Optimising follow-up strategy based on cytology and human papillomavirus after fertility-sparing surgery for early stage cervical cancer: a nationwide, population-based, retrospective cohort study.

BACKGROUND: The optimal follow-up strategy to detect recurrence after fertility-sparing surgery for early stage cervical cancer is unknown. Tailored surveillance based on individual risks could contribute to improved efficiency and, subsequently, reduce costs in health care. The aim of this study was to establish the predictive value of cervical cytology and high-risk human papillomavirus (HPV) testing to detect recurrent cervical intraepithelial neoplasia grade 2 or worse (CIN2+; including recurrent cervical cancer) after fertility-sparing surgery. METHODS: In this nationwide, population-based, retrospective cohort study, we used data from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Databank. All patients aged 18-40 years with cervical cancer of any histology who received fertility-sparing surgery (ie, large loop excision of the transformation zone, conisation, or trachelectomy) between Jan 1, 2000, and Dec 31, 2020, were included. Pathology data from diagnosis, treatment, and during follow-up were analysed. The primary and secondary outcomes were the cumulative incidence of recurrent CIN2+ and recurrence-free survival, overall and stratified by results for cytology and high-risk HPV. FINDINGS: 1548 patients were identified, of whom 1462 met the inclusion criteria. Of these included patients, 19 568 pathology reports were available. The median age at diagnosis was 31 years (IQR 30-35). After a median follow-up of 6·1 years (IQR 3·3-10·8), recurrent CIN2+ was diagnosed in 128 patients (cumulative incidence 15·0%, 95% CI 11·5-18·2), including 52 patients (cumulative incidence 5·4%, 95% CI 3·7-7·0) with recurrent cervical cancer. The overall 10-year recurrence-free survival for CIN2+ was 89·3% (95% CI 87·4-91·3). By cytology at first follow-up visit within 12 months after fertility-sparing surgery, 10-year recurrence-free survival for CIN2+ was 92·1% (90·2-94·1) in patients with normal cytology, 84·6% (77·4-92·3) in those with low-grade cytology, and 43·1% (26·4-70·2) in those with high-grade cytology. By high-risk HPV status at first follow-up visit within 12 months after surgery, 10-year recurrence-free survival for CIN2+ was 91·1% (85·3-97·3) in patients who were negative for high-risk HPV and 73·6% (58·4-92·8) in those who were positive for high-risk HPV. Cumulative incidence of recurrent CIN2+ within 6 months after any follow-up visit (6-24 months) in patients negative for high-risk HPV with normal or low-grade cytology was 0·0-0·7% and with high-grade cytology was 0·0-33·3%. Cumulative incidence of recurrence in patients positive for high-risk HPV with normal or low-grade cytology were 0·0-15·4% and with high-grade cytology were 50·0-100·0%. None of the patients who were negative for high-risk HPV without high-grade cytology, at 6 months and 12 months, developed recurrence. INTERPRETATION: Patients who are negative for high-risk HPV with normal or low-grade cytology at 6-24 months after fertility-sparing surgery, could be offered a prolonged follow-up interval of 6 months. This group comprises 80% of all patients receiving fertility-sparing surgery. An interval of 12 months seems to be safe after two consecutive negative tests for high-risk HPV with an absence of high-grade cytology, which accounts for nearly 75% of all patients who receive fertility-sparing surgery. FUNDING: KWF Dutch Cancer Society.

Strategies for Success: Simple Education Interventions to Equip Nursing Students in Rural Liberia.

Severe shortages of skilled health workforce remain a major barrier to universal health coverage in low income countries including Liberia where nurses and midwives form more than 50% of the health workforce. According to the 2018 Service Availability and Readiness Assessment (SARA) report, Liberia has 10.7 core healthcare workers per 10,000 people, far below the WHO benchmark of 23/10,000 people. High quality training for nurses and midwives is one of the most important strategies to addressing these health workforce shortages. Since 2015, William V.S Tubman University (TU) faculty and Partners in Health (PIH) have partnered in nursing and midwifery education to address nursing and midwifery workforce shortages in Southeast Liberia. In our collaboration we have sought to not only increase the quantity of graduate nurses and midwives but also improve the quality of the training to ensure they are equipped to serve the population. TU strives to produce highly competent generic nurses who will excel in their clinical practice and future specialized training. By applying the theory of deliberate practice, learners are allowed to practice and self-evaluate repeatedly until they attain proficiency. Simulation training was adopted early in the training of nurses and midwives at TU to ensure students are well-prepared for real-life patient care. TU also established a preceptorship program to ensure that students receive skilled mentorship during clinical rotations. Internship for graduating senior Nursing/Midwifery students, where they focus on enhancing psychomotor and assessment skills, professional communication, safety and organization, medication administration and documentation, ensures successful integration into clinical practice after graduation. This progression of the student nurse or midwife from the exposure in the skills lab during pre-clinical modules, to individual preceptorship during clinical rotations to a structured internship experience with an intensive pre-internship "boot camp" have been the major innovations that have helped our partnership flourish. The foundation of these interventions is strong and sustained investment in nursing and midwifery faculty both at the university and the health facilities.

Case Report of Novel Genetic Variant in KCNT1 Channel and Pharmacological Treatment With Quinidine. Precision Medicine in Refractory Epilepsy.

Case introduction: In this work we present a female infant patient with epilepsy of infancy with migrating focal seizures (EIMFS). Although many pharmacological schemes were attempted, she developed an encephalopathy with poor response to antiepileptic drugs and progressive cerebral dysfunction. Aim: To present the pharmacological response and therapeutic drug monitoring of a paediatric patient with a severe encephalopathy carrying a genetic variant in KCNT1 gene, whose identification led to include quinidine (QND) in the treatment regimen as an antiepileptic drug. Case report: Patient showed slow rhythmic activity (theta range) over left occipital areas with temporal propagation and oculo-clonic focal seizures and without tonic spasms three months after birth. At the age of 18 months showed severe impairments of motor and intellectual function with poor eye contact. When the patient was 4 years old, a genetic variant in the exon 24 of the KCNT1 gene was found. This led to the diagnosis of EIMFS. Due to antiepileptic treatment failed to control seizures, QND a KCNT1 blocker, was introduced as a therapeutic alternative besides topiramate (200 mg/day) and nitrazepam (2 mg/day). Therapeutic drug monitoring (TDM) of QND plasma levels needed to be implemented to establish individual therapeutic range and avoid toxicity. TDM for dose adjustment was performed to establish the individual therapeutic range of the patient. Seizures were under control with QND levels above 1.5 mcg/ml (65-70 mg/kg q. i.d). In addition, QND levels higher than 4.0 mcg/ml, were related to higher risk of suffering arrhythmia due to prolongation of QT segment. Despite initial intention to withdrawal topiramate completely, QND was no longer effective by itself and failed to maintain seizures control. Due to this necessary interaction between quinidine and topiramate, topiramate was stablished in a maintenance dose of 40 mg/day. Conclusion: The implementation of Precision Medicine by using tools such as Next Generation Sequencing and TDM led to diagnose and select a targeted therapy for the treatment of a KCNT1-related epilepsy in a patient presented with EIMFS in early infancy and poor response to antiepileptic drugs. QND an old antiarrhythmic drug, due to its activity as KCNT1 channel blocker, associated to topiramate resulted in seizures control. Due to high variability observed in QND levels, TDM and pharmacokinetic characterization allowed to optimize drug regimen to maintain QND concentration between the individual therapeutic range and diminish toxicity.

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma.

BACKGROUND: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. PATIENTS AND METHODS: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. RESULTS: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n = 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n = 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n = 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group. CONCLUSIONS: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC.

INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/ß-catenin signaling in breast cancer.

INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P2 to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-mutant ER+ breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA-mutant ER+ breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P2 to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3ß lysosomal degradation and activation of Wnt/ß-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER+ breast cancer via PI(3,4)P2 to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/ß-catenin therapies.

Strategies to load therapeutics into polysaccharide-based nanogels with a focus on microfluidics: A review.

Nowadays nanoparticles are increasingly investigated for the targeted and controlled delivery of therapeutics, as suggested by the high number of research articles (2400 in 2000 vs 8500 in 2020). Among them, almost 2% investigated nanogels in 2020. Nanogels or nanohydrogels (NGs) are nanoparticles formed by a swollen three-dimensional network of synthetic polymers or natural macromolecules such as polysaccharides. NGs represent a highly versatile nanocarrier, able to deliver a number of therapeutics. Currently, NGs are undergoing clinical trials for the delivery of anti-cancer vaccines. Herein, the strategies to load low molecular weight drugs, (poly)peptides and genetic material into polysaccharide NGs as well as to formulate NGs-based vaccines are summarized, with a focus on the microfluidics approach.

Integrative Imaging Reveals SARS-CoV-2-Induced Reshaping of Subcellular Morphologies.

Pathogenesis induced by SARS-CoV-2 is thought to result from both an inflammation-dominated cytokine response and virus-induced cell perturbation causing cell death. Here, we employ an integrative imaging analysis to determine morphological organelle alterations induced in SARS-CoV-2-infected human lung epithelial cells. We report 3D electron microscopy reconstructions of whole cells and subcellular compartments, revealing extensive fragmentation of the Golgi apparatus, alteration of the mitochondrial network and recruitment of peroxisomes to viral replication organelles formed by clusters of double-membrane vesicles (DMVs). These are tethered to the endoplasmic reticulum, providing insights into DMV biogenesis and spatial coordination of SARS-CoV-2 replication. Live cell imaging combined with an infection sensor reveals profound remodeling of cytoskeleton elements. Pharmacological inhibition of their dynamics suppresses SARS-CoV-2 replication. We thus report insights into virus-induced cytopathic effects and provide alongside a comprehensive publicly available repository of 3D datasets of SARS-CoV-2-infected cells for download and smooth online visualization.

Frontline treatment with the combination obinutuzumab ± chlorambucil for chronic lymphocytic leukemia outside clinical trials: Results of a multinational, multicenter study by ERIC and the Israeli CLL study group.

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O ± Clb in unfit patients with CLL, in a "real-world" setting. Patients with documented del (17p13.1)/TP53 mutation were excluded. A total of 437 patients (median age, 75.9 years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min) were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95% CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del (11q22.3) and/or IGHV-unmutated], lymph nodes of diameter > 5 cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a "real-world" setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del (11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease.

Feasibility of a tailored ERAS programme in octogenarian patients undergoing minimally invasive surgery for colorectal cancer.

BACKGROUND: The enhanced recovery after surgery (ERAS) is nowadays a widely accepted multimodal programme of care in colorectal surgery, but still there is some reluctance in its application to very elderly patients. AIM: The aim of this study is to investigate short-term outcomes of laparoscopic resection for colorectal cancer in octogenarian patients within the ERAS programme. METHODS: Data on 162 consecutive patients aged ≥ 80 years receiving elective minimally invasive colorectal resections within ERAS programme were collected in a multicentre, retrospective database in the period 2008-2017 in Italy. Univariate and multivariate analyses were performed to assess possible risk factors for poor clinical outcomes. RESULTS: The postoperative minor morbidity rate (Clavien-Dindo 1 and 2) was 25.9%. The incidence of postoperative major morbidity rate (severe medical and surgical complications defined as Clavien-Dindo 3 and 4) accounted 6.1% and only 1.8% had an anastomotic leakage. Reoperation rate was 5.5%, perioperative 30-day mortality was 1.8%, and 30-day readmission rate was 6.8%. On average, patients were released after 6 days. A univariate analysis showed that possible risk factors for severe medical complications were: low preoperative albumin level, high Charlson Age Comorbidity Index Score and number of days in the intensive care unit (ICU); risk factors for severe surgical complications were: low preoperative albumin level; risk factors for late hospital discharge were: multivisceral resections, number of days in ICU and body mass index (BMI) > 25 kg/m2. The multivariate analysis confirmed a low level of preoperative albumin and a longer ICU stay as independent risk factors for both postoperative severe surgical complications and late hospital discharge. DISCUSSION: The minimal invasive nature of the laparoscopic approach together with a multimodal analgesia therapy, the early resumption to oral diet and mobilisation could minimize the surgical stress and play an essential role in order to reduce medical morbidity in high-risk patients. CONCLUSION: Colorectal surgery within ERAS programme in octogenarians is a safe and flexible treatment in high-volume centres.

Histamine-mediated potentiation of transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 signaling in submucosal neurons in patients with irritable bowel syndrome.

Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with irritable bowel syndrome (IBS). Sensitization of TRP ankyrin 1 (TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with IBS. Rectal biopsies were collected from patients with IBS and healthy subjects (HS) to study neuronal sensitivity to TRPA1 and TRPV4 agonists (cinnamaldehyde and GSK1016790A) using intracellular Ca2+ imaging. In addition, the effect of supernatants of rectal biopsies on patients with IBS and HS was assessed on TRPA1 and TRPV4 responses in murine dorsal root ganglion (DRG) sensory neurons. Finally, we evaluated the role of histamine and histamine 1 receptor (H1R) in TRPA1 and TRPV4 sensitization. Application of TRPA1 and TRPV4 agonists evoked significantly higher peak amplitudes and percentage of responding submucosal neurons in biopsies of patients with IBS compared with HS. In HS, pretreatment with histamine significantly increased the Ca2+ responses to cinnamaldehyde and GSK1016790A, an effect prevented by H1R antagonism. IBS supernatants, but not of HS, sensitized TRPA1 and TRPV4 on DRG neurons. This effect was reproduced by histamine and prevented by H1R antagonism. We demonstrate that the mucosal microenvironment in IBS contains mediators, such as histamine, which sensitize TRPV4 and TRPA1 via H1R activation, most likely contributing to increased visceral pain perception in IBS. These data further underscore H1R antagonism as potential treatment for IBS. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 sensitization in irritable bowel syndrome (IBS) via histamine 1 receptor (H1R) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of IBS and provide novel mechanistic insights into the therapeutic potential of H1R antagonism in IBS.

Paradoxical embolism with thrombus stuck in a patent foramen ovale: a review of treatment strategies.

OBJECTIVE: Paradoxical embolism represents a rare condition occurring when a thrombus originating from venous system produces pulmonary embolism and systemic embolization through an intracardiac or pulmonary shunt. The evidence of a thrombus entrapped in a patent foramen ovale (PFO) is an even more rare condition. There is uncertainty about the optimal treatment strategy. PATIENTS AND METHODS: A 58-year-old male patient was admitted to our Internal Medicine Unit with the diagnosis of bilateral bronchopneumonia. During hospitalization, the co-occurrence of chest pain and amaurosis led us to hypothesize a paradoxical embolism. RESULTS: Transthoracic echocardiography showed the presence of a thrombus stuck over the interatrial septum. A contrast-enhanced chest CT scan showed multiple pulmonary embolisms and brain CT scan documented a hypodense area, of ischemic significance, in the left occipital lobe near tentorium. In order to prevent further embolization, emergency cardiac surgery (right atriotomy, removal of thrombus and closure of the PFO, pulmonary thrombectomy) was performed without complications. CONCLUSIONS: Although rare, the evidence of a thrombus stuck in a patent foramen ovale represents a clinical emergency. The optimal therapeutic approach is still debated. The surgical correction seems to be a safe and effective option for these patients.

Variation in the isotopic composition of striped weakfish Cynoscion guatucupa of the Southwest Atlantic Ocean in response to dietary shifts / Variação na composição isotópica do Cynoscion guatucupa no Oceano Atlântico Sul

Abstract The aim of this study was to analyze the isotopic composition in muscle of striped weakfish Cynoscion guatucupa from Southwest Atlantic Ocean in order to evaluate a possible variation in δ13C and δ15N in response to dietary shifts that occur as animals grow. We also explored for isotopic evidence of differences between sample locations. The results showed an agreement between isotope analysis and previous conventional studies. Differences in the isotope composition between sampling location were not observed. A positive relation exists between isotope values and total body length of the animals. The Cluster analysis defined three groups of size classes, validated by the MDS. Differences in the relative consumption of prey species in each size class were also observed performing isotope mixing models (SIAR). Variation in δ15N among size classes would be associated with the consumption of a different type of prey as animals grow. Small striped weakfish feed on small crustaceans and progressively increase their consumption of fish (anchovy, Engraulis anchoita), increasing by this way their isotope values. On the other hand, differences in δ13C values seemed to be related to age-class specific spatial distribution patterns. Therefore, large and small striped weakfish remain specialized but feeding on different prey at different trophic levels. These results contribute to the study of the diet of striped weakfish, improve the isotopic ecology models and highlight on the importance of accounting for variation in the isotopic composition in response to dietary shifts with the size of one of the most important fishery resources in the region.

Resumo O objetivo deste estudo foi analisar a composição isotópica no músculo de Cynoscion guatucupa no Oceano Atlântico Sul Ocidental, a fim de avaliar uma possível variação de δ13C e δ15N como resposta às mudanças ontogenéticas na dieta. Foram também exploradas evidências isotópicas de diferenças entre os locais de amostragem. Os resultados mostraram uma concordância entre a análise de isótopos e os estudos convencionais prévios. Diferenças na composição isotópica entre locais de amostragem não foram observadas. Uma relação positiva existe entre valores isotópicos e comprimento total dos animais. A análise de cluster definiu três grupos de classes de tamanho, validados pelo MDS. Foram também observadas, através de modelos isotópicos mistos (SIAR), diferenças no consumo relativo de espécies de presas para cada classe de tamanho. Variações em δ15N entre as classes de tamanho estariam associadas ao consumo de diferentes tipos de presas ao longo do crescimento dos animais. Indivíduos pequenos alimentam-se de pequenos crustáceos e progressivamente aumentam seu consumo de peixes (Engraulis anchoita), aumentando assim os seus valores isotópicos. Por outro lado, as diferenças nos valores de δ13C parecem estar relacionadas com variações no padrão de distribuição espacial específico de cada classe idade. Desta maneira, tanto C. guatucupa grandes como pequenos permanecem especializados, porém alimentando-se de presas diferentes, em diferentes níveis tróficos e em diferentes áreas. Estes resultados contribuem para o estudo da dieta de C. guatucupa, melhoram os modelos de ecologia isotópica e ressaltam a importância de se considerar a variação na composição isotópica na resposta às mudanças de dieta relacionadas ao tamanho de um dos principais recursos pesqueiros da região.

OR2H2 regulates the differentiation of human myoblast cells by its ligand aldehyde 13-13.

Olfactory receptors (ORs) regulate various cellular processes in the human body. The receptors' participation in physiological and pathophysiological processes could be demonstrated in several studies. In addition to the regulation of sperm motility, respiratory physiology, and heart contraction, ORs play a crucial role in cancer cells. In murine myoblasts, mOR23 regulates the myogenesis and branching of skeletal muscle cells. To date, the expression and physiological role of ORs in human skeletal muscle cells have not been thoroughly elucidated. We demonstrate that four different ORs are expressed at the transcript level in differentiated myoblasts, and one other OR is expressed in undifferentiated myoblasts. Moreover, we characterized the expression of OR2H2 in differentiated human myoblasts and identified a specific ligand, aldehyde 13-13. We could observe a concentration-dependent Ca2+ increase in differentiated human myoblasts upon aldehyde 13-13 stimulation, which is mediated by PI3K signaling. Aldehyde 13-13 has a reducing effect on myoblast fusion. We conclude that OR2H2 could have a regulatory role in myoblast differentiation. To the best of our knowledge, this report presents the first verification of the expression of ORs in human myoblasts. OR2H2 might be an interesting candidate for playing a role in the complex mechanism of myogenesis.

Variation in the isotopic composition of striped weakfish Cynoscion guatucupa of the Southwest Atlantic Ocean in response to dietary shifts.

The aim of this study was to analyze the isotopic composition in muscle of striped weakfish Cynoscion guatucupa from Southwest Atlantic Ocean in order to evaluate a possible variation in δ13C and δ15N in response to dietary shifts that occur as animals grow. We also explored for isotopic evidence of differences between sample locations. The results showed an agreement between isotope analysis and previous conventional studies. Differences in the isotope composition between sampling location were not observed. A positive relation exists between isotope values and total body length of the animals. The Cluster analysis defined three groups of size classes, validated by the MDS. Differences in the relative consumption of prey species in each size class were also observed performing isotope mixing models (SIAR). Variation in δ15N among size classes would be associated with the consumption of a different type of prey as animals grow. Small striped weakfish feed on small crustaceans and progressively increase their consumption of fish (anchovy, Engraulis anchoita), increasing by this way their isotope values. On the other hand, differences in δ13C values seemed to be related to age-class specific spatial distribution patterns. Therefore, large and small striped weakfish remain specialized but feeding on different prey at different trophic levels. These results contribute to the study of the diet of striped weakfish, improve the isotopic ecology models and highlight on the importance of accounting for variation in the isotopic composition in response to dietary shifts with the size of one of the most important fishery resources in the region.

Faecal microRNAs: indicators of imbalance at the host-microbe interface?

The enteric microbiota is characterised by a balance and composition that is unique to the host. It is important to understand the mechanisms through which the host can maintain the composition of the gut microbiota. MicroRNAs (miRNA) are implicated in intercellular communication and have been isolated from bodily fluids including stool. Recent findings suggest that miRNA produced by the host's intestinal epithelial cells (IECs) participate in shaping the microbiota. To investigate whether miRNA expression was influenced by the gut microbiota we measured the expression of miRNAs expressed by intestinal epithelial cells in faeces. Specifically, we measured miRNA expression in faeces from germ-free (GF) and conventional mice and similarly in a rat model of antibiotic-mediated depletion of the gut microbiota control rats. In adult male GF and conventional mice and adult Sprague Dawley (SD) rats were treated with a combination of antibiotics for 8 weeks; total RNA was extracted from faecal pellets taken at week 0, 2, 4, 6 week 8 and the expression of let-7b-3p, miR-141-3p, miR-200a-3p and miR-1224-5p (miRNAs known to be expressed in IECs) were measured relative to U6 at each time point using qRT-PCR. In GF animals the expression of let-7b, miR-141 and miR-200a in faeces was lower compared to conventional mice. Following antibiotic-mediated depletion of gut microbiota, rats showed two divergent profiles of miRNA expression. Following two weeks of antibiotic treatment, the expression of let-7b and miR-1224 dropped significantly and remained low for the remainder of the study. The expression of miR-200a and miR-141 was significantly higher at week 2 than before antibiotic treatment commenced. Subsequently, the expression of miR-200a and miR-141 decreased at week 4 and continued to decrease at week 6. This data demonstrates that miRNAs can be used as an independent, non-invasive marker of microbial fluctuations along with gut pathology in the intestine.

MECOM, HBS1L-MYB, THRB-RARB, JAK2, and TERT polymorphisms defining the genetic predisposition to myeloproliferative neoplasms: A study on 939 patients.

Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classical myeloproliferative neoplasms (MPN), characterized by specific somatic mutations in JAK2, CALR or MPL genes. JAK2 46/1 and TERT rs2736100 polymorphisms are known to significantly predispose to MPN. This study aimed to establish the additional contribution of the recently described MECOM rs2201862, HBS1L-MYB rs9376092 and THRB-RARB rs4858647 polymorphisms to the occurrence of MPN. These three polymorphisms, along with JAK2 46/1 and TERT rs2736100 were genotyped in 939 MPN patients (454 with ET, 337 with PV and 148 with PMF) and 483 controls. MECOM rs2201862 associated significantly with each MPN entity, except for ET, and with all major molecular sub-types, especially those CALR-mutated (OR = 1.4; 95% CI = 1.1-1.8; P-value = .005). HBS1L-MYB rs9376092 associated only with JAK2 V617F-mutated ET (OR = 1.4; 95% CI = 1.1-1.7; P-value = .003). THRB-RARB rs4858647 had a weak association with PMF only (OR = 1.5; 95% CI = 1-2.1; P-value = .04). Surprisingly, JAK2 46/1 haplotype was associated significantly not only with JAK2 V617F-mutated MPN, but also with CALR-mutated MPN (OR = 1.4; 95% CI = 1.1-1.8; P-value = .01). TERT rs2736100 was associated equally strong with all MPN, regardless of phenotype or molecular sub-type. In conclusion, JAK2 46/1, TERT rs2736100 and MECOM rs2201862 are the chief predisposing polymorphisms to MPN.

