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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

To evaluate the safety and feasibility of stereotactic body radiation therapy (SBRT) with simultaneous integrated boost (SIB) and simultaneous integrated protection (SIP) in borderline resectable and locally advanced pancreatic ductal adenocarcinoma.Patients receiving SBRT following induction chemotherapy from January 2017 to December 2018 were included in this observational analysis. SBRT was delivered in five consecutive daily fractions by administering 30 Gy to the planning target volume while simultaneously delivering a 50 Gy SIB to the tumour-vessel interface. SIP was created by lowering the dose to 25 Gy on the overlap area between the planning target volume and the planning organ at risk volume. The primary end point was acute and late gastrointestinal grade ≥3 toxicity. Secondary end points were freedom from local progression, overall survival and progression-free survival (PFS).Fifty-nine consecutive patients (27 borderline resectable and 32 locally advanced) were included. Fifty-eight patients (98.3%) completed the SBRT planned treatment and 35 patients (59.4%) received surgical resection following SBRT. No acute or late grade ≥3 SBRT-related adverse events were observed. The median follow-up time was 15.1 months in the overall cohort and 18.1 months in censored patients. One- and 2-year freedom from local progression rates were 85% and 80% versus 79.7% and 60.6% in resected and unresected patients, respectively (P = 0.33). The median overall survival and PFS were 30.2 months and 19 months from diagnosis and 19.1 months and 10.7 months from SBRT in the entire cohort. Resected patients had improved 2-year overall survival rates (72.5% versus 49%, P = 0.012) and median PFS (13 months versus 5 months; P 0.001) relative to unresected patients. There was no survival difference between borderline resectable and locally advanced patients.SBRT with SIB/SIP had an excellent toxicity profile and could be administered safely on pancreatic ductal adenocarcinoma patients, even in a total neoadjuvant setting.

PURPOSE: To evaluate the effectiveness of propranolol at mitigating FDG uptake in brown adipose tissue (BAT) of pediatric patients with known or suspected malignancies. METHODS: PET/CT scans of 3 cohorts of patients treated from 2005–2017 were scored for presence of FDG uptake by BAT at 7 sites: right or left neck/supraclavicular area, right or left axilla, anterior mediastinum, posterior thorax, and abdomen/pelvis. Uptake was scored as follows: 0-none, 1-mild uptake < liver, 2-moderate uptake = liver, 3-intense uptake > liver. Group 1 consisted of 323 patients (630 scans) who had no specific preparation to mitigate FDG uptake by BAT. Group 2 consisted of 345 patients (705 scans) who underwent only warming in an uptake room with a fixed temperature at 24°C. Group 3 consisted of 622 patients (1457 scans) who underwent warming. In Group 3, patients 8 years and older, 471 patients (1114 scans), were also pre-medicated with oral propranolol 60 minutes before injection of FDG. Generalized estimation equation, using the logit link method, was used to model the relationship between the incidence of BAT score > 0, in any site, as a function of age, sex, seasonal effect, and body surface area (BSA). RESULTS: In patients aged 8 years or older, the incidence of BAT uptake was 35 – 44% and declined to 15% with propranolol. BAT was most frequent in the neck (26%), axilla (18%), posterior thorax (18%), mediastinum (14%), and abdomen/pelvis (8%); BAT was less common in warm months (p=0.001). No substantial benefit was shown with pre-injection warming alone. No significant effect was found for age, sex, or BSA separately. When BAT uptake was present, it was usually intense. CONCLUSION: Propranolol preparation minimizes FDG uptake by BAT and should be considered routine for pediatric FDG PET/CT cancer-related protocols in children, adolescents, and young adults.

Background/aim To assess predictors of local control (LC) for stereotactic ablative radiotherapy (SAbR) in pulmonary oligometastatic disease (OMD) from gastrointestinal (GI) malignancies. Patients and methods Patients with pulmonary OMD treated with SAbR from January 2016 to December 2018 were included in this observational analysis. Primary endpoint was LC. Uni- and multivariate analyses to assess variable correlations were conducted. Results Thirty-seven patients and 59 lung metastases were evaluated. The delivered dose was 30-60 Gy in 3-8 fractions. After a median follow-up of 23.0 months (range=6.3-50.4 months), LC rate at 1/2 years was 89.7%/85.0%, and increased to 96.0%/91.0% for lesions treated with a biologically effective dose (BED10) ≥100 Gy (p=0.03). RECIST response at 6 months was predictive for LC (p=0.002). Conclusion SAbR is an effective option for pulmonary OMD from GI malignancies. A BED10 ≥100 Gy and radiological response at 6 months can affect LC.

Radiation-induced phantosmia has been reported both in children and adults. A fraction of these patients have nausea and vomiting triggered by phantosmia. Radiation-induced phantosmia, although transient, can be distressing enough to prevent a patient from staying still during radiation therapy. To date, specific interventions for radiation-induced phantosmia, including anesthesia, have not been reported. We report for the first time anesthesia as an intervention for transient severe radiation-induced phantosmia, in a 16-year-old girl with ependymoma undergoing proton therapy, and we discuss the pros and cons of techniques for anesthesia and airway management.

A 77-year-old woman with a 1 years history of Multiple Myeloma (MM) presented with headache, fatigue, and bone pain. She underwent whole body multi-detector computed tomographic (MD-CT) to evaluate possible lytic bone lesions. MD-CT showed small, multiple osteolytic lesions, particularly at the skull level (Figure 1, 2). MM is a plasma cell disorder. It is characterized by the monoclonal proliferation of malignant plasma cells (1,2). These cells, among their various characteristics, determine an infiltrate haemopoietic locations (1). Pathogenesis of MM related bone disease is the uncoupling of the bone remodelling process. There is an increased activity of osteoclastogenesis with the suppressed osteoblastic one, resulting in bone loss (1- 3). This process creates lytic lesions without reactive bone formation (2). Bone disease could be from single lytic lesion to multiple lytic lesions affecting any part of skeleton, preferably skull, spine and long bones (3). MD-CT, with dedicated low-dose protocols, is able to provide whole body skeletal volume information with a greater sensitivity than conventional X-ray studies in MM patients (3). Whole body CT with lowdose protocols can detect lesions with less than 5% trabecular bone destruction, and it is the first-line diagnostic imaging procedure for the diagnosis of lytic bone disease in patients affected by MM (4). When skull is involved, its most common MD-CT presentation is by numerous, well-circumscribed and punched-out lytic bone lesions, without reactive bone formation and diffuse osteopenia (1-5), as in the case presented.

Sickle cell disease causes osteonecrosis (20% to 50% of patients) and collapse of the femoral head that result in secondary osteoarthritis. Total hip arthroplasty (THA) is a valid alternative for these patients. We define the difficulties that can be encountered when undertaking THA in sickle cell disease patients and give advice on how to deal with these technically demanding procedures. We undertook total hip arthroplasty procedures on 12 patients (4 females and 8 males) with osteonecrosis of the femoral head. Two bilateral prostheses were performed. We had only one type of stem, only one type of acetabular cup and only 28 mm cobalt chrome heads. The procedures were performed through either an anterior or a direct lateral approach. The average size of the Cup was 46 (Versafit, Medacta), the average size of the femoral stem was 0 (Amistem, Medacta), the most used size of the modular head was a S. Standard stem that was used in nine patients, while three patients received a lateralizing stem. Three patients had periprosthetic fracture, treated by cerclage. Total hip replacement is an excellent alternative for patients with osteonecrosis from sickle cell disease. The preparation of the acetabulum and the femur is difficult and requires attention, time and appropriate equipment.

Abstarct Methods and Materials From July 2006 to December 2015, 295 patients suitable for breast-conserving therapy entered a single-arm phase II study and were treated with IOERT as radical treatment. Inclusion criteria were age >50, postmenopausal status, cT1N0M0 stage, grade G1-G2, positive estrogen receptor status; unicentric and unifocal disease, histologically proven invasive ductal carcinoma no previous breast irradiation, good performance status. Results With a median follow-up of 7.1 years (95% CI, 6.5;7.4) 6 women (2.0%) experienced a true local recurrence (reappearance of the tumour in the same quadrant). Five-year overall survival and local recurrence-free survival were 96% (95% CI, 92.9;97.8) and 94.9% (95% CI, 91.6;97.0) respectively. Conclusion Our trial suggests that, in highly selected early stage breast cancers, a single-dose IOERT can be safely delivered with excellent results and very low long-term recurrence rates.

To examine whether anesthesia exposure is associated with neurocognitive decline in pediatric medulloblastoma.Patients were treated at St. Jude Children's Research Hospital and completed ≥2 protocol-directed neurocognitive assessments (n = 107) as part of a multisite clinical trial for pediatric medulloblastoma (NCT00085202). Patients received risk-adapted craniospinal photon irradiation, followed by four cycles of high-dose chemotherapy and stem cell rescue. Neurocognitive testing was completed at study baseline (after surgery and2 weeks of starting radiation therapy) and annually for 5 years. Data on anesthesia exposure during treatment was abstracted from medical records.Patients were 10.2 years at diagnosis on average (SD = 4.5; 37% female, 73% average-risk). Mean cumulative anesthesia duration was 20.4 h (SD = 15.2; range 0.7-55.6 h). In the overall group, longer anesthesia duration was associated with greater declines in IQ (Estimate = -0.08, P 0.001), attention (Estimate = -0.10, P .001) and processing speed (Estimate = -0.13, P 0.001). Similar results were shown in subgroups of patients who were7 years at diagnosis (IQ = -0.14, P = 0.027; Attention = -0.25: P = 0.011), ≥7 years at diagnosis (Attention = -0.07, P = 0.039; Processing Speed = -0.08, P = 0.022), treated for high-risk disease (IQ = -0.09, P = 0.024; Attention = -0.11, P = 0.034; Processing Speed = -0.13, P = 0.001), or treated for average-risk disease (IQ = -0.05, P = .022; Attention = -0.08, P = 0.011; Processing Speed = -0.10, P 0.001).Greater anesthesia exposure is a risk factor for clinically significant neurocognitive decline, in addition to factors of age at diagnosis and treatment risk arm. This result is notable as there are evidence-based strategies that can limit the need for anesthesia. Limiting anesthesia exposure, as feasible, may mitigate neurocognitive late effects, and thus, improve quality of life for survivors.

To evaluate fetal ventricular diastolic function in pregnancies of women with gestational diabetes (GD), to determine whether minimal anomalies of glucose metabolism may influence fetal cardiac function.Fetal ventricular filling time was measured by transabdominal ultrasound in singleton pregnancies between 34 and 37 weeks of gestation. We used a measurement which consists in the ratio between the diastolic time and the whole cardiac cycle time.The study included 35 women with a GD and 217 non-diabetic. Right ventricular filling time (RVFT) was significantly lower in the GD group (mean of RVFT = 39.2 ± 4.4 vs 43.6 ± 4.6; p 0.01). Likewise, left ventricular filling time (LVFT) was shorter in the GD group compared to the non-GD group, though the difference was not significant (mean of LVFT = 43.6 ± 4.6 vs 44.6 ± 5.5; p = 0.33).Fetal right cardiac function is altered also in pregnancies where gestational diabetes is well controlled.

Eosinophils are key effector cells in allergic diseases. Here we investigated Mcl-1 (an anti-apoptotic protein) in experimental allergic airway inflammation using transgenic overexpressing human Mcl-1 mice (hMcl-1) and reducing Mcl-1 by a cyclin-dependent kinase inhibitor. Overexpression of Mcl-1 exacerbated allergic airway inflammation, with increased bronchoalveolar lavage fluid cellularity, eosinophil numbers and total protein, and an increase in airway mucus production. Eosinophil apoptosis was suppressed by Mcl-1 overexpression, with this resistance to apoptosis attenuated by cyclin-dependent kinase inhibition which also rescued Mcl-1-exacerbated allergic airway inflammation. We propose that targeting Mcl-1 may be beneficial in treatment of allergic airway disease.

A 77-year-old woman with a history of hypertension developed acute onset of aphasia and right hemiplegia and hemisensory loss. She was urgently referred to emergency department. Cerebral multidetector computed tomographic angiography (MD-CTA) revealed an acute ischemic stroke due to the occlusion of the left middle cerebral artery (Figure 1). Since the symptoms started three hours previously, the patient was candidate for mechanical thrombectomy. The patient then performed a selective digital subtraction angiography (DSA) of the left internal carotid artery that confirmed occlusion of the ipsilateral middle cerebral artery (Figure 2) and subsequently successfully performed the endovascular mechanical thrombectomy (Figure 2). Her clinical course has shown neurological symptoms improvement over time. Acute ischemic stroke can be caused by several factors, but the main ones are arterial and cardiac embolism, arterial wall disease or variants(1-4). The National Institutes of Health Stroke Scale (NIHSS) score, is widely used as clinical assessment for neurological deficits related to ischemic stroke(1). MDCTA and Magnetic Resonance Imaging are the two gold standard methods for diagnosis in acute ischemic stroke patients(1-5). Thrombolytic therapy of this pathological state began in the fifties, while the endovascular mechanical thrombectomy was defined as a new standard of care in 2015(1,5,6). This recent technique have added tissue window" to the existing "time window" (5,6). So, nowadays patients with small ischemic core, large penumbra, and good collaterals vessel may benefit from endovascular mechanical thrombectomy(1,5,6); even if they arrive within 6-24 h of stroke onset(5.

The aim of our study is a retrospective evaluation of effectiveness and safety of Computed Tomography (CT)-guided radiofrequency ablation (RFA) therapy of primary and metastatic lung lesions in patients that cannot be considered surgical candidates. From February 2007 to September 2017, we performed 264 CT-guided ablation sessions on 264 lesions in 174 patients (112M and 62 F; mean age, 68years; range 36–83years) affected by primary and metastatic lung lesions. The 45% of patients was affected by primary lung cancer, with size range lesion of 10–50mm, and the 55% by metastatic lung lesions with size range of 5–49mm. All patients had no more than three metastases in the lung and pulmonary relapses were treated up to three times. Overall Survival (OS), Progression-Free Survival (PFS), Local Progression-Free Survival (LPFS) and Cancer-specific survival (CSS) at 1, 3 and 5years were calculated both in primary lung tumors and in metastatic patients. Immediate and late RFA-related complications were reported. Pulmonary function tests were evaluated after the procedures. The effectiveness of RFA treatment was evaluated by contrast-enhanced CT. In patients affected by primary lung lesions, the OS rates were 66.73% at 1year, 23.13% at 3years and 16.19% at 5years. In patients affected by metastatic lung lesions, the OS rates were 85.11%, 48.86% and 43.33%, respectively, at 1, 3 and 5years. PFS at 1, 3 and 5years were 79.8%, 60.42%, 15.4% in primary lung tumors and 78.59%, 51.8% and 6.07% in metastatic patients. LPFS at 1, 3 and 5years were 79.8%, 64.69%, 18.87% in primary lung tumors and 86.29%, 69.15% and 44.45% in metastatic patients. CSS at 1, 3 and 5years was 95.56%, 71.84%, 56.72% in primary lung tumors and 94.07%, 71% and 71% in metastatic patients. Immediate RFA-related complications (pneumothorax, pleural effusion and subcutaneous emphysema) were observed, respectively, in 42, 53 and 13 of 264 procedures (15.9%, 20% and 5%). There also occurred one major complication (lung abscess, 0.36%). No significant worsening of pulmonary function was noted. Our retrospective evaluation showed long-term effectiveness, safety and imaging features of CT-guided RFA in patients affected by primary and metastatic lung cancer as an alternative therapy in non-surgical candidates.

Programmed cell death or apoptosis is a central biological process that is dysregulated in many diseases, including inflammatory conditions and cancer. The detection and quantification of apoptotic cells in vivo is hampered by the need for fixatives or washing steps for non-fluorogenic reagents, and by the low levels of free calcium in diseased tissues that restrict the use of annexins. In this manuscript, we report the rational design of a highly stable fluorogenic peptide (termed Apo-15) that selectively stains apoptotic cells in vitro and in vivo in a calcium-independent manner and under wash-free conditions. Furthermore, using a combination of chemical and biophysical methods, we identify phosphatidylserine as a molecular target of Apo-15. We demonstrate that Apo-15 can be used for the quantification and imaging of drug-induced apoptosis in preclinical mouse models, thus creating opportunities for assessing the in vivo efficacy of anti-inflammatory and anti-cancer therapeutics., Programmed cell death or apoptosis is an essential biological process that is impaired in some diseases and can be used to assess the effectiveness of drugs. Here the authors design Apo-15 as a fluorogenic peptide for the detection and real-time imaging of apoptotic cells.

Renal cell carcinoma (RCC) local recurrence after radical nephrectomy is uncommon. When feasible, surgical removal remains the primary treatment strategy; nevertheless, local RCC relapse management is controversial, and less invasive procedures may represent an attractive option to achieve oncologic control. The aim of our study was to assess the feasibility, safety, and clinical outcomes of image-guided percutaneous microwave ablation (MWA) for RCC local recurrence in patients initially treated with nephrectomy with curative intent. 10 consecutive patients underwent CT-guided percutaneous MWA of a total of 10 retroperitoneal nodules. Inclusion criteria were: histologically verified retroperitoneal metastases, previous radical nephrectomy, lesion no larger than 3cm, no other metastatic site elsewhere. All the procedures were performed under moderate sedation choosing the most favorable patient decubitus. If deemed necessary, pneumodissection was induced before ablation. After the antenna placement inside the target lesion, thermal ablation was achieved by maintenance of a power of 100W for a total time between 2 and 4min. All patients were observed overnight and discharged the following day if clinically stable. Technical success was obtained in 100% of patients. One patient was re-treated to complete oncologic response with repeat MWA. No major complications were observed. No patients demonstrated local recurrence at a mean follow-up of 26months. MWA is a safe and effective treatment strategy for loco-regional relapse of RCC following radical nephrectomy. This technique may represent a valuable approach for patients who are not eligible for surgery.

This study aimed to create a new quantitative and qualitative Mealtime Assessment Tool (MAT) to be administered by the not institutional caregiver to explore the dysphagic patient's mealtime behavior.The development and validation process consisted of three steps: firstly, identification of items for the questionnaire, then pilot testing phase of the first version of the instrument and finally a psychometric evaluation in which the test was administered to the target population (adult inpatients with diagnosed and undiagnosed oropharyngeal dysphagia).A factorial analysis explained 51% of the variance and grouped the 12 items of the scale into three categories that defined: a) structural setting and compliance at mealtime, b) behavioral attitude at mealtime, c) structural setting as a function of possible distractibility. The concurrent validity using the Dysphagia Outcome Severity Scale and Three Oz Water Swallow Test, as the gold standard, was r =0.01. Cronbach's alpha was 0.709. Stability test-retest reliability had ICC values of 0.980 p=0.01. The ROC curve using as state variable the De Pippo test as a dichotomius variable showed the under-curve area as 0.830 (95% CI, 0.763 to 0.897).The validation process led to the conclusion that the MAT is a valid, reliable and stable scale for caregivers.

Despite recent evidence on the relation between motor development and language development in infancy, this relation is still little explored in the late second and third year. This study investigated whether gross and/or fine motor skills affect language outcomes in this age range and whether any such effects narrow over time to specific language categories related to motor experience, such as spatial vocabulary. Thirty-six Italian monolingual toddlers (58% girls) participated, divided into two groups based on their age. They were assessed twice: the younger group at 18 (Time-1) and 24 months (Time-2); the older group at 24 (Time-1) and 30 months (Time-2). At Time-1 motor and language abilities were measured using the Griffiths Mental Development Scales. At Time-2, only language outcomes (three vocabularies: nouns, predicates, and spatial terms) were assessed, using the Picture Naming Game-PiNG. Hierarchical linear regressions show that motor skills affect language abilities also in the late second and third year, but the impact varies according to the type of motor skills (gross vs. fine) and children's age. At 18 months, controlling for linguistic abilities, a global score of gross motor skills predicted predicate production, and a specific gross-motor coordination skill: general dynamic coordination (GDC) predicted noun production at 24 months. At 24 months, controlling for linguistic abilities, GDC predicted predicate production, and a combination of fine- and gross-motor coordination skills (bilateral coordination and GDC) predicted spatial vocabulary comprehension at 30 months. Overall, results suggest that the relation between motor and language development is not simple or stable over time, but rather dynamic.

ation. No significant past medical history except for pharmacologically controlled mild hypertension. During the neurological examination the patient appeared alert, oriented and showed no deficit of strength, sensitivity and coordination. An expressive temporary aphasia was confirmed and Transient Ischemic Attacks (TIA) was suspected. Cranial Computed Tomography Angiography (CTA) showed hypoplasia of left Internal Carotid Artery (ICA) with a focal duplication in the intracavernous segment (Figure 1, arrowhead). Circle of Willis appears to be regular, with the left middle cerebral artery supported by the vertebrobasilar system through the left posterior communicating artery of increased caliber, and by the contralateral ICA via anterior communicating artery. Consequently, patient underwent Digital Subtraction Angiography (DSA) lateral view that confirmed the segmental duplication of the left intracavernous ICA (Figure 2, arrowhead). Vessels had a lightly winding course within the cavernous sinus and the intracranial branches downstream of their confluence presented a slight delay in visualization. After few hours her symptoms completely regressed and, in agreement with clinical and imaging data, diagnosis of TIA was made. The transient ischemic event was, in fact, most likely caused by low flow to the left cerebral hemisphere due to hypoplasia of the ICA and aforementioned abnormalities of its intracavernous tract that caused alteration and reduction of intracranial flow distribution. Medical treatment with anti-platelet drugs was started and patient was discharged with a clinical, laboratory and imaging follow-up program. Duplications of ICA in the intracranial tract are very rare(1,2). Most of the cases are localized in the supraclinoid segment. To our knowledge this is the first case described in literature of true duplication of ICA in the intracavernous tract. Patients with congenital variants or acquired pathology of ICA are mostly asymptomatic, but when symptoms appear, patients must be investigated(1-3). CTA is considered the first line non-invasive diagnostic method for intracranial vascular anatomy. At present, medical treatment remains the choice in patients with no-complicated duplications of ICA in the intracranial tract.

