Improving breast cancer care coordination and symptom management by using AI driven predictive toolkits.

Integrated breast cancer care is complex, marked by multiple hand-offs between primary care and specialists over an extensive period of time. Communication is essential for treatment compliance, lowering error and complication risk, as well as handling co-morbidity. The director role of care, however, becomes often unclear, and patients remain lost across departments. Digital tools can add significant value to care communication but need clarity about the directives to perform in the care team. In effective breast cancer care, multidisciplinary team meetings can drive care planning, create directives and structured data collection. Subsequently, nurse navigators can take the director's role and become a pivotal determinant for patient care continuity. In the complexity of care, automated AI driven planning can facilitate their tasks, however, human intervention stays needed for psychosocial support and tackling unexpected urgency. Care allocation of patients across centres, is often still done by hand and phone demanding time due to overbooked agenda's and discontinuous system solutions limited by privacy rules and moreover, competition among providers. Collection of complete outcome information is limited to specific collaborative networks today. With data continuity over time, AI tools can facilitate both care allocation and risk prediction which may unveil non-compliance due to local scarce resources, distance and costs. Applied research is needed to bring AI modelling into clinical practice and drive well-coordinated, patient-centric cancer care in the complex web of modern healthcare today.

Initial collection of an inadequate 24-hour urine sample in children does not predict subsequent inadequate collections.

INTRODUCTION: Approximately half of adult stone formers submit specimens that are either under or over collections as determined by 24-h creatinine/kg. Previously identified predictors of inadequate collection in adults include female sex, older age, higher body mass index (BMI), vitamin D supplementation, and weekday collection. OBJECTIVE: The objective of this study is to determine risk factors for inadequate 24-h urinary specimen collection in the pediatric population. STUDY DESIGN: A retrospective analysis of all children (<18 years of age) with renal and/or ureteral calculi evaluated at the study tertiary care pediatric center from 2005 to 2015 was performed. Those who had at least one 24-h urinary metabolic profile after a clinical visit for kidney and/or ureteral stones were included; children with bladder stones were excluded. Adequate collections had a urine creatinine of 10-15 mg/kg/24 h. A bivariate analysis of potential factors associated with inadequate collection of the initial urinary metabolic profile, including child demographics, parental socio-economic factors, history of stone surgery, and weekday vs. weekend urine collection, was performed. A mixed-effects logistic regression, controlling for correlation of specimens from the same patient, was also performed to determine whether an initial inadequate collection predicted a subsequent inadequate collection. RESULTS: Of 367 patients, 80 had an adequate collection (21.9%): median age, 13 years (interquartile range, 8-16); 61.1% female; 93.5% white; 19.5% obese; and 13.0% overweight. No parental or child factors were associated with inadequate collection (Summary Table). Of inadequate collections, more than 80% were over collections. In the 175 patients with more than one 24-h urinary specimen collection, the effect of an initial inadequate collection on subsequent inadequate collections was not significant after controlling for the correlation of samples from the same patient (p = 0.8). DISCUSSION: Any parental or child factors associated with the collection of inadequate 24-h urine specimens in children were not found. An initial inadequate collection does not predict subsequent inadequate collections. It was surprising that >80% of the inadequate collections were over collections rather than under collections. Possible explanations are that children collected urine samples for longer than the 24-h period or that stone-forming children produce more creatinine per 24-h period than healthy children due to hyperfiltration. CONCLUSION: Inadequate collections are very common, and the risk factors for them are unclear. A repeat collection would be suggested if the first is inadequate. Further studies must be planned to explore barriers to accurate specimen collection using qualitative research methodology.

A head coil system with an integrated orbiting transmission point source mechanism for attenuation correction in PET/MRI.

The combination of positron emission tomography (PET) and magnetic resonance imaging (MRI) provides a benefit for diagnostic imaging. Still, attenuation correction (AC) is a challenge in PET/MRI compared to stand-alone PET and PET-computed tomography (PET/CT). In the absence of photonic transmission sources, AC in PET/MRI is usually based on retrospective segmentation of MR images or complex additional MR-sequences. However, most methods available today are still challenged by either the incorporation of cortical bone or substantial anatomical variations of subjects. This leads to a bias in quantification of tracer concentration in PET. Therefore, we have developed a fully integrated transmission source system for PET/MRI of the head to enable direct measurement of attenuation coefficients using external positron emitters, which is the reference standard in AC. Based on a setup called the 'liquid drive' presented by Jones et al (1995) two decades ago, we built a head coil system consisting of an MR-compatible hydraulic system driving a point source on a helical path around a 24-channel MR-receiver coil to perform a transmission scan. Sinogram windowing of the moving source allows for post-injection measurements. The prototype was tested in the Siemens Biograph mMR using a homogeneous water phantom and a phantom with air cavities and a Teflon (PTFE) cylinder. The second phantom was measured both with and without emission activity. For both measurements air, water and Teflon were clearly distinguishable and homogeneous regions of the phantom were successfully reproduced in the AC map. For water the linear attenuation coefficient was measured as (0.096 ± 0.005) cm-1 in accordance with the true physical value. This combined MR head coil and transmission source system is, to our knowledge, the first working example to use an orbiting point source in PET/MRI and may be helpful in providing fully-quantitative PET data in neuro-PET/MRI.

The ability of a limited metabolic assessment to identify pediatric stone formers with metabolic abnormalities.

INTRODUCTION: American Urological Association guidelines recommend a urinary metabolic evaluation after the first stone event in all pediatric stone patients. Prior studies identified hypercalciuria and urine hypovolemia as the most common abnormalities in children with urolithiasis. Recent data suggest that hypocitraturia is most prevalent. It was hypothesized that a limited evaluation would detect the majority of clinically significant metabolic abnormalities in pediatric stone formers. MATERIAL AND METHODS: A retrospective analysis of all children (<18 years of age) with renal/ureteral calculi evaluated at the study institution from 2005 to 2015 was performed. Children with ≥ one 24-h urinary metabolic profile after a clinical visit for renal/ureteral calculi were included. Those with bladder stones and those with undercollection or overcollection or missing urinary creatinine were excluded. Demographics and data from the first urinary metabolic profile and stone analyses were collected. The sensitivity, specificity, and positive and negative predictive value (NPV) of a limited urinary metabolic evaluation consisting of four parameters (24-h calcium, citrate, and oxalate and low urinary volume) were compared to a complete urinary metabolic profile. The number and type of metabolic abnormalities that would have been missed with this limited evaluation weredetermined. RESULTS: Of 410 patients, 21 were excluded for age ≥18 years, 13 for bladder stones, 248 for overcollections, 38 for undercollections, and 10 for missing creatinine. This left 80 patients for inclusion: median age 11.4 years, 60% female, and 96.3% white. Of the entire cohort, 69.6% had hypocitraturia, 52.5% had low urine volume, and 22.5% had hypercalciuria. Sensitivity was 87.5%. Specificity could not be calculated because no patients had a normal complete metabolic evaluation. The NPV was zero, and the positive predictive value was 100%, but these are artifacts resulting from the absence of patients with a normal complete metabolic evaluation. Of the 80 patients, 10 had at least one abnormality missed by a limited metabolic evaluation (Table 1). The missed abnormalities were high pH (n = 6), abnormal 24-h phosphorus (low in 1 patient and high in 1 patient), low 24-h magnesium (n = 3), low 24-h potassium (n = 3), and high 24-h sodium (n = 4). DISCUSSION: A limited urinary metabolic evaluation would have detected the vast majority of clinically significant metabolic abnormalities in the study sample. Approximately two-thirds of the study patients submitted inadequate 24-h urine specimens. CONCLUSIONS: A simplified approach to metabolic evaluation in first-time stone formers with a stone analysis available was proposed. This streamlined approach could simplify the metabolic evaluation and reduce health care costs.

Immediate and delayed neuroendocrine responses to social exclusion in males and females.

Social exclusion is a complex phenomenon, with wide-ranging immediate and delayed effects on well-being, hormone levels, brain activation and motivational behavior. Building upon previous work, the current fMRI study investigated affective, endocrine and neural responses to social exclusion in a more naturalistic Cyberball task in 40 males and 40 females. As expected, social exclusion elicited well-documented affective and neural responses, i.e., increased anger and distress, as well as increased exclusion-related activation of the anterior insula, the posterior-medial frontal cortex and the orbitofrontal cortex. Cortisol and testosterone decreased over the course of the experiment, whereas progesterone showed no changes. Hormone levels were not correlated with subjective affect, but they were related to exclusion-induced neural responses. Exclusion-related activation in frontal areas was associated with decreases in cortisol and increases in testosterone until recovery. Given that results were largely independent of sex, the current findings have important implications regarding between-sex vs. within-sex variations and the conceptualization of state vs. trait neuroendocrine functions in social neuroscience.

Does the presence of an occlusal indicator product affect the contact forces between full dentitions?

Studies have explored occlusal marking interpretation, repeatability and accuracy. But, when an occlusion detection product is interposed between teeth, direct tooth-tooth occlusal contact relationships are replaced by tooth-material-tooth structures. Thus, the marks cannot reflect the original contacts. This has been shown for single tooth pair contacts. The purpose of this laboratory study was to similarly examine full dentitions. A dentiform was set into Class I centric occlusion with the mandible supported by a load cell. The maxillary arch was guided by precision slides. As the weighted (~52 N) upper assembly was lowered onto and raised off the mandibular arch, the loads on the mandible were measured. With and without (control) occlusal marking material, the steps were as follows: (cleaning - control 1 - material 1) … (cleaning - control 6 - material 6). The six materials were as follows: Accufilm I and II, Rudischhauser Thick and Thin, Hanel Articulating Silk and T-Scan. Then, the six sets of (cleaning - control - material) measurements were repeated with the mandibular assembly shifted, in turn, by 0·1 mm in the Anterior, Posterior, Right and Left directions. The five (Centric and four 0·1 mm shifted) occlusal relationships produced grossly different tooth-tooth (control) load profiles. And, in general, these controls were affected, in different ways, by the marking products. Among the five conventional products, the Rudischhausers fared the worst and the electronic T-Scan was an extreme outlier. Thus, in general, popular occlusal detection products alter the occlusal contact forces, and therefore, their markings cannot characterise the actual occlusion.

Validation of antibiotic charges in administrative data for outpatient pediatric urologic procedures.

INTRODUCTION: The use of administrative health data for research has prompted questions about its validity for this purpose. OBJECTIVE/STUDY DESIGN: The purpose of this study was to determine the concordance of Pediatric Health Information System (PHIS) perioperative antibiotic charges with the institution's medication administration data for males <10 years old and who underwent outpatient penile/inguinal procedures from July 2013 to March 2015. RESULTS: There was 93.9% positive and negative agreement between perioperative antibiotic charges versus administration. The sensitivity and specificity were 96.8% and 87.2%, respectively. The positive and negative predictive values were 94.6% and 92.2%, respectively. CONCLUSION: This study indicated strong agreement between PHIS pharmacy charges and medication administration.

Aetiology of adult burns treated from 2000 to 2012 in a Swiss University Hospital.

BACKGROUND: Burns in Switzerland are frequent and lead to high economic and social costs. However, little is known about the aetiology of burns suffered by patients seeking treatment in hospital emergency departments. This knowledge could be used to develop preventive measures. METHODS: This retrospective analysis included all patients (≥16 years old) with acute thermal injuries of known cause admitted to the adult emergency department in Bern University Hospital (Switzerland, not a specialised burns unit) between 2000 and 2012. Clinical and sociodemographic data were extracted from medical records, i.e. the environment in which the burn occurred, as well as details of burn severity and aetiology. RESULTS: Seven hundred and one (701) patients with a mean age of 35.0±14.5 years (56% men) were included in the analysis. The winter season and the days around Christmas, turn of the year and Swiss National Day were identified as times with high risk of burns. Household (45%) and workplace (31%) were the most common locations/settings in which the burns occurred. Approximately every second burn was caused by scald, every fourth by flame and every seventh by hot objects. The analysis identified cooking, tar and electricity in workplace accidents, barbecues and the use of gasoline as aetiological factors in burns in leisure time, together with water in domestic thermal injuries. Burns occurred predominantly on non-protected skin on the hand and arms. The most severe burns were seen in electrical and flame burns. Men suffered more severe burns than women in all settings except psychopathology. CONCLUSIONS: The data suggest that the incidence and severity of burns in Switzerland could be reduced by preventive strategies and public campaigns, including education on fire protection systems, raising awareness about the times and locations where the risks of burns are greater, further improvement in workplace safety, particularly with cooking facilities and electrical equipment, and the development of innovative safety devices (i.e. machines, protective gloves). These findings have to be interpreted carefully, as this study includes only adult patients who presented in our ED and, in most cases, the burns covered less than 20% of the body surface.

