bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic review: psychosocial factors associated with pain in inflammatory bowel disease
Authors: Sweeney L. , Moss‐Morris R. , Czuber‐Dochan W. , Meade L. , Chumbley G. , Norton C.
Published: January 2018

Background

Pain is a frequently reported symptom of inflammatory bowel disease (IBD) experienced by patients in active disease and remission. Psychological factors play a significant role in pain, but have not been systematically reviewed in IBD.

Aim

To review psychosocial factors associated with pain in adults diagnosed with IBD.

Methods

Electronic (PsycInfo, MEDLINE, EMBASE, Cochrane Library, CINAHL, Web of Science), and hand‐searching were conducted February‐May 2017. Two authors carried out screening and data extraction.

Results

Fifteen studies including 5539 IBD patients were identified. Emotional, cognitive‐behavioural and personality factors were associated with IBD‐pain. Depression and anxiety were the most commonly explored constructs, followed by perceived stress and pain catastrophising, all of which were positively associated with greater pain. Greater abdominal pain was associated with a concurrent mood disorder over fivefold (OR 5.76, 95% CI 1.39, 23.89). Coping strategies and pain fear avoidance correlated with pain levels. Perceived social support (r = .26) and internal locus of control (r = .33) correlated with less pain. Patients reporting pain in IBD remission more frequently had an existing diagnosis of a mood disorder, a chronic pain disorder and irritable bowel syndrome. Six studies controlled for disease activity, of which 4 found that psychosocial factors significantly predicted pain. The majority of studies (n = 10) were of high quality.

Conclusion

Psychosocial factors appear to play a significant role in IBD‐pain. Further research is required to explore psychosocial constructs in relation to IBD‐pain, with use of validated pain measures, large sample sizes and clearer characterisation of disease activity.
Review article: long‐term safety of oral anti‐viral treatment for chronic hepatitis B
Authors: Wong G. L.‐H. , Seto W.‐K. , Wong V. W.‐S. , Yuen M.‐F. , Chan H. L.‐Y.
Published: January 2018

Background

Safety profile of nucleos(t)ide analogues is an important issue in view of its widespread use for decades in patients with chronic hepatitis B (CHB).

Aim

To review and evaluate the latest evidence on the safety profiles of the six approved nucleoside analogues.

Methods

Relevant articles related to nucleoside analogue safety were selected for review following extensive language‐ and date‐unrestricted, electronic searches of the literature.

Results

Nephrotoxicity has been well reported in patients receiving older generations of nucleotide analogues, namely adefovir dipivoxil and tenofovir disoproxil fumarate (TDF). Yet risks of renal failure and renal replacement therapy were similar in patients treated with nucleoside analogues versus nucleotide analogues in real‐life setting. Bone toxicity is closely related to nucleoside analogue effect on renal proximal tubular and phosphaturia. Real‐life data demonstrated increased risk of hip fracture in patients receiving adefovir but not TDF. The newly approved tenofovir alafenamide (TAF) has improved renal and bone safety profiles compared to TDF. Long‐term use of nucleoside analogues eg entecavir does not increase the risk of other cancers. Muscular toxicity may be seen in telbivudine‐treated patients so regular monitoring is advised. Peripheral neuropathy and lactic acidosis are rare adverse events. Latest international guidelines support the use of TDF, telbivudine and lamivudine during pregnancy; breastfeeding is not contraindicated during TDF therapy.

Conclusions

Long‐term safety profile of nucleoside analogues is now better defined with more data from large real‐life cohorts and clinical trials with long‐term follow‐up. The new nucleotide analogue, TAF is now available with favourable renal and bone safety profiles.
A Utility-Based Design for Randomized Comparative Trials with Ordinal Outcomes and Prognostic Subgroups
Authors: Murray Thomas A. , Yuan Ying , Thall Peter F. , Elizondo Joan H. , Hofstetter Wayne L.
Published: January 2018

A design is proposed for randomized comparative trials with ordinal outcomes and prognostic subgroups. The design accounts for patient heterogeneity by allowing possibly different comparative conclusions within subgroups. The comparative testing criterion is based on utilities for the levels of the ordinal outcome and a Bayesian probability model. Designs based on two alternative models that include treatment-subgroup interactions are considered, the proportional odds model and a non-proportional odds model with a hierarchical prior that shrinks toward the proportional odds model. A third design that assumes homogeneity and ignores possible treatment-subgroup interactions also is considered. The three approaches are applied to construct group sequential designs for a trial of nutritional prehabilitation versus standard of care for esophageal cancer patients undergoing chemoradiation and surgery, including both untreated patients and salvage patients whose disease has recurred following previous therapy. A simulation study is presented that compares the three designs, including evaluation of within-subgroup type I and II error probabilities under a variety of scenarios including different combinations of treatment-subgroup interactions.
PDCD1 and CTLA4 polymorphisms affect the susceptibility to, and clinical features of, chronic immune thrombocytopenia
Authors: Kasamatsu Tetsuhiro , Ino Rumi , Takahashi Noriyuki , Gotoh Nanami , Minato Yusuke , Takizawa Makiko , Yokohama Akihiko , Handa Hiroshi , Saitoh Takayuki , Tsukamoto Norifumi , Murakami Hirokazu
Published: January 2018

Programmed death‐1 (PD‐1, PDCD1) and cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4, CTLA4) play central roles in immune checkpoint pathways. Single nucleotide polymorphisms (SNPs) of PDCD1 and CTLA4 have been reported to be associated with susceptibility to some autoimmune diseases. However, the potential association between SNPs in these immune checkpoint genes and risk of chronic immune thrombocytopenia (cITP) remain controversial and obscure. The aims of this study were to clarify the influence of PDCD1 and CTLA4 SNPs on the risk of developing cITP and its clinical features. We obtained genomic DNA from 119 patients with cITP and 223 healthy controls; their genotypes were determined by the polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method. Patients with cITP had a significantly higher frequency of the PDCD1 +7209 TT genotype compared with healthy controls. The CTLA4 −1577 GG genotype and CT60 GG genotype showed higher frequencies of platelet count <5 × 109/l at diagnosis, minimum platelet count <5 × 109/l, and bleeding symptoms. Moreover, the PDCD1 −606 AA genotype and +63379 TT genotype were significantly associated with a lower number of patients who achieved a complete response to prednisolone treatment. Our results suggest that the immune checkpoint polymorphisms may affect the susceptibility to the clinical features of cITP, and treatment response of the affected patients.
Pre‐ and post‐transplant minimal residual disease predicts relapse occurrence in children with acute lymphoblastic leukaemia
Authors: Lovisa Federica , Zecca Marco , Rossi Bartolomeo , Campeggio Mimma , Magrin Elisa , Giarin Emanuela , Buldini Barbara , Songia Simona , Cazzaniga Giovanni , Mina Tommaso , Acquafredda Gloria , Quarello Paola , Locatelli Franco , Fagioli Franca , Basso Giuseppe
Published: January 2018

Relapse remains the leading cause of treatment failure in children with acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem cell transplantation (HSCT). We retrospectively investigated the prognostic role of minimal residual disease (MRD) before and after HSCT in 119 children transplanted in complete remission (CR). MRD was measured by polymerase chain reaction in bone marrow samples collected pre‐HSCT and during the first and third trimesters after HSCT (post‐HSCT1 and post‐HSCT3). The overall event‐free survival (EFS) was 50%. The cumulative incidence of relapse and non‐relapse mortality was 41% and 9%. Any degree of detectable pre‐HSCT MRD was associated with poor outcome: EFS was 39% and 18% in patients with MRD positivity <1 × 10−3 and ≥1 × 10−3, respectively, versus 73% in MRD‐negative patients (P < 0·001). This effect was maintained in different disease remissions, but low‐level MRD had a very strong negative impact only in patients transplanted in second or further CR. Also, MRD after HSCT enabled patients to be stratified, with increasing MRD between post‐HSCT1 and post‐HSCT3 clearly defining cohorts with a different outcome. MRD is an important prognostic factor both before and after transplantation. Given that MRD persistence after HSCT is associated with dismal outcome, these patients could benefit from early discontinuation of immunosuppression, or pre‐emptive immuno‐therapy.
Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects
Authors: Hershkovitz‐Rokah Oshrat , Pulver Dana , Lenz Georg , Shpilberg Ofer
Published: January 2018

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder comprising about 6–10% of all B cell lymphoma cases. Ibrutinib is an inhibitor of Bruton tyrosine kinase (BTK), a key component of early B‐cell receptor (BCR) signalling pathways. Although treatment with ibrutinib has significantly improved the outcome of MCL patients, approximately one‐third of the patients have primary drug resistance while others appear to develop acquired resistance. Understanding the molecular events leading to the primary and acquired resistance to ibrutinib is essential for achieving better outcomes in patients with MCL. In this review, we describe the biology of the BCR signalling pathway and summarize the landmark clinical trials that have led to the approval of ibrutinib. We review the molecular mechanisms underlying primary and acquired ibrutinib resistance as well as recent studies dealing with overcoming ibrutinib resistance.
From Dualism to Dynamism: Fairbairn's Critique of Libido Theory 1930–1950
Authors: Forbes‐Pitt Kate
Published: January 2018

In 1930 Fairbairn wrote ‘Libido theory re‐evaluated’, which remained unpublished until 1994. It contains the beginnings of theoretical arguments that, I argue, resulted in his more famous 1940s papers. I posit that Fairbairn's critique of Freud's analytical dualist theoretical foundation is consistent with, and lays the ground for, his later work. Using the papers ‘Schizoid factors in the personality’ (1940), ‘The repression and return of bad objects’ (1943), ‘Endopsychic structure considered in terms of object‐relationships’ (1944), and ‘Object‐relationships and dynamic structure’ (1946), I show how Fairbairn's critique is relevant to his later propositions and elucidate Fairbairn's metatheoretical assumptions, about which he was not explicit after 1930. I argue that his theoretical propositions arise as a result of his longstanding, consistent critique that led him to replace analytical dualism with dynamical structure. Further, I argue that Klein, and Khan and Winnicott's criticism is unjustified; Fairbairn did not challenge the content of a theory he describes as ‘truths of fundamental importance’, he challenged its theorization. Because it resulted in his important theoretical propositions, Fairbairn's longstanding critique of libido theory is important within the history of psychoanalytic thought and deserves scholarly attention.
External validation of the prostascore model in patients with metastatic hormone‐sensitive prostate cancer recruited to the CHAARTED study
Authors: Abdel‐Rahman Omar , Cheung Winson Y.
Published: January 2018

Objective

To externally validate ‘prostascore’ in patients with metastatic hormone‐sensitive prostate cancer recruited to the phase III CHAARTED study.

Methods

We conducted a retrospective analysis of the prospectively collected data from patients with metastatic hormone‐sensitive prostate cancer in the CHAARTED study, a phase III multicentre study conducted between 2006 and 2014. The main outcome of the present analysis was overall survival, assessed using Kaplan–Meier analysis or log‐rank testing, in the whole cohort according to different prostascores. In addition, patients with different scores were compared according to treatment arm.

