Publisher Correction: Prokineticin receptor 2 affects GnRH3 neuron ontogeny but not fertility in zebrafish

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Italian Oncological Pain Survey (IOPS) A Multicentre Italian Study of Breakthrough Pain Performed in Different Settings

Objective: A survey of breakthrough pain (BTP) was performed in five palliative care units (PCU), seven oncology departments (ONC), and nine pain clinics (OPC). Methods: A standard algorithm was used to confirm the diagnosis of BTP of patients refereed to different settings. Results: 1,412 evaluable cancer patients were enrolled. 53.9% were males and the mean age was 63.7±13.1 years. The mean intensity of background pain was 2.8±0.73. Patients reported 2.4±1.1 BTP episodes/day with a mean intensity of 7.37±1.28. 80.6% patients reported that the BTP had a significant negative impact in everyday life. The majority of patients reported a fast onset of BTP, which was predictable in 50.7% of cases, while BTP with a gradual onset (>10 min) was less predictable (29%) (P=0.001). PCU patients were older, had lower Karnofsky levels, a lower number of BTP episodes/day, a slow onset of BTP onset, and a less predictable BTP. Cancer diagnosis was performed a mean of 23.5 months (SD±32.8) before the assessment. The mean duration of background pain was 3.5 months (SD±3.5), and the mean duration of any analgesic treatment was 2.5 months (SD±3). BTP started a mean of 2.2 months (SD±1.9) before the assessment. Characteristics of BTP were influenced by the course of disease, as well as the duration of background pain and initiation of BTP. Most patients took rapid onset opioids and were satisfied with the treatment. BTP diagnosis was prevalently made by ONC and OPC physicians, and rarely by GPs. Conclusion: This survey performed by an Italian observatory expert review group, has confirmed that the BTP represents a clinically relevant condition with a negative impact on the patient’s quality of life. BTP was detected in all settings involved. A number of factors are associated with the BTP. Also factors regarding the course of disease and setting of care have been assessed. This information may help in stratifying patients or predicting the risk of development of BTP with specific characteristics

Systematic versus on-demand early palliative care: A randomised clinical trial assessing quality of care and treatment aggressiveness near the end of life

Aim Early palliative care (EPC) in oncology has shown sparse evidence of a positive impact on patient outcomes, quality of care outcomes and costs. Patients and methods Data for this secondary analysis were taken from a trial of 207 outpatients with metastatic pancreatic cancer randomly assigned to receive standard cancer care plus on-demand EPC (standard arm) or standard cancer care plus systematic EPC (interventional arm). After 20 months\u2019 follow-up, 149 (80%) had died. Outcome measures were frequency, type and timing of chemotherapy administration, use of resources, place of death and overall survival. Results Some indices of end-of-life (EoL) aggressiveness had a favourable impact from systematic EPC. Interventional arm patients showed higher use of hospice services: a significantly longer median and mean period of hospice care (P = 0.025 for both indexes) and a significantly higher median and mean number of hospice admissions (both P < 0.010). In the experimental arm, chemotherapy was performed in the last 30 days of life in a significantly inferior rate with respect to control arm: 18.7% versus 27.8% (adjusted P = 0.036). Other non-significant differences were seen in favour of experimental arm. Conclusions Systematic EPC showed a significant impact on some indicators of EoL treatment aggressiveness. These data, reinforced by multiple non-significant differences in most of the other items, suggest that quality of care is improved by this approach. This study is registered on ClinicalTrials.gov (NCT01996540)

Toward an operative diagnosis in sepsis: a latent class approach

<p>Abstract</p> <p>Background</p> <p>Recent data have suggested that 18 million of new sepsis cases occur each year worldwide, with a mortality rate of almost 30%. There is not consensus on the clinical definition of sepsis and, because of lack of training or simply unawareness, clinicians often miss or delay this diagnosis. This is especially worrying; since there is strong evidence supporting that early treatment is associated with greater clinical success. There are some difficulties for sepsis diagnosis such as the lack of an appropriate gold standard to identify this clinical condition. This situation has hampered the assessment of the accuracy of clinical signs and biomarkers to diagnose sepsis.</p> <p>Methods/design</p> <p>Cross-sectional study to determine the operative characteristics of three biological markers of inflammation and coagulation (D-dimer, C-reactive protein and Procalcitonin) as diagnostic tests for sepsis, in patients admitted to hospital care with a presumptive infection as main diagnosis.</p> <p>Discussion</p> <p>There are alternative techniques that have been used to assess the accuracy of tests without gold standards, and they have been widely used in clinical disciplines such as psychiatry, even though they have not been tested in sepsis diagnosis. Considering the main importance of diagnosis as early as possible, we propose a latent class analysis to evaluate the accuracy of three biomarkers to diagnose sepsis.</p

Multiple Organ System Defects and Transcriptional Dysregulation in the Nipbl+/− Mouse, a Model of Cornelia de Lange Syndrome

Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75–80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only ∼30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/− mice and in individuals with CdLS

Pentraxin 3 (PTX3) Is Associated with Severe Sepsis and Fatal Disease in Emergency Room Patients with Suspected Infection: A Prospective Cohort Study

Background Early diagnostic and prognostic stratification of patients with suspected infection is a difficult clinical challenge. We studied plasma pentraxin 3 (PTX3) upon admission to the emergency department in patients with suspected infection. Methods The study comprised 537 emergency room patients with suspected infection: 59 with no systemic inflammatory response syndrome (SIRS) and without bacterial infection (group 1), 67 with bacterial infection without SIRS (group 2), 54 with SIRS without bacterial infection (group 3), 308 with sepsis (SIRS and bacterial infection) without organ failure (group 4) and 49 with severe sepsis (group 5). Plasma PTX3 was measured on admission using a commercial solid-phase enzyme-linked immunosorbent assay (ELISA). Results The median PTX3 levels in groups 1–5 were 2.6 ng/ml, 4.4 ng/ml, 5.0 ng/ml, 6.1 ng/ml and 16.7 ng/ml, respectively (p<0.001). The median PTX3 concentration was higher in severe sepsis patients compared to others (16.7 vs. 4.9 ng/ml, p<0.001) and in non-survivors (day 28 case fatality) compared to survivors (14.1 vs. 5.1 ng/ml, p<0.001). A high PTX3 level predicted the need for ICU stay (p<0.001) and hypotension (p<0.001). AUCROC in the prediction of severe sepsis was 0.73 (95% CI 0.66–0.81, p<0.001) and 0.69 in case fatality (95% CI 0.58–0.79, p<0.001). PTX3 at a cut-off level for 14.1 ng/ml (optimal cut-off value for severe sepsis) showed 63% sensitivity and 80% specificity. At a cut-off level 7.7 ng/ml (optimal cut-off value for case fatality) showed 70% sensitivity and 63% specificity in predicting case fatality on day 28.In multivariate models, high PTX3 remained an independent predictor of severe sepsis and case fatality after adjusting for potential confounders. Conclusions A high PTX3 level on hospital admission predicts severe sepsis and case fatality in patients with suspected infection.Public Library of Science open acces

In Vitro and In Vivo Development of Horse Cloned Embryos Generated with iPSCs, Mesenchymal Stromal Cells and Fetal or Adult Fibroblasts as Nuclear Donors

The demand for equine cloning as a tool to preserve high genetic value is growing worldwide; however, nuclear transfer efficiency is still very low. To address this issue, we first evaluated the effects of time from cell fusion to activation (<1h, n = 1261; 1-2h, n = 1773; 2-3h, n = 1647) on in vitro and in vivo development of equine embryos generated by cloning. Then, we evaluated the effects of using different nuclear donor cell types in two successive experiments: I) induced pluripotent stem cells (iPSCs) vs. adult fibroblasts (AF) fused to ooplasts injected with the pluripotency-inducing genes OCT4, SOX2, MYC and KLF4, vs. AF alone as controls; II) umbilical cord-derived mesenchymal stromal cells (UC-MSCs) vs. fetal fibroblasts derived from an unborn cloned foetus (FF) vs. AF from the original individual. In the first experiment, both blastocyst production and pregnancy rates were higher in the 2-3h group (11.5% and 9.5%, respectively), respect to <1h (5.2% and 2%, respectively) and 1-2h (5.6% and 4.7%, respectively) groups (P<0.05). However, percentages of born foals/pregnancies were similar when intervals of 2-3h (35.2%) or 1-2h (35.7%) were used. In contrast to AF, the iPSCs did not generate any blastocyst-stage embryos. Moreover, injection of oocytes with the pluripotency-inducing genes did not improve blastocyst production nor pregnancy rates respect to AF controls. Finally, higher blastocyst production was obtained using UC-MSC (15.6%) than using FF (8.9%) or AF (9.3%), (P<0.05). Despite pregnancy rates were similar for these 3 groups (17.6%, 18.2% and 22%, respectively), viable foals (two) were obtained only by using FF. In summary, optimum blastocyst production rates can be obtained using a 2-3h interval between cell fusion and activation as well as using UC-MSCs as nuclear donors. Moreover, FF line can improve the efficiency of an inefficient AF line. Overall, 24 healthy foals were obtained from a total of 29 born foals

Diagnosis and management of Cornelia de Lange syndrome:first international consensus statement

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning