Living related kidney transplantation (LRT) is underutilized, particularly among African Americans. The effectiveness of informational and financial interventions to enhance informed decision-making among African Americans with end stage renal disease (ESRD) and improve rates of LRT is unknown.We report the protocol of the Providing Resources to Enhance African American Patients’ Readiness to Make Decisions about Kidney Disease (PREPARED) Study, a two-phase study utilizing qualitative and quantitative research methods to design and test the effectiveness of informational (focused on shared decision-making) and financial interventions to overcome barriers to pursuit of LRT among African American patients and their families. Study Phase I involved the evidence-based development of informational materials as well as a financial intervention to enhance African American patients’ and families’ proficiency in shared decision-making regarding LRT. In Study Phase 2, we are currently conducting a randomized controlled trial in which patients with new-onset ESRD receive 1) usual dialysis care by their nephrologists, 2) the informational intervention , or 3) the informational intervention in addition to the option of participating in a live kidney donor financial assistance program. The primary outcome of the randomized controlled trial will include patients’ self-reported rates of consideration of LRT .Results from the PREPARED study will provide needed evidence on ways to enhance the decision to pursue LRT among African American patients with ESRD.ClinicalTrials.gov NCT01439516 African Americans are less likely than Whites to receive kidney transplants, despite their up to four-fold greater likelihood to develop end stage renal disease (ESRD) . SeveralAfrican Americans’ poor awareness of the risks and benefits of LRT as well as their limited access to potential live kidney donors represent important potential barriers to their receipt of LRT . EvidencWe describe the protocol of a two-phase study in which we 1) developed informational and financial interventions to enhance African Americans’ shared and informed decision-making about LRT and 2) are currently testing the effectiveness of these interventions in a randomized controlled trial.The Providing Resources to Enhance African American Patients’ Readiness to Make Decisions about Kidney Disease (PREPARED) Study is a two-phase study to design and test the effectiveness of informational and financial interventions to overcome barriers to pursuit of LRT among African American patients and families. In Phase 1, we developed an informational intervention, including an educational video and handbook, to assist patients with new-onset ESRD and their families with informed decision-making regarding the choice of LRT and other renal replacement therapy options. We also developed a financial assistance intervention for potential live kidney donors identified by patients with ESRD, which we adapted from an existing national program . In PhasTo inform the development of informational interventions, we performed qualitative focus groups as well as directed interviews of patients with kidney disease and their family members. Full details have been previously published . We alsoThe informational intervention consists of an educational video and written handbook that we designed to assist patients with kidney disease  and their family members  with making informed decisions about LRT. The informational materials are intended to expose potential recipients and donors to a variety of experiences of others receiving various forms for renal replacement therapy, including LRT.The educational video features patients and their family members describing their experiences with LRT as well as with other forms of renal replacement therapy . The educational video also features medical professionals  describing positive and negative experiences patients could have with the various forms of renal replacement therapy. The written handbook provides a summary of scientific evidence describing the risks and benefits of LRT and other forms of renal replacement therapy in lay language. Together, the educational video and handbook promote shared and informed decision-making regarding LRT on the part of patients, their families, and health care providers by achieving commonly accepted goals for informational shared decision-making aids .We will offer potential recipients the opportunity to enroll their family members or friends  in a program that will reimburse potential donors up to $1600.00 for approved financial assistance through the study by submitting formal original invoices, receipts, and other documentation of their qualifying medical and non-medical expenses related to live kidney donation evaluation, donation, or convalescence (up to 10 weeks post live donor/LRT procedures). Qualifying expenses include travel/lodging, meals, incidental expenses , lost wages, and childcare costs incurred by the potential donor as part of: (1) donor evaluation, clinic visit or hospitalization, (2) hospitalization for the living donor surgical procedure, and/or (3) medical or surgical follow-up clinic visits or hospitalization within 90 days following the living donation procedure. Participants will be permitted to utilize the $1600.00 for multiple approved purposes, as long as the total reimbursement is not greater than $1600.00. Also, more than one potential donor may draw from these funds, as long as the total value of reimbursed expenses does not exceed $1600.00 per patient study participant. This program covers a broader array of expenses related to live kidney donation than other national programs and does not limit reimbursement of potential donors based on their personal incomes.We are currently conducting a randomized controlled trial to assess the individual and combined effectiveness of informational and financial assistance interventions to enhance rates of LRT. The combined intervention will be tested to detect any additive or multiplicative effects of the financial assistance intervention. Recruitment of study participants began in August, 2012. Figure Our population includes English-speaking African American patients with ESRD who are age 18 years or older and who have initiated dialysis within one year prior to study enrollment. We exclude participants if they have dementia (assessed in-person)  or if thWe recruit participants from academically affiliated and community-based dialysis centers in the Baltimore, MD metropolitan region, which we have selected to provide an adequate number of African American participants with new-onset ESRD. We recruit patients on-site from different dialysis centers on different days. We systematically rotate recruitment days at sites so variations in patient scheduling at all sites can be covered to achieve the maximum number of recruitment opportunities. Upon confirmation of their eligibility to participate, we randomly assign patients into intervention groups.Potential kidney donors only become aware of the financial assistance program through direct referral by enrolled study participants. Research study staff do not contact or attempt to contact any family, friends, or acquaintances of enrolled patient participants. Therefore, enrolled participants will be directed to contact study staff in the event they want to refer potential donors to the program. To be eligible to participate, potential donors must speak English and be 18 years or older. Once potential donors contact study staff, study staff arrange for a time to meet with the potential donor(s) in person and mail them the brochure describing the financial assistance program. At that time, study staff explain the financial assistance program to potential donors, including what they will be asked to do as part of the study. Potential donors are notified that participation in the financial assistance program offered by the study may preclude them from receiving financial assistance from any other program . If potential donors wish to participate in the financial assistance program, we obtain consent for their participation in the study using approved consent procedures.Using blind and secure allocation by computer, we randomly assign participants to one of three intervention arms: 1) control group ; 2) the informational intervention ; and 3) the informational plus the financial assistance interventions . Randomization is blocked by recruitment site to ensure equal allocation within each dialysis facility.Participants randomly assigned to receive Usual Care proceed with their clinical care in dialysis centers as already routinely implemented by their physicians. At study conclusion, participants will receive informational materials provided in PREPARED  after follow up assessments have been completed.Participants randomly assigned to the PREPARED program receive the informational intervention, which consists of an educational video and written handbook intended to be used together to inform patients’ decisions about their kidney disease treatment choices. These materials are provided to participants on a day when they do not receive dialysis in the dialysis center. Participants meet with trained research study staff during which time they are oriented to the book and watch the video. Study staff members also encourage participants to share the materials with their families and health care providers. Participants randomly assigned to the PREPARED plus Financial Assistance program receive the informational intervention at the time of enrollment in a similar fashion with a similar approach to the PREPARED assignment. In addition, participants in this group are invited to participate in the live kidney donor financial assistance program as described above.All patient participants enrolled in the study are assessed using an in-person questionnaire at the time of recruitment and a structured telephone interview at baseline, 1 month, 3 months, and 6 months. Trained study staff administer all telephone interviews. For the informational and financial intervention arms, participants are contacted via telephone to determine whether they have viewed the materials provided to them  again at home. Participants are also asked if they have shared or discussed the content of intervention materials with family members.The primary outcome of interest is patients’ pursuit of LRT over six months of follow up. This outcome is measured as participants’ achievement of at least one of six key steps toward pursuing LRT, including: 1) execution of patient-family discussions about LRT; 2) execution of patient-physician discussions about LRT; 3) initiation of the recipient evaluation for LRT; 4) completion of the recipient evaluation for LRT, 5) identification of a potential live kidney donor, and 6) being listed at a transplant center. Pursuit of LRT will be assessed via questionnaires administered via telephone questionnaire at baseline, 1 month, 3 months and 6 months follow-up time periods. For participants reporting being registered on a transplant waiting list, we will contact transplant centers to determine whether there have been any live donor inquiries on behalf of the participant. We will also assess whether patient participants receive LRT and whether patient participants’ family members inquire about or use the financial assistance program .Other measures include assessment of participants’ 1) knowledge of LRT; (2) interest in LRT; (3) perceived barriers to LRT; (4) preferred role in decision-making about LRT; (5) concerns about the risks of LRT to themselves and to donors -45; (6)  knowledgRandomly assigned intervention group  will be the main independent variable for intent-to-treat analyses. In our primary analyses, we will assess the proportion of participants in each group achieving at least one new LRT pursuit behavior over 6 months. We will use multivariable models (e.g. logistic regression) to assess differences in the odds of achieving LRT pursuit behaviors among study groups while adjusting for study site characteristics and other baseline characteristics found not to be balanced by randomization. Secondary analyses will include exploratory analyses among persons within subgroups defined post-randomization--for example, analyses among persons with greater versus lesser knowledge of LRT at baseline. We will conduct primary analyses under the assumption that data is missing at random, however, we will also perform sensitivity analyses based on other scenarios (i.e. patterns of missing data) to evaluate the robustness of our assumptions.We are aware of no other randomized controlled trials evaluating the effectiveness of informational (focused on shared decision-making) or financial interventions on commitment to LRT in incident dialysis patients. In our own work, an educational intervention resulted in patients’ greater pursuit of LRT  . Our ownInadequate resources to promote shared decision-making about LRT and financial barriers to live kidney donation may contribute to lower rates of LRT among African American compared to Whites -58. We dESRD: End stage renal disease; LRT: Living related kidney transplants or transplantation, PREPARED, Providing Resources to Enhance African American Patients’ Readiness to Make Decisions about Kidney Disease.The authors do not declare any competing interests.PLE contributed to the study design, intervention development, study conduct, and drafting and approval of the manuscript. NRP contributed to the study conception and design, intervention development, study conduct, and drafting and approval of the manuscript. HR contributed to the study conception and design, intervention development, study conduct, and drafting and approval of the manuscript. JA contributed to the intervention development and drafting and approval manuscript. PA contributed to the intervention development and drafting and approval of the manuscript. LLB contributed to the intervention development and drafting and approval of the manuscript. RCG contributed to the intervention development and drafting and approval of the manuscript. DCC contributed to the intervention development and drafting and approval of the manuscript. TSP contributed to the intervention development and drafting and approval of the manuscript. BGG contributed to the intervention development and drafting and approval of the manuscript. ND contributed to the intervention development and drafting and approval of the manuscript. LEB led the study conception and design, intervention development, study conduct, and drafting and approval of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/13/135/prepub


Targeting patients for multimorbid care management interventions requires accurate and comprehensive assessment of patients’ need in order to direct resources to those who need and can benefit from them the most. Multimorbid patient selection is complicated due to the lack of clear criteria - unlike disease management programs for which patients with a specific condition are identified. This ambiguity can potentially result in inequitable selection, as biases in selection may differentially affect patients from disadvantaged population groups. Patient selection could in principal be performed in three ways: physician referral, patient screening surveys, or by statistical prediction algorithms. This paper discusses equity issues related to each method. We conclude that each method may result in inequitable selection and bias, such as physicians’ attentiveness or familiarity, or prediction models’ reliance on prior resource use, potentially affected by socio-cultural and economic barriers. These biases should be acknowledged and dealt with. We recommend combining patient selection approaches to achieve high care sensitivity, efficiency and equity. Two major challenges are at play in the design of current and future health care delivery: the growing diversity of patient populations and the increasing burden of multiple long term conditions. The majority of persons 65 and older have multiple chronic conditions, and almost half experience functional limitations associated with chronic disease . MultimoProviding care for persons with multimorbidity requires a shift from the prevailing single-disease biomedical health care model, characterized by: lack of scientific evidence on treatments for patients with multiple conditions and deficiencies in teamwork, despite essential participation of professionals from various specialties . PatientThe ability of multimorbid care management programs to meet the needs of their target population is, at least in part, contingent on the way patients are selected for entering such programs. Inclusion of patient who are “too ill” and due to their overall morbidity might require other types of care  or “too healthy” and do not necessarily need intensive care management, will result in inefficiencies and possibly lack of ability to show program effectiveness.Patient selection – commonly called case finding – could in principal be performed in three ways: i) physician referral, ii) patient screening tools/Health Risk Assessment (HRA), or iii) statistical prediction of future outcomes. Primary care physicians’ referral decisions are influenced by a complex mix of patient, physician, and health care system characteristics, with no standardized approach to referral decision making . While pPatient screening tools provide a standardized approach for patient selection, based on the fulfillment of specific criteria. An additional virtue of screening tools is that they enable to incorporate information on patient characteristics with administrative and cost data to assess overall risk. Information collected via screening surveys can elicit information which may not be straightforwardly evident to the physician, whose referral is based mainly on clinical knowledge . SimilarPatient selection tools are commonly used in clinical practice for directing patients for receipt of appropriate health care services, mostly for single disease or single condition programs. Identification of patients for multimorbidity care management provides additional challenges. First, the types of conditions considered and the way multimorbidity is measured define the target population for the program. Measuring multimoridity using a limited set of conditions inevitably implies that selection is limited to patients with one or more conditions from that list. Whether, for example, mental health conditions and/or low prevalence conditions which might be more common in specific population groups, are considered, depends on these a-priori criteria. A “whole-patient oriented” view of disease is more accurate and equitable than an additive account of several conditions. The greater likelihood of occurrence, severity, and adverse effects of health conditions within certain population groups is compounded even further by multiple illnesses, multiple serious illnesses, and greater likelihood of adverse events from incompatible interventions . Thus, mAdditionally, multimorbid case finding may be based on a predetermined number and types of chronic conditions either by physician referral and/or screening tools like “Probability of Repeated Admissions” (Pra and Pra Plus)  or “Idenwillingness and ability to participate in care management programs that are able to mitigate their needs [Compared with physician referral, PM identify patients at higher risk of healthcare utilization but with lower care sensitivity, i.e. likelihood that preventive care will be successful in these cases. Care sensitivity implies three key dimensions: patients’ ir needs . A revieir needs .High-risk case identification is intended to tailor resources to patients who need them the most. While horizontal equity aims to achieve equal distribution of resources, vertical equity exists when people with greater needs are provided with greater resources . Thus, tThe attainment of equity, however, is contingent on the type of high-risk case identification measure used. Approaches that fail to account for the entire spectrum of morbidity may inaccurately reflect need , thus rePhysician identification for inclusion in care management interventions follows the rational of any medical referral, in which physicians/providers have the responsibility and prerogative to refer patients to services and treatments, according to need. Physicians have information on the entire health and health related needs of patients, often not captured in clinical or administrative databases ,25,26. PAnother danger of PM tools is in the potential for misuse – PMs may impede access to care for most vulnerable patients if using socioeconomic status as proxy for non-compliance and therefore non-selection into intensive care management . NonethePatient selection according to physician referral however, is prone to several types of biases. Standardized approaches like PM and patient screening identify patients based on objective criteria rather than relying on physicians attentiveness  or persoActive selection of eligible patients for multimorbidity care management is an equity issue. Each of the different case finding approaches provides opportunities for both increasing and decreasing equity in healthcare. Benefits of objective criteria for case finding in PM for example, may at least partly be outweighed by data inputs needs or ‘inequitable’ modeling algorithms. Conversely, physicians may be prone to select their more engaging patients for inclusion in intensive care management, overlooking patients with complex care needs with a history of lower care engagement which may be due to socio-cultural barriers to care. Therefore, health care providers and health authorities should be aware of equity issues whenever selecting multimorbid patients for tailored care management as any selection method principally comes along with not-selecting others, who may be in need of intensified care services. When non-selected patients are more likely to come from disadvantaged population groups (as demonstrated by the “inverse care” law [are” law ) equity To conclude, this overview of equity in multimorbid patient selection approaches suggests that combining different case finding approaches like PM and physician referral may help to overcome the pitfalls of each of the two ,25. AlthES is co-editor in chief of the International Journal for Equity in Health (unpaid). TF has no competing interests to declare.ES and TF conceptualized the paper, summarized the literature findings and drafted the manuscript. Both authors read and approved the final manuscript.


Large, simple, pragmatic, low-risk, maintenance treatment trials may seem straightforward to design, run and analyse. However, if trial case record forms (CRFs) are completed infrequently, the reliability of patient recall over these long time-periods is questionable, especially when recording individual incidences and severity of toxicities of specific interest to the trial. It is essential to know these detailed toxicities as it forms an indication of the reduced level of exposure when comparing treatment duration in a non-inferiority trial. Optimal methods of achieving accurate data are required.PERSEPHONE is an investigator-led phase III trial of trastuzumab treatment duration where patients on each trial arm are treated every 21 days for either 9 or 18 cycles of treatment. Treatments are administered in chemotherapy outpatient departments or at the patient’s home via Healthcare at Home Ltd. PERSEPHONE CRFs, which include all adverse events of interest, are completed by the site research team at the 3-monthly clinic visits where PERSEPHONE patients are routinely followed up for the first year following start of trastuzumab treatment.To optimise reporting, the PERSEPHONE team have developed Patient Diary Sheets which list the common expected toxicities. For each trastuzumab cycle, patients are requested to record how much they are ‘troubled by each of the possible side-effects’ using patient-friendly severity ratings .To date 1260 patients have been recruited into the PERSEPHONE trial with adverse event information summarised on over 10,000 trastuzumab doses. At the 3-monthly clinic visits, the site research team discuss the detailed patient diary information with the patient and accurately interpret the information into incidences of toxicities and relevant Common Terminology Criteria for Adverse Events (CTCAE) grades for entry onto the trial CRFs. The patient diaries are not entered onto the database for analysis as they are used solely as memory aids.Feedback from the clinical research teams at sites indicates that the method adopted in the PERSEPHONE trial appears to work well. The Patient Diary Sheet is indeed well received and utilised by the patients and reported as a very useful memory aid at clinic visits. Whilst it may seem counterintuitive to ask for additional data which will never be scrutinised by the PERSEPHONE trial team, the strength of the final data collected has been optimised by the use of these data triggers.


A negative sentinel lymph node (SLN) biopsy spares many breast cancer patients the complications associated with lymph node irradiation or additional surgery. However, patients at high risk for nodal involvement based on clinical characteristics may remain at unacceptably high risk of axillary disease even after a negative SLN biopsy result. A Bayesian nomogram was designed to combine the probability of axillary disease prior to nodal biopsy with customized test characteristics for an SLN biopsy and provides the probability of axillary disease despite a negative SLN biopsy. Users may individualize the sensitivity of an SLN biopsy based on factors known to modify the sensitivity of the procedure. This tool may be useful in identifying patients who should have expanded upfront exploration of the axilla or comprehensive axillary irradiation. In breast cancer, metastases to the axilla are associated with an increased risk of distant micrometastatic disease –3. SentiLike any diagnostic test, SLN biopsy can yield false-negative results. Several factors can affect the sensitivity of an axillary SLN biopsy . Large tlow-risk patients an SLN biopsy when the probability of nodal involvement is low [high-risk patients when used in combination with estimates of the false-negative rate of SLN biopsy to calculate the risk of having residual nodal disease in the setting of a negative SLN. We developed a nomogram that combines this probability of axillary disease with estimates of the sensitivity of SLN biopsy, to calculate the risk of residual axillary disease despite a negative SLN biopsy.Breast cancer risk calculators are being increasingly used to guide adjuvant systemic and local treatment –17. Usint is low . HoweverBayes' rule combines the pretest probability of a given diagnosis with results from a test with known sensitivity and specificity to yield a posttest probability of having the diagnosis. In this analysis, the pretest probability is the probability of having axillary disease prior to any nodal evaluation; the posttest probability is the probability of axillary disease given a negative SLN biopsy; the false-negative rate (1-sensitivity) of SLN biopsy can be estimated from In this setting, Bayes' rule takes the following form: Using this formula we can estimate the probability that a breast cancer patient has residual axillary disease despite a negative SLN biopsy. A Bayesian nomogram was constructed in MATLAB  using the mathematical relationship above. We used a range of pretest probabilities from 5 to 85% and a 4 estimates of sensitivity  for the SLN biopsy procedure.We created a Bayesian nomogram for the probability of axillary nodal involvement despite a negative SLN biopsy . The nomFor example, the nomogram can be used to calculate the risk of residual nodal disease in a 62-year-old woman who presents after a lumpectomy revealing a 1.5 cm, grade 2 invasive ductal carcinoma, hormone receptor-negative, with no lymphovascular invasion and an SLN biopsy yielding 3 negative nodes. According to the MSKCC model her risk of axillary disease prior to SLN biopsy is 19%. Assuming 95% for the sensitivity of SLN biopsy in this situation, the nomogram reveals that the probability of having residual axillary disease is 1.2%. Even if the sensitivity of SLN biopsy was assumed to be 85%, the posttest probability remains low at 3.4%.Likewise, the nomogram can be used to calculate the probability of residual axillary disease despite a negative SLN biopsy in a woman at higher risk of axillary involvement. A 64-year-old patient with a 2 cm, grade 3, hormone receptor-positive, invasive ductal carcinoma with lymphovascular invasion has a 62% pretest probability of metastases to the axilla based on her pathology. Using a sensitivity of 85% for SLN biopsy, the nomogram reveals that the probability of residual axillary nodal involvement is 20%. In other words, despite a negative SLN biopsy, she still has a 20% probability of finding metastatic disease with completion ALND. If the SLN biopsy procedure has a 95% sensitivity the nomogram reveals that the risk of additional axillary disease after a negative SLN biopsy decreases to 7.5%.The presence of axillary disease is the most important prognostic factor in breast cancer. Disease in the axilla can indicate biological aggressiveness and extent of tumor involvement, often suggesting systemic spread and the need for additional therapy. In addition, the link between locoregional disease control and overall survival in breast cancer has been firmly established by meta-analyses of randomized data . The potOur nomogram is intended to be flexible and enable increased personalization of cancer care. Specifically, our analysis is most applicable to two clinical scenarios and argues thatfor a patient who had a negative SLN biopsy, but still has a high posttest probability of axillary disease, comprehensive axillary radiation may be warranted;for a patient who has not yet undergone any axillary surgery, who has a high pretest probability of positive axillary nodes based on clinical features and who also has clinical characteristics that might decrease the sensitivity of SLN biopsy as in , expandeThese conclusions seek to limit overtreatment in the form of multiple surgeries (SLN biopsy followed by ALND) and undertreatment in the form of omission of axillary radiation in breast patients with high-risk disease. We created a nomogram to estimate the risk of residual axillary disease despite a negative SLN biopsy as a function of the sensitivity of the SLN biopsy procedure and the pretest probability of axillary disease prior to axillary evaluation. Our nomogram reveals that for patients with a high pretest probability of axillary metastases and factors associated with a lower SLN biopsy sensitivity, the posttest probability of axillary disease often remains high despite a negative biopsy. While SLN biopsy is the appropriate test for most breast cancer patients, a preemptive expanded assessment of the axilla may be a better choice for high-risk patients or in cases where an SLN biopsy is predicted to be less sensitive . after a positive SLN, our decision tool estimates the probability of nonsentinel axillary nodal disease without prior pathologic assessment of the axilla [In contrast to other probability calculators which estimate the risk of nonsentinel axillary nodal disease in a woman with breast cancer only e axilla –17, 21. In patients identified by the nomogram to have an unacceptably high-risk of residual axillary disease despite negative SLN biopsy, more aggressive preemptive exploration of the axilla will necessarily mean a higher risk of lymphedema, nerve injury and general surgical complications compared to SLN biopsy; nevertheless, with modern ALND where only levels I-II are removed, these risks are less than observed historically . AnotherUse of this nomogram after a breast biopsy is not expected to result in excessive axillary treatment because it is likely to slightly underestimate rather than overestimate the probability of residual nodal disease. This is because the MSKCC risk calculator used above to obtain a pretest probability of having nodal disease was validated with information from complete pathologic specimens whereas, in practice, physicians are likely to substitute incomplete biopsy specimens such as findings from core needle biopsy, resulting in underdetection (due to undersampling) of certain negative prognostic factors, such as lymphovascular invasion, multifocality, and higher-grade tumor areas, which if found, increase the probability of having nodal disease. Therefore, use of only biopsy information would lead to underestimation of the pretest probability of having axillary involvement, which in turn would lead to underestimation of the posttest probability when using the nomogram. Another possible source of error associated with the use of incomplete biopsy specimens is that tumor size estimate entered into the MSKCC risk calculator must be estimated indirectly, based on imaging. However, assessment of tumor size by MRI, mammography and ultrasound does appear to correlate well with size as determined by pathologic exam , 24. Although the recently published ACOSOG Z0011 and NSABP B-32 trials show similar rates of local control in both their SLN alone and ALND arms, the patients included in these trials were conservatively chosen and by definition had a low-risk profile , 25. ForFor high-risk patients systemic therapy recommendations are also unlikely to change based on the output of this nomogram, because many of the factors which prompt addition of adjuvant therapy are the same factors that increase the pretest  probability of having axillary disease. However, with regard to local management of the axilla, using this nomogram may change management, especially in light of the NCIC CTG MA.20 trial which included high-risk patients and suggests that residual untreated nodal disease may affect distant disease even in the absence of a clinically evident nodal recurrence. This nomogram is anticipated to apply to the small proportion of breast cancer patients who present with clinically high-risk disease. Randomized studies for this subset are difficult to perform because most breast cancer patients present with early-stage disease. Therefore, Bayesian estimation of risk based on a mathematically sound extrapolation from available data is especially useful in this clinical situation. Our nomogram is a particularly important tool for this group of high-risk patients because they may benefit from more extensive surgery or axillary radiation.


Epigenetic variation is likely to contribute to the phenotypic plasticity and adaptative capacity of plant species, and may be especially important for long-lived organisms with complex life cycles, including forest trees. Diverse environmental stresses and hybridization/polyploidization events can create reversible heritable epigenetic marks that can be transmitted to subsequent generations as a form of molecular “memory”. Epigenetic changes might also contribute to the ability of plants to colonize or persist in variable environments. In this review, we provide an overview of recent data on epigenetic mechanisms involved in developmental processes and responses to environmental cues in plant, with a focus on forest tree species. We consider the possible role of forest tree epigenetics as a new source of adaptive traits in plant breeding, biotechnology, and ecosystem conservation under rapid climate change. Epigenetics refers to the study of meiotically or mitotically heritable changes in gene function that do not result from changes in DNA sequence . In developmentally regulated genes, epigenetic marks allow switches in gene expression in response to developmental transitions and/or environmental cues. After sexual reproduction, uniparental expression of parental alleles, imprinting, is associated with discrete differentially methylated regions (DMRs) that act in a genome context-independent manner  gene expression during vernalization illustrates how environmental cues are perceived and translated into epigenetic marks that affect plant development . On the other hand, stable, that is, heritable, epialleles can occur naturally and might confer specific phenotypes. Examples in plants include floral symmetry in In contrast to the transient nature of many developmental epigenetic marks, those affecting TEs are more stable  have been considered as well . Notably, altered DNA methylation patterns were transmitted to the non-stressed progeny in this species and the potential role of stress-induced epigenetic inheritance in evolution has been discussed  have emphasized the relationship between response to environmental conditions and epigenetic phenomena. In Forest trees are long-lived organisms with complex life cycles, which must contend with a variable environment over their long lifetimes  and orchids of the Dactylorhiza majalis complex  can occur naturally in contrasting habitats and can exhibit striking differences in morphological traits , and a positive correlation was established among these variables in well-watered conditions  while clear DNA methylation differences existed between ecotypes that did not correlate with nucleotide sequence variation, but with their flowering time  was found to correlate with distinct DNA methylation patterns, but not with DNA sequence variation  epigenetic variation occurs in natural populations, ecotypes, and species; (2) this variation can correlate with naturally occurring phenotypic variation; and (3) there is a potential role for epigenetic variation in adaptation and potentially in evolution. Despite the commonalities that have emerged from these studies, many questions remain unresolved. For example, is epigenetic variation in natural populations a wide-spread phenomenon? Moreover, the key molecular mechanisms involved and how they are regulated remain to be determined. Finally, it remains unclear to what extent epialleles arise and how stable they are when considered in an evolutionary context , a decrease in global DNA methylation level and concomitant increase in acetylation of histone 4 were observed during bud burst when conditions were favorable for active growth. The opposite pattern , indicative of more repressive chromatin states, was detected during bud set when environmental conditions were less favorable for growth  support the involvement of DNA methylation in this process. Changes in global DNA methylation levels of up to 25% during maturation have been reported in this species  and mature (phyllode) morphology were observed in this acacia species when analyzing global DNA methylation levels in physiologically active apical buds of in vitro grown plant material. Here, the degree of DNA methylation was higher in juvenile than in mature tissue, and might be influenced by in vitro culture conditions  in addition to maturation-related processes  and might also reflect underlying mechanistic differences in the relationship between aging and epigenetic marks  methylation associated with greater repression of gene expression than was promoter methylation. In addition, Vining et al.  crosses, Scots pine, Larix spp., and longleaf pine (Dormling and Johnsen Betula pendula), a small-scale study within a population revealed a close genetic relationship between trees that had established in a year of similar temperature , DICER-LIKE 2 (PaDCL2), and SUPPRESSOR OF GENE SILENCING 3-LIKE (PaSGS3), as well as transposon-related genes, had altered transcript abundance in epigenetically different progeny with phenotypic differences in bud burst and bud set . This phenotypic variant, found in about five percent of regenerants, is characterized by abnormal inflorescence development and has been associated with global DNA hypomethylation, but not to changes in genomic structure or nucleotide sequence  regenerated by somatic embryogenesis. Genetic variation was investigated using single sequence repeat (SSR) markers, and epigenetic variability was assessed by methylation-sensitive amplified polymorphism (MSAP), a method to detect genome-wide but anonymous DNA methylation patterns. Contrary to predictions, after an initial increase, a decrease in both genetic and epigenetic divergence between leaves of regenerants and the ortet plant was observed after the culture had reached an age of about 10 weeks  have been developed in Pinus pinea), represent ideal study subjects. To separate heritable from non-heritable epigenetic variation , it is necessary to study, when available, clonally propagated genotypes, the progeny of different natural populations or maternal families in a common environment, and to use the resemblance of epigenetic patterns among relatives as an indication of epigenetic inheritance  represents a novel method to directly detect DNA methylation  using antibodies that recognize specific histone modifications, followed by either microarray hybridization (ChIP on chip) or by next generation sequencing (ChIP-Seq; Ku et al. Next generation sequencing technologies enable mapping of epigenetic modifications at single-base resolution. The nature and large amount of data generated by such technologies will demand new approaches in data analysis techniques. Inference of the methylation status of bisulfite-treated DNA by BS-Seq can be challenging as the data obtained do not exactly match the reference sequence. Consequently, both DNA strands must be considered separately, and methylation at a specific site can be a percentage rather than a total presence or absence. Nevertheless, a number of tools has been developed to facilitate these analyses and are now available for application to tree epigenomes (Chen et al. Drosophila melanogaster and in A. thaliana have substantially revised our understanding of chromatin (Roudier et al. versus a compacted, silent heterochromatin is likely to be an oversimplification of the real chromatin architecture. It appears that chromatin might be composed of several types differing in their epigenetic marks as well as in their nuclear localization and chromatin-associated proteins. These types could favor or prevent association with transcription factors, thus defining gene expression patterns. Whether these chromatin types exist in perennial species is not known, and the stability of these chromatin types in long-living organisms is to be established. Similarly, the maintenance of these types during clonal and in vitro culture propagation will give important clues about the effect of these biotechnologies on gene expression control.Many questions remain about the mechanisms and roles of epigenetic processes in enabling rapid adaptation of plants to their environment, especially in forest trees. Recently, genome-wide studies of chromatin-bound proteins and epigenetic marks in that is, non-coding highly repeated sequences get separated from low-copy sequence and transcriptionally active regions. The differential methylation of genic and non-genic regions observed across plant taxa may be involved in decreasing transcriptional “noise” (Rabinowicz et al. It has been observed that the induction of alternative epigenetic states not only triggers the formation of new epialleles but also promotes the movement of DNA transposons and retroelements that are very abundant in plant genomes (Mirouze and Paszkowski From an economic and ecological point of view, it is important to integrate information on epigenetic control of environmental and developmental processes in both forest resources management and breeding. In quantitative genetic studies, estimates of genetic variance over the total phenotypic variance are typically used to assess the heritability of a trait. Akin to other genetic characters, variance in epigenetic characters will contribute to genetic variance and/or phenotypic variance, but might go undetected in some studies, or might be confounded with normal Mendelian-based quantitative inheritance (Kalisz and Purugganan in vitro manipulation, it may be considered and utilized as a means to amplify or release epigenetic variation of value to breeding programs. Transgenic perturbation of epigenetic mechanisms might have similar effects; however, testing such effects using a transgenic approach with forest trees at a scale relevant to application and ecological variation are, at present, constrained by government regulations (Viswanath et al. Recent developments show that both energy efficiency and energy homeostasis, which are integral parts of yield, have an epigenetic component that can be directed and stabilized by artificial selection (i.e., selective breeding; De Block and Van Lijsebettens Genome perturbation, including epigenetic components, might be important for increasing the raw material for adaptive evolution under severe stress (Kalisz and Purugganan The analysis of the epigenetic processes in an ecological context, known as “ecological epigenetics” is set to transform our understanding of the way in which organisms function on the landscape. Forest trees offer excellent opportunities to examine some of the most compelling questions of ecological epigenetics (Bossdorf et al.


Key roles for connective tissue growth factor (CTGF/CCN2) are demonstrated in the wound repair process where it promotes myofibroblast differentiation and angiogenesis. Similar mechanisms are active in tumor-reactive stroma where CTGF is expressed. Other potential roles include prevention of hypoxia-induced apoptosis and promoting epithelial-mesenchymal transistion (EMT). CTGF expression in tumors has been associated to both tumor suppression and progression. For example, CTGF expression in acute lymphoblastic leukemia, breast, pancreas and gastric cancer correlates to worse prognosis whereas the opposite is true for colorectal, lung and ovarian cancer. This discrepancy is not yet understood.High expression of CTGF is a hallmark of ileal carcinoids, which are well-differentiated endocrine carcinomas with serotonin production originating from the small intestine and proximal colon. These tumors maintain a high grade of differentiation and low proliferation. Despite this, they are malignant and most patients have metastatic disease at diagnosis. These tumors demonstrate several phenotypes potentially related to CTGF function namely: cell migration, absent tumor cell apoptosis, as well as, reactive and well vascularised myofibroblast rich stroma and fibrosis development locally and in distal organs. The presence of CTGF in other endocrine tumors indicates a role in the progression of well-differentiated tumors. It is well established that connective tissue growth factor (CTGF/CCN2) is a key component in wound repair. A consensus for the role of CTGF in tumorigenesis, however, has been surprisingly difficult to reach despite studies in many tumor types and cell-lines. Directly opposing effects have been demonstrated in different tumor types and even within the same tumor diagnosis (summarized in Table 1). This review provides a brief summary of our current knowledge and treats possible explanations for discrepancies between studies. Extra focus will be given to ileal carcinoids, which express high levels of CTGF, as their unique phenotype and tumor behavior may provide a model for understanding CTGF function.Tissue-specific developmental programs are often reactivated in solid tumors and understanding CTGF's role in development may be relevant to its role in tumorigenesis. CTGF knockout mice die at birth due to skeletal defects in the ribcage that impair respiration . This phCTGF is a 349-amino acid polypeptide consisting of four domains  and collagen. In the same study, in the presence of C-terminal CTGF, proliferating fibroblast were observed, which neither express α-SMA nor produce collagen . This stIn vivo, full length CTGF is often glycosylated and this increases the molecular weight from 33 kD to 42 kD or more. This glycosylation may be important for function. For example, in a renal fibroblast cell line, overexpression of CTGF results in growth arrest, whereas exogenously added recombinant CTGF increased proliferation .We aimed to examine the role of CTGF in tumorigenesis. Medline articles, other reviews and citation lists in relevant articles were searched for studies on CTGF's expression in human tumor specimens, primary human tumor cell cultures, knock-out mice and normal tissue (see supplement for search terms). Articles were published between the years 1997-2010. Studies that only showed results from cell lines were excluded. CTGF expression in tumors tissue was compared to normal tissue. Studies were sorted according to the cancer type and endocrine phenotype and according to reported CTGF correlation to tumor progression.CTGF's role in tumor development can be divided into 3 categories seen in additional file The complicated nature of CTGF in tumor progression is evident in the group C tumors. In ovarian cancer, for example, CTGF is normally expressed in apical cytoplasm of normal ovarian epithelial cells. Gene methylation and reduced expression, in relation to normal cells, of CTGF is frequently observed in primary ovarian cancer tissues. High CTGF expression in early stage ovarian tumors appears to have a protective effect procuring prolonged survival but this must be verified in a larger cohort. In vitro studies on a panel of ovarian cancer cell lines support CTGF's putative tumor growth suppressive effect: in cells lacking CTGF, both exogenous restoration of expression and treatment with recombinant CTGF inhibited proliferation while knockdown of CTGF in cells with endogenous expression accelerated proliferation . SurprisFactors other than CTGF differ between the tumor groups. These factors may include the presence of other growth factors and posttranscriptional modifications of CTGF.Several potential functions for CTGF in tumor development in the group A tumors involve both direct action on the tumor cells and modification of tumor microenvironment. CTGF, in this manner, encourages tumor invasion, cell survival and angiogenesis.Metastases formation requires that the cell detach from the matrix and adopt cytoskeltal changes reminiscent of mesenchymal cells. Normally, detachment from ECM results in cell death, which must also be avoided for tumor development. The process of epithelial to mesenchymal transition (EMT), seen during embryonic development, describes the process where epithelial cells acquire a mesenchymal cell phenotype, which is more prone to migrate and invade. EMT is also thought to be a key component in both malignant epithelial tumor progression  and fibrA central part of CTGF's role in endothelial cell function and angiogenesis may involve direct interaction with integrins in mediating cell migration and to avoid cell death. Integrins anchor cells to the extracellular matrix and are involved in defining cell shape and motility and are even implicated in regulating cell cycle. CTGF stimulates integrin expression and is shown to bind directly to endothelial cell surface integrins ,21 to meCTGF is capable of up-regulating both matrix metalloproteinases (MMPs) and their inhibitors  and has the potential to activate both the synthesis and degradation of the extracellular matrix. Some tumors involve a desmoplastic reaction, a process that closely resembles chronic fibroproliferative disease that may serve to protect tumor cells from immune detection and chemotherapy. CTGF involvement in this process has been demonstrated in pancreatic cancer .Hypoxia is a strong inducer of CTGF expression. CTGF co-localizes with hypoxia marker CAIX and the CTGF promoter contains a recognition site for hypoxia growth factor, HIF ,24. In sIn some tumors (group B), CTGF may act as a tumor suppressor gene. In these cases, CTGF is often expressed in the normal cells and its expression decreases with the grade of malignancy. CTGF action in some tumors is also in sharp contrast to what is seen in others. For example, in lung cancer, CTGF appears to be acting through inhibition of phosphorylation of ERK1/2 ,14,27. CEndocrine tumors are rare hormone producing tumors derived from endocrine cells in many different organs in the body. Their common endocrine nature is the reason they are often grouped for study. They display, however, wide variations in symptoms, malignant potential and tumor biology and are classified according to the WHO classification scheme which sorts tumors according to primary tumor site, metastases development, hormone production and proliferation . Our stuIleal carcinoids, also known as midgut carcinoids, are serotonin producing endocrine tumors found in the small intestine and proximal colon. These tumors are particularity interesting as they ubiquitously express very high levels of CTGF  and provIleal carcinoids have a pronounced association with fibrosis development -35. FibrThe association between serotonin and CTGF is evident in the literature. Serotonin induction of CTGF expression in renal mesangial cells is accompanied by activation of serotonin receptor 5HT2A . SerotonIleal carcinoids maintain a high grade of differentiation and low proliferation. Despite this, they are truly malignant; most patients have metastatic disease at diagnosis and those who initially undergo "radical" surgery are frequently (50-80%) diagnosed with metastatic recurrence within 5-15 years -59. TherIt is generally presumed that ileal carcinoids are derived from serotonin producing enterochromaffin (EC) cells in the small intestine. Using double staining techniques, we have recently shown that while EC cells in the stomach are CTGF negative, both CTGF-positive and negative fractions of EC cells are found in the intestine . The funWhile the enterochromaffin-like cell carcinoids (ECL-CCs) displayed CTGF expression far lower than the ileal carcinoids, we were intrigued by the variation in expression between different types of ECL-CCs and the finding that CTGF immunoreactivity was strongest in tumor cells facing the fibrovascular stroma. CTGF expression is absent in normal enterochromaffin-like (ECL) cells and in foci of ECL-like cell hyperplasia. CTGF expression shows up first in the type I ECL-CCs larger than 5 mm, and its expression was correlated with a tumor size >1 cm. CTGF immunoreactivity in large type I ECL-CCs may be related to hypoxia, which occurs when tumor size exceeds the distance oxygen can diffuse into the tissue. CTGF is induced by hypoxia and is known to be a potent angiogenic factor (see above). CTGF and advanced tumor stage in well-differentiated ECL-CCs correlated but no correlation with serotonin expression was found. These results suggest that CTGF may be involved in initiating or promoting the neoplastic process. CTGF expression was absent in gastric poorly differentiated endocrine carcinomas (PDECs), and this may imply that CTGF is mainly involved in early pathogenesis becoming less important in the presence of further genetic aberrations and loss of differentiation.CTGF is not correlated to proliferation in ileal carcinoids whereas, in ECL-CCs, the correlation between CTGF expression and Ki-67 proliferative index is negative ,60. We hOur observations can be summarized as follows; CTGF is highly expressed in a subgroup of well-differentiated endocrine tumors. In these tumors, proliferation is generally low and the endocrine phenotype is apparent. CTGF is often, but not always, in conjunction with serotonin production and in cases where high expression of both is present, extensive myofibroblast-rich stroma is found. Abundant expression of CTGF in some tumor types seems to correlate with increased size and tumor stage. We believe that CTGF may be involved in early neoplastic processes that allow for advanced tumor stage and metastases development. In contrast to this, CTGF expression in the highly proliferative, PDEC is most often lost ,60. CTGFRegulating the TGF-β pathway has long been a goal for treatment of both cancer and fibrotic disease. TGF-β signaling is however more complicated than initially thought and strategies that block downstream events in the cascade may offer more selective effects. CTGF is potentially an important therapy target. Our understanding of its functions is still in the early stages and more knowledge is needed about its processing in vivo to reliably predict its function in vivo. CTGF has been shown to bind several receptors but there is to date no known CTGF-specific receptor.Results from animal models of cancer where CTGF signaling is blocked have shown promise. CTGF-specific antibodies (FG-3019) inhibit pancreatic tumor growth and metastasis in nude mice  as well The potential tumor suppressive effect of CTGF should not, however, be forgotten. Based on our current understanding, there is a risk that treatment which results in down regulation of CTGF may also remove its simultaneous tumor suppressive effects. Under this concept, there is an additional risk of stimulating development or progress of an additional tumor in another organ where CTGF has a tumor suppressive effect. This risk may be a limiting factor when deciding to treat other tumor forms with better prognosis than pancreas cancer.CTGF in the context of cancer is a clearly intriguing molecule and a potential candidate for therapeutic targeting. A full characterization of its regulation, in particular, understanding the determinates of its opposite actions in different cell-lines and cancer types is essential for predicting and preventing paradoxal tumor reactions.The authors declare that they have no competing interests.AJ and JLC have 1) made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; 2) have been involved in drafting the manuscript or revising it critically for important intellectual content; and 3) have given final approval of the version to be published.Summary of current knowledge concerning CTGF expression in tumors and corresponding normal tissues in relation to tumor progression.Click here for file


These pathological processes which evolve via different cell death mechanisms are discussed as a paradigm to apply MEA recording for detailed mapping of the functional damage and its time-dependent evolution.Microelectrode arrays (MEAs) represent an important tool to study the basic characteristics of spinal networks that control locomotion in physiological conditions. Fundamental properties of this neuronal rhythmicity like burst origin, propagation, coordination, and resilience can, thus, be investigated at multiple sites within a certain spinal topography and neighboring circuits. A novel challenge will be to apply this technology to unveil the mechanisms underlying pathological processes evoked by spinal cord injury (SCI). To achieve this goal, it is necessary to fully identify spinal networks that make up the locomotor central pattern generator (CPG) and to understand their operational rules. In this review, the use of isolated spinal cord preparations from rodents, or organotypic spinal slice cultures is discussed to study rhythmic activity. In particular, this review surveys our recently developed  Spinal cord injury (SCI) is one of the most prominent causes of severe disability worldwide, with lifelong devastating dysfunction, and high medical and social costs. Most of the six million SCI patients worldwide are of young age and for them the chances of recovery are very low  show good survival n Kiehn, . Chemican Kiehn, . In partn Kiehn, , fictiven Kiehn, , or othen Kiehn, , or by iThe CPG functional structure implies a series of interconnected oscillators with regular discharges organized into a rhythm (Selverston and Moulins, + and low Mg2+ (Streit et al., These studies suggested a common rhythm-generating network that can be activated in organotypic slices by different protocols that comprise disinhibition (with pharmacological blockers; Ballerini and Galante, The CPG networks that are genetically programmed to express locomotion often remain relatively intact following SCI which simply causes their disconnection from descending command centers (Meacham et al., in vitro survival of slices or isolated preparations. This is feasible study since, at least within the first 24 h after the primary lesion, the damage evolution progresses with similar properties in isolated preparations and organotypic cultures (Mazzone et al., In our laboratory, isolated spinal cord preparations of neonatal rats as well as spinal organotypic cultures have been used to investigate the molecular mechanisms involved in the delayed cell death of locomotor networks after acute experimental injury (Kuzhandaivel et al., Alternatively, the MEA could also be applied to freshly-cut spinal cord slices, in analogy to studies of rat neocortical and hippocampal brain slices (Becker et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This study examines obstetrician/gynecologists and family medicine physicians' reported care patterns, attitudes and beliefs and predictors of adherence to postpartum testing in women with a history of gestational diabetes mellitus.In November–December 2005, a mailed survey went to a random, cross-sectional sample of 683 Oregon licensed physicians in obstetrician/gynecologists and family medicine from a population of 2171.Routine postpartum glucose tolerance testing by both family physicians (19.3%) and obstetrician/gynecologists physicians (35.3%) was reportedly low among the 285 respondents (42% response rate). Factors associated with high adherence to postpartum testing included physician stated priority  and physician beliefs about norms or typical testing practices . Specialty, sex of physician, years of practice, location, type of practice, other attitudes and beliefs were not associated with postpartum glucose tolerance testing.Postpartum glucose tolerance testing following a gestational diabetes mellitus pregnancy was not routinely practiced by responders to this survey. Our findings indicate that physician knowledge, attitudes and beliefs may in part explain suboptimal postpartum testing. Although guidelines for postpartum care are established, some physicians do not prioritize these guidelines in practice and do not believe postpartum testing is the norm among their peers. Gestational diabetes mellitus (GDM) is an important public health concern as it increases the future risk of developing type 2 diabetes for both mother and child A systematic review of GDM patients from 1965–2001 found the cumulative incidence of type 2 diabetes increased markedly in the first 5 years after a GDM pregnancy and appeared to plateau after 10 years There is evidence that lifestyle modification can prevent or delay the development of type 2 diabetes in high-risk populations There are inconsistent recommendations for postpartum testing published by the American Diabetes Association (ADA) This study explores the extent to which physicians report performing impaired glucose tolerance testing in the postpartum period in one US state and explores physician characteristics, knowledge, attitudes and beliefs that may elucidate the observed sub-optimal follow-up care that has been previously reported.This cross-sectional study assessed physician knowledge, attitudes, beliefs and practice patterns regarding the care of women with gestational diabetes. A representative sample of Oregon physicians (MDs) holding active licenses with the Oregon Board of Medical Examiners in Family Medicine (FM) and Obstetrics/Gynecology (Ob/Gyn) received a survey at the end of 2005. The total population of MDs in these two specialties was 2171 (1614 FM and 557 Ob/Gyns). A disproportionate random sample of 750 MDs was selected using Stata Intercooled  with a larger proportion of Ob/Gyn physicians sampled to adequately represent the specialty that most often care for pregnant women. Three-hundred Ob/Gyn physicians and 450 FM physicians were sent surveys using a three pass method in which first a letter of explanation was sent with the initial survey, second a reminder postcard, and third a new cover letter and another copy of the survey over a three week period. This project was approved by the Institutional Review Board at Oregon State University.The survey was designed to examine physician care patterns both during pregnancy and in the postpartum period; the current study focuses on only the postpartum period. Physicians responded to statements regarding postpartum care knowledge following GDM on a five-point likert-scale  and additional statements reflecting their attitudes and beliefs about glucose testing in the postpartum period using a four-point likert-scale . Physicians also responded to one question about the priority of postpartum glucose testing on a four-point likert-scale . Likert-scale questions were further dichotomized for summary and analyses in the following manner: five-point likert-scale items never, rarely, sometimes to “no” while most of the time and always were dichotomized to “yes” the four point likert-scale items were dichotomized to “disagree” for strongly disagree and somewhat disagree while somewhat agree and strongly agree were dichotomized to “agree” and the four point likert-scale question regarding priority was dichotomized in the same manner as high and low. The survey questions were presented in a skip pattern format so that if a physician did not work with pregnant women they could skip to the questions regarding postpartum care. Physicians identified their practice area as rural, urban, or suburban based on their own perceptions rather than defined population parameters. All variables included in the analyses were self-reported including the physicians primary practice area. Multivariate logistic regression was used to examine factors that might explain differences in reported adherence to postpartum glucose testing. All analyses were carried out using Stata 11.2, College Station, Texas 77845 USA.A total of 285 of 683 eligible physicians participated in the GDM care survey, representing a response rate of 42%. Forty-five MDs did not participate because of inactive status or relocation. Twenty-two physicians identified their primary practice specialty as “other” and they were excluded from the analysis; of these 4 were licensed in FM and 18 in Ob/Gyn. FM physicians returned 166/383 completed surveys, a response rate of 44%, and Ob/Gyn physicians returned 119/300 completed surveys, a response rate of 40%.A summary of respondent demographic characteristics is shown in Logistic regression results  indicateWe found postpartum testing for women with a history of GDM was not routinely practiced in this statewide sample. Although guidelines for postpartum care are established, many physicians do not prioritize these guidelines in practice and do not believe postpartum testing is the norm among their peers. Our findings indicate that physician beliefs and attitudes partly explain suboptimal postpartum testing while other physician characteristics do not seem to influence practice patterns.et al. reported a 33.7% follow-up in a US academic center cohort et al.Although our study relies solely on self-reported physician practice patterns, suboptimal postpartum glucose testing was reported. Other studies examining postpartum testing have also found suboptimal postpartum glucose testing. A systematic review reported only half of women in most populations are screened The practice type to which a woman is referred for postpartum follow-up care may influence the likelihood of her receiving a glucose tolerance test. Russell et al. reported that women attending follow-up visits at a hospital-based clinic, as opposed to a hospital-affiliated community clinic, were twice as likely to complete the recommended postpartum glucose testing 1C, alone or combined with a fasting glucose test, compared to an oral glucose tolerance test for use in the postpartum period as a means of reclassify women with a history of GDM 1C test alone or in combination with fasting glucose was not sensitive or specific enough for diagnosis A lack of consensus regarding when to test, which test to perform, and who is responsible may create a barrier to postpartum testing. Although the American Diabetes Association guidelines The influence of respected peers may also be a barrier. Physicians may be aware of, understand and agree with clinical practice guidelines, but their decision to adopt and act on new information is often influenced by the perceived opinions of their respected peers Additionally, postpartum women may have their own set of barriers. Bennett et al. explored barriers and facilitators in a qualitative study with 22 postpartum women et al. reported that automated orders for follow-up testing in parallel with notifications to physicians and electronically generated reminders to patients by telephone and email may increase follow-up et al. reported that improved communication between patients and health care provider team are recommended A number of recent studies have explored factors that might increase screening Prevention measures are critical; women of reproductive age are currently experiencing increases in the prevalence of chronic diseases such as type 2 diabetes The main strength of this study is its investigation of practice patterns, including knowledge, attitudes and beliefs, among a random sample of physicians who are responsible for providing postpartum care to women with a history of GDM. Our study supports earlier evidence that poor clinical awareness of gestational diabetes, methods of testing and local guidelines affect the standard and consistency of care provided This study has the following limitations. First, the response rate is low but typical for physician surveys. Second, the study relies on self-reported practice patterns and, therefore, all questions may not have been answered truthfully, or responses could have been influenced by social desirability bias. Third, all physicians surveyed were based in a single US state and, therefore, the results may not be reflective of physician practice patterns throughout the US. Forth, the survey content may have limited the results as only physicians were assessed and therefore, we could not consider the influence of patient-related factors, organizational, structural, philosophical and financial barriers that may have affected postpartum glucose tolerance testing. Finally, data was collected a number of years ago, but despite this limitation, our findings seem to be supported by more recent studies which indicate testing is suboptimal, health practitioners continue to inform their patients that GDM is transient in some cases, and that postpartum screening is still not a universal norm.Postpartum glucose testing is low and this may be influenced by priorities in practice and practice norms. Clear, non-conflicting postpartum practice guidelines should be agreed upon and adopted to aid in removing potential barriers. Clear messaging to physicians would likely improve adherence to postpartum follow-up testing. Physicians may need help in understanding their role in the broader, public health system that aims to modify health risks and promote women's health.