Results

A total of 702 cases had complete baseline data, allowing calculation of prostascores and inclusion in the present analysis. Overall survival was assessed according to prostascores in the entire cohort and the P value for overall survival trend was significant (P < 0.001). Likewise, progression‐free survival was assessed according to prostascores in the entire cohort and the P value for progression‐free survival trend was also significant (P < 0.001). Overall survival comparisons according to treatment arm were evaluated among different prostascores. Notably, the P value for overall survival difference was not significant for a prostascore = 2 (P = 0.702), but was significant for scores of 3, 4 and 5 (P < 0.05). The cause‐specific hazard ratio for cancer‐specific survival (adjusted for treatment arm used) was also evaluated. The P value for pairwise comparisons between different scores was significant (P < 0.01) except for the comparison between scores 4 and 5.

Conclusion

The present study further confirms the role of prostascore in predicting the outcomes of patients with metastatic hormone‐sensitive prostate cancer and also highlights its potential role in therapeutic decision‐making.
Robot‐assisted partial nephrectomy for large renal masses: a multi‐institutional series
Authors: Delto Joan C. , Paulucci David , Helbig Michael W. , Badani Ketan K. , Eun Daniel , Porter James , Abaza Ronney , Hemal Ashok K. , Bhandari Akshay
Published: January 2018

Objectives

To compare peri‐operative outcomes after robot‐assisted partial nephrectomy (RAPN) for cT2a (7 to <10 cm) to cT1 tumours.

Materials and Methods

Patients with a cT1a (n = 1 358, 76.4%), cT1b (n = 379, 21.3%) or cT2a (n = 41, 2.3%) renal mass were identified from a multi‐institutional RAPN database. Intra‐ and postoperative outcomes were compared for cT2a masses vs cT1a and cT1b masses using multivariable regression models (linear, logistic, Poisson etc.), adjusting for operating surgeon and a modified R.E.N.A.L. nephrometry score that excluded the radius component.

Results

The median sizes for cT1a, cT1b and cT2a tumours were 2.5, 5.0 and 8.0 cm, respectively (P < 0.001) with modified R.E.N.A.L. nephrometry scores being 6.0, 6.5 and 7.0, respectively (cT1a, P < 0.001; cT1b, P = 0.105). RAPN for cT2a vs cT1a masses was associated with a 12% increase in operating time (P < 0.001), a 32% increase in estimated blood loss (P < 0.001), a 7% increase in ischaemia time (P = 0.008), a 3.93 higher odds of acute kidney injury at discharge (95% confidence interval [CI] 1.33, 8.76; P = 0.009) and a higher risk of recurrence (hazard ratio [HR] 10.9, 95% CI 1.31, 92.2; P = 0.027). RAPN for cT2a vs cT1b masses was associated with a 12% increase in blood loss (P = 0.036), a 5% increase in operating time (P = 0.062) and a marginally higher risk of recurrence (HR 11.2, 95% CI 0.77, 11.5; P = 0.059). RAPN for cT2a tumours was not associated with differences in complications (cT1a, P = 0.535; cT1b, P = 0.382), positive margins (cT1a, P = 0.972; cT1b, P = 0.681), length of stay (cT1a, P = 0.507; cT1b, P = 0.513) or renal function decline up to 24 months post‐RAPN (cT1a, P = 0.124; cT1b, P = 0.467).

Conclusion

For T2a tumours RAPN is a feasible treatment option in a select patient population when performed by experienced surgeons in institutions equipped to manage postoperative complications. Although RAPN was associated with greater blood loss and longer operating and ischaemia time in T2a tumours, it was not associated with greater complication or positive surgical margin rates compared with T1 tumours. Renal function preservation rates were equivalent for up to 24 months postoperatively; however, 12‐month recurrence‐free survival was significantly lower in the T2a group. Extended follow‐up is required to further evaluate long‐term survival.
Open radical cystectomy in England: the current standard of care – an analysis of the British Association of Urological Surgeons (BAUS) cystectomy audit and Hospital Episodes Statistics (HES) data
Authors: Jefferies Edward R. , Cresswell Joanne , McGrath John S. , Miller Catherine , Hounsome Luke , Fowler Sarah , Rowe Edward W. ,   BAUS Section on Oncology
Published: January 2018

Objective

To establish the current standard for open radical cystectomy (ORC) in England, as data entry by surgeons performing RC to the British Association of Urological Surgeons (BAUS) database was mandated in 2013 and combining this with Hospital Episodes Statistics (HES) data has allowed comprehensive outcome analysis for the first time.

Patients and Methods

All patients were included in this analysis if they were uploaded to the BAUS data registry and reported to have been performed in the 2 years between 1 January 2014 and 31 December 2015 in England (from mandate onwards) and had been documented as being performed in an open fashion (not laparoscopic, robot assisted or the technique field left blank). The HES data were accessed via the HES website. Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures version 4 (OPCS‐4) Code M34 was searched during the same 2‐year time frame (not including M34.4 for simple cystectomy or with additional minimal access codes Y75.1‐9 documenting a laparoscopic or robotic approach was used) to assess data capture.

Results

A total of 2 537 ORCs were recorded in the BAUS registry and 3 043 in the HES data. This indicates a capture rate of 83.4% of all cases. The median operative time was 5 h, harvesting a median of 11–20 lymph nodes, with a median blood loss of 500–1 000 mL, and a transfusion rate of 21.8%. The median length of stay was 11 days, with a 30‐day mortality rate of 1.58%.

Conclusions

This is the largest, contemporary cohort of ORCs in England, encompassing >80% of all performed operations. We now know the current standard for ORC in England. This provides the basis for individual surgeons and units to compare their outcomes and a standard with which future techniques and modifications can be compared.
A clinician‐centred programme for behaviour change in the optimal use of staging investigations for newly diagnosed prostate cancer
Authors: Rutledge Alison B. , McLeod Nicholas , Mehan Nicholas , Regan Timothy W. , Ainsworth Paul , Chong Peter , Doyle Terrence , White Martin , Sanson‐Fisher Rob W. , Martin Jarad M.
Published: January 2018

Objectives

To improve imaging utilisation and reduce the widespread overuse of staging investigations, in the form of computed tomography (CT) and whole‐body bone scans for men with newly diagnosed prostate cancer in the Hunter region of NSW, Australia, by implementation of a multifaceted clinician‐centred behaviour change programme.

Patients and Methods

Records of all patients with a new diagnosis of prostate cancer were reviewed prior to the intervention (July 2014 to July 2015), and the results of this audit were presented to participating urologists by a clinical champion. Urologists then underwent focused education based on current guidelines. Patterns of imaging use for staging were then re‐evaluated (November 2015 to July 2016). Patients were stratified into low‐, intermediate‐ and high‐risk groups as described by the D'Amico classification system.

Results

A total of 144 patients were retrospectively enrolled into the study cohort. The use of diagnostic imaging for staging purposes significantly decreased in men with low‐ and intermediate‐risk disease post intervention. In low‐risk patients, the use of CT decreased from 43% to 0% (P = 0.01). A total of 21% of patients underwent bone scans in the pre‐intervention group compared with18% in the post‐intervention group (P = 0.84). In intermediate‐risk patients, the use of CT decreased from 89% to 34% (P < 0.001), whilst the use of bone scan decreased from 63% to 37% (P = 0.02). In high‐risk patients, the appropriate use of imaging was maintained, with CT performed in 87% compared with 85% and bone scan in 87% compared with 65% (P = 0.07).

Conclusion

Our results show that a focused, clinician‐centred education programme can lead to improved guideline adherence at a regional level. The assessment of trends and application of such a programme at a state‐based or national level could be further assessed in the future with the help of registry data. This will be particularly important in future with the advent of advanced imaging, such as prostate‐specific membrane antigen positron‐emission tomography.
Radiotherapy‐related complications presenting to a urology department: a more common problem than previously thought?
Authors: Ma Joyce L. , Hennessey Derek B. , Newell Bradley P. , Bolton Damien M. , Lawrentschuk Nathan
Published: January 2018

Objective

To quantify the burden of the side effects of radiotherapy on a tertiary referral urology department.

Patients and Methods

A prospective study of all urology admissions to a public urology department at a tertiary hospital in a 6‐month period was performed. Patients admitted with complications attributable to radiotherapy were included in the study. Data obtained included patient demographics, radiotherapy details, complication type and management required.

Results

A total of 1198 patients were admitted; 921 (77%) were elective and 277 (23%) were emergency admissions. Thirteen out of the 921 (1.4%) elective admissions and 20 out of the 277 (7.2%) emergency admissions were attributable to radiotherapy complications. Radiotherapy complications was the fourth most common reason for emergency admission, ahead of acute urinary retention. These 33 admissions were accounted for by 21 patients. A total of 39 separate complications attributable to radiotherapy were diagnosed, with some patients having multiple complications. The median (interquartile range) time to onset of complications was 4 (1–9) years. The surgical intervention rate was 67%. The commonest procedures were washout with/without clot evacuation or diathermy in theatre (15.8%) and urethral dilatation/bladder neck incision (15.8%). Two urinary diversions and two cystoprostatectomies plus urinary diversion were performed.

Conclusion

Radiotherapy complications are consequential and account for a substantial proportion of a tertiary urology department's emergency workload. These complications generally occur years after radiotherapy and frequently require surgical intervention.
Performance comparison of two androgen receptor splice variant 7 (AR‐V7) detection methods
Authors: Bernemann Christof , Steinestel Julie , Humberg Verena , Bögemann Martin , Schrader Andres Jan , Lennerz Jochen K.
Published: January 2018

Objectives

To compare the performance of two established androgen receptor splice variant 7 (AR‐V7) mRNA detection systems, as paradoxical responses to next‐generation androgen‐deprivation therapy in AR‐V7 mRNA‐positive circulating tumour cells (CTC) of patients with castration‐resistant prostate cancer (CRPC) could be related to false‐positive classification using detection systems with different sensitivities.

Materials and Methods

We compared the performance of two established mRNA‐based AR‐V7 detection technologies using either SYBR Green or TaqMan chemistries. We assessed in vitro performance using eight genitourinary cancer cell lines and serial dilutions in three AR‐V7‐positive prostate cancer cell lines, as well as in 32 blood samples from patients with CRPC.

Results

Both assays performed identically in the cell lines and serial dilutions showed identical diagnostic thresholds. Performance comparison in 32 clinical patient samples showed perfect concordance between the assays. In particular, both assays determined AR‐V7 mRNA‐positive CTCs in three patients with unexpected responses to next‐generation anti‐androgen therapy. Thus, technical differences between the assays can be excluded as the underlying reason for the unexpected responses to next‐generation anti‐androgen therapy in a subset of AR‐V7 patients.

Conclusions

Irrespective of the method used, patients with AR‐V7 mRNA‐positive CRPC should not be systematically precluded from an otherwise safe treatment option.
Children's Early Decontextualized Talk Predicts Academic Language Proficiency in Midadolescence
Authors: Uccelli Paola , Demir‐Lira Özlem Ece , Rowe Meredith L. , Levine Susan , Goldin‐Meadow Susan
Published: January 2018

This study examines whether children's decontextualized talk—talk about nonpresent events, explanations, or pretend—at 30 months predicts seventh‐grade academic language proficiency (age 12). Academic language (AL) refers to the language of school texts. AL proficiency has been identified as an important predictor of adolescent text comprehension. Yet research on precursors to AL proficiency is scarce. Child decontextualized talk is known to be a predictor of early discourse development, but its relation to later language outcomes remains unclear. Forty‐two children and their caregivers participated in this study. The proportion of child talk that was decontextualized emerged as a significant predictor of seventh‐grade AL proficiency, even after controlling for socioeconomic status, parent decontextualized talk, child total words, child vocabulary, and child syntactic comprehension.
Diet soft drink is associated with increased odds of proliferative diabetic retinopathy
Authors: Fenwick Eva K , Gan Alfred TL , Man Ryan EK , Sabanayagam Charumathi , Gupta Preeti , Khoo Krystal , Aravindhan Amudha , Wong Tien Y , Lamoureux Ecosse L
Published: January 2018

Importance

While consumption of soft drink may increase the risk of cardiovascular disease, the relationship between soft drink consumption and diabetes complications is unknown.

Background

To explore the association between regular and diet soft drink consumption, and diabetic retinopathy (DR) and diabetic macular oedema (DME).

Design

Clinical, cross‐sectional study.

Participants

Adult patients with diabetes recruited from a tertiary eye hospital (Melbourne, Australia) answered a Food Frequency Questionnaire.

Methods

None, moderate and high soft drink consumption was defined as <1, 1–4 and >4 cans/bottles (375 mL) per week, respectively. Due to missing data, data were imputed using the multiple imputation chained equation procedure. Multivariable logistic regression models determined the associations between soft drink consumption, and presence and severity of DR/DME.

Main Outcome Measures

Presence and severity of DR/DME.

Results

Of the 609 participants (mean age ± standard deviation: 64.6 ± 11.6 years; males = 210), 285 (46.8%) and 190 (31.2%) consumed diet and regular soft drink, respectively. A total of 230 (37.8%), 36 (5.9%), 154 (25.3%), 28 (4.6%) and 146 (24.0%) had no DR, mild non‐proliferative DR (NPDR), moderate NPDR, severe NPDR and proliferative DR (PDR), respectively. High diet soft drink consumption was independently associated with increased likelihood of having PDR (odds ratio = 2.51, 95% confidence interval = 1.05–5.98), compared to no consumption. In contrast, regular soft drink was not associated with DR or DME.

Conclusions and Relevance

Consuming >4 cans (1.5 L)/week of diet soft drink is associated with a more than twofold risk of having PDR in patients with diabetes. Longitudinal studies are needed to further elucidate the association and its underpinning mechanisms.
Pluripotency Deconstructed
Authors: Kinoshita Masaki , Smith Austin
Published: January 2018

Pluripotency denotes the flexible capacity of single cells to give rise to all somatic lineages and typically also the germline. Mouse ES cells and post‐implantation epiblast‐derived stem cells (EpiSC) are widely used pluripotent cell culture systems. These two in vitro stem cell types have divergent characteristics. They are considered as representative of distinct developmental stages, distinguished by using the terms “naïve” and “primed”. A binary description is an over‐simplification, however. Here, we discuss an intermediate stage of pluripotency that we term “formative”. Formative pluripotency features a gene regulatory network switch from the naïve state and comprises capacitation of enhancers, signaling pathways and epigenetic machinery in order to install competence for lineage specification.
Parent‐reported health‐related quality of life of children with Down syndrome: a descriptive study
Authors: Shields Nora , Leonard Helen , Munteanu Shannon , Bourke Jennifer , Lim Polly , Taylor Nicholas F , Downs Jenny
Published: January 2018

Aim

To describe health‐related quality of life of Australian children and adolescents with Down syndrome and compare it with norm‐referenced data.

Method

A cross‐sectional survey was conducted with parents of 75 children and adolescents (43 males, 32 females) with Down syndrome aged 5 to 18 years (mean age 13y 2mo, SD 4y 8mo). The proxy‐report KIDSCREEN‐27 questionnaire was administered and five dimensions of health‐related quality of life were measured. Data were analysed descriptively and compared with normative data.

Results

Total group mean scores for psychological well‐being, autonomy and parent relation, and school environment dimensions were within normal threshold values, whereas mean scores for physical well‐being, and social support and peers dimensions, were poorer. For participants with Down syndrome aged 8 to 18 years, the difference with normative data for proxy‐reported physical well‐being, psychological well‐being, and social support and peers dimensions favoured typically developing children. Adolescents (13–18y) with Down syndrome scored poorer on all dimensions than children (5–12y) with Down syndrome.

Interpretation

Our findings assist a better understanding of the lived experiences of children and adolescents with Down syndrome, as perceived by their parents, and suggest aspects of health that could be influenced to optimize their quality of life.

What this paper adds

Proxy‐reported psychological well‐being and autonomy were within the normal range for children with Down syndrome.

Physical well‐being and social support scores were significantly lower than normative data.