Breast cancer under age 40: a different approach.

Breast cancer (BC) under age 40 is a complex disease to manage due to the additionally fertility-related factors to be taken in consideration. More than 90% of young patients with BC are symptomatic. Women<40 years are more likely to develop BC with worse clinicopathological features and more aggressive subtype. This has been frequently associated with inferior outcomes. Recently, the prognostic significance of age<40 has been shown to differ according to the BC subtype, being associated with worst recurrence-free survival (RFS) and overall survival (OS) for luminal BC. The biology of BC<40 has also been explored through analysis of large genomic data set, and specific pathways overexpressed in these tumors have been identified which can lead to the development of targeted therapy in the future. A multidisciplinary tumor board should determine the optimal locoregional and systemic management strategies for every individual patient with BC before the start of any therapy including surgery. This applies to both early (early breast cancer (EBC)) and advanced (advanced breast cancer (ABC)) disease, before the start of any therapy. Mastectomy even in young patients confers no overall survival advantage when compared to breast-conserving treatment (BCT), followed by radiotherapy. Regarding axillary approach, indications are identical to other age groups. Young age is one of the most important risk factors for local recurrence after both breast-conserving surgery (BCS) and mastectomy, associated with a higher risk of distant metastasis and death. Radiation after BCS reduces local recurrence from 19.5 to 10.2% in BC patients 40 years and younger. The indications for and the choice of systemic treatment for invasive BC (both early and advanced disease) should not be based on age alone but driven by the biological characteristics of the individual tumor (including hormone receptor status, human epidermal growth factor receptor 2 (HER-2) status, grade, and proliferative activity), disease stage, and patient's comorbidities. Recommendations regarding the use of genomic profiles such as MammaPrint, Oncotype Dx, and Genomic grade index in young women are similar to the general BC population. Especially in the metastatic setting, patient preferences should always be taken into account, as the disease is incurable. The best strategy for these patients is the inclusion into well-designed, independent, prospective randomized clinical trials. Metastatic disease should always be biopsied whenever feasible for histological confirmation and reassessment of biology. Endocrine therapy is the preferred option for hormone receptor-positive disease (HR+ve), even in presence of visceral metastases, unless there is concern or proof of endocrine resistance or there is a need for rapid disease response and/or symptom control. Recommendations for chemotherapy (CT) should not differ from those for older patients with the same characteristics of the metastatic disease and its extent. Young age by itself should not be an indication to prescribe more intensive and combination CT regimens over the sequential use of monotherapy. Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) represent an important group of promising drugs in managing patients with breast cancer susceptibility gene (BRCA)-1- or BRCA-2-associated BC. Specific age-related side effects of systemic treatment (e.g., menopausal symptoms, change in body image, bone morbidity, cognitive function impairment, fertility damage, sexual dysfunction) and the social impact of diagnosis and treatment (job discrimination, taking care for children) should also be carefully addressed when planning systemic long-lasting therapy, such as endocrine therapy. Survivorship concerns for young women are different compared to older women, including issues of fertility, preservation, and pregnancy.

Unexplained high BMD in DXA-scanned patients is generalized throughout the skeleton and characterized by thicker cortical and trabecular bone.

Unexplained high bone mineral density (BMD) is a rare condition and the mechanisms responsible are yet to be described in detail. The aim of the study was to identify patients with unexplained high BMD from a local DXA database and compare their radiological phenotype with an age- and a gender-matched group of population-based controls. We defined high BMD as a DXA Z-score ≥ + 2.5 at the total hip and lumbar spine. We characterized the findings as "unexplained" if no osteodegenerative changes, bone metabolic disease, or arthritis at the hip or lumbar spine was observed. All participants were investigated with high-resolution peripheral quantitative computed tomography (HR-pQCT), QCT, DXA, fasting blood samples, a 24-h urine sample, and questionnaires. The DXA database contained data on 25,118 patients. Initially, 138 (0.55%) potential participants with high BMD were identified, and during the study ten additional cases were identified from new DXA scans. Sixty-seven patients accepted to participate in the study, and among these we identified 15 women and one man with unexplained high BMD. These 15 women had higher BMD throughout the skeleton relative to controls, similar area/volume at the hip and the distal extremities, a higher number of trabeculae, which was thicker than in the controls, and a higher finite element estimated bone strength. The 15 women were heavier and had a higher fat mass then controls. We conclude that patients with unexplained high BMD have a generalized high BMD phenotype throughout their skeleton, which is characterized with a denser microarchitecture.

