Metabolic control during the neonatal period in phenylketonuria: associations with childhood IQ.

BACKGROUND: In phenylketonuria, treatment and subsequent lowering of phenylalanine levels usually occur within the first month of life. This study investigated whether different indicators of metabolic control during the neonatal period were associated with IQ during late childhood/early adolescence. METHODS: Overall phenylalanine concentration during the first month of life (total "area under the curve"), proportion of phenylalanine concentrations above upper target level (360 µmol/L) and proportion below lower target level (120 µmol/L) during this period, diagnostic phenylalanine levels, number of days until phenylalanine levels were <360 µmol/L, and lifetime and concurrent phenylalanine levels were correlated with IQ scores of 64 PKU patients (mean age 10.8 years, SD 2.9). RESULTS: Overall phenylalanine concentration and proportion of phenylalanine concentrations >360 µmol/L during the first month of life negatively correlated with IQ in late childhood/early adolescence. Separately, phenylalanine concentrations during different periods within the first month of life (0-10 days, 11-20 days, 21-30 days) were negatively correlated with later IQ as well, but correlation strengths did not differ significantly. No further significant associations were found. CONCLUSIONS: In phenylketonuria, achievement of target-range phenylalanine levels during the neonatal period is important for cognition later in life, also when compared to other indicators of metabolic control. IMPACT: In phenylketonuria, it remains unclear during which age periods or developmental stages metabolic control is most important for later cognitive outcomes. Phenylalanine levels during the neonatal period were clearly and negatively related to later IQ, whereas no significant associations were observed for other indices of metabolic control. This emphasizes the relative importance of this period for cognitive development in phenylketonuria. No further distinctions were observed in strength of associations with later IQ between different indicators of metabolic control during the neonatal period. Thus, achievement of good metabolic control within 1 month after birth appears "safe" with respect to later cognitive outcomes.

Diagnostic accuracy of follow-up tests for detecting colorectal cancer recurrences in primary care: A systematic review and meta-analysis.

INTRODUCTION: Traditionally, follow-up of colorectal cancer (CRC) is performed in secondary care. In new models of care, the screening part care could be replaced to primary care. We aimed to synthesise evidence on the diagnostic accuracy of commonly used screeners in CRC follow-up applicable in primary care: carcinoembryonic antigen (CEA), ultrasound and physical examination. METHODS: Medline, EMBASE, Cochrane Trial Register and Web of Science databases were systematically searched. Studies were included if they provided sufficient data for a 2 × 2 contingency tables. QUADAS-2 was used to assess methodological quality. We performed bivariate random effects meta-analysis, generated a hypothetical cohort, and reported sensitivity and specificity. RESULTS: We included 12 studies (n = 3223, median recurrence rate 19.6%). Pooled estimates showed a sensitivity for CEA (≤ 5 µg/l) of 59% [47%-70%] and a specificity of 89% [80%-95%]. Only few studies reported sensitivities and specificities for ultrasound (36-70% and 97-100%, respectively) and clinical examination (23% and 27%, respectively). CONCLUSION: In practice, GPs could perform CEA screening. Radiological examination in a hospital setting should remain part of the surveillance strategy. Personalised algorithms accounting for recurrence risk and changes of CEA-values over time might add to the diagnostic value of CEA in primary care.

BH4 treatment in BH4-responsive PKU patients: preliminary data on blood prolactin concentrations suggest increased cerebral dopamine concentrations.

In phenylketonuria (PKU), cerebral neurotransmitter deficiencies have been suggested to contribute to brain dysfunction. Present treatment aims to reduce blood phenylalanine concentrations by a phenylalanine-restricted diet, while in some patients blood phenylalanine concentrations also respond to cofactor treatment with tetrahydrobiopterin (BH4). Recently, a repurposing approach of BH4 was suggested to increase cerebral neurotransmitter synthesis. To investigate whether BH4 may improve cerebral dopamine concentrations in PKU patients beyond its effect through lowering blood phenylalanine concentrations, we investigated blood prolactin concentrations-as a parameter of brain dopamine availability. We retrospectively compared blood prolactin in relation to blood phenylalanine concentrations of nine (male) BH4-responsive PKU patients, when being treated without and with BH4. Blood prolactin concentrations positively correlated to blood phenylalanine concentrations (p=0.002), being significantly lower with than without BH4 treatment (p=0.047). In addition, even in this small number of male patients, blood prolactin concentrations tended to be lower at increasing BH4 dose (p=0.054), while taking blood phenylalanine concentrations into account (p=0.002). In individual BH4-responsive patients, median blood prolactin concentrations were significantly lower while using BH4 than before using BH4 treatment (p=0.024), whereas median blood phenylalanine concentrations tended to be lower, but this did not reach statistical significance (p=0.107). Therefore, these data show that high blood phenylalanine in BH4-responsive PKU male patients seems to be associated with increased blood prolactin concentrations, suggesting reduced cerebral dopamine availability. Moreover, these data suggest that BH4 treatment in itself could decrease blood prolactin concentrations in a dose-responsive way, independent of blood phenylalanine concentrations. We conclude that these preliminary data indicate that BH4 treatment may improve cerebral dopamine concentrations in PKU patients beyond its effect through lowering blood phenylalanine concentrations, possibly in a dose-dependent manner, but further research would be warranted.

Is BRIEF a useful instrument in day to day care of patients with phenylketonuria?

OBJECTIVES: Despite early and continuous treatment many patients with phenylketonuria (PKU) still experience neurocognitive problems. Most problems have been observed in the domain of executive functioning (EF). For regular monitoring of EF, the use of the Behavior Rating Inventory of Executive Function (BRIEF) has been proposed. The aim of this study was to investigate whether the BRIEF is indeed a useful screening instrument in monitoring of adults with PKU. STUDY DESIGN: Adult PKU patients (n = 55; mean age 28.3 ± 6.2 years) filled out the BRIEF-A (higher scores=poorer EF) and performed computerized tasks measuring executive functions (inhibition, cognitive flexibility, and working memory). The outcome of the BRIEF-A questionnaire was compared with the neurocognitive outcome as measured by three tasks from the Amsterdam Neuropsychological Tasks (ANT). RESULTS: Forty-two percent of the PKU patients scored in the borderline/clinical range of the BRIEF-A. Six of the 55 patients (11%) scored >1 SD above the normative mean, mostly on the Metacognition Index. With respect to ANT measurements, patients mainly showed deficits in inhibitory control (34-36%) and cognitive flexibility (31-40%) as compared to the general Dutch population. No significant correlations between the two methods were found, which was confirmed with the Bland-Altman approach where no agreement between the two methods was observed. Only with respect to inhibitory control, patients scored significantly worse on both BRIEF-A and ANT classifications. No other associations between classification according to the BRIEF-A and classifications according to the ANT tasks were found. CONCLUSIONS: Patients reporting EF problems in daily life are not necessarily those that present with core EF deficits. The results of this study suggest that regular self-administration of the BRIEF-A is not a sufficient way to monitor EF in adult PKU patients.

Cancer follow-up in primary care after treatment with curative intent: Views of patients with breast and colorectal cancer.

OBJECTIVE: Increased cancer survival leads to more patients requiring oncological follow-up. Debate about how best to coordinate this care has led to the proposed involvement of general practitioners (GPs) rather than continued reliance on hospital care. However, we still require patient opinions to inform this debate. METHODS: This qualitative interview study explored opinions about organization of follow-up care of patients treated curatively for breast and colorectal cancer. Thematic analysis was applied. RESULTS: We interviewed 29 patients and identified three themes concerning care substitution: "benefits and barriers," "requirements," and "suitable patient groups." Benefits included accessibility, continuity, contextual knowledge, and psychosocial support. Barriers included concerns about cancer-specific expertise of GPs and longer waiting times. Requirements were sufficient time and remuneration, sufficient training, clear protocols, and shared-care including efficient communication with specialists. CONCLUSIONS: According to patients with cancer, formal GP involvement appears feasible, although important barriers must be overcome before instituting care substitution. A possible solution are personalized follow-up plans based on three-way conversations with the specialist and the GP after the initial hospital care. PRACTICE IMPLICATIONS: With adequate training, time, and remuneration, formal GP involvement could ensure more comprehensive care, possibly starting with less complex cases.

Follow-up of curatively treated cancer in primary care: a qualitative study of the views of Dutch GPs.

BACKGROUND: Follow-up for cancer typically occurs in secondary care, and improved survival has increased demands on these services. Other care models may alleviate this burden, such as moving (parts of) follow-up care for curatively treated patients from secondary to primary care (care substitution). AIM: To explore the opinions of GPs regarding the potential benefits, barriers, and requirements of care substitution for breast and colorectal cancer. DESIGN AND SETTING: A qualitative study of the opinions of purposively sampled GPs in Dutch primary care. METHOD: Focus group sessions and individual semi-structured interviews were recorded and transcribed verbatim. Data were analysed by two independent researchers using thematic analysis. RESULTS: Two focus groups (n = 14) were conducted followed by nine individual interviews. Three main themes were identified: perceived benefits, perceived barriers, and perceived requirements. Perceived benefits included better accessibility and continuity of care, and care closer to patients' homes. Uncertainty about cancer-related competences and practical objections were perceived as barriers. Requirements included close specialist collaboration, support from patients for this change, and stepwise implementation to avoid loss of existing care quality. CONCLUSION: Most GPs reported that they were not in favour of complete care substitution, but that primary care could have greater formal involvement in oncological follow-up if there is close collaboration with secondary care (that is, shared care), support from patients, sufficient resource allocation, stepwise implementation with clear guidelines, and monitoring of quality. Clear and broadly supported protocols need to be developed and tested before implementing follow-up in primary care.