SLC20A2 gene in families from China, Spain and Brazil, suggesting that Familial Idiopathic Basal Ganglia Calcification (IBGC) might be a phosphate imbalance disorder. Expressing wild-type human SLC20A2 and the mutated variants, using transport assays in Xenopus oocytes, resulted in significant impaired Pi transport. On the other hand, mutants did not have an obvious effect on the Pi transport activity when co-expressed with the wild-type PiT2 protein, encoded by SLC20A2. This suggests that such mutations have an effect through haploinsufficiency  concentration into the organism. Moreover, together with SLC20A1, these genes act at the Pi uptake under different conditions of pH and dietary Pi (Villa-Bellosta et al., Families affected with IBGC also show a variable clinical manifestation and a lack of full penetrance. Recent functional studies aiming to access the expression profiles of Calcification is an unspecific biochemical process occurring normally even under physiological conditions, through phosphate deposition and hydroxyapatite crystals formation, similar to the mineral fraction of the bones. However, disturbances in this process, which are often related to phosphate transport alterations at epithelial cells of blood vessels, lead to calcification around these tissues, jeopardizing the vessels' elasticity and leading to arteriosclerosis as well (Villa-Bellosta and Sorribas, Curiously, Wang et al.  and otheCaenorhabditis elegans. These analyses state that this phenomenon may occur due to mitigating mechanisms involving “genetic interaction partners,” that is, genes involved in common molecular networks (Burga et al., Other approaches to investigate the lack of full penetrance in genetic traits have been based on functional studies using the one-thousand-cells nematode On this perspective, two molecular mechanisms have been described: the first one involves a high expression of homologous genes, which because of its similar coding sequence, still bears related functions, enabling them to play the role which should have been done by the damaged gene. The other mechanism involves Heat Shock Proteins, which, by folding proteins into its biologically active conformation, ends up attenuating the effects of mutations along the peptidic sequence (Burga et al., Xenopus oocites lead us to speculate that in asymptomatic carriers of those deleterious mutations must have an altered pattern of expression of paralog genes. This assumption would be in accordance with the first mechanism described by Burga and colleagues (The haploinsufficiency effect described by Wang et al.  when explleagues . FunctioPrevious studies with clinical heterogeneity of familial IBGC shows that ~40% of the patients carrying basal ganglia calcification do not show symptoms. We reported previously that symptoms were present in only 28 patients with IBGC, from a total of 47 subjects with calcifications detected during a linkage analysis of 6 families (Oliveira et al., We suggest considering two levels of penetrance in IBGC: one for the calcification formations and another for the clinical manifestation but only a proper follow-up of asymptomatic subjects with calcifications will detect the exact timing of the appearance the first symptoms and will define the limits of brain resilience to calcifications. An animal model will most likely provide this answer.The concept of brain resilience is intrinsically associated to IBGC pathophysiology, since this is the most probable mechanism underlying the absence of clinical manifestations pathogenic SCL20A2 mutation carriers. This lack of concordance between the genetic and phenotypic statuses, gives rise to the probabilistic concept of penetrance in human genetics, that is, the likelihood of a given damaging genotype turns out to develop a clinical entity in its carriers.As for IBGC, the concept of incomplete penetrance should be further elaborated, in order to better categorize phenotipically the individuals present in a given heredogram. On this perspective, we propose the term “radiological penetrance.”Imaging genetics is a promising strategy to integrate genotypic and phenotypic data and more studies—especially those focusing brain imaging in asymptomatic IBGC carriers—are necessary to properly test such hypotheses.


Brain plasticity allows the central nervous system of a given organism to cope with environmental demands. Therefore, the quality of mental processes relies partly on the interaction between the brain’s physiological maturation and individual daily experiences. In this review, we focus on the neural implementation of musical expertise at both an anatomical and a functional level. We then discuss how this neural implementation can explain transfers from musical learning to a broad range of non-musical cognitive functions, including language, especially during child development. Finally, given that brain plasticity is still present in aging, we gather arguments to propose that musical practice could be a good environmental enrichment to promote cerebral and cognitive reserves, thereby reducing the deleterious effect of aging on cognitive functions. To adapt to changing environmental requirements, the brain has structural and functional dynamic properties that allow regularities to be encoded and skills to be learned and refined through regular practice . In retuMastering a musical instrument is a particularly complex multimodal and multiprocesses behavior because it requires a theoretical learning of the solfeggios rules, as well as a repeated training for translating visual codes (the written scores) into precise motor sequences and auditory events . MusicalIn this article, we review (1) the structural plasticity effects induced by musical practice, to point out that they can be located in general cognitive related-areas outside the auditory-motor domain; (2) the functional differences that exist between musically naïve and musically trained subject when they perform auditory-motor tasks, to show that trained subjects can rely on general cognitive processes when the task become harder; (3) the transfers effect that occur from musical practice toward other cognitive functions, because it justify the use of music, notably in rehabilitation program for developmental disorders or brain injuries. Finally, (4) we present works and arguments to suggest that musical practice could also be encourage as a particularly good environmental enrichment to promote a successful brain aging.Structural brain plasticity phenomenon  can be longitudinally and cross-sectionally recorded in human using morphometric method of MRI data analysis . In a loCross-sectional studies conducted with adult expert musicians have confirmed this anatomical brain shaping on several occasions. Adult violinists have a more highly elaborated topographic representation of their left hand in the right somatosensory cortex . MoreoveStructural brain plasticity phenomenon also appears to take place in white matter tracts. The corpus callosum exhibits enlargement in musicians because they engage more frequently in bimanual behavior , and posTo resume, performing music involves elaborated, coordinated, and rules-based motor, auditory, and visual skills. Regular musical training therefore leads to an anatomical shaping of auditory, motor and visual-related areas, but some results showed that brain regions involved in more general non-musical cognitive processes, such as language, attention, or executive functions, are also affected by musical training-related structural plasticity . This inanatomical remodeling of auditory and motor-related areas, as they also exhibit functional brain differences with non-musicians when they perform tasks similar to music exercises .The impressive auditory skills and manual dexterity of musicians are not solely explained by the fMRI studies have shown that when professional pianists and violinists are asked to perform complex uni- or bi-manual tapping tasks, they exhibit reduced activation of the primary and secondary motor areas  as well Regarding auditory skills, once again, besides the structural shaping of the auditory areas, particularities in neural responses have been recorded when expert musicians process musically relevant auditory stimuli. They have an enhanced cortical representation of the musical scale tones in the tonotopic map of the auditory cortex  that leaMusicians’ enhanced cortical representations of musical rules turn also in a pre-attentive memory-based processing for musical sound encoding, maybe through the auditory corticofugal pathway. Indeed, modulations in both cortical and subcortical electrophysiological responses to the perception of musical irregularities have even been recorded when musicians’ attention is diverted away from the stimuli. It is reflected in the appearance or increase of the MisMatch Negativity (MMN) component in the auditory cortex of musicians versus non-musicians when they are exposed to a melodic contour or interval change , and in Concerning the subcortical level, musicians display faster neural synchronization and stronger brainstem encoding of chord arpeggios in both in tune and out of tune conditions. Interestingly, the magnitude of the brainstem response is predictive of the participants’ performances in a pitch discrimination task .Neuroimaging studies using fMRI have also been designed to explore whether musically trained individuals process the auditory aspects of music differently from non-musicians. When they are passively exposed to music or have to judge whether chords are consonant or dissonant, musically trained participants display a right to left shift in the activation of auditory temporal areas  and fronMoreover, musical expertise also leads to an auditory-motor coupling, as reflected by the activity displayed within the primary motor cortex when musicians hear a piece they have learned to play . ConversTo sum up so far, the expert auditory and motor performances of musicians are sustained by the functional reorganization of typical underlying neural processes, due to automation and better memory-based (top-down) processing. This makes the basic auditory and motor skills less costly for musicians, thereby allowing them to allocate resources to strategic processes when tasks become harder. Similar effects have also been observed for expert performance in other activities such as object and pattern recognition by chess master players  or workiMusical hearing and practice seem not to be sustained by specific brain areas, but involve rather general pre-existing skills and cognitive functions. As musical learning put a high demand on it, it can result in transfers of improvements from one activity (music making) to others .There is a longstanding debate about the division or sharing of the brain substrates of language and music. Although some famous neuropsychological cases of double dissociation have been reported , we knowAlthough they are less central to language than to music, pitch modulations are still important for speech in order to convey emotion. Cross-sectional , and lonMusicians also process the temporal features of speech sounds differently than non-musicians. Faster cortical neural responses to voice onset time, as well as to vowel or syllable duration, have been attested both attentively and pre-attentively for children who take part in music lessons . As elecApart from the benefit of perceiving prosody in native and foreign languages, phonological awareness is also crucial for learning tone languages , hearingAnother point that music and language have in common is that they consist of auditory elements that unfold over time according to complex rules referred to collectively as syntax. Although the neural representations of these regularities are stored in different parts of the brain, their processing requires the same limited neural resources, allowing for transfer effects . When exWe have seen that regular musical training results in the reinforcement of auditory-motor coupling. This coupling is also essential for speech, and its stimulation through musical practice seems to contribute to the rehabilitation of stroke patients with language impairments .Finally, it seems that the short-term storage and manipulation of speech relies partly on the same neural networks and cognitive mechanisms in working memory as music . RegardiTo conclude, it appears that the brain areas thought to be dedicated to language and speech processing are rather involved whenever a behavior calls for fine-grained auditory analysis and implies an auditory motor coupling. Because musical experts rely on these brain mechanisms to process and play music, it turns to implications of language-related areas for processing music and to transfers from musical practice to language processes.executive functions, serve all the other cognitive domains and all kinds of learning. Accordingly, just like school learning does, taking music lessons as an out-of-school activity should enhance IQ in a non-specific manner  into account,c manner .To conclude, according to some authors, taking music lessons during childhood seem to act as a particularly powerful environmental