Control of pathogenic effector T-cell activities in situ by PD-L1 expression on respiratory inflammatory dendritic cells during respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) infection is a leading cause of severe lower respiratory tract illness in young infants, the elderly and immunocompromised individuals. We demonstrate here that the co-inhibitory molecule programmed cell death 1 (PD-1) is selectively upregulated on T cells within the respiratory tract during both murine and human RSV infection. Importantly, the interaction of PD-1 with its ligand PD-L1 is vital to restrict the pro-inflammatory activities of lung effector T cells in situ, thereby inhibiting the development of excessive pulmonary inflammation and injury during RSV infection. We further identify that PD-L1 expression on lung inflammatory dendritic cells is critical to suppress inflammatory T-cell activities, and an interferon-STAT1-IRF1 axis is responsible for increased PD-L1 expression on lung inflammatory dendritic cells. Our findings suggest a potentially critical role of PD-L1 and PD-1 interactions in the lung for controlling host inflammatory responses and disease progression in clinical RSV infection.

Technical Note: evaluation of the uncertainties in (choline + creatine)/citrate ratios measured by proton MR spectroscopic imaging in patients suspicious for prostate cancer.

The presented evaluation of the relative uncertainty (δ'CCC) of the (choline + creatine)/citrate (CC/C) ratios can provide objective information about the quality and diagnostic value of prostate MR spectroscopic imaging data. This information can be combined with the numeric values of CC/C ratios and provides metabolic-quality maps enabling accurate cancer detection and user-independent data evaluation. In addition, the prostate areas suffering most from the low precision of CC/C ratios (e. g., prostate base) were identified.

Cryopreservation, semen use and the likelihood of fatherhood in male Hodgkin lymphoma survivors: an EORTC-GELA Lymphoma Group cohort study.

STUDY QUESTION: How does the successful cryopreservation of semen affect the odds of post-treatment fatherhood among Hodgkin lymphoma (HL) survivors? SUMMARY ANSWER: Among 334 survivors who wanted to have children, the availability of cryopreserved semen doubled the odds of post-treatment fatherhood. WHAT IS KNOWN ALREADY: Cryopreservation of semen is the easiest, safest and most accessible way to safeguard fertility in male patients facing cancer treatment. Little is known about what proportion of patients achieve successful semen cryopreservation. To our knowledge, neither the factors which influence the occurrence of semen cryopreservation nor the rates of fatherhood after semen has been cryopreserved have been analysed before. STUDY DESIGN, SIZE, DURATION: This is a cohort study with nested case-control analyses of consecutive Hodgkin survivors treated between 1974 and 2004 in multi-centre randomized controlled trials. A written questionnaire was developed and sent to 1849 male survivors. PARTICIPANTS/MATERIALS, SETTING, METHODS: Nine hundred and two survivors provided analysable answers. The median age at treatment was 31 years. The median follow-up after cryopreservation was 13 years (range 5-36). MAIN RESULTS AND THE ROLE OF CHANCE: Three hundred and sixty-three out of 902 men (40%) cryopreserved semen before the start of potentially gonadotoxic treatment. The likelihood of semen cryopreservation was influenced by age, treatment period, disease stage, treatment modality and education level. Seventy eight of 363 men (21%) used their cryopreserved semen. Men treated between 1994 and 2004 had significantly lower odds of cryopreserved semen use compared with those treated earlier, whereas alkylating or second-line (chemo)therapy significantly increased the odds of use; no other influencing factors were identified. We found an adjusted odds ratio of 2.03 (95% confidence interval 1.11-3.73, P = 0.02) for post-treatment fatherhood if semen cryopreservation was performed. Forty-eight out of 258 men (19%) who had children after HL treatment became a father using cryopreserved semen. LIMITATIONS, REASONS FOR CAUTION: Data came from questionnaires and so this study potentially suffers from response bias. We could not perform an analysis with correction for duration of follow-up or provide an actuarial use rate due to lack of dates of semen utilization. We do not have detailed information on either the techniques used in cryopreserved semen utilization or the number of cycles needed. STUDY FUNDING/COMPETING INTERESTS: Lance Armstrong Foundation, Dutch Cancer Foundation, René Vogels Stichting, no competing interests.

Effect of sitagliptin on glucose control in adult patients with Type 1 diabetes: a pilot, double-blind, randomized, crossover trial.

AIMS: Patients with Type 1 diabetes have significantly elevated postprandial glucagon secretion. Dipeptidyl peptidase IV inhibitors improve HbA(1c) by several mechanisms, including increasing glucagon-like peptide 1 and glucose-dependent insulinotropic peptide concentrations, which decreases postprandial rises in glucagon in both Type 1 and Type 2 diabetes. This study evaluates the clinical implications of sitagliptin in adult patients with Type 1 diabetes. METHODS: This investigator-initiated, double-blind, randomized, crossover, 8-week, pilot study enrolled 20 adult subjects with Type 1 diabetes. Subjects received sitagliptin 100 mg/day or placebo for 4 weeks and then crossed over. Outcomes included 2-h postprandial blood glucose and 24-h area under the curve changes in glucose measurements from continuous glucose monitoring, HbA(1c) , fructosamine and insulin dose. RESULTS: Sitagliptin significantly reduced blood glucose (2-h postprandial and 24-h area under the curve) despite reduced total and prandial insulin dose. Based on continuous glucose monitor findings, sitagliptin improved measures of glycaemic control, including mean blood glucose (-0.6 mmol/l; P = 0.012) and time in euglycaemic range 4.4-7.8 mmol/l (0.4 ± 0.2 h; P = 0.046). Significant reductions were also observed in M100, Glycemic Risk Assessment Diabetes Equation (GRADE) and J-index. After controlling for period, treatment and insulin dose, the HbA(1c) was also significantly reduced [-0.27 ± 0.11% (-2.91 ± 1.16 mmol/mol); P = 0.025] when patients were taking sitagliptin. CONCLUSIONS: Sitagliptin significantly improved overall glucose control, including postprandial and 24-h glucose control, in adult patients with Type 1 diabetes, while significantly reducing prandial insulin requirements. Further investigation is warranted in patients with Type 1 diabetes in a larger cohort designed to assess both clinical outcomes and mechanism of action.

Effects of colesevelam on LDL-C, A1c and GLP-1 levels in patients with type 1 diabetes: a pilot randomized double-blind trial.

AIM: colesevelam is indicated to lower low density lipoprotein cholesterol (LDL-C) in hyperlipidaemia and improve glycaemic control in adults with type 2 diabetes. This short-term pilot study evaluates its effects in type 1 diabetes. METHODS: this double-blind, randomized, investigator-initiated, single-centred, 12-week pilot study evaluated 40 adults (age = 36.4 ± 9.4 years) with type 1 diabetes (duration = 20.4 ± 8.5 years) and hyperlipidaemia. It was powered to show a treatment difference of >10% LDL-C reduction. Subjects received 3.75 g/day colesevelam (n = 20) or placebo (n = 20) for 12 weeks. LDL-C and haemoglobin A1c (A1c) levels were assessed at screening (week 2), baseline (week 0) and every 4 weeks throughout the treatment duration. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) levels were measured during 4-h meal (Boost Plus, Nestle HealthCare Nutrition Inc., Florham Park, New Jersey, USA) challenge tests (MCT) at baseline and 12 weeks. RESULTS: colesevelam treatment resulted in a significant reduction in LDL-C values at 4 weeks [-12.1% (95% CI: -20.1 to -4.1), p = 0.004] which was sustained for the study duration (p = 0.005 at 12 weeks). The treatment group also showed a significant change in A1c from baseline at week 4; however, this was not significant for the study duration. There was a significant median increase in GLP-1 levels during the first 2 h of the baseline MCT in the treated group but no difference at 12 weeks. CONCLUSIONS: during this short-term pilot study, colesevelam treatment effectively lowered LDL-C in patients with type 1 diabetes. Improvements in A1c seen at week 4 were not sustained. Effects on glycaemic control in subjects with type 1 diabetes may be related to a postprandial rise in GLP-1 levels and require further clinical study.

Model-free fMRI group analysis using FENICA.

Exploratory analysis of functional MRI data allows activation to be detected even if the time course differs from that which is expected. Independent Component Analysis (ICA) has emerged as a powerful approach, but current extensions to the analysis of group studies suffer from a number of drawbacks: they can be computationally demanding, results are dominated by technical and motion artefacts, and some methods require that time courses be the same for all subjects or that templates be defined to identify common components. We have developed a group ICA (gICA) method which is based on single-subject ICA decompositions and the assumption that the spatial distribution of signal changes in components which reflect activation is similar between subjects. This approach, which we have called Fully Exploratory Network Independent Component Analysis (FENICA), identifies group activation in two stages. ICA is performed on the single-subject level, then consistent components are identified via spatial correlation. Group activation maps are generated in a second-level GLM analysis. FENICA is applied to data from three studies employing a wide range of stimulus and presentation designs. These are an event-related motor task, a block-design cognition task and an event-related chemosensory experiment. In all cases, the group maps identified by FENICA as being the most consistent over subjects correspond to task activation. There is good agreement between FENICA results and regions identified in prior GLM-based studies. In the chemosensory task, additional regions are identified by FENICA and temporal concatenation ICA that we show is related to the stimulus, but exhibit a delayed response. FENICA is a fully exploratory method that allows activation to be identified without assumptions about temporal evolution, and isolates activation from other sources of signal fluctuation in fMRI. It has the advantage over other gICA methods that it is computationally undemanding, spotlights components relating to activation rather than artefacts, allows the use of familiar statistical thresholding through deployment of a higher level GLM analysis and can be applied to studies where the paradigm is different for all subjects.

Hippocampal granule cells opt for early retirement.

Increased excitability and plasticity of adult-generated hippocampal granule cells during a critical period suggests that they may "orthogonalize" memories according to time. One version of this "temporal tag" hypothesis suggests that young granule cells are particularly responsive during a specific time period after their genesis, allowing them to play a significant role in sculpting CA3 representations, after which they become much less responsive to any input. An alternative possibility is that the granule cells active during their window of increased plasticity, and excitability become selectively tuned to events that occurred during that time and participate in later reinstatement of those experiences, to the exclusion of other cells. To discriminate between these possibilities, rats were exposed to different environments at different times over many weeks, and cell activation was subsequently assessed during a single session in which all environments were revisited. Dispersing the initial experiences in time did not lead to the increase in total recruitment at reinstatement time predicted by the selective tuning hypothesis. The data indicate that, during a given time frame, only a very small number of granule cells participate in many experiences, with most not participating significantly in any. Based on these and previous data, the small excitable population of granule cells probably correspond to the most recently generated cells. It appears that, rather than contributing to the recollection of long past events, most granule cells, possibly 90-95%, are effectively "retired." If granule cells indeed sculpt CA3 representations (which remains to be shown), then a possible consequence of having a new set of granule cells participate when old memories are reinstated is that new representations of these experiences might be generated in CA3. Whatever the case, the present data may be interpreted to undermine the standard "orthogonalizer" theory of the role of the dentate gyrus in memory.

Fully exploratory network ICA (FENICA) on resting-state fMRI data.

Independent component analysis (ICA) is one of the most valuable explorative methods for analyzing resting-state networks (RSNs) in fMRI, representing a data-driven approach that enables decomposition of high-dimensional data into discrete components. Extensions to a group-level suffer from the drawback of evaluating single-subject resting-state components of interest either using a predefined spatial template or via visual inspection. FENICA introduced in the context of group ICA methods is based solely on spatially consistency across subjects directly reflecting similar networks. Therefore, group data can be processed without further visual inspection of the single-subject components or the definition of a template (Schöpf et al., 2009). In this study FENICA was applied to fMRI resting-state data from 28 healthy subjects resulting in eight group RSNs. These RSNs resemble the spatial patterns of the following previously described networks: (1) visual network, (2) default mode network, (3) sensorimotor network, (4) dorsolateral prefrontal network, (5) temporal prefrontal network, (6) basal ganglia network, (7) auditory processing network, and (8) working memory network. This novel analysis approach for identifying spatially consistent networks across a group of subjects does not require manual or template-based selection of single-subject components and, therefore, offers a truly explorative procedure of assessing RSNs.