction: Multiparametric MRI (mpMRI) and MRI targeted biopsies (MRtb) are a new standard in prostate cancer (PCa) screening and diagnosis. Guidelines already include this approach for patients at risk. We aimed to gather information from German urologists about their knowledge, routine use, and attitude toward mpMRI and consecutive biopsy methods. Materials and Methods: An anonymous online questionnaire was sent via Survey Monkey to the members of the German Society of Urology (DGU). Statistical analyses were performed using SPSS version 25.0. Results: 496 members with a median age of 48.6 years (±11.7) participated in the survey. The majority rated mpMRI of the prostate as a very useful diagnostic tool (72.7%). MRtb of the prostate was considered as very advantageous (71.5%). MpMRI was used by 95.9%, and 83.2% also recommended MRtb predominantly in clinical institutions. For targeted biopsy, MRI-ultrasound fusion biopsy was clearly favored (75.8%). MpMRI was mostly used in patients with previously negative biopsy (90.9%) and in patients under active surveillance (60.9%). Arguments against the use of prostate mpMRI are costs (84.9%) and/or lack of sufficient radiological infrastructure (17.4%). Conclusion: Our data illustrate the meanwhile high acceptance and clinical use of the prostate mpMRI and MRtb in Germany.

The objective of this study was to determine medium-term morbidity and mortality of patients who have undergone device closure of an extracardiac Fontan fenestration with an Amplatzer Vascular Plug II (AVPII) or Septal Occluder (ASO). A secondary objective was to compare medium-term morbidity and mortality between these patients and other fenestrated Fontan patients. A retrospective chart review was performed on patients who underwent an extracardiac fenestrated Fontan procedure between 1992 and 2015 at Cardinal Glennon Children's Medical Center. Procedural and follow-up data were obtained and compared between those who underwent fenestration closure and those who did not. Additional outcome measures included whether the fenestration had spontaneously closed, morbidity and mortality, oxygen saturations, and hemodynamics pre- and post-closure. Fifty-nine of 118 patients (50%) with a fenestrated Fontan underwent 60 device closures of the fenestration. Thirty-two (53%) of these were with the AVPII and 28 (47%) with the ASO. There was one device embolization. At a median follow-up of 3.9 years, five patients suffered morbidity, including 2 with arrhythmias, 1 with plastic bronchitis, 1 with protein losing enteropathy, and 1 with stroke. There were no cardiopulmonary deaths in this group. Twenty-three of 118 patients (19%) had spontaneous closure. There was no difference in morbidity and mortality between patients who underwent percutaneous fenestration closure and those who either had spontaneous closure or a persistently patent fenestration. Device closure of Fontan fenestrations is a safe and effective procedure with minimal morbidity and mortality comparable to other patients with fenestrations.

Aims The aim of this study was to determine the contemporary use of reperfusion therapy in the European Society of Cardiology (ESC) member and affiliated countries and adherence to ESC clinical practice guidelines in patients with ST-elevation myocardial infarction (STEMI). Methods and results Prospective cohort (EURObservational Research Programme STEMI Registry) of hospitalized STEMI patients with symptom onset Conclusions The use of reperfusion therapy for STEMI in the ESC member and affiliated countries was high. Primary PCI was the most frequently used treatment and associated total in-hospital mortality was below 5%. However, there was geographic variation in the use of primary PCI, which was associated with differences in in-hospital mortality.

Background Nucleic acid-based amplification tests (NAAT), above all (q)PCR, have been applied for the detection of Mycobacterium leprae in leprosy cases and household contacts with subclinical infection. However, their application in the field poses a range of technical challenges. Loop-mediated isothermal amplification (LAMP), as a promising point-of-care NAAT does not require sophisticated laboratory equipment, is easy to perform, and is applicable for decentralized diagnosis at the primary health care level. Among a range of gene targets, the M. leprae specific repetitive element RLEP is regarded as highly sensitive and specific for diagnostic applications. Methods Our group developed and validated a dry-reagent-based (DRB) RLEP LAMP, provided product specifications for customization of a ready-to-use kit (intended for commercial production) and compared it against the in-house prototype. The assays were optimized for application on a Genie® III portable fluorometer. For technical validation, 40 “must not detect RLEP” samples derived from RLEP qPCR negative exposed and non-exposed individuals, as well as from patients with other conditions and a set of closely related mycobacterial cultures, were tested together with 25 “must detect RLEP” samples derived from qPCR confirmed leprosy patients. For clinical validation, 150 RLEP qPCR tested samples were analyzed, consisting of the following categories: high-positive samples of multibacillary (MB) leprosy patients (> 10.000 bacilli/extract), medium-positive samples of MB leprosy patients (1.001–10.000 bacilli/extract), low-positive samples of MB leprosy patients (1–1.000 bacilli/extract), endemic controls and healthy non-exposed controls; each n = 30. Results Technical validation: both LAMP formats had a limit of detection of 1.000 RLEP copies, i.e. 43–27 bacilli, a sensitivity of 92% (in-house protocol)/100% (ready-to-use protocol) and a specificity of 100%. Reagents were stable for at least 1 year at 22 °C. Clinical validation: Both formats showed a negativity rate of 100% and a positivity rate of 100% for high-positive samples and 93–100% for medium positive samples, together with a positive predictive value of 100% and semi-quantitative results. The positivity rate for low-positive samples was 77% (in-house protocol)/43% (ready-to-use protocol) and differed significantly between both formats. Conclusions The ready-to-use RLEP DRB LAMP assay constitutes an ASSURED test ready for field-based evaluation trials aiming for routine diagnosis of leprosy at the primary health care level.

Introduction Women receive less evidence-based care than men and have higher mortality after myocardial infarctions than men. But it is not known how the gender difference in risk factors, treatments and outcomes differs between European countries. Purpose In order to investigate the gender differences in European countries with different economic predispositions we aimed to describe and compare baseline characteristics, in-hospital management, medications at discharge and death outcomes of man and woman ST-elevation infarction (STEMI) patients following routine clinical practice in Sweden, Norway, Hungary and Estonia. Methods The study population is patients over the age of 18 with STEMI who were treated in hospital 2014–2017 (for Norway between 2013–2016) and registered in one of the national myocardial infarction registers. Patients with non-ST elevation infarction and unstable angina were excluded. Risk factors, hospital treatment, and prescription medications were obtained from the national myocardial infarction registries from each country. Mortality in-hospital, after 30 days and after 1 year, was obtained from national death registers. Results Women were on average older, had more comorbidities and higher mortality in hospital, after 30 days and one year after hospitalization. Women received coronary angiography, percutaneous coronary intervention, left ventricular ejection fraction assessment and evidence-based drugs to a lesser extent than men. Conclusions The study illustrates that there are differences in characteristics, management, treatments and outcomes between men and women in all of the studied countries no matter economic predispositions. Generally, women are treated with guideline recommended therapy to a lesser extent than men in the studied countries. Funding Acknowledgement Type of funding sources: None.

Acute appendicitis (AA) is the most common surgical disease, and appendectomy is the treatment of choice in the majority of cases. A correct diagnosis is key for decreasing the negative appendectomy rate. The management can become difficult in case of complicated appendicitis. The aim of this study is to describe the worldwide clinical and diagnostic work-up and management of AA in surgical departments., info:eu-repo/semantics/publishedVersion

INTRODUCTION Anti-CD19 CAR T-cell immunotherapy is promising for patients with relapsed/refractory CLL. Hypogammaglobinemia can result from normal CD19+ B-cell depletion by CAR-T cells. CLL patients are already at risk for infections due to impaired immune function, lymphodepletion prior to CAR-T cells infusion, and immunosuppressive therapies. Intravenous immunoglobulin (IVIG) is used to manage hypogammaglobulinemia, although standard criteria for IVIG administration in this setting has not been established. We studied the incidence of hypogammaglobinemia and report infectious complications, risk factors, IVIG use, and clinical outcomes for CLL patients treated with anti-CD19 CAR-T cells. METHODS Adult CLL patients who received CD19-directed CAR-T therapy in 3 clinical trials (NCT01029366, NCT01747486, NCT02640209) from July 2010 to February 2020 were included. We reviewed demographics, available IgG levels, IVIG use, and clinical outcomes with a particular focus on infectious complications. Hypogammaglobulinemia was defined as IgG RESULTS Records of 71 adult patients with CLL were reviewed; 4 were excluded from further analysis as they did not have IgG levels after CAR-T. The median age at time of CAR-T was 63 years (range 43-78 years). 31 patients (46%) were alive, 31 (46%) were deceased, and 5 (7%) were lost to follow up at time of review. Median follow up for all patients was 33 months (range 2-114 months). Of the 55 patients with an IgG level prior to CAR-T infusion, 24 (44%) had hypogammaglobulinemia at baseline After CAR-T infusion, 54 of 67 patients (81%) developed new or persistent hypogammaglobulinemia, and 40 of these patients (74%) received IVIG (Table 1). Forty-eight patients (72%) received at least one infusion of IVIG after CAR-T. Median time to initiation of IVIG after CAR-T infusion was 2.8 months (range 0.1-71.2 months). IVIG was used in 29 of 35 (83%) responders (defined as PR or CR) vs 19 of 32 (59%) in non-responders (defined as NR or PD) (p=0.056). There was no difference in survival observed based on whether or not patients had hypogammaglobulinemia (Figure). 42 patients (63%) had documented infections not related to chemotherapy-induced neutropenia. Fifteen (22%) had one documented infection, and 27 (40%) had more than one documented infection. There were 13 infections documented in patients who did not have hypogammaglobulinemia; the most common were ENT/sinus infections (5), bacteremia (2), URI (2), and other (2). There were 94 infections documented in patients who developed or had persistent hypogammaglobulinemia; the most common were lower respiratory tract infection/pneumonia (21), URI (20), and ENT/sinus infections (13). Complete and partial responders had more infections compared to non-responders or those who progressed (p = 0.01). Patients with hypogammaglobulinemia after CAR-T had an average of 1.74 (range 0-15) infections vs 1 (range 0-3) in patients without hypogammaglobulinemia. Patients who received IVIG had more infections (p=0.003); without IVIG the average number of infections was 0.58 (range 0-3), and with IVIG, the average number of infections was 2.00 (range 0-15). CONCLUSION Evaluating clinical outcomes with infections after CAR-T and potential strategies to minimize infection risk may improve morbidity and mortality in CLL patients. Use of IVIG was driven by individual practice, with heterogeneity regarding indication, frequency, and duration of treatment, though there was no difference in patient characteristics or response in patients who did or did not develop hypogammaglobulinemia. Patients who responded to CAR-T had more frequent infections, as might be expected in the setting of transient or persistent B- cell aplasia or hypoplasia. Patients who had more infections were more likely to receive IVIG. Further studies to define criteria for IVIG repletion in CLL patients treated with CD19-directed CAR-T cells may be incorporated in a standard clinical management algorithm. Table 1 Disclosures Frey: Amgen: Consultancy, Honoraria; Syntax: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria. Davis:Tmunity Therapeutics, Inc.: Consultancy, Patents & Royalties, Research Funding; Cellares Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis Institutes for Biomedical Research: Patents & Royalties. Hexner:Blueprint Medicines Corporation: Other: serves on a data safety monitoring committee, Research Funding; Novartis: Research Funding; Samus Therapeutics: Research Funding; American Board of Internal Medicine: Other: member of the hematology exam committee. Schuster:Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria. Gill:Fate: Consultancy; Sensei: Consultancy; Aileron: Consultancy; Tmunity Therapeutics: Research Funding; Carisma Therapeutics: Patents & Royalties, Research Funding; Novartis: Research Funding. Grupp:Servier: Research Funding; Kite/Gilead: Research Funding; Roche: Consultancy; GlaxoSmithKline: Consultancy; Humanigen: Consultancy; CBMG: Consultancy; Jazz: Other: SSC; Adaptimmune: Other: SAB; TCR2: Other: SAB; Cellectis: Other; Juno/BMS: Other; Janssen/JnJ: Consultancy; CRISPR Therapeutics/Vertex Pharmaceuticals: Other; Allogene: Other; Novartis: Consultancy, Other: SSC, Research Funding. Melenhorst:Johnson & Johnson: Consultancy, Other: Speaker; Novartis: Other: Speaker, Research Funding; Kite Pharma: Research Funding; IASO Biotherapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Poseida Therapeutics: Consultancy; Simcere of America: Consultancy. Lacey:Novartis: Patents & Royalties: CAR T cells, Research Funding; Tmunity: Research Funding; Cabaletta: Research Funding; Carisma: Research Funding. Fraietta:Tmunity: Research Funding. Hwang:Novartis: Research Funding; Tmunity Therapeutics: Research Funding. Siegel:Novartis: Patents & Royalties; Tmunity: Patents & Royalties; Poseida: Membership on an entity's Board of Directors or advisory committees; Vetigenics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Levine:Terumo: Consultancy; Novartis: Consultancy, Patents & Royalties: Dr. Levine has a patent Methods for treatment of cancer (US 8906682) (US 8916381)(US 9101584) with royalties paid to University of Pennsylvania, a patent Compositions for treatment of cancer (US 8911993) (US 9102761) (US 9102760) with royalties paid to U; Lilly Asia Ventures: Consultancy; Avectas: Membership on an entity's Board of Directors or advisory committees; Patheon: Membership on an entity's Board of Directors or advisory committees; Immuneel: Membership on an entity's Board of Directors or advisory committees; Incysus: Membership on an entity's Board of Directors or advisory committees; Ori Biotech: Membership on an entity's Board of Directors or advisory committees; Vycellix: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Current equity holder in private company, Research Funding. June:Bluesphere Bio: Membership on an entity's Board of Directors or advisory committees; Cabaletta Bio: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Carisma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cellares: Membership on an entity's Board of Directors or advisory committees; Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees; DeCART Therapeutics: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees; Kiadis Pharma: Current equity holder in private company; Novartis: Patents & Royalties, Research Funding; Tmunity Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Ziopharm Oncology: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Porter:Tmunity: Patents & Royalties; Novartis: Honoraria, Other: Advisory board, Patents & Royalties: CAR T cells for CD19+ malignancies, Research Funding; American Board of Internal Medicine: Other: Member, exam writing committee (end date Oct 2019); National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Advisory board; Genentech/Roche: Current equity holder in publicly-traded company, Other: Spouse employment (ended Sept 2020); her salary includes stock/options; Glenmark: Other: Advisory board; Adicet bio: Other: Advisory board; Incyte: Other: Advisory board; Kite/Gilead: Other: Advisory board. OffLabel Disclosure: CAR T cells for CLL

In 1980, the 5-year overall survival rate for patients with acute myeloid leukemia (AML) in the United States (US) was a truly dismal 7%. Over 30 years later in 2012, approximately 30% of adult pat...

Chimeric antigen receptor–engineered T cells targeting CD19 (CART19) provide an effective treatment for pediatric acute lymphoblastic leukemia but are less effective for chronic lymphocytic leukemia (CLL), focusing attention on improving efficacy. CART19 harbor an engineered receptor, which is delivered through lentiviral vector integration, thereby marking cell lineages and modifying the cellular genome by insertional mutagenesis. We recently reported that vector integration within the host TET2 gene was associated with CLL remission. Here, we investigated clonal population structure and therapeutic outcomes in another 39 patients by high-throughput sequencing of vector-integration sites. Genes at integration sites enriched in responders were commonly found in cell-signaling and chromatin modification pathways, suggesting that insertional mutagenesis in these genes promoted therapeutic T cell proliferation. We also developed a multivariate model based on integration-site distributions and found that data from preinfusion products forecasted response in CLL successfully in discovery and validation cohorts and, in day 28 samples, reported responders to CLL therapy with high accuracy. These data clarify how insertional mutagenesis can modulate cell proliferation in CART19 therapy and how data on integration-site distributions can be linked to treatment outcomes.

Up to 30% of patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) never respond or develop resistance to 177Lu-labeled PSMA-targeted radioligand monotherapy. Single-agent PSMA-targeted radioligand therapy (PRLT) with the alpha-emitter 225Ac showed promise against mCRPC but may cause severe and/or persistent xerostomia, which may substantially impair patients’ quality-of-life. We hypothesized that when 177Lu-PSMA ligand alone is ineffective, tandem therapy with low-activity 225Ac-PSMA ligand plus full activity of the beta emitter may enhance efficacy while minimizing xerostomia severity. We retrospectively analyzed pilot experience with 1 course of 225Ac-PSMA-617/177Lu-PSMA-617 tandem therapy in our first 20 patients with mCRPC receiving this intervention after insufficiently responding to 177Lu-PSMA-617 monotherapy. This cohort had late-stage/end-stage disease with high baseline prostate-specific antigen (PSA) concentration (median 215 ng/mL), heavy pre-treatment (abiraterone and/or enzalutamide, and 177Lu-PRLT [median cumulative activity, 26.3 GBq] in 20/20 patients, 100%; docetaxel and/or cabazitaxel in 13/20 patients, 65%), and frequent Eastern Cooperative Oncology Group performance status of 2 (8/20 patients, 40%). Median (minimum–maximum) administered activities were 225Ac-PSMA-617, 5.3 (1.5–7.9) MBq, and 177Lu-PSMA-617, 6.9 (5.0–11.6) GBq. Significant responders to tandem therapy received 177Lu-PSMA-617 monotherapy as maintenance (median [minimum–maximum]: 1 [0–5] cycle). After a median (minimum–maximum) 22 (14–63) weeks’ follow-up, 13/20 patients (65%) had as best biochemical response a PSA decline > 50%. Median (95% confidence interval) progression-free survival was 19 (12–26) weeks, and overall survival was 48 (4–92) weeks post-tandem therapy administration. Xerostomia was reported as grade 1 (very mild) in 8/20 patients (40%), grade 2 (mild) in 5/20 (25%), and grade 3/4 in 0/20. Our results suggest that a single course of tandem therapy with low-activity 225Ac-PSMA-617/full-activity 177Lu-PSMA-617 may safely enhance response to PRLT in men with late-stage/end-stage mCRPC while minimizing xerostomia severity. Formal study of this combination is warranted.