Proxy‐reported scores for adolescents with Down syndrome were consistently poorer than for children with Down syndrome and the differences were clinically important.
Antibiotic exposure in early life and childhood overweight and obesity: A systematic review and meta‐analysis
Authors: Rasmussen Sara H. , Shrestha Sarita , Bjerregaard Lise G. , Ängquist Lars H. , Baker Jennifer L. , Jess Tine , Allin Kristine H.
Published: January 2018

We conducted a systematic review and meta‐analysis of observational studies investigating the association between antibiotic exposure in infancy and risk of childhood overweight and obesity. Thirteen studies, including a total of 527 504 children, were included in the systematic review and 8 were included in meta‐analyses. Exposure to antibiotics in infancy was associated with an increased odds ratio (OR) of childhood overweight and obesity (OR 1.11, 95% confidence interval [CI] 1.02‐1.20). Whereas exposure to 1 treatment only and exposure between 6 and 24 months were not associated with increased risk of childhood overweight and obesity, exposure to >1 treatment was associated with an OR of 1.24 (95% CI 1.09‐1.43) and exposure within the first 6 months of life was associated with an OR of 1.20 (95% CI 1.04‐1.37). In conclusion, antibiotic exposure in infancy was associated with a slightly increased risk of childhood overweight and obesity, mainly if children were exposed to repeated treatments or treatment within the first 6 months of life. It is unclear whether this association is mediated via direct effects of antibiotics on the gut microbiota.
Optimizing the management of hypoglycaemia in individuals with type 2 diabetes: A randomized crossover comparison of a weight‐based protocol compared with two fixed‐dose glucose regimens
Authors: Krebs Jeremy D. , Weatherall Mark , Corley Brian , Wiltshire Esko , McTavish Lindsay
Published: January 2018

Aims

To determine whether an individualized body weight‐based glucose treatment in adults with type 2 diabetes (T2DM) is more likely to resolve hypoglycaemia with a single treatment without excessive rebound hyperglycaemia compared to fixed doses of 12 or 30 g of glucose.

Methods

Adults with T2DM were enrolled in a cross‐over study. Each episode of hypoglycaemia (capillary glucose <4.0 mmol/L) was randomly assigned to 1 of 3 treatment protocols: 0.3 g glucose/kg body‐weight or a fixed dose of either 12 or 30 g glucose, independent of weight. All participants received each treatment in random order for up to 15 hypoglycaemic episodes. Glucose was re‐tested 10 minutes after treatment, with a repeat dose if still <4 mmol/L.

Results

Mean (SD) age of the 30 participants was 68 (8.1) years, mean weight was 91.5 (16.8) kg and mean HbA1c was 58.7 (9.2) mmol/mol. Among a total of 244 episodes of hypoglycaemia, 10 participants had 15 treatment episodes and 18 participants had fewer than 10 treatment episodes. The odds ratio, adjusted for multiple comparisons, for resolution of hypoglycaemia at 10 minutes, comparing weight‐based treatment and 12 g treatment was 3.2 (95% CI, 1.1–9.0), P = .009, comparing 30 g treatment and 12 g treatment was 8.9 (95% CI, 2.2–36.6), P < .001, and comparing weight‐based treatment and 30 g treatment was 0.36 (95% CI, 0.08–1.67) P = .10.

Conclusion

In T2DM, both a weight‐based 0.3 g/kg treatment and a fixed 30 g glucose treatment result in higher blood glucose than a 12 g treatment, along with increased probability of resolution of hypoglycaemia after 10 minutes. Both treatments result in an excess of mild rebound hyperglycaemia (>8 mmol/L) at 30 minutes.
The effects of fish oil on gene expression in patients with polycystic ovary syndrome
Authors: Rahmani Elham , Jamilian Mehri , Dadpour Bahareh , Nezami Zahra , Vahedpoor Zahra , Mahmoodi Samaneh , Aghadavod Esmat , Taghizadeh Mohsen , Beiki Hassan Abolfazl , Asemi Zatollah
Published: January 2018

Background

This study was conducted to determine the effects of fish oil administration on gene expression related to insulin, lipid and inflammation in women with polycystic ovary syndrome (PCOS).

Materials and methods

This randomized, double‐blind, placebo‐controlled trial was conducted among 40 subjects with PCOS, aged 18‐40 years. Subjects were randomly allocated into two groups to take either 1000 mg omega‐3 fatty acids from fish oil (n = 20) or placebo (n = 20) twice a day for 12 weeks. Gene expression related to insulin, lipid and inflammation was quantified in peripheral blood mononuclear cells (PBMC) of PCOS women with RT‐PCR method.

Results

Our study demonstrated that after the 12‐week intervention, compared with the placebo, fish oil supplementation upregulated gene expression of peroxisome proliferator‐activated receptor gamma (PPAR‐γ) (P < .001) in PBMC of subjects with PCOS. In addition, compared to the placebo, taking fish oil supplements downregulated gene expression of interleukin‐1 (IL‐1) (P = .02) and interleukin‐8 (IL‐8) (P = .01) in PBMC of subjects with PCOS. We did not observe any significant effect of fish oil supplementation on gene expression of lipoprotein(a) [LP(a)], low‐density lipoprotein receptor (LDLR), glucose transporter 1 (GLUT‐1), tumour necrosis factor alpha (TNF‐α) and transforming growth factor beta (TGF‐β) in PBMC of subjects with PCOS.

Conclusions

Overall, fish oil supplementation for 12 weeks to subjects with PCOS significantly improved gene expression of PPAR‐γ, IL‐1 and IL‐8, but did not influence gene expression of LP(a), LDLR, GLUT‐1, TNF‐α and TGF‐β.
Bone marrow‐derived mononuclear cell therapy for nonischaemic dilated cardiomyopathy—A meta‐analysis
Authors: Wen Yanting , Ding Jingjing , Zhang Bin , Gao Qian
Published: January 2018

Objective

The therapeutic effects of bone marrow‐derived mononuclear cells (BMMNCs) transplantation in patients with nonischaemic dilated cardiomyopathy (DCM) are still under debate. Current randomized controlled trials (RCTs) reported conflicting results. The aim of this study was to assess the effects of BMMNCs transplantation on left ventricular ejection fraction (LVEF) in patients with nonischaemic DCM.

Methods

A comprehensive search of PubMed, EMBASE and Cochrane Controlled Trials Register was performed. We included RCTs reporting data on LVEF in patients with nonischaemic DCM after BMMNCs transplantation.

Results

Seven RCTs including 463 patients were included. BMMNCs transplantation significantly improved LVEF by 3.79% (95% CI: 0.56%‐7.03%; P = .007) and LVESV by −24.36 mL (95% CI: −46.36 to −2.36 mL; P = .03), while had no impact on the risk of all‐cause death (OR 0.92; 95% CI: 0.41 to 2.08%; P = .84). Subgroup analysis demonstrated a more significant improvement of LVEF in patients with longer follow‐up (~15 months to 5 years) than shorter ones (12 months). Moreover, using bone marrow mononuclear cells was more effective than using G‐CSF‐stimulated bone marrow/peripheral blood stem cells in the improvement of LVEF in patients with nonischaemic DCM.

Conclusions

Bone marrow‐derived mononuclear cells transplantation is associated with a moderate, but significant, improvement in LVEF in patients with nonischaemic DCM. This meta‐analysis supports further RCT conductions using BMMNCs transplantation with larger patient's population and longer term follow‐up.
Low plasma protein Z levels are associated with an increased risk for perioperative bleedings
Authors: Hinterleitner Clemens , Kreisselmeier Klaus‐Peter , Pecher Ann‐Christin , Mauz Paul‐Stefan , Kanz Lothar , Kopp Hans‐Georg , Jaschonek Karl G.
Published: January 2018

Background and objectives

Protein Z (PZ) deficiency has been implicated both in bleeding diatheses and in thrombophilia. Considering its ambiguous nature and the conflicting clinical data so far, we set out to evaluate the impact of low PZ on perioperative bleeding in patients who underwent surgical (ENT) interventions involving a high risk of bleeding.

Patients and methods

After exclusion of other coagulation disorders, 154 Patients were stratified into quartiles according to PZ plasma concentrations to evaluate the relation between PZ and bleeding complications.

Results

Low PZ levels were associated with increased blood loss (P < .001), increased need for blood transfusions (P < .001), and a higher rate of surgical revisions (P = .009) in a concentration‐dependent fashion. Low PZ caused earlier (within 24 hours) and repetitive bleedings (P = .005). The number of major bleeding episodes was significantly increased when low PZ was combined with bleeding history (P < .05). Finally, ROC analyses confirmed the predictive value of low PZ for bleeding complications and PZ‐thresholds for clinical practice were determined.

Conclusions

Low PZ appears to be an underestimated risk factor for perioperative bleeding. Determination of PZ plasma concentrations might be useful in the preoperative workup in patients with a bleeding history, when detailed clotting analyses remain inconclusive.
Pretreatment with standard‐dose intravenous methylprednisolone does not improve outcomes in newly diagnosed immune thrombocytopenia (ITP)
Authors: Essilini Anaïs , Comont Thibault , Germain Johanne , Brun Natacha , Dingremont Claire , Castel Brice , Arista Sophie , Madaule Serge , Sailler Laurent , Lapeyre‐Mestre Maryse , Beyne‐Rauzy Odile , Godeau Bertrand , Adoue Daniel , Moulis Guillaume ,   the CARMEN investigators group
Published: January 2018

Objective

To assess the benefits and harms to initiate corticosteroids with intravenous methylprednisolone at a conventional dose (1 mg/kg/d) to treat adults with immune thrombocytopenia (ITP).

Methods

Population stemmed from the prospective multicenter CARMEN registry and included newly diagnosed hospitalized ITP adults with platelet counts<30 × 109/L. We compared the patients treated with conventional‐dose methylprednisolone (CDMP) before continuing with oral prednisone to patients treated with just conventional‐dose oral prednisone (CDOP). The primary outcome was the time until response. Secondary outcomes were time until complete response, response rate, complete response rate, duration of hospital stay, and occurrence of adverse drug reactions. Analyzes were adjusted for propensity score and for exposure to intravenous immunoglobulin.

Results

Among the included 87 patients, the median time to response was 3 days in the CDMP group vs 4 in the CDOP group (adjusted hazard ratio [aHR]: 1.35; 95%CI: 0.76‐2.41). The CDMP group had an earlier complete response (aHR: 2.29; 95%CI: 1.20‐4.36). There was no difference between the groups regarding other secondary outcomes.