Variation in the isotopic composition of striped weakfish Cynoscion guatucupa of the Southwest Atlantic Ocean in response to dietary shifts

Abstract The aim of this study was to analyze the isotopic composition in muscle of striped weakfish Cynoscion guatucupa from Southwest Atlantic Ocean in order to evaluate a possible variation in 13C and 15N in response to dietary shifts that occur as animals grow. We also explored for isotopic evidence of differences between sample locations. The results showed an agreement between isotope analysis and previous conventional studies. Differences in the isotope composition between sampling location were not observed. A positive relation exists between isotope values and total body length of the animals. The Cluster analysis defined three groups of size classes, validated by the MDS. Differences in the relative consumption of prey species in each size class were also observed performing isotope mixing models (SIAR). Variation in 15N among size classes would be associated with the consumption of a different type of prey as animals grow. Small striped weakfish feed on small crustaceans and progressively increase their consumption of fish (anchovy, Engraulis anchoita), increasing by this way their isotope values. On the other hand, differences in 13C values seemed to be related to age-class specific spatial distribution patterns. Therefore, large and small striped weakfish remain specialized but feeding on different prey at different trophic levels. These results contribute to the study of the diet of striped weakfish, improve the isotopic ecology models and highlight on the importance of accounting for variation in the isotopic composition in response to dietary shifts with the size of one of the most important fishery resources in the region.

Resumo O objetivo deste estudo foi analisar a composição isotópica no músculo de Cynoscion guatucupa no Oceano Atlântico Sul Ocidental, a fim de avaliar uma possível variação de 13C e 15N como resposta às mudanças ontogenéticas na dieta. Foram também exploradas evidências isotópicas de diferenças entre os locais de amostragem. Os resultados mostraram uma concordância entre a análise de isótopos e os estudos convencionais prévios. Diferenças na composição isotópica entre locais de amostragem não foram observadas. Uma relação positiva existe entre valores isotópicos e comprimento total dos animais. A análise de cluster definiu três grupos de classes de tamanho, validados pelo MDS. Foram também observadas, através de modelos isotópicos mistos (SIAR), diferenças no consumo relativo de espécies de presas para cada classe de tamanho. Variações em 15N entre as classes de tamanho estariam associadas ao consumo de diferentes tipos de presas ao longo do crescimento dos animais. Indivíduos pequenos alimentam-se de pequenos crustáceos e progressivamente aumentam seu consumo de peixes (Engraulis anchoita), aumentando assim os seus valores isotópicos. Por outro lado, as diferenças nos valores de 13C parecem estar relacionadas com variações no padrão de distribuição espacial específico de cada classe idade. Desta maneira, tanto C. guatucupa grandes como pequenos permanecem especializados, porém alimentando-se de presas diferentes, em diferentes níveis tróficos e em diferentes áreas. Estes resultados contribuem para o estudo da dieta de C. guatucupa, melhoram os modelos de ecologia isotópica e ressaltam a importância de se considerar a variação na composição isotópica na resposta às mudanças de dieta relacionadas ao tamanho de um dos principais recursos pesqueiros da região.

Spatial Models of Abundance and Habitat Preferences of Commerson's and Peale's Dolphin in Southern Patagonian Waters.

Commerson's dolphins (Cephalorhynchus c. commersonii) and Peale's dolphins (Lagenorhynchus australis) are two of the most common species of cetaceans in the coastal waters of southwest South Atlantic Ocean. Both species are listed as Data Deficient by the IUCN, mainly due to the lack of information about population sizes and trends. The goal of this study was to build spatially explicit models for the abundance of both species in relation to environmental variables using data collected during eight scientific cruises along the Patagonian shelf. Spatial models were constructed using generalized additive models. In total, 88 schools (212 individuals) of Commerson's dolphin and 134 schools (465 individuals) of Peale's dolphin were recorded in 8,535 km surveyed. Commerson's dolphin was found less than 60 km from shore; whereas Peale's dolphins occurred over a wider range of distances from the coast, the number of animals sighted usually being larger near or far from the coast. Fitted models indicate overall abundances of approximately 22,000 Commerson's dolphins and 20,000 Peale's dolphins in the total area studied. This work provides the first large-scale abundance estimate for Peale's dolphin in the Atlantic Ocean and an update of population size for Commerson's dolphin. Additionally, our results contribute to baseline data on suitable habitat conditions for both species in southern Patagonia, which is essential for the implementation of adequate conservation measures.