Objective. Two million adults under fifty years of age have a cerebral stroke every year worldwide. Neuropsychological assessment is the best way to identify poststroke cognitive dysfunction, but it is often time-consuming and can be tiring for the patient, and hospitals vary in their availability of neuropsychological expertise. A valid and reliable cognitive screening method could be advantageous in identifying patients who need comprehensive neuropsychological examination. Our purpose in this study was to validate a newly developed cognitive screening method as an identifier of cognitive dysfunction after stroke in working-aged patients. Methods. We analyzed new cognitive screening method concurrent validity by comparing it in two groups formed on the basis of a comprehensive neuropsychological examination for 77 stroke patients. We identified the best balance of sensitivity and specificity by using receiver operating characteristic curve analysis and investigated the impact of the sociodemographic variables to the screening method total score variation. Results. We found a significant correlation between the method’s total score and performance in neuropsychological examination. The cognitive method’s internal consistency was strong; Cronbach’s alpha for all items was .818. The best balance of sensitivity (88%) and specificity (50%) was found at a total score cut point of 138. Subjects’ age and length of education were each responsible for 10% of total score variation. Conclusions. This study shows promising results for this new cognitive screening tool’s ability to identify poststroke cognitive decline and patients’ need for further detailed neuropsychological examination.

In the last years, iron poisoning has gained more attention in fluid catalytic cracking operations across the globe. While more and more insights into the mechanisms of its deactivating effects on FCC catalyst particles are available, the early detection of Fe poisoning of FCC catalysts is complicated by the various sources of Fe. This paper describes the use of magnetic susceptibility determinations and digital microscopy for this purpose. The application of magnetic susceptibility shows that the magnetic properties of FCC catalysts change at about 0.30 wt % added Fe indicating that the deleterious effects of the contaminant Fe occur beyond this limit. The combination with inverse gas chromatography and mercury porosimetry determinations confirm the pore restricting effects by Fe poisoning.

Background The negative media attention surrounding vaginal mesh procedures has seen a rise in demand for minimally invasive non-mesh options for the treatment of stress urinary incontinence (SUI). The laparoscopic Burch colposuspension (LBC) is a non-mesh alternative to synthetic midurethral slings (MUS) with similar short-term outcomes. However, long-term outcomes are not well established. Aims To evaluate the long-term outcomes of LBC for treatment of SUI in women. Material and methods One hundred and fifty-one cases of LBC were performed by a single surgeon over two private hospital settings between January 2010 and January 2016. Follow-up subjective outcomes were obtained in 137 cases (90.7%) utilising standardised questionnaires. Primary outcome was successful treatment of SUI, defined as subjective cure or significant improvement of stress incontinence symptoms. Secondary outcomes included new-onset or worsened symptoms of overactive bladder (OAB), voiding dysfunction, prolapse, and perioperative complications. Results One hundred and thirty-seven patients were analysed with a mean follow-up of 50.6 months (range: 13-89 months). Primary outcome of successful treatment was achieved in 90.5% of women. New-onset or worsened symptoms of OAB was reported in 10.2%, with a further 8.8% of women experiencing symptomatic voiding dysfunction. Sixteen patients (11.7%) reported new-onset or worsening symptoms of prolapse. There were no major surgical complications. Conclusions LBC is a safe and effective long-term treatment for SUI, with low failure rates and minimal adverse outcomes. It is a suitable alternative for women with contraindications to mesh or those having concomitant laparoscopic procedures.

Background: Clear cell renal cell carcinoma (ccRCC) is molecularly diverse and distinct molecular subtypes show different clinical outcomes. MicroRNAs (miRNAs) are essential components of gene regulatory networks and play a crucial role in progression of many cancer types including ccRCC. Objective: Identify prognostic miRNAs and determine the role of miR-22 in ccRCC. Methods: Hierarchical clustering was done in R using gene expression profiles of over 450 ccRCC cases in The Cancer Genome Atlas (TCGA). Kaplan-Meier analysis was performed to identify prognostic miRNAs in the TCGA dataset. RNA-Seq was performed to identify miR-22 target genes in primary ccRCC cells and Matrigel invasion assay was performed to assess the effects of miR-22 overexpression on cell invasion. Results: Hierarchical clustering analysis using 2,621 prognostic genes previously identified by our group demonstrated that ccRCC patients with longer overall survival expressed lower levels of genes promoting proliferation or immune responses, while better maintaining gene expression associated with cortical differentiation and cell adhesion. Targets of 26 miRNAs were significantly enriched in the 2,621 prognostic genes and these miRNAs were prognostic by themselves. MiR-22 was associated with poor overall survival in the TCGA dataset. Overexpression of miR-22 promoted invasion of primary ccRCC cells in vitro and modulated transcriptional programs implicated in cancer progression including DNA repair, cell proliferation and invasion. Conclusions: Our results suggest that ccRCCs with differential clinical outcomes have distinct transcriptomes for which miRNAs could serve as master regulators. MiR-22, as a master regulator, promotes ccRCC progression at least in part by enhancing cell invasion.

Ischemia reperfusion injury (IRI) involvement in pressure ulcers (PU) progression via a surge of oxidative stress and inflammatory responses is well documented. IRI strongly depends on the mechanical loading history. We present a generalized IRI model considering external loading, dynamic tissue healing capacity, accumulating mechanical and reperfusion-mediated damages and competing repair processes of saturating nature. Reperfusion depends on strain and strain rate to enhance loading history sensitivity. Tissue-specific ulceration susceptibility is assumed dependent on variable accumulated damage. We study damage evolution under cyclic loading having several strain expulsion profiles and demonstrate load relief history has critical impact on PU progression. Abrupt load removal generally follows existing models representing extreme repair/damage. We show (first time in silico) that under certain conditions (previously experimentally identified), IRI becomes repairing rather than damaging. In particular, we recapitulate the preconditioning and postconditioning IRI hallmarks. Finally, it is customary among physicians and nurses to promptly alleviate mechanical load applied to patients lying in bed for extended periods and in risk of developing PUs. We demonstrate this practice can be harmful. If load removal is performed early while reperfusion is still beneficial, then this conduct is suitable. However, if critical tissue damage has been crossed, then abrupt expulsion can constitute the worst-case scenario for patient outcome. If no preliminary patient documentation is available, we recommend gradual load removal since risks of accelerated damage eventually leading to ulceration supersede the improved repair potential benefit.

On August 30, 2017 the US Food and Drug Administration approved tisagenlecleucel (Kymriah; Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present, ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring, and disease assessments. To address these issues experts representing the American Society for Blood and Marrow Transplant, the European Society for Blood and Marrow Transplantation, the International Society of Cell and Gene Therapy, and the Foundation for the Accreditation of Cellular Therapy formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.

Background Recent investigations noted noninferiority in short-course antimicrobial treatments following source control in abdominal infections. We set out to investigate noninferiority of a short and fixed (24 hours) antibiotic administration compared to extended treatment after source control in complicated appendicitis in a prospective single-center open-label randomized controlled trial. Methods After Institutional Review Board (IRB) approval, all consecutive adult patients (age, ≥ 18 years) with complicated appendicitis including gangrenous appendicitis, perforated appendicitis, and appendicitis with periappendicular abscess between May 2016 and February 2018 were randomly allocated to antibacterial therapy limited to 24 hours (short) vs. >24 hours (extended) administration after appendectomy. Primary outcomes included composite postoperative complications and Comprehensive Complication Index (CCI). Secondary outcome was hospital length of stay (HLOS). Follow-up analysis at 1 month was conducted per intention and per protocol. Results A total of 80 patients were enrolled with 39 and 41 cases allocated to the short and the extended therapy group, respectively. Demographic profile and disease severity was similar between the study groups. Overall rate of complications was 17.9% and 29.3% in the short and extended group, respectively (p = 0.23). Mean CCI did not differ between the study groups (p = 0.29). Hospital length of stay was significantly reduced in the short therapy group (61 ± 34 hours vs. 81 ± 40 hours, p = 0.005). Conclusion In the current prospective randomized investigation, the short (24 hours) antibiotic administration following appendectomy did not result in a worse primary outcome in complicated appendicitis. The short interval administration resulted in a significant reduction in HLOS with a major cost-saving and antibacterial stewardship perspective. Level of evidence Therapeutic Level IV.

Objective: Multiple sclerosis (MS) is a multifactorial chronic disease that affects the central nervous system (CNS). Toll-like receptors (TLRs) play a central role in cytokine production after pathogen- and danger-associated molecular patterns (PAMPs and DAMPs) and contribute to CNS damage in MS patients. Here, we evaluated the effects of interferon (IFN)-β treatment in TLR2 and TLR4-dependent cytokine production and mRNA expression in whole-blood cell cultures from MS patients. Methods: We evaluated cytokine production by ELISA from whole-blood cell culture supernatants and mRNA expression by real-time polymerase chain reaction in peripheral blood mononuclear cells (PBMCs). Results: In patients treated with IFN-β, tumor necrosis factor (TNF)-α production after exposure to TLR2 agonist (Pam3Cys) was lower than in healthy controls and untreated MS patients. However, IFN-β treatment had no significant effect on TNF-α production after TLR4 agonist (LPS) stimulation. On the other hand, interleukin (IL)-10 production was increased in TLR4- but not in TLR2-stimulated whole-blood cell culture from MS patients under IFN-β treatment when compared to the controls. No differences in TNF-α or IL-10 mRNA expression in PBMCs from healthy controls and untreated or treated MS patients were detected, although PBMCs from treated patients presented higher levels of IL-32γ mRNA than those from controls. Conclusions: Our data suggest that IFN-β treatment alters the TLR-dependent immune response of PBMCs from MS patients. This may contribute to the beneficial effects of IFN-β treatment.

We evaluated the effect of in vitro fertilization (IVF) on sexual function in men, particularly for erectile dysfunction.A prospective case-control study at a tertiary medical center. The study group comprised men of infertile couples that required IVF to conceive. The control group comprised men of couples who conceived spontaneously. The effects of IVF on sexual and erectile function were assessed based on the International Index of Erectile Function (IIEF-15) and the Self-Esteem and Relationship (SEAR) questionnaires. Participants were followed up to 1 year postpartum.Compared to the control group (378), for the IVF group (356), mean IIEF-15 scores were significantly lower: prior to pregnancy (31.7±4.5 vs 64.4±7.2, p0.0001), at mid-pregnancy (37.3±5.1 vs 66.4±5.5, p0.0001) and up to one year postpartum (42.3±4.9 vs 68.6±4.3, p0.0001). Compared to the control group, in the IVF group, mean SEAR scores were significantly lower at these 3 respective time points (29.9±6.3 vs 66.5±8.3; 34.1±5.8 vs 66.9±7.2; and 40.9±6.7 vs 67.3±5.6; p0.0001). At the 3 time points, for the IVF compared to the control group, the median monthly sexual intercourse rate was lower; and both the use of phosphodiesterase-5 inhibitor and psychologist/sexologist care were higher.The prevalence of erectile dysfunction among men participating in IVF in order to conceive is significantly higher compared to couples that conceived spontaneously, thus leading to an extremely high rate of phosphodiesterase-5 inhibitor use.

Introduction: Staphylococcus lugdunensis (SL), a tube coagulase negative Staphylococcus , is known to be pathogenic in adults, causing mainly skin infections. Gap Statement: Previous studies assessing SL's role in paediatric populations are sparse and are mainly limited to case reports. Aim: Present the clinical characteristics consistent with SL infections and its putative role as a pathogen in the paediatric population. Methodology: A retrospective multicentre study was conducted in four paediatric medical centres in Israel. Patients with isolates of SL presenting between 2009–2019 were included. Results: SL was isolated from 40 patients. Average (±SD) age at presentation was 5.9 (±6.2) years, with 22 (55 %) being female. Skin, soft tissue and musculoskeletal infections were the most common (n=20, 50%) followed by ear infections (n=13, 32.5%). Five cases of urine isolates and two isolates from blood culture samples were also reported. Skin abscess was the most common infection among skin and soft tissue isolates, reported in 17 children (85%) with SL being the only pathogen in 15 (75%). Otitis media was the most common ear infection accounting for 12 (92%) of all cases with SL as the only isolate reported in 6 (46%). Five cases of SL isolates from urine specimens were reported, all of which with poor growth of bacteria and normal urinalysis. Two cases of SL growth in blood culture were found in children presenting with signs and symptoms consistent with invasive blood stream infection. Conclusions: In the paediatric population, studied infections caused by SL are increasingly observed. The results of this study highlight its role as a pathogen in soft tissue infections and its putative role in otitis media and invasive blood stream infections. However, the role of SL as an uropathogen was not established.

The adoptive transfer of T lymphocytes reprogrammed to target tumor cells has demonstrated significant potential in various malignancies. However, little is known about the long-term potential and the clonal stability of the infused cells. Here, we studied the longest persisting CD19 redirected chimeric antigen receptor (CAR) T cells to date in two chronic lymphocytic leukemia (CLL) patients who achieved a complete remission in 2010. CAR T-cells were still detectable up to 10+ years post-infusion, with sustained remission in both patients. Surprisingly, a prominent, highly activated CD4+ population developed in both patients during the years post-infusion, dominating the CAR T-cell population at the late time points. This transition was reflected in the stabilization of the clonal make-up of CAR T-cells with a repertoire dominated by few clones. Single cell multi-omics profiling via Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq) with TCR sequencing of CAR T-cells obtained 9.3 years post-infusion demonstrated that these long-persisting CD4+ CAR T-cells exhibited cytotoxic characteristics along with strong evidence of ongoing functional activation and proliferation. Our data provide novel insight into the CAR T-cell characteristics associated with long-term remission in leukemia.

Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid β precursor-like protein 1 (Aplp1) forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by α-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for α-syn PFF induced pathology advances our understanding of the molecular mechanism of cell-to-cell transmission of pathologic α-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson’s disease and related α-synucleinopathies.One Sentence SummaryAplp1 forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-synuclein.Graphical AbstractAplp1 and the Aplp1-Lag3 complex facilitates transmission of pathologic α-synuclein.Aplp1 is a receptor that drives pathologic α-syn transmission, and genetic depletion of Aplp1 can significantly reduce the α-synuclein pathogenesis. Aplp1 and Lag3 forms an Aplp1-Lag3 complex that accounts for substantial binding of pathologic α-syn to cortical neurons. Together Aplp1 and Lag3 play a major role in pathologic α-syn internalization, transmission and toxicity. Double knockout of Aplp1 and Lag3 and or a Lag3 antibody that disrupts the Aplp1 and Lag3 complex almost completely blocks α-syn PFF-induced neurodegeneration.

Chimeric antigen receptor (CAR) T cells have emerged as a powerful therapeutic modality for cancer. Following encouraging clinical results, autologous anti-CD19 CAR-T cells first secured regulatory approval from the U.S. Food and Drug Administration in 2017 for the treatment of pediatric B cell acute lymphoblastic leukemia and for diffuse large B cell lymphoma (DLBCL), followed recently by mantle cell lymphoma. While long-term immunosurveillance is among the most important requirements for durable remissions in leukemia and a major potential benefit of immunotherapy, the exact determinants of CAR-T cell persistence remain elusive. Furthermore, it is less clear that long-term persistence is required for durable remission in lymphoma. In this review, we aim to describe the factors governing CAR-T cell persistence as well as unique approaches to exert control over engineered lymphocyte populations post-infusion. Additionally, we explore potential risks and associated clinical considerations arising from prolonged surveillance by highly reactive cytotoxic T lymphocytes.

Objective: To analyze the contextual factors associated with type II diabetes mellitus in Belo Horizonte City. Methods: Cross-sectional study with 5,779 adults living in Belo Horizonte City, participating in the Risk and Protection Factors Surveillance System for Chronic Diseases through Telephone Survey (Vigitel), in 2008, 2009, and 2010. Multilevel regression models were used to test the association between contextual indicators of physical and social environments, and self-reported diagnosis of diabetes, adjusted for individual sociodemographic and lifestyle factors. Descriptive analyzes and multilevel logistic regression models were used, considering a 5% significance level. Results: The prevalence of diabetes was 6.2% (95%CI 5.54 – 6.92), and 3.1% of the variability of chance of presenting diabetes were explained by contextual characteristics. Living in areas with high density of private places for physical activity and high income was associated with a lower chance of having diabetes. The areas with high level of social vulnerability were strongly associated with the chance of presenting diabetes, adjusted for individual characteristics. Conclusion: Characteristics of physical and social environments were associated with the chance of diabetes occurrence. Urban centers with opportunities to adopt healthy behaviors can help to reduce the occurrence of diabetes and its complications. RESUMO: Objetivo: Analisar os fatores contextuais associados ao diabetes mellitus tipo II em Belo Horizonte (MG). Métodos: Estudo transversal com 5.779 adultos residentes em Belo Horizonte, participantes do Sistema de Vigilância de Fatores de Risco e Proteção para Doenças Crônicas por Inquérito Telefônico, nos anos de 2008, 2009 e 2010. Foram utilizados modelos de regressão multinível para testar a associação entre indicadores contextuais do ambiente físico e social e diagnóstico autorreferido de diabetes, ajustados por fatores individuais sociodemográficos e de estilo de vida. Utilizaram-se análises descritivas e modelos de regressão logística multinível, considerando um nível de significância de 5%. Resultados: A prevalência de diabetes foi de 6,2% (IC95% 5,54–6,92), e 3,1% da variabilidade da chance de diabetes nas áreas de abrangência estudadas foi explicada por características contextuais. Residir em áreas com alta densidade de locais privados para prática de atividade física e com alta renda associou-se a menor chance de ter diabetes. As áreas com alto índice de vulnerabilidade social foram fortemente associadas ao diabetes, independentemente de características individuais. Conclusão: A ocorrência de diabetes está associada com as características do ambiente físico e social. Centros urbanos com oportunidades para adoção de comportamentos saudáveis podem ajudar a reduzir a ocorrência de diabetes e as suas complicações.

Background Most comparisons between robot-assisted (RAPN) and open partial nephrectomy (OPN) indicate the superiority of RAPN, but the learning curve is often not considered. Methods All consecutive partial nephrectomies from the very first RAPN at a single tertiary referral center (n=818, 500 RAPN vs. 313 OPN) were retrospectively analyzed. Complications, success rates, and surgical outcomes were compared. Inequalities between cohorts and the inherent learning curve were controlled by subgroup comparisons, regression analyses, and propensity score matching. Results Overall, RAPN had fewer complications, less blood loss, and shorter length of stay. However, an inherent learning curve caused higher complications for the first 4 years. Thereafter, perioperative outcomes clearly favored RAPN, even for more complex tumors. Conclusions In one of the largest monocentric cohorts over more than 10 years, RAPN was found to be superior to OPN. However, not all advantages of RAPN are immediate because a learning curve must be passed. This article is protected by copyright. All rights reserved.