OBJECTIVE: To examine the contribution of anesthesia exposure during treatment for childhood medulloblastoma to neurocognitive outcomes 3 years after tumor diagnosis. STUDY DESIGN: In this retrospective study, anesthesia data were abstracted from medical records for 111 patients treated with risk-adapted protocol therapy at St. Jude Children’s Research Hospital. Neurocognitive testing data were obtained for 90.9% of patients. RESULTS: For the 101 patients (62.4% male) who completed testing, mean age at diagnosis was 10.1 years and 74.3% were staged to have average-risk disease. Anesthesia exposure during treatment ranged from 1–52 events (mean = 19.9); mean cumulative duration per patient was 21.1 hours (range 0.7–59.7). Compared with normative expectations (16%), the group had a significantly higher frequency of at-risk scores (

Preterm birth (PTB), the leading cause of neonatal morbidity and mortality, urgently requires novel therapeutic agents. Spontaneous PTB, resulting from preterm labor, is commonly caused by intrauterine infection/ inflammation. Statins are well‐established, cholesterol‐lowering drugs that can reduce inflammation and inhibit vascular smooth muscle contraction. We show that simvastatin reduced the incidence of PTB in a validated intrauterine LPS‐induced PTB mouse model, decreased uterine proinflammatory mRNA concentrations (IL‐6, Cxcl1, and Ccl2), and reduced serum IL‐6 concentration. In human myometrial cells, simvastatin reduced proinflammatory mediator mRNA and protein expression (IL‐6 and IL‐8) and increased anti‐inflammatory cytokine mRNA expression (IL‐10 and IL‐13). Critically, simvastatin inhibited myometrial cell contraction, basally and during inflammation, and reduced phosphorylated myosin light chain concentration. Supplementation with mevalonate and geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, abolished these anticontractile effects, indicating that the Rho/Rho‐associated protein kinase pathway is critically involved. Thus, simvastatin reduces PTB incidence in mice, inhibits myometrial contractions, and exhibits key anti‐inflammatory effects, providing a rationale for investigation into the repurposing of statins to treat preterm labor in women.—Boyle, A. K., Rinaldi, S. F., Rossi, A. G., Saunders, P. T. K., Norman, J. E. Repurposing simvastatin as a therapy for preterm labor: evidence from preclinical models. FASEB J. 33, 2743–2758 (2019). www.fasebj.org

Acute leukemia is the most frequent malignant disease in childhood. Acute lymphoblastic leukemia represents 75% and acute myeloblastic leukemia 25% of them. Erythroleukemia is a rare entity, corresponding to less than 5% of acute myeloblastic leukemia. Its definition has changed over the time. WHO in 2017 defines erythroleukemia when the percentage of erythroblasts represent 80% of the total cellularity of the bone marrow aspirate. This analytical and retrospective study was performed with the aim of reviewing morphology, flow cytometry and cytogenetic features, response to treatment and outcome of cases previously defined as erythroleukemia in our center during the last 25 years and, in addition to reclassify those cases which do not meet the new WHO 2017 criteria. From January 1990 to December 2015, 576 patients were diagnosed as acute myeloblastic leukemia and 11 (1.9%) of them were classified as erythroleukemia. Ten cases were evaluable. Sex distribution was 1:1 and the median age at diagnosis was 5 (range: 0.9-14) years. Six of them had presented with previous myelodysplastic syndrome. None of the analyzed cases can be currently defined as erythroleukemia, according to the new criteria. When reclassified, the cases were defined as leukemias of subsets with poor prognosis such as acute undifferentiated leukemia, without differentiation and megakaryoblastic leukemia. Only 2 patients remain leukemia-free and this could be explained both by the unfavorable prognosis of these leukemia subtypes, and the antecedent of myelodysplastic syndrome in most of the cases.

Studies conducted in Western countries document the special role of mother-infant face-to-face exchanges for early emotional development including social smiling. A few cross-cultural studies have shown that the Western pattern of face-to-face communication is absent in traditional rural cultures, without identifying other processes that promote emotional Co-regulation. The present study compared three different samples: Western middle-class families in Italy, rural traditional Nso farmer families in Cameroon, and West African sub-Saharan immigrant families in Italy using biweekly observations of 20 mother-infant dyads from each cultural context from age 4 to 12 weeks. Longitudinal sequential analysis of maternal and infant behaviors showed that from as early as 4 weeks, in Italian dyads maternal affectionate talking is linked with infant active attention to mother in sequences of face-to-face contact; this link fosters the subsequent emergence of infant smiling/cooing, and then sequences of positive feedback between infant and maternal emotional expressions that, by the 3rd month, dynamically stabilize. In contrast, for Cameroonian/Nso dyads over the 2nd and 3rd month, maternal motor stimulation marked by rhythmic vocalizing is linked with infant active attention to surroundings. The relatively few smiling/cooing actions of Nso babies at their mothers were answered mainly with tactile stimulation that did not foster the maintenance of face-to-face visual contact. Finally, West African immigrant dyads showed a combination of both face-to-face and sensorimotor coregulated exchanges observed in their new and native cultures. These findings suggest that emotional Co-regulation in early infancy can occur via multiple, culture-specific pathways that may be substantially different from the western pattern of face-to-face communication. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Three-dimensional fluorescence time-lapse imaging of the beating heart is extremely challenging, due to the heart's constant motion and a need to avoid pharmacological or phototoxic damage. Although real-time triggered imaging can computationally "freeze" the heart for 3D imaging, no previous algorithm has been able to maintain phase-lock across developmental timescales. We report a new algorithm capable of maintaining day-long phase-lock, permitting routine acquisition of synchronised 3D + time video time-lapse datasets of the beating zebrafish heart. This approach has enabled us for the first time to directly observe detailed developmental and cellular processes in the beating heart, revealing the dynamics of the immune response to injury and witnessing intriguing proliferative events that challenge the established literature on cardiac trabeculation. Our approach opens up exciting new opportunities for direct time-lapse imaging studies over a 24-hour time course, to understand the cellular mechanisms underlying cardiac development, repair and regeneration.

Intrahepatic Biliary Ductal Dilatation A 72-year-old woman presented with weight loss, abdominal pain, and jaundice. Imaging revealed a hepatic hilar mass with marked bilateral biliary ductal dilat...

PURPOSE: Reliable biomarkers for predicting subsequent sepsis among patients with suspected acute infection are lacking. In patients presenting to emergency departments (EDs) with suspected acute infection, we aimed to evaluate the reliability and discriminant ability of 47 leukocyte biomarkers as predictors of sepsis (Sequential Organ Failure Assessment score ≥ 2 at 24 h and/or 72 h following ED presentation).METHODS: In a multi-centre cohort study in four EDs and intensive care units (ICUs), we standardised flow-cytometric leukocyte biomarker measurement and compared patients with suspected acute infection (cohort-1) with two comparator cohorts: ICU patients with established sepsis (cohort-2), and ED patients without infection or systemic inflammation but requiring hospitalization (cohort-3).RESULTS: Between January 2014 and February 2016, we recruited 272, 59 and 75 patients to cohorts 1, 2, and 3, respectively. Of 47 leukocyte biomarkers, 14 were non-reliable, and 17 did not discriminate between the three cohorts. Discriminant analyses for predicting sepsis within cohort-1 were undertaken for eight neutrophil (cluster of differentiation antigens (CD) CD15; CD24; CD35; CD64; CD312; CD11b; CD274; CD279), seven monocyte (CD35; CD64; CD312; CD11b; HLA-DR; CD274; CD279) and a CD8 T-lymphocyte biomarker (CD279). Individually, only higher neutrophil CD279 [OR 1.78 (95% CI 1.23-2.57); P = 0.002], higher monocyte CD279 [1.32 (1.03-1.70); P = 0.03], and lower monocyte HLA-DR [0.73 (0.55-0.97); P = 0.03] expression were associated with subsequent sepsis. With logistic regression the optimum biomarker combination was increased neutrophil CD24 and neutrophil CD279, and reduced monocyte HLA-DR expression, but no combination had clinically relevant predictive validity.CONCLUSIONS: From a large panel of leukocyte biomarkers, immunosuppression biomarkers were associated with subsequent sepsis in ED patients with suspected acute infection.CLINICAL TRIAL REGISTRATION: NCT02188992.

Rationale: Excessive neutrophilic airway inflammation is the central feature of bronchiectasis, but little is known about neutrophils in bronchiectasis.Objectives: To assess blood neutrophil phenotype in patients with bronchiectasis while stable and during exacerbations.Methods: In the clinically stable arm of this study, there were eight healthy volunteers, eight patients with mild bronchiectasis, and eight patients with severe bronchiectasis. In addition, six patients with severe bronchiectasis were compared with six patients with community-acquired pneumonia at the start and end of an exacerbation. We assessed neutrophils for spontaneous apoptosis, cell surface marker expression, degranulation, reactive oxygen species generation, phagocytosis, and killing of Pseudomonas aeruginosa (PAO1). In addition, blood neutrophil function was compared with airway neutrophil function in bronchiectasis.Measurements and Main Results: In stable bronchiectasis, compared with healthy volunteers, blood neutrophils had significantly prolonged viability, delayed apoptosis, increased CD62L shedding, upregulated CD11b expression, increased myeloperoxidase release, and impaired neutrophil phagocytosis and killing of PAO1. Bronchiectatic airway neutrophils had significantly lower bacterial phagocytosis and killing than their matched autologous blood neutrophils. Both blood and airway neutrophil phagocytosis and killing were impaired at the start of an exacerbation and improved following antibiotic treatment. In pneumonia, there was a significant improvement in phagocytosis and killing after treatment with antibiotics. During infections, there was no difference in phagocytosis, but there was significantly increased bacterial killing at the start and end of infection in pneumonia compared with bronchiectasis exacerbations.Conclusions: In bronchiectasis stable state, peripheral blood neutrophils are reprogrammed and have prolonged survival. This impairs their functional ability of bacterial phagocytosis and killing, thereby perpetuating the vicious circle in bronchiectasis.

Purpose Cellular immune dysfunctions, which are common in intensive care patients, predict a number of significant complications. In order to effectively target treatments, clinically applicable measures need to be developed to detect dysfunction. The objective was to confirm the ability of cellular markers associated with immune dysfunction to stratify risk of secondary infection in critically ill patients. Methods Multi-centre, prospective observational cohort study of critically ill patients in four UK intensive care units. Serial blood samples were taken, and three cell surface markers associated with immune cell dysfunction [neutrophil CD88, monocyte human leucocyte antigen-DR (HLA-DR) and percentage of regulatory T cells (Tregs)] were assayed on-site using standardized flow cytometric measures. Patients were followed up for the development of secondary infections. Results A total of 148 patients were recruited, with data available from 138. Reduced neutrophil CD88, reduced monocyte HLA-DR and elevated proportions of Tregs were all associated with subsequent development of infection with odds ratios (95% CI) of 2.18 (1.00–4.74), 3.44 (1.58–7.47) and 2.41 (1.14–5.11), respectively. Burden of immune dysfunction predicted a progressive increase in risk of infection, from 14% for patients with no dysfunction to 59% for patients with dysfunction of all three markers. The tests failed to risk stratify patients shortly after ICU admission but were effective between days 3 and 9. Conclusions This study confirms our previous findings that three cell surface markers can predict risk of subsequent secondary infection, demonstrates the feasibility of standardized multisite flow cytometry and presents a tool which can be used to target future immunomodulatory therapies. Trial registration The study was registered with clinicaltrials.gov (NCT02186522). Electronic supplementary material The online version of this article (10.1007/s00134-018-5247-0) contains supplementary material, which is available to authorized users.

Background Due to common evolutionary origins, mitochondrial DNA (mtDNA) shares many similarities with immunogenic bacterial DNA. MtDNA is recognized as a pro-inflammatory damage-associated molecular pattern (DAMP) with a pathogenic role in several inflammatory diseases. We hypothesised that mtDNA is released during active disease, serving as a key pro-inflammatory factor in inflammatory bowel disease (IBD). Methods Between 2014 and 2015, we collected plasma separated within 2 hours of sampling from 97 prospectively recruited IBD patients (67 ulcerative colitis [UC] and 30 Crohn’s disease [CD]) and 40 non-IBD controls. We measured circulating mtDNA using quantitative polymerase chain reaction (amplifying mitochondria COXIII/ND2 genes) and also in mouse colitis induced by dextran sulfate-sodium (DSS). We used a mass spectometry approach to detect free plasma mitochondrial formylated peptides. Furthermore, we examined for mitochondrial damage using electron microscopy (EM) and TLR9 expression, the target for mtDNA, in human intestinal IBD mucosa. Results Plasma mtDNA levels were increased in UC and CD (both P < 0.0001) compared with non-IBD controls. These levels were significantly correlated to blood (C-reactive protein, albumin, white cell count), clinical and endoscopic markers of severity, and disease activity. In active UC, we identified 5 mitochondrial formylated peptides (the most abundant being fMMYALF with known chemoattractant function) in plasma. We observed mitochondrial damage in inflamed UC mucosa and significantly higher fecal MtDNA levels (vs non-IBD controls [P < 0.0001]), which supports gut mucosal mitochondrial DAMP release as the primary source. In parallel, plasma mtDNA levels increased during induction of acute DSS colitis and were associated with more severe colitis (P < 0.05). In active IBD, TLR9+ lamina propria inflammatory cells were significantly higher in UC and CD compared with controls (P < 0.05). Conclusions We present the first evidence to show that mtDNA is released during active IBD. MtDNA is a potential mechanistic biomarker, and our data point to mtDNA-TLR9 as a therapeutic target in IBD.