Conclusions

Initiating methylprednisolone at a conventional dose provided no significant benefit compared to giving oral prednisone only to adults with ITP.
Cholinergic interneurons in the rat striatum modulate substitution of habits
Authors: Aoki Sho , Liu Andrew W. , Akamine Yumiko , Zucca Aya , Zucca Stefano , Wickens Jeffery R.
Published: January 2018

Behavioural flexibility is crucial for adaptive behaviour, and recent evidence suggests that cholinergic interneurons of the striatum play a distinct role. Previous studies of cholinergic function have focused on strategy switching by the dorsomedial or ventral striatum. We here investigated whether cholinergic interneurons in the dorsolateral striatum play a similar role at the level of switching of habitual responses. Because the dorsolateral striatum is particularly involved in habitual responding, we developed a habit substitution task that involved switching habitual lever‐press responses to one side to another. We first measured the effect of cholinergic activation in the dorsolateral striatum on this task. Chemogenetic activation of cholinergic interneurons caused an increase in the response rate for the substituted response that was significantly greater than the increase normally seen in control animals. The increase was due to burst‐like responses with shorter inter‐press intervals. However, there was no effect on inhibiting the old habit, or on habitual responding that did not require a switch. There was also no effect on lever‐press performance and its reversal before lever‐press responses became habitual. Conversely, neurochemically specific ablation of cholinergic interneurons did not significantly change habitual responding or response substitution. Thus, activation –but not ablation –of cholinergic interneurons in the dorsolateral striatum modulates expression of a new habit when an old habit is replaced by a new one. Together with previous work, this suggests that striatal cholinergic interneurons facilitate behavioural flexibility in both dorsolateral striatum in addition to dorsomedial and ventral striatum.
Effects of chronic ketamine on hippocampal cross‐frequency coupling: implications for schizophrenia pathophysiology
Authors: Michaels Timothy I. , Long Lauren L. , Stevenson Ian H. , Chrobak James J. , Chen Chi‐Ming A.
Published: January 2018

Disrupted neuronal oscillations have been identified as a potentially important biomarker for the perceptual and cognitive symptoms of schizophrenia. Emerging evidences suggest that interactions between different frequency bands, cross‐frequency coupling (CFC), serve an important role in integrating sensory and cognitive information and may contribute to disease pathophysiology. In this study, we investigated the effects of 14‐day consecutive administration of ketamine (30 mg/kg i.p.) vs. saline on alterations in amplitude and changes in the coupling of low‐frequency (0–30 Hz) phase and high‐frequency (30–115 Hz) amplitude in the CA1 hippocampus of Long Evans rats. Intracranial electrode recordings were conducted pre‐ and post‐injection while the animals performed a foraging task on a four‐arm rectangular maze. Permutation analysis of frequency band‐specific change in amplitudes revealed between‐group differences in theta (6–12 Hz) and slow gamma (25–50 Hz) but not fast gamma (65–100 Hz) bands at both slow and fast speeds. Chronic ketamine challenge resulted in decreased coupling (pre to post) at slow speeds but increased coupling at faster speeds, compared to either no or modest increased coupling in the saline group. These results demonstrate that chronic ketamine administration alters the interaction of low‐frequency phase and high‐frequency oscillations chronically and that such coupling varies as a function of locomotive speed. These findings provide evidence for the potential relevance of CFC to the pathophysiology of schizophrenia.
Predicting age from cortical structure across the lifespan
Authors: Madan Christopher R. , Kensinger Elizabeth A.
Published: January 2018

Despite interindividual differences in cortical structure, cross‐sectional and longitudinal studies have demonstrated a large degree of population‐level consistency in age‐related differences in brain morphology. This study assessed how accurately an individual's age could be predicted by estimates of cortical morphology, comparing a variety of structural measures, including thickness, gyrification and fractal dimensionality. Structural measures were calculated across up to seven different parcellation approaches, ranging from one region to 1000 regions. The age prediction framework was trained using morphological measures obtained from T1‐weightedMRIvolumes collected from multiple sites, yielding a training dataset of 1056 healthy adults, aged 18–97. Age predictions were calculated using a machine‐learning approach that incorporated nonlinear differences over the lifespan. In two independent, held‐out test samples, age predictions had a median error of 6–7 years. Age predictions were best when using a combination of cortical metrics, both thickness and fractal dimensionality. Overall, the results reveal that age‐related differences in brain structure are systematic enough to enable reliable age prediction based on metrics of cortical morphology.
Larger Q10 of carbon decomposition in finer soil particles does not bring long‐lasting dependence of Q10 on soil texture
Authors: Ding F. , Sun W. , Huang Y. , Hu X.
Published: January 2018

Soil particle‐size fractionation is a reliable approach for the separation of carbon (C) pools with different stabilities. Our previous study found that C decomposition in fine soil particles had greater temperature sensitivity (Q10) than in coarse particles in grassland and forest soils. However, it is not known whether this phenomenon occurs in cropland soil and whether it generally suggests a dependence of Q10 on soil texture. We carried out a 107‐day incubation of isolated soil particles from cropland soil, including paddy and upland, with contrasting fertilizer applications. The incubation was carried out over three short‐term cycles of sequentially changing temperatures between 5 and 30°C at 5°C intervals. The results indicated that C decomposition was faster in the sand (>50 μm) fraction than in the silt (2–50 μm) and clay (<2 μm) fractions. However, Q10 was generally larger in the clay fractions than in the other two fractions for all types of cropland soil, which is in accordance with our previous study. This suggested that the passive C pool is more sensitive to climate warming than the labile C pool. Considering the aforementioned Q10 pattern across soil particles, we hypothesized that fine‐textured soil should have a larger Q10 than coarse‐textured soil. However, we observed this outcome in the first and second temperature cycles only, but not in the third. In conclusion, a larger Q10 in finer soil particles is probably a widespread phenomenon, but it does not bring a long‐lasting dependence of Q10 on soil texture.

Highlights

Does cropland C flux in finer soil particles have larger Q10 as in grassland and forest?

Larger Q10 in clay fractions than in sand particles is widespread.

The passive C pool is more sensitive to climate warming than the labile C pool.

Larger Q10 in finer soil particles does not bring long‐lasting dependence of Q10 on soil texture.