Level of evidence used in recommendations by the National Comprehensive Cancer Network (NCCN) guidelines beyond Food and Drug Administration approvals.

BACKGROUND: A previous analysis of 113 National Comprehensive Cancer Network® (NCCN®) recommendations reported that NCCN frequently recommends beyond Food and Drug Administration (FDA)-approved indications (44 off-label recommendations) and claimed that the evidence for these recommendations was weak. METHODS: In order to determine the strength of the evidence, we carried out an in-depth re-analysis of the 44 off-label recommendations listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). RESULTS: Of the 44 off-label recommendations, 14 were later approved by the FDA and/or are supported by randomized controlled trial (RCT) data. In addition, 13 recommendations were either very minor extrapolations from the FDA label (n = 8) or were actually on-label (n = 5). Of the 17 remaining extrapolations, 8 were for mechanism-based agents applied in rare cancers or subsets with few available treatment options (median response rate = 43%), 7 were based on non-RCT data showing significant efficacy (>50% response rates), and 2 were later removed from the NCCN Guidelines because newer therapies with better activity and/or safety became available. CONCLUSION: Off-label drug use is a frequent component of care for patients with cancer in the United States. Our findings indicate that when the NCCN recommends beyond the FDA-approved indications, the strength of the evidence supporting such recommendations is robust, with a significant subset of these drugs later becoming FDA approved or supported by RCT. Recommendations without RCT data are often for mechanism-based drugs with high response rates in rare cancers or subsets without effective therapies.

Reward-related neural activity and structure predict future substance use in dysregulated youth.

BACKGROUND: Identifying youth who may engage in future substance use could facilitate early identification of substance use disorder vulnerability. We aimed to identify biomarkers that predicted future substance use in psychiatrically un-well youth. METHOD: LASSO regression for variable selection was used to predict substance use 24.3 months after neuroimaging assessment in 73 behaviorally and emotionally dysregulated youth aged 13.9 (s.d. = 2.0) years, 30 female, from three clinical sites in the Longitudinal Assessment of Manic Symptoms (LAMS) study. Predictor variables included neural activity during a reward task, cortical thickness, and clinical and demographic variables. RESULTS: Future substance use was associated with higher left middle prefrontal cortex activity, lower left ventral anterior insula activity, thicker caudal anterior cingulate cortex, higher depression and lower mania scores, not using antipsychotic medication, more parental stress, older age. This combination of variables explained 60.4% of the variance in future substance use, and accurately classified 83.6%. CONCLUSIONS: These variables explained a large proportion of the variance, were useful classifiers of future substance use, and showed the value of combining multiple domains to provide a comprehensive understanding of substance use development. This may be a step toward identifying neural measures that can identify future substance use disorder risk, and act as targets for therapeutic interventions.

Predicting clinical outcome from reward circuitry function and white matter structure in behaviorally and emotionally dysregulated youth.

Behavioral and emotional dysregulation in childhood may be understood as prodromal to adult psychopathology. Additionally, there is a critical need to identify biomarkers reflecting underlying neuropathological processes that predict clinical/behavioral outcomes in youth. We aimed to identify such biomarkers in youth with behavioral and emotional dysregulation in the Longitudinal Assessment of Manic Symptoms (LAMS) study. We examined neuroimaging measures of function and white matter in the whole brain using 80 youth aged 14.0 (s.d.=2.0) from three clinical sites. Linear regression using the LASSO (Least Absolute Shrinkage and Selection Operator) method for variable selection was used to predict severity of future behavioral and emotional dysregulation measured by the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M)) at a mean of 14.2 months follow-up after neuroimaging assessment. Neuroimaging measures, together with near-scan PGBI-10M, a score of manic behaviors, depressive behaviors and sex, explained 28% of the variance in follow-up PGBI-10M. Neuroimaging measures alone, after accounting for other identified predictors, explained ~1/3 of the explained variance, in follow-up PGBI-10M. Specifically, greater bilateral cingulum length predicted lower PGBI-10M at follow-up. Greater functional connectivity in parietal-subcortical reward circuitry predicted greater PGBI-10M at follow-up. For the first time, data suggest that multimodal neuroimaging measures of underlying neuropathologic processes account for over a third of the explained variance in clinical outcome in a large sample of behaviorally and emotionally dysregulated youth. This may be an important first step toward identifying neurobiological measures with the potential to act as novel targets for early detection and future therapeutic interventions.

Final results of phase II trial of doxorubicin HCl liposome injection followed by bexarotene in advanced cutaneous T-cell lymphoma.

BACKGROUND: High response rates for doxorubicin HCl liposome injection (DLI) in cutaneous T-cell lymphoma (CTCL) have been reported with vague criteria until recently. Approximately 50% of CTCL patients respond to bexarotene (Bex). PATIENTS AND METHODS: A phase II trial was carried out to clarify the true overall response rate (ORR) for DLI and to assess the role of sequential Bex. Patients were treated with DLI 20 mg/m(2) i.v. every 2 weeks for 16 weeks (8 doses) followed by 16 weeks with Bex 300 mg/m(2) orally. Response assessments were carried out after 16 (DLI) and 32 weeks (Bex). Skin responses were measured by the modified Severity-Weighted Assessment Tool (mSWAT) and the Composite Assessment of Index Lesion Severity (CA). RESULTS: Thirty-seven patients were treated: stage IV (22, 8 with Sézary syndrome), IIB (10), earlier stage refractory to skin-directed therapies or radiation therapy (5). For 34 assessable patients: ORR 14/34 [41%: partial response (PR) 12, clinical complete response (CCR) 2]. Maximum responses were all seen after 16 weeks DLI. Median progression-free survival (PFS) was 5 months. There were 22 deaths: 21 of disease and 1 of heart failure. Twenty-seven grade 3 and 5 grade 4 toxic events were observed. CONCLUSION(S): With strict criteria, DLI ORR is among the highest reported for single agents in CTCL. Sequential Bex did not increase the response rate or duration.

Behavioral and emotional dysregulation trajectories marked by prefrontal-amygdala function in symptomatic youth.

BACKGROUND: Neuroimaging measures of behavioral and emotional dysregulation can yield biomarkers denoting developmental trajectories of psychiatric pathology in youth. We aimed to identify functional abnormalities in emotion regulation (ER) neural circuitry associated with different behavioral and emotional dysregulation trajectories using latent class growth analysis (LCGA) and neuroimaging. METHOD: A total of 61 youth (9-17 years) from the Longitudinal Assessment of Manic Symptoms study, and 24 healthy control youth, completed an emotional face n-back ER task during scanning. LCGA was performed on 12 biannual reports completed over 5 years of the Parent General Behavior Inventory 10-Item Mania Scale (PGBI-10M), a parental report of the child's difficulty regulating positive mood and energy. RESULTS: There were two latent classes of PGBI-10M trajectories: high and decreasing (HighD; n=22) and low and decreasing (LowD; n=39) course of behavioral and emotional dysregulation over the 12 time points. Task performance was >89% in all youth, but more accurate in healthy controls and LowD versus HighD (p<0.001). During ER, LowD had greater activity than HighD and healthy controls in the dorsolateral prefrontal cortex, a key ER region, and greater functional connectivity than HighD between the amygdala and ventrolateral prefrontal cortex (p's<0.001, corrected). CONCLUSIONS: Patterns of function in lateral prefrontal cortical-amygdala circuitry in youth denote the severity of the developmental trajectory of behavioral and emotional dysregulation over time, and may be biological targets to guide differential treatment and novel treatment development for different levels of behavioral and emotional dysregulation in youth.

Inter-rater reliability of the Pediatric Transplant Rating Instrument (P-TRI): challenges to reliably identifying adherence risk factors during pediatric pre-transplant evaluations.

The purpose of this study was to assess the inter-rater reliability of the P-TRI, a 17-item instrument developed to identify risk factors associated with poor treatment adherence in pediatric solid organ transplant candidates. Because factors influencing treatment adherence may vary with age, the 89 subject samples were divided into pre-adolescent (0-11 yr) and adolescent (12-19 yr) groups. Each subject received two independent P-TRI ratings based on pretransplant psychosocial assessments separately conducted by a PSYC and a SWTC. Inter-rater reliability was assessed using the delta statistic. Overall, agreement was higher in the pre-adolescent group, with delta>0.70 for five items and delta<0.30 for two items. For the adolescent group, one item had a delta>0.70 and seven items had a delta<0.30. Overall, PSYC P-TRI ratings indicated fewer areas of concern on items assessing family dynamics compared with SWTC P-TRI ratings, whereas the reverse was true for items related to psychiatric history. Results highlight the challenges of conducting a reliable pretransplant assessment of adherence-related risk factors and suggest the need for revisions to the P-TRI prior to its use in clinical practice.

Diffusion imaging markers of bipolar versus general psychopathology risk in youth at-risk.

Bipolar disorder (BD) is highly heritable. Thus, studies in first-degree relatives of individuals with BD could lead to the discovery of objective risk markers of BD. Abnormalities in white matter structure reported in at-risk individuals could play an important role in the pathophysiology of BD. Due to the lack of studies with other at-risk offspring, however, it remains unclear whether such abnormalities reflect BD-specific or generic risk markers for future psychopathology. Using a tract-profile approach, we examined 18 major white matter tracts in 38 offspring of BD parents, 36 offspring of comparison parents with non-BD psychopathology (depression, attention-deficit/hyperactivity disorder), and 41 offspring of healthy parents. Both at-risk groups showed significantly lower fractional anisotropy (FA) in left-sided tracts (cingulum, inferior longitudinal fasciculus, forceps minor), and significantly greater FA in right-sided tracts (uncinate fasciculus and inferior longitudinal fasciculus), relative to offspring of healthy parents (P < 0.05). These abnormalities were present in both healthy and affected youth in at-risk groups. Only offspring (particularly healthy offspring) of BD parents showed lower FA in the right superior longitudinal fasciculus relative to healthy offspring of healthy parents (P < 0.05). We show, for the first time, important similarities, and some differences, in white matter structure between offspring of BD and offspring of non-BD parents. Findings suggest that lower left-sided and higher right-sided FA in tracts important for emotional regulation may represent markers of risk for general, rather than BD-specific, psychopathology. Lower FA in the right superior longitudinal fasciculus may protect against development of BD in offspring of BD parents.

Adherence to treatment and health outcomes.

Adherence (or compliance) is the extent to which a person's behavior coincides with medical or health advice. Recent evidence indicates that patients who adhere to treatment, even when that treatment is a placebo, have better health outcomes than poorly adherent patients. Based on this evidence, we now believe that the outcomes of treatment are not solely attributable to the specific action of a drug, but may also depend on other nonspecific therapeutic effects. We consider the implications of these findings for the design and interpretation of clinical research as well as for the care of patients.

A simple index to identify occult bacterial infection in adults with acute unexplained fever.

Patients with acute fever (less than three weeks' duration) and no localizing symptoms or physical findings to suggest a source (unexplained fever) may have self-limited illness or occult bacterial infection requiring prompt treatment. To develop a management strategy for patients with unexplained fever, we studied 880 adults who were evaluated for acute fever in an emergency room. At presentation, 135 (15%) patients had unexplained fever. Occult bacterial infection was found in 48 (35%) of these 135 patients, and 21 (44%) of 48 infected patients had bacteremia. Four bacteremic patients were incorrectly discharged from the emergency room without antimicrobial therapy. Neither a "toxic" appearance of the patient nor an initial temperature of greater than or equal to 39.4 degrees C (103 degrees F) were predictive of occult bacterial infection. An index of predictive features was developed that included: age 50 years or older; diabetes mellitus; a white blood cell count greater than or equal to 15,000/mm3 (15 X 10(9)/L); a neutrophil band cell count greater than or equal to 1500/mm3 (1.5 X 10(9)/L); and a Wintrobe erythrocyte sedimentation rate greater than or equal to 30 mm/h. In patients with 0, 1, 2, or 3 or more index features present, the proportions having occult bacterial infection were 5% (1/21), 33% (15/45), 39% (15/38), and 55% (17/31), respectively. All four bacteremic patients incorrectly discharged had two or more of the index features. Adults presenting with acute unexplained fever often have life-threatening bacterial infection. A simple clinical index can be used to estimate the likelihood of occult infection and may reduce the frequency of diagnostic error.

Documentation of discussions about prognosis with terminally ill patients.

PURPOSE: Previous studies have suggested the importance of communicating with patients about prognosis at the end of life, yet the prevalence, content, and consequences of such communication have not been fully investigated. The purposes of this study were to estimate the proportion of terminally ill inpatients with documented discussions about prognosis, describe the nature and correlates of such discussions, and assess the association between documented discussions about prognosis and subsequent advance care planning. SUBJECTS AND METHODS: Inpatients (n = 232) at least 65 years old who had brain, pancreas, liver, gall bladder, or inoperable lung cancer were randomly selected from six randomly chosen community hospitals in Connecticut. The presence and content of discussions about prognosis, advanced care planning efforts, and sociodemographic and clinical factors were ascertained by comprehensive review of medical records using a standardized abstraction form. RESULTS: Discussions about prognosis were documented in the medical records of 89 (38%) patients. Physicians and patients were both present during the discussion in 46 (52%) of these cases. Time until expected death was infrequently documented. Having a documented discussion about prognosis was associated with documented discussions of life-sustaining treatments (adjusted odds ratio [OR] = 5.8; 95% confidence interval [CI]: 2.8 to 12.0) and having a do-not-resuscitate order (adjusted OR = 2.2; 95% CI: 1.1 to 4.2). CONCLUSIONS: Among terminally ill patients with cancer, discussions about prognosis as documented in medical charts are infrequent and limited in scope. In some cases, such documented discussions may be important catalysts for subsequent discussions of patient and family preferences regarding treatment and future care.

Specialized assessments for children in foster care.

OBJECTIVE: To investigate the differences in health problems identified and health services received by children newly entering foster care who participated in a comprehensive multidisciplinary program, compared with children newly entering foster care who received customary community-based services. METHODS: Using a 2-group quasiexperimental design, 120 young children entering foster care were enrolled in a multidisciplinary intervention program (n = 62) or were followed by customary care providers (n = 58). An interview with the foster parent; a complete medical examination; and a battery of developmental, psychological, speech/language, and motor assessments were completed for each child at baseline. Children in both groups participated in follow-up assessments at 6 and 12 months. RESULTS: No significant differences between the 2 groups existed in medical, educational, developmental, or mental health problems identified by foster mothers. However, children in the intervention group were more likely to be identified with developmental (56.5% vs 8.6%) and mental health problems (37.1% vs 13.8%) by providers than children in the comparison group. Children in the intervention group were also more likely to be referred for health services at baseline (71.0% vs 43.1%) and receive follow-up care at 6 and 12 months of age than children in the comparison group. CONCLUSIONS: Findings indicate that community providers identify medical and educational needs but do not recognize developmental and mental health needs of young children newly entering foster care. The discrepancies in the number of recommended services and follow-up care between the 2 groups make a case for the establishment of specialized services for children entering out-of-home care.

Evaluating intensive family preservation programs: a methodological review.

OBJECTIVES: To determine the adequacy of evaluations of family preservation services (FPS), which are designed to support families and prevent out-of-home placements of children at risk of abuse or neglect, and to assess the effectiveness of FPS at reducing out-of-home placements of children. DATA SOURCES: References published from 1977 to 1993 were identified from a computerized search of databases for English-language publications using the key phrases "family preservation," "child abuse," and "family-based services." Unpublished references were identified by mail or phone from a listing of more than 200 programs in a national directory. SELECTION OF STUDIES: Of 802 references initially identified, 46 program evaluations were reviewed. Ten studies met the following inclusion criteria: (1) evaluated an intensive family preservation program, (2) included outcome data in the report, and (3) used a comparison group. Five were randomized trials, and 5 were quasi-experimental studies (nonrandomized). DATA EXTRACTION: Descriptive information about the programs and evaluations was collected. To determine methodological quality, two independent raters used a 15-item questionnaire to examine the assignment of families to treatment groups, the interventions provided, and the outcomes assessed. A composite score of 11 or greater represented an acceptable study, 6 to 10 represented an adequate study, and 5 or less represented an unacceptable study. RESULTS: Only two studies were rated acceptable, four were adequate, and four were unacceptable. Methodological shortcomings included poorly defined assessment of risk, inadequate descriptions of the interventions provided, and nonblinded determination of the outcomes. Rates of out-of-home placements were 21% to 59% among families who received FPS and 20% to 50% among comparison families. The relative risk of placement was significantly reduced by FPS in only two studies (one randomized trial and one quasi-experimental study). CONCLUSIONS: Despite current widespread use of FPS to prevent out-of-home placements of children, evaluations of FPS are methodologically difficult and show no benefit in reducing rates of out-of-home placements of children at risk of abuse or neglect in 8 of 10 studies. Consistent, methodologically rigorous evaluations are needed to determine the effectiveness of FPS and to guide social policy for high-risk children and their families.

School-age mothers: predictors of long-term educational and economic outcomes.

The long-term effects of school-age pregnancy were investigated in a 20-year follow-up of a cohort of women who were pregnant adolescents in the late 1960s. Of the 149 living young black primiparas in the original cohort, 121 (81%) were located and interviewed. At follow-up the study population ranged in age from 32 to 38 years, 68% were unmarried, 71% had finished high school, 82% were completely self-supporting, and 27% reported living in public housing. Long-term success, defined as currently employed or supported by a spouse and a high school education (62%) or its equivalent, was associated with six features: having completed more school prior to becoming pregnant (odds ratio [OR] = 18; 95% confidence interval [CI] 2.3, 139.5); participating more actively in a program intervention offered to these pregnant teenagers 20 years ago (OR = 11.11; 95% CI 1.54, 79.87); being in school with no subsequent pregnancy at 26 months postpartum (OR = 10.1; 95% CI 1.64, 62.07); feeling in control of one's life (OR = 5.4; 95% CI 1.36, 21.54) and little social isolation (OR = 8.24; 95% CI 1.56, 43.50) at 26 months postpartum; and lifetime fertility control defined as one or two children after the index child (OR = 14.19; 95% CI 3.28, 61.29). It is concluded that most former teenage mothers complete a reasonable amount of education and are economically self-sufficient.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification and management of psychosocial and developmental problems in community-based, primary care pediatric practices.

The importance of psychological and social issues for children's well-being has long been recognized and their importance in the practice of pediatrics is well documented. However, many of the studies looking at this issue have emphasized psychiatric problems rather than issues commonly referred to as the new morbidity. The goal of this research was to refocus interest on the problems of the new morbidity. This study examined the rates and predictors of psychological problems in 19 of 23 randomly chosen pediatric practices in the greater New Haven area. Families of all 4- to 8-year-old children were invited to participate and to complete the Child Behavior Checklist prior to seeing a clinician. Clinicians completed a 13-category checklist of psychosocial and developmental problems based on a World Health Organization-sponsored primary care, child-oriented classification system. Of the 2006 eligible families, 1886 (94%) participated. Clinicians identified at least one psychosocial or developmental problems in 515 children (27.3%). Thirty-one percent of the children with problems received no active intervention, 40% received intervention by the clinician, and 16% were referred to specialty services. Not surprisingly, children whose problems were rated as moderate or severe were twice as likely to be referred compared with children with mild problems. Recognition of a problem was related to four characteristics: if the visit was for well child rather than acute care; if the clinician felt he or she knew a child well; if the child was male; and if the child had unmarried parents (all P less than or equal to .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Psychological sequelae of medical complications during pregnancy.

To determine whether mothers with complicated pregnancies are at increased risk of postpartum depression and whether their children are at increased risk of being perceived as vulnerable, the investigators conducted an interview survey of mothers of 1095 children aged 4 to 8 in a community-based sample of primary care pediatric practices. The offspring were viewed as vulnerable by 17% of the women with severe pregnancy complications and 9% of the women without pregnancy complications (relative risk = 1.88; 95% confidence interval = 1.11, 2.63). Women with a severe complication of pregnancy were significantly more likely to report postpartum depression than those without a complication (27% vs 11%; relative risk = 2.45; 95% confidence interval = 1.55, 3.01). These relationships persisted after adjustment for prematurity, neonatal hospitalization, and demographic factors. It is concluded that pregnancy complications may place a woman at increased risk of postpartum depression and may have important effects on a mother's long-term perceptions of her child's vulnerability to illness.

Maternal employment, maternal care and pediatric visits for minor acute illnesses.

The purpose of these analyses, based on a prospective follow-up of 532 children, was to describe reported use of three maternal care actions for minor illness episodes, and to determine if maternal employment, as well as other sociodemographic factors, were associated with maternal care behaviors prior to each child's first pediatric acute-care visit. Two factors were associated with greater use of maternal care prior to an illness episode: the mother not working outside the home and less satisfaction with medical care. These results are consistent with the hypothesis that employed women with child-care arrangements are more likely than are other women to seek medical care for symptoms that are minor and can be managed with family-initiated care.

Physician gender and cesarean sections.

BACKGROUND: Among consumers insurers, and providers there is pervasive concern regarding the high incidence of cesarean section delivery. To date, attempts to reduce these rates have focused on the clinical behavior of providers resulting in only minimal changes. Therefore, non-medical variables must be investigated as potential explanatory factors for the decision to perform cesarean delivery. METHODS: Data were collected on clinical and non-clinical factors for obstetrician-gynecologists delivering at Yale-New Haven Medical Center to measure the impact of these factors on the performance of cesarean sections. Specifically, variation in patient demographic, ante- and intra-partum risk variables, practice setting, and doctor-specific characteristics were examined. Using contingency table and logistic regression analyses the contribution of selected factors was evaluated. RESULTS: Multivariate modeling revealed that male physicians were significantly more likely than their female colleagues to perform cesarean section. This relationship was particularly strong in the university practice setting. CONCLUSIONS: Efforts to reduce the incidence of cesarean section need to focus on the continuing education of health care providers and the delineation of non-clinical factors as essential elements in the election of specific clinical therapies.

The influence of psychological and social factors on accuracy of self-reported blood pressure.

The data reported here document levels of accuracy in reports of blood pressure and identify correlates of inaccurate reporting. The data come from a long-term follow-up of a cohort of African-American women who registered for antepartum care between September, 1967 and June, 1969. At the follow-up interview, these women were asked whether they had ever received a diagnosis of hypertension from a physician. The self-reports of hypertension were compared with information contained in the medical records of these women. Twenty-five percent reported having high blood pressure but 53% of these reports were unconfirmed by their medical records (overall misreporting rates was 15.9% with 2.5% underreporting and 13.4% overreporting). The factors related to misreporting included a psychiatric diagnosis (based on the Diagnostic Interview Schedule) of major depressive disorder or drug and/or alcohol abuse and a small social network. The conjunction of these three variables significantly affected accuracy of reporting (100% misreporting with all three variables). These results suggest that, using currently standard methodology, there is an unreliable subpopulation of respondents in health surveys that may require the collection of data on health status from a second source to confirm data from self-reported health measures.

Widespread growth retardation and variable growth recovery in foster children in the first year after initial placement.

OBJECTIVES: To determine children's growth patterns in the first year of foster care placement and to compare catch-up growth with initial height percentile as indicators of prior growth retardation. DESIGN: Inception cohort. SUBJECTS: Forty-five children aged 1 1/2 to 6.0 years in their first year of foster care. SETTING: Urban, community-based primary care center. MAIN OUTCOME MEASURES: Height, weight, weight-for-height, and annual growth velocity z scores 1 year after placement. RESULTS: The group entered foster care with an overall height deficit (height z = -0.21), grew at an above-average rate (velocity z = +0.33), and eliminated the height deficit by the end of the year (height z = -0.02; P < .05). Weight increased (baseline weight z = -0.16; year-end weight z = +0.35) and correlated with height z change (r = 0.385, P = .009). Weight for expected weight-for-height-age was above average and did not change (baseline weight for expected weight-for-height-age z = +0.30; year-end weight for expected weight-for-height-age z = +0.40). Baseline age correlated with velocity z (r = .413, P = .005) but not with change in height z. Baseline height z did not correlate with either velocity z or change in height z. Three patterns of growth were seen: 21 (47%) showed catch-up growth (height velocity z = 1.34; gain in height z = +0.61); 16 (36%) showed stable growth; and 8 (18%) showed poor growth (height velocity z = -1.49; decrease in height z = -0.49). CONCLUSIONS: Almost half of the children showed significant catch-up growth in the first year after foster care placement, indicating probable prior growth failure. Initial height was not predictive of future growth, and simple screening (such as height less than the fifth percentile) would have missed the majority of children who showed catch-up growth. A substantial minority (18%) continued to decline across height percentiles after placement. The initial and subsequent growth failure and catch-up growth in this population did not appear to be related to nutritional changes.