A validated clinical end point is needed to assess response to therapies in bronchiectasis.The goal of this study was to assess the reliability, validity, and responsiveness of the incremental shuttle walk test (ISWT) as a clinical end point in bronchiectasis.In clinically stable patients (n = 30), the ISWT was performed twice, 6 months apart. Correlation between the St. George's Respiratory Questionnaire (SGRQ) and the ISWT (n = 94) was performed. The 1-year gentamicin study was reanalyzed to assess the area under the curve (percent change of ISWT with a ≥ 4 unit improvement in total SGRQ). ISWT was performed prior to and following 14 days of antibiotics for an exacerbation (94 oral courses and 30 IV courses, n = 124) and reanalysis of the 1-year gentamicin study (n = 57).The ISWT did not significantly change over 6 months while clinically stable. The ISWT correlated inversely with the SGRQ (rs = -0.60; P .0001), Bronchiectasis Severity Index score (rs = -0.44; P .0001), and sedentary time (rs = -0.48; P = .0007) but correlated with physical activity (rs = 0.42; P = .004). The area under the curve for percent change in ISWT with ≥ 4 unit improvement in SGRQ was 0.79 (95% CI, 0.66-0.91; P = .001). A threshold of 5% improvement in the ISWT had a 92% sensitivity but 50% specificity, and from the responsiveness studies would capture 73% of all patients.This study confirmed the ISWT to be reliable, valid, and responsive to change in patients with bronchiectasis. The authors propose that a minimum clinically important difference of 5% improvement in the ISWT would be a useful objective end point to assess therapies in bronchiectasis.

Background Laparoscopic lavage was proposed in the 1990s to treat purulent peritonitis in patients with perforated acute diverticulitis. Prospective randomized trials had mixed results. The aim of this study was to determine the success rate of laparoscopic lavage in sepsis control and to identify a group of patients that could potentially benefit from this treatment. Methods This retrospective multicentre international study included consecutive patients from 24 centres who underwent laparoscopic lavage from 2005 to 2015. Results A total of 404 patients were included, 231 of whom had Hinchey III acute diverticulitis. Sepsis control was achieved in 172 patients (74·5 per cent), and was associated with lower Mannheim Peritonitis Index score and ASA grade, no evidence of free perforation, absence of extensive adhesiolysis and previous episodes of diverticulitis. The operation was immediately converted to open surgery in 19 patients. Among 212 patients who underwent laparoscopic lavage, the morbidity rate was 33·0 per cent; the reoperation rate was 13·7 per cent and the 30-day mortality rate 1·9 per cent. Twenty-one patients required readmission for early complications, of whom 11 underwent further surgery and one died. Of the 172 patients discharged uneventfully after laparoscopic lavage, a recurrent episode of acute diverticulitis was registered in 46 (26·7 per cent), at a mean of 11 (range 2–108) months. Relapse was associated with younger age, female sex and previous episodes of acute diverticulitis. Conclusion Laparoscopic lavage showed a high rate of successful sepsis control in selected patients with perforated Hinchey III acute diverticulitis affected by peritonitis, with low rates of operative mortality, reoperation and stoma formation.

Objective Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation. Design Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals. Methods We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8). Results 90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann’s syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH. Conclusions Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.

Background Eosinophils play a central role in propagation of allergic diseases, including asthma. Both recruitment and retention of eosinophils regulate pulmonary eosinophilia, but the question of whether alterations in apoptotic cell clearance by phagocytes contributes directly to resolution of allergic airway inflammation remains unexplored. Objectives In this study we investigated the role of the receptor tyrosine kinase Mer in mediating apoptotic eosinophil clearance and allergic airway inflammation resolution in vivo to establish whether apoptotic cell clearance directly affects the resolution of allergic airway inflammation. Methods Alveolar and bone marrow macrophages were used to study Mer-mediated phagocytosis of apoptotic eosinophils. Allergic airway inflammation resolution was modeled in mice by using ovalbumin. Fluorescently labeled apoptotic cells were administered intratracheally or eosinophil apoptosis was driven by administration of dexamethasone to determine apoptotic cell clearance in vivo. Results Inhibition or absence of Mer impaired phagocytosis of apoptotic human and mouse eosinophils by macrophages. Mer-deficient mice showed delayed resolution of ovalbumin-induced allergic airway inflammation, together with increased airway responsiveness to aerosolized methacholine, increased bronchoalveolar lavage fluid protein levels, altered cytokine production, and an excess of uncleared dying eosinophils after dexamethasone treatment. Alveolar macrophage phagocytosis was significantly Mer dependent, with the absence of Mer attenuating apoptotic cell clearance in vivo to enhance inflammation in response to apoptotic cells. Conclusions We demonstrate that Mer-mediated apoptotic cell clearance by phagocytes contributes to resolution of allergic airway inflammation, suggesting that augmenting apoptotic cell clearance is a potential therapeutic strategy for treating allergic airway inflammation.

Objective: Several authors have identified a bidirectional link between patient metacognitive functioning and the therapeutic alliance. Specifically, metacognition might be enhanced by a positive alliance with the clinician, whereas metacognitive deficits might impede the alliance. Interestingly, the therapist’s technical interventions might influence both therapeutic alliance and metacognitive functioning. However, little is known about the interactions between these dimensions. The aim of the present study is to explore these interactions more fully in the earliest phase of the therapeutic process. Method: Participants included 24 patients and 12 therapists in training. The Metacognition Assessment Scale-Revised, Collaborative Interaction Scale, and Psychodynamic Intervention Rating Scale were employed in the first three sessions of psychotherapy. Results: Sequential analyses revealed that different therapist interventions co-occurred with three different levels of the therapeutic alliance: A first level characterized by a positive collaboration, a second characterized by a neutral collaboration, and a third characterized by ruptures. Importantly, the patient’s metacognitive functioning was found to mediate the relationship between the therapeutic intervention and the therapeutic alliance in the positive and neutral levels of collaboration but not in the ruptures one. Conclusions: These findings suggest that a specific interdependence exists among the therapeutic alliance, technical intervention, and metacognitive functioning. Clinical or methodological significance of this article: From a methodological standpoint, the originality of the present study lies in the combination of an interactionist approach, which conceives process factors as interrelated dimensions interacting in non-additive and often nonlinear ways, with analyses at both micro- and macro-analytic levels (i.e., sequential and mediation analyses). From a theoretical standpoint, findings of the present study indicate that specific therapist's interventions are related to specific levels of the therapeutic alliance (i.e., positive, neutral and negative), hence providing crucial insights into the clinical understanding of the psychotherapy process

A 16-year-old boy had a past medical history of primary hypogonadism, due to bilateral anorchia. He presented with gallstones located in the gallbladder and a mild dilatation of the intrahepatic biliary tree. The histology study reported cholesterol gallstones. The patient had been treated with testosterone replacement therapy since infancy. We suggest a possible correlation between testosterone replacement therapy and the presence of cholesterol gallstones.

There are no randomized controlled trials of statin therapy in patients with severe bronchiectasis who are chronically infected with Pseudomonas aeruginosa.Thirty-two patients chronically infected with P aeruginosa were recruited in this double-blind cross-over randomized controlled trial. Sixteen patients were recruited in each arm, were given atorvastatin 80 mg or placebo for 3 months followed by a washout period for 6 weeks, and then crossed over and administered the alternative therapy for 3 months.Twenty-seven patients completed the study. Atorvastatin did not significantly improve the primary end point of cough as measured by the Leicester Cough Questionnaire (mean difference, 1.92; 95% CI for difference, -0.57-4.41; P = .12). However, atorvastatin treatment resulted in an improved St. Georges Respiratory Questionnaire (-5.62 points; P = .016) and reduced serum levels of CXCL8 (P = .04), tumor necrosis factor (P = .01), and intercellular adhesion molecule 1 (P = .04). There was a trend toward improvement in serum C-reactive protein and serum neutrophil counts (P = .07 and P = .06, respectively). We demonstrated in vitro that atorvastatin 10 μM reduced formyl-methionyl-leucyl phenylalanine-induced upregulation of CD11b expression and changes in calcium flux, reflecting an ability to decrease neutrophil activation.We demonstrated that atorvastatin reduced systemic inflammation and improved quality of life in patients with bronchiectasis who were infected with P aeruginosa. These effects may be due to an ability of atorvastatin to modulate neutrophil activation.ClinicalTrials.gov; No.: NCT01299194; URL: www.clinicaltrials.gov.

Hyperintense FLAIR signal in the cerebral sulci of anesthetized children is attributed to supplemental oxygen (fraction of inspired oxygen) but resembles FLAIR hypersignal associated with perfusion abnormalities in Moyamoya disease and carotid stenosis. We investigated whether cerebral perfusion, known to be altered by anesthesia, contributes to diffuse signal intensity in sulci in children and explored the relative contributions of supplemental oxygen, cerebral perfusion, and anesthesia to signal intensity in sulci.Supraventricular signal intensity in sulci on pre- and postcontrast T2 FLAIR images of 24 propofol-sedated children (6.20 ± 3.28 years) breathing supplemental oxygen and 18 nonsedated children (14.28 ± 2.08 years) breathing room air was graded from 0 to 3. The Spearman correlation of signal intensity in sulci with the fraction of inspired oxygen and age in 42 subjects, and with dynamic susceptibility contrast measures of cortical CBF, CBV, and MTT available in 25 subjects, were evaluated overall and compared between subgroups. Factors most influential on signal intensity in sulci were identified by stepwise logistic regression.CBV was more influential on noncontrast FLAIR signal intensity in sulci than the fraction of inspired oxygen or age in propofol-sedated children (CBV: r = 0.612, P = .026; fraction of inspired oxygen: r = -0.418, P = .042; age: r = 0.523, P = .009) and overall (CBV: r = 0.671, P = .0002; fraction of inspired oxygen: r = 0.442, P = .003; age: r = -0.374, P = .015). MTT (CBV/CBF) was influential in the overall cohort (r = 0.461, P = .020). Signal intensity in sulci increased with contrast in 45% of subjects, decreased in none, and was greater (P.0001) in younger propofol-sedated subjects, in whom the signal intensity in sulci increased with age postcontrast (r = .600, P = .002).Elevated cortical CBV appears to contribute to increased signal intensity in sulci on noncontrast FLAIR in propofol-sedated children. The effects of propofol on age-related cerebral perfusion and vascular permeability may play a role.

Parturition is associated with a leukocyte influx into the intrauterine tissues; however, the exact role these leukocytes play in the onset of labor remains unclear. Neutrophil infiltration of the uteroplacental tissues has been particularly associated with infection-associated preterm labor (PTL) in both women and mouse models. In this study, we investigated the role of neutrophils in a mouse model of infection-induced PTL. Intrauterine administration of LPS on day 17 of gestation resulted in a 7-fold increase in the number of decidual neutrophils compared with control mice receiving PBS (p < 0.01; n = 8–11). We hypothesized that neutrophil influx is necessary for PTL and that neutrophil depletion would abolish preterm birth. To test this hypothesis, mice were depleted of neutrophils by treatment with anti–Gr-1, anti–Ly-6G, or the appropriate IgG control Ab on day 16 of gestation prior to LPS on day 17 (n = 6–7). Successful neutrophil depletion was confirmed by flow cytometry and immunohistochemistry. Neutrophil depletion with Gr-1 resulted in reduced uterine and placental Il-1β expression (p < 0.05). Neutrophil depletion with Ly-6G reduced uterine Il-1β and Tnf-α expression (p < 0.05). However, neutrophil depletion with either Ab did not delay LPS-induced preterm birth. Collectively, these data show that decidual neutrophil infiltration is not essential for the induction of infection-induced PTL in the mouse, but that neutrophils contribute to the LPS-induced inflammatory response of the uteroplacental tissues.

Background:Short-term group schema cognitive behavior therapy (SCBT-g) showed improvements in overall symptomatology, early maladaptive schemas (EMS) and schema modes, both in adults and adolescents with personality disorder (PD) features and long-standing mood disorders. However, no research has yet been carried out on the effect in older adults. Therefore, in a proof of concept study, we explored the effect of SCBT-g in older outpatients with PD features and longstanding mood disorders.Method:Thirty-one older outpatients, aged 60–78 years with PD features and/or longstanding mood disorders were included in a proof of concept study with pre-mid-post design. Primary outcome was psychological distress (Brief Symptom Inventory) and intermediate outcomes were EMS (Young Schema Questionnaire) and schema modes (Schema Mode Inventory), assessed at baseline, mid-treatment and end-of-treatment. Paired samples t-tests were conducted, and Cohen's d effect sizes reported for pre mid- and post-treatment. As proof of concept analysis, hierarchical regression analyses with residual change scores were used to analyse whether early process changes in EMS (intermediate outcomes) predicted later outcome changes in symptoms.Results:SCBT-g led to significant improvement in all three measures of psychological symptoms, EMS and modes with medium effect sizes. Pre-treatment to mid-treatment changes in schema severity predicted symptom improvement from mid- to end-of-treatment.Conclusion:This proof of concept study shows that SCBT-g has potential to change EMS and to show significant effect at symptom level in older outpatients with PD features. A control condition in a randomized controlled trial is a necessary step for further research.

Objectives To assess the potential impact of obesity on the success rate of single incision slings (SIS). Study design This was a retrospective cohort study of women who underwent the SIS procedure for primary stress urinary incontinence. Women were divided into three different groups by body mass index (BMI) according to the WHO classification. The International Consultation on Incontinence-short form (ICIQ-SF), Women Irritative Prostate Symptoms Score (W-IPSS), Patient Global Impression of Severity (PGI-S) and Patient Global Impression of Improvement (PGI-I) questionnaires were used. Objective and subjective outcomes were the primary outcome measures of the study. SPSS software was used for data analysis. Results 206 patients who underwent the SIS procedure were reviewed. At 1 year follow-up there were 196 women available for the analysis: 69 were normal weight subjects, 91 overweight and 36 obese. Patients in all BMI groups reported a significant improvement in their condition. Nevertheless there was a trend towards lesser objective efficacy of SIS with increasing body weight, with a significant difference between obese women and normal subjects: 75% vs 91.3%, p = 0.049; OR 3.74 (95% CI 1.19–11.76). Analysis of the ICIQ-SF and PGI-I showed significant lower mean ± SD improvement in obese women when compared with their normal or overweight counterparts, together with a significantly lower number of obese patients reporting themselves as very much improved or much improved. Conclusions Single incision slings seem to be an effective treatment regardless of BMI, but obese women had nearly 4 times the odds of objective failure as compared to normal weight women.

STUDY QUESTION Is labour, both at term and preterm, associated with alterations in decidual lymphocyte densities and widespread changes to the decidual transcriptome? SUMMARY ANSWER The onset of parturition, both at term and preterm, is associated with widespread gene expression changes in the decidua, many of which are related to inflammatory signalling, but is not associated with changes in the number of any of the decidual lymphocyte populations examined. WHAT IS KNOWN ALREADY Given its location, directly at the maternal–foetal interface, the decidua is likely to play a pivotal role in the onset of parturition, however, the molecular events occurring in the decidua in association with the onset of labour, both at term and preterm, remain relatively poorly defined. Using flow cytometry and microarray analysis, the present study aimed to investigate changes to the immune cell milieu of the decidua in association with the onset of parturition and define the decidual gene signature associated with term and preterm labour (PTL). STUDY DESIGN, SIZE, DURATION This study used decidual samples collected from 36 women across four clinical groups: term (38–42 weeks of gestation) not in labour, TNL; term in labour, TL; preterm (

INTRODUCTION: Critically ill patients are at high risk of nosocomial infections, with between 20% and 40% of patients admitted to the intensive care unit (ICU) acquiring infections. These infections result in increased antibiotic use, and are associated with morbidity and mortality. Although critical illness is classically associated with hyperinflammation, the high rates of nosocomial infection argue for an importance of effect of impaired immunity. Our group recently demonstrated that a combination of 3 measures of immune cell function (namely neutrophil CD88, monocyte HLA-DR and % regulatory T cells) identified a patient population with a 2.4-5-fold greater risk for susceptibility to nosocomial infections.METHODS AND ANALYSIS: This is a prospective, observational study to determine whether previously identified markers of susceptibility to nosocomial infection can be validated in a multicentre population, as well as testing several novel markers which may improve the risk of nosocomial infection prediction. Blood samples from critically ill patients (those admitted to the ICU for at least 48 hours and requiring mechanical ventilation alone or support of 2 or more organ systems) are taken and undergo whole blood staining for a range of immune cell surface markers. These samples undergo analysis on a standardised flow cytometry platform. Patients are followed up to determine whether they develop nosocomial infection. Infections need to meet strict prespecified criteria based on international guidelines; where these criteria are not met, an adjudication panel of experienced intensivists is asked to rule on the presence of infection. Secondary outcomes will be death from severe infection (sepsis) and change in organ failure.ETHICS AND DISSEMINATION: Ethical approval including the involvement of adults lacking capacity has been obtained from respective English and Scottish Ethics Committees. Results will be disseminated through presentations at scientific meetings and publications in peer-reviewed journals.TRIAL REGISTRATION NUMBER: NCT02186522; Pre-results.

Myoxinol is a complex of oligopeptides obtained from the seeds of Hibiscus esculentus used in cosmetic as natural alternative to botulin toxin. The aim of the study was to evaluate the safety and effectiveness of local myoxinol for the treatment of acute anal fissure. All the consecutive patients with acute fissure treated from January to June 2014 underwent 30 days of topical treatment (twice/day) with a mioxinol based ointment. Pain, symptomatic relief, fissure healing and re-epithelization, 1-year recurrence rate, subjective satisfaction and need for further treatments were evaluated. During the study period 157 patients were eligible for data analysis (91 males: 58%; mean age 38 years: range 17–83). Median anal pain score was 7.1 pre-treatment and 1.7 and 0.9 after 30 days and 12 months from treatment, respectively (p: 0.0001). After the treatment period complete healing was achieved in 103 patients (65.5%), relevant improvement in 31 (20%) and no improvement in 21 patients (13.5%). Overall efficacy rate was 85.5%. A significant difference was reported considering patients with pre-treatment VAS between 1–5 and 6–10 (p: 0.004). Twenty-nine patients (18.5%) required further treatments. Hydrolyzed Hibiscus esculentus extract was proven to be an effective and well-tolerated topical treatment for acute fissure, with a high healing rate, a significant reduction of pain and a low 1-year recurrence rate.

INTRODUCTION: Sepsis is an acute illness resulting from infection and the host immune response. Early identification of individuals at risk of developing life-threatening severe sepsis could enable early triage and treatment, and improve outcomes. Currently available biomarkers have poor predictive value for predicting subsequent clinical course in patients with suspected infection. Circulating leucocytes provide readily accessible tissues that reflect many aspects of the complex immune responses described in sepsis. We hypothesise that measuring cellular markers of immune responses by flow cytometry will enable early identification of infected patients at risk of adverse outcomes. We aim to characterise leucocyte surface markers (biomarkers) and their abnormalities in a population of patients presenting to the hospital emergency department with suspected sepsis, and explore their ability to predict subsequent clinical course.METHODS AND ANALYSIS: We will conduct a prospective, multicentre, clinical, exploratory, cohort observational study. To answer our study question, 3 patient populations will be studied. First, patients with suspected sepsis from the emergency department (n=300). To assess performance characteristics of potential tests, critically ill patients with established sepsis, and age and gender matched patients without suspicion of infection requiring hospital admission (both n=100) will be recruited as comparator populations. In all 3 groups, we plan to assess circulating biomarker profiles using flow cytometry. We will select candidate biomarkers by cross-cohort comparison, and then explore their predictive value for clinical outcomes within the cohort with suspected sepsis.ETHICS AND DISSEMINATION: The study will be carried out based on the principles in the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice. Ethics approval has been granted from the Scotland A Research Ethics Committee (REC) and Oxford C REC. On conclusion of this study, the results will be disseminated via peer-reviewed journals.TRIAL REGISTRATION NUMBER: NCT02188992; Pre-results.

To present the results of our experience with cyanoacrylic glue percutaneous injection to treat post-surgical non-healing enteric fistulae after failure of standard treatments. Eighteen patients (14 males; age range 33–84, mean 69 years) were treated for a non-healing post-surgical enteric fistula after failure of standard treatments. Under computed tomography and/or fluoroscopic guidance, a mixture of cyanoacrylic glue (Glubran 2, GEM, Viareggio, Italy) and ethiodized oil was injected at the site of the fistula. Fistula was considered healed when no material was drained by the percutaneous drainage and a subsequent computed tomography confirmed the disappearance of any fluid collection. In all cases, it was possible to reach the site of the fistula using a percutaneous access. A median of 1 injection (range 1–5) was performed. Fistula healing was achieved in 16/18 (89 %) patients. One patient died for other reasons before fistula healing. Median time for fistula healing was 0 days (mean 8, range 0–58 days). No complications occurred. Reoperation was needed in one patient. Percutaneous injection of cyanoacrylic glue is feasible, safe, and effective to treat non-healing post-surgical enteric fistulae. It may represent a further option to avoid surgical reoperation in frail patients.