enrichment to potentiate all cognitive development through the potentiation of general cognitive resources such as executive functions.Brain reserve is based on the brain’s anatomical characteristics and the fact that a higher gray matter volume counteracts atrophy and delays the appearance of the first clinical symptoms. Cognitive reserve refers to neurocognitive mechanisms, such as enhancing the efficiency of the brain networks engaged to carry out a task, or using either supplementary or entirely alternative networks, reflecting recourse to compensatory strategies. These functional changes must allow maintaining efficient cognitive performances in the face of age-related physiological disturbances  Musurbances  that greurbances  and reguurbances . Interesurbances  and synaurbances , as wellurbances . But theAt this moment, to our knowledge, only two studies have focused on the influence of musical practice on cognitive aging quality. One study, comparing professional musicians with amateur musicians and control participants aged from 60 to 83 years old, revealed that performances on the deferred recall of a geometrical shape, verbal denomination, and executive function tasks differed significantly in favor of professional musicians, with the amateur musicians’ performances lying midway between those of the professional musicians and the controls . As it hTo resume, among others determinants, socio-cognitive lifestyle behavior influences the quality of cognitive aging, through brain and cognitive reserve potentiation. We think that theoretical arguments  as well as empirical results from studies conducted with children and adults subjects must encourage works aiming at validate its use in the field of aging [as done byTo conclude, music is built on and constrained by the human brain and its cognitive capacities. Becoming a musician places a heavy demand on these capacities, in engaging them simultaneously and in a coordinated manner. Through regular practice, behavioral improvements are sustained by anatomical and functional brain changes, as well as by the application of strategic processes. Transfers occur from regular musical practice to non-musical skills, such as language, that rely upon the same neural resources and cognitive mechanisms. Moreover, during childhood, some authors argue that music lessons act as a particularly comprehensive source of environmental enrichment for promoting general cognitive development, perhaps through executive functions potentiation.During aging, the main cognitive difficulties seems to deal with executive processes , therefoThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This paper reviews evidence on the neural basis of how positive mood states can modulate cognition, particularly during creative problem-solving. Studies performed over the past few decades demonstrate that individuals in a positive mood engage in a broader scope of attention, enhancing their access to distant and unusual semantic associations, and increasing task-shifting and problem-solving capacities. In this review, we summarize these behavioral studies; we then present recent findings on the changes in brain activation patterns that are induced by a positive mood when participants engage in problem-solving tasks and show how these relate to task performance. Additionally, we integrate findings on the neuromodulatory influence of positive mood on cognition as mediated by dopaminergic signaling in the prefrontal cortex and we describe how this system can go awry during pathological states of elevated mood as in mania. Finally, we describe current and future research directions using psychotherapeutic and real-time fMRI neurofeedback approaches to up-regulate positive mood and facilitate optimal creative cognitive performance. We conclude with some speculations on the clinical implications of this emerging area of research. When Abraham Lincoln said, “People are just as happy as they make up their minds to be,” he was suggesting that happiness is a state of mind which to a certain extent is under our control. This is an important point since happiness is arguably the single most important factor for enhancing life satisfaction and success  was created by Mednick  to invesWe modified Mednick's  RAT taskInsightful problem solving requires engagement of cognitive control mechanisms involved in task switching and alternate response selection because there is frequently an impasse where solvers feel stuck, and believe they are making no progress toward the solution. To overcome this impasse, solvers need to inhibit prepotent albeit irrelevant associations in order to allow access and integration of remote yet solution-relevant concepts. Solvers are then able to suddenly recognize connections that had previously eluded them, and instantly see the solution in a new light in the “Eureka!” experience. Therefore, insightful problem-solving requires inhibition of task-irrelevant but prepotent responses, as well as task-switching to broader but non-dominant solution-relevant associations  solved more CRA problems overall, and specifically solved more CRA problems with insight, compared to college students lower in assessed positive mood. We also found that a positive mood was associated with increased brain activity in the medial prefrontal region during a preparatory interval preceding each solved problem. A positive mood was correlated with stronger preparatory signal that led to insight vs. analytical solutions, thus biasing participants toward insightful problem-solving; it appears that increased mPFC activity was associated with greater prefrontal cognitive control, which in turn allowed solvers to switch between broad attentional modes (required for detection of distant remote solution candidates) and focused attention for response selection (required to converge upon the correct solution).Consistent with this interpretation, Baumann and Kuhl  demonstrSwitching can occur between global and local modes of attention, and also between strategies  problems . Metaphoric comprehension is considered a type of creative cognition, and involves linking previously unassociated meanings in order to create a new understanding of one item in terms of another . According to the Gradient Salience Hypothesis  as well as novel (unfamiliar) metaphors . Conventional metaphoric processing involves recalling a familiar closely-connected meaning  represents a neural correlate of positive mood, nor that positive mood states will always benefit cognition. We also do not mean to suggest that the mPFC is the only brain region which mediates positive mood-cognition interactions. Indeed, other regions such as the basal ganglia—that are central to both cognition  thinking, it is important to note that Rowe et al.  demonstrChermahini and Hommel  investigThe investigators found that the positive mood induction increased EBR and increased flexibility on the divergent thinking task compared to baseline. The more positive participants became, the more flexible they were on the divergent thinking task and the more their EBRs increased. These results indicate that the changes in EBR  induced by a positive mood were related to the increases in flexibility. This relationship was not found for the negative mood condition. Interestingly, upon closer inspection, when the investigators conducted a median split of EBR at baseline, they found that the induction of a positive mood improved flexibility in the low-EBR group only. These data indicate that the relationship between positive mood, dopamine tone, and creative problem-solving is non-linear, and suggest that positive mood induction methods might have the most cognitive impact on individuals who have low basal dopamine tone.To extend upon Chermahini and Hommel's  study, wBy contrast, positive mood inductions in individuals with abnormally high states of elevated mood, such as occurs during a manic episode, would be contraindicated, as this would contribute to further impairment in already impaired cognitive control processes Figure . IndividA number of behavioral interventions have been developed from the “positive psychology” model, and include: practicing optimistic thinking, increasing attention and memory of positive stimuli and experiences, practicing mindfulness and acceptance, and increasing socializing behaviors. Sin and Lyubomirsky  conducteIn the past few years, a novel approach to positive mood interventions has emerged which allows for participants to volitionally up-regulate positive mood states via neurofeedback techniques such as real-time fMRI. Participants can be trained to voluntarily control neural fMRI signal from target regions implicated in positive emotional processes ? Only carefully designed mood-induction studies, as well as probes into mood, reward responsivity, and creative problem-solving across different behavioral phenotypes, can answer these questions.Another caveat in terms of the existing literature is the chicken-and-egg question of which mechanisms are primary and which are secondary. Does adopting a positive mood state induce increased dopaminergic tone in prefrontal regions and enhance access to distant semantic associations? Or do individuals with broader and more rapidly accessible semantic association networks tend to exhibit positive mood states? Or are both of these phenomena— a certain We also need to add a word of caution about potential clinical applications. It may very well be the case that inducing a positive mood with the goal of enhancing more far-ranging semantic associations could be deleterious in the case of people predisposed to mania or to schizophrenia. In the former, one might precipitate an actual manic episode (as can happen when such people are treated with antidepressants). In the latter, one might worsen symptoms of thought disorder, since some forms of schizophrenia are in fact characterized by the presence of too many broad and maladaptive associations. Sometimes, too much “creativity” can be deleterious.It is highly likely that people can learn—through a variety of methods—to increase their positive mood volitionally, using a range of straightforward behavioral techniques, and also through real-time fMRI neurofeedback. The question will be: For whom are these approaches most beneficial? And how should they be combined with other approaches in order to maximize healthy functioning and well-being? Enhancing broader semantic associations and greater cognitive flexibility may be very useful for a person with cocaine addiction who is in an active treatment program learning new critical psychosocial skills, but may be very maladaptive for the same individual when they are in their “using” environment. A depressed individual with low motivation and many perseverative ruminations about past failures may benefit greatly from mood enhancement that broadens their scope of attention and facilitates examining alternative interpretations through cognitive behavioral therapy. But absent such psychological treatment, the same broadening of attention may lead the depressed individual to contemplate various methods of self-harm/suicide as a viable alternative.We have entered a new era in our understanding of how to optimize learning in educational environments, and interestingly, it is an era that recognizes the importance of developing creative problem-solving capacities, rather than simply drilling the rote memorization of facts and figures. We now understand that critical learning occurs best in social contexts, under conditions of high intrinsic motivation, and is facilitated by appropriate rewards—all conditions that generate and sustain positive mood states. In the coming years, we can look forward to an even more knowledgeable and nuanced grasp of how to use these positive moods to help learners develop their skills as innovative and creative problem-solvers.Similarly, there is a sea change in our approach to facilitating health and well-being in individuals with psychiatric illness. In the past decade, the field of mental health treatment has embraced a model of autonomy, dignity, and recovery for people with psychiatric illness; this has generated a growing emphasis on preventive interventions, on the techniques of positive psychology, and on developing therapies that go beyond the palliation of symptoms and that instead generate optimal well-being and community functioning. With a new focus on the important role that expectation and motivation play in the recovery process, and with a greater understanding of the many behavioral elements that can induce positive changes in mood state, we can expect to become even more refined in our ability to create mood-enhancing interventions to help individuals engage in adaptive problem-solving and creative skill-learning and coping.Finally, the nascent but rapidly growing area of computerized cognitive training for psychiatric illnesses is moving in the direction of “gamification”—adapting the techniques of game developers and interactive software experts to make the cognitive training as engaging, fun, and rewarding as possible (Vinogradov et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.