A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.

Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAXArg60Gln (Max∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAXArg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.

Use of Telemedicine in Pediatric Services for 4 Representative Clinical Conditions: Scoping Review.

BACKGROUND: Telemedicine is becoming routine in health care. Postpandemic, a universal return to face-to-face consultations may risk a loss of some of the advantages of telemedicine. However, rapid implementation and adoption without robust evaluation of usability, efficacy, and effectiveness could potentially lead to suboptimal health outcomes and downstream challenges to providers. OBJECTIVE: This review assesses telemedicine interventions against international guidance and sufficiency of evidence to support postpandemic utilization in pediatric settings. METHODS: This scoping review was performed following searches on PubMed, Embase, and CINAHL databases on April 15, 2021, and May 31, 2022, and examined studies focused on telemedicine, remote consultation, video call, or remote patient monitoring in children (0-18 years) receiving outpatient care for diabetes, asthma, epilepsy, or renal disease. Exclusion criteria included studies published before 2011 as the technologies used have likely been improved or replaced, studies in adult populations or where it was not possible to disaggregate data for participants younger than 18 years as the focus of the review was on pediatric care, and studies not published in English. Data were extracted by 4 authors, and the data were corroborated by a second reviewer. Studies were examined for feasibility and usability, clinical and process outcomes, and cost-effectiveness. RESULTS: Of the 3158 studies identified, 56 were suitable for final inclusion and analysis. Data on feasibility or usability of interventions (48 studies) were overwhelmingly positive in support of telemedicine interventions, with common themes including convenience, perceived cost savings, and ease of use. However, use in preference to usual care was rarely explored. Clinical and process outcome data (31 studies) were mostly positive. Across all studies, there was limited measurement of standardized clinical outcomes, although these were more commonly reported in asthma (peak flow) and diabetes (glycated hemoglobin [HbA1c]). Implementation science data generally supported cost-effectiveness of telemedicine with a reduction of health care costs. CONCLUSIONS: There is promising evidence supporting telemedicine in pediatric settings. However, there is a lack of evaluation of telemedicine in comparison with usual outpatient care for noninferiority of clinical outcomes, and this review highlights the need for a more standardized approach to evaluation of digital interventions.

Coronary Heart Disease and Dietary Carbohydrate, Glycemic Index, and Glycemic Load: Dose-Response Meta-analyses of Prospective Cohort Studies.

OBJECTIVE: To clarify the role of dietary carbohydrate, glycemic index (GI), and glycemic load (GL) in progression from health to coronary heart disease (CHD) by determining disease-nutrient risk relation (RR) values needed for intake ranges within jurisdictions and across the globe. METHODS: We performed a literature search of MEDLINE and EMBASE for prospective cohort studies that used truly valid dietary instruments in heathy adults published from January 1, 2000, to June 5, 2018. Relevant observations were extracted by 2 reviewers independently. We used dose-response meta-analysis accounting for nonindependence of results within studies. Bradford-Hill criteria were used to assess causality. RESULTS: Eligible studies had a mean follow-up of 11 years (range, 5-19 years), were conducted in North America, Europe, and East Asia, and yielded combined RRs of 1.44 (95% CI, 1.25-1.65) per 65 g/d GL (11 studies) and 1.24 (95% CI, 1.12-1.38) per 10 U GI (10 studies) (glucose scale). The CHD-carbohydrate RR on GI was 1.66 (95% CI, 1.23-2.25) per 98 g/d of carbohydrates per 10 units GI. The 65 g/d GL, 10 U GI, and 98 g/d carbohydrate values corresponded to oral intakes from the 10th to the 90th percentiles within sampled populations. Inconsistencies were minor (I 2 ≤20%), as were small-study effects (P=.61 for GL and P=.26 for GI). Funnel plots were symmetric. Cubic spline dose-response meta-analysis yielded RRs as follows: across the global range for GL (55-290 g/d), 5.5 (95% CI, 3.1-9.8) (I 2 =0); for GI (47-82 U), 2.71 (95% CI, 1.47-4.40) (I 2 =0); and for the CHD-carbohydrate dependence on GI (50-80 U), 4.57 (95% CI, 1.86-11.4) (I 2 =16%). Bradford-Hill criteria indicated that these relations were probably causal. CONCLUSION: Strong and probably causal CHD-GL and GI RRs exist within populations. The RRs were remarkably higher across global exposures. The results support the consideration of these markers of carbohydrate food quality in dietary guidelines for general populations. TRIAL REGISTRATION: PROSPERO Identifier: CRD42013004504.

Dietary Glycemic Index and Load and the Risk of Type 2 Diabetes: Assessment of Causal Relations.

While dietary factors are important modifiable risk factors for type 2 diabetes (T2D), the causal role of carbohydrate quality in nutrition remains controversial. Dietary glycemic index (GI) and glycemic load (GL) have been examined in relation to the risk of T2D in multiple prospective cohort studies. Previous meta-analyses indicate significant relations but consideration of causality has been minimal. Here, the results of our recent meta-analyses of prospective cohort studies of 4 to 26-y follow-up are interpreted in the context of the nine Bradford-Hill criteria for causality, that is: (1) Strength of Association, (2) Consistency, (3) Specificity, (4) Temporality, (5) Biological Gradient, (6) Plausibility, (7) Experimental evidence, (8) Analogy, and (9) Coherence. These criteria necessitated referral to a body of literature wider than prospective cohort studies alone, especially in criteria 6 to 9. In this analysis, all nine of the Hill's criteria were met for GI and GL indicating that we can be confident of a role for GI and GL as causal factors contributing to incident T2D. In addition, neither dietary fiber nor cereal fiber nor wholegrain were found to be reliable or effective surrogate measures of GI or GL. Finally, our cost-benefit analysis suggests food and nutrition advice favors lower GI or GL and would produce significant potential cost savings in national healthcare budgets. The high confidence in causal associations for incident T2D is sufficient to consider inclusion of GI and GL in food and nutrient-based recommendations.

Dietary Glycemic Index and Load and the Risk of Type 2 Diabetes: A Systematic Review and Updated Meta-Analyses of Prospective Cohort Studies.

Published meta-analyses indicate significant but inconsistent incident type-2 diabetes(T2D)-dietary glycemic index (GI) and glycemic load (GL) risk ratios or risk relations (RR). It is nowover a decade ago that a published meta-analysis used a predefined standard to identify validstudies. Considering valid studies only, and using random effects dose-response meta-analysis(DRM) while withdrawing spurious results (p < 0.05), we ascertained whether these relationswould support nutrition guidance, specifically for an RR > 1.20 with a lower 95% confidence limit>1.10 across typical intakes (approximately 10th to 90th percentiles of population intakes). Thecombined T2D-GI RR was 1.27 (1.15-1.40) (p < 0.001, n = 10 studies) per 10 units GI, while that forthe T2D-GL RR was 1.26 (1.15-1.37) (p < 0.001, n = 15) per 80 g/d GL in a 2000 kcal (8400 kJ) diet.The corresponding global DRM using restricted cubic splines were 1.87 (1.56-2.25) (p < 0.001, n =10) and 1.89 (1.66-2.16) (p < 0.001, n = 15) from 47.6 to 76.1 units GI and 73 to 257 g/d GL in a 2000kcal diet, respectively. In conclusion, among adults initially in good health, diets higher in GI or GLwere robustly associated with incident T2D. Together with mechanistic and other data, thissupports that consideration should be given to these dietary risk factors in nutrition advice.Concerning the public health relevance at the global level, our evidence indicates that GI and GLare substantial food markers predicting the development of T2D worldwide, for persons ofEuropean ancestry and of East Asian ancestry.

Is there a dose-response relation of dietary glycemic load to risk of type 2 diabetes? Meta-analysis of prospective cohort studies.

BACKGROUND: Although much is known about the association between dietary glycemic load (GL) and type 2 diabetes (T2D), prospective cohort studies have not consistently shown a positive dose-response relation. OBJECTIVE: We performed a comprehensive examination of evidence on the dose response that links GL to T2D and sources of heterogeneity among all prospective cohort studies on healthy adults available in the literature. DESIGN: We conducted a systematic review of all prospective cohort studies and meta-analyses to quantify the GL-T2D relation both without and with adjustment for covariates. RESULTS: Among 24 prospective cohort studies identified by August 2012, the GL ranged from ∼60 to ∼280 g per daily intake of 2000 kcal (8.4 MJ). In a fully adjusted meta-analysis model, the GL was positively associated with RR of T2D of 1.45 (95% CI: 1.31, 1.61) for a 100-g increment in GL (P < 0.001; n = 24 studies; 7.5 million person-years of follow-up). Sex (P = 0.03), dietary instrument validity (P < 0.001), and ethnicity (European American compared with other; P = 0.04) together explained 97% of the heterogeneity among studies. After adjustment for heterogeneities, we used both funnel and trim-and-fill analyses to identify a negligible publication bias. Multiple influence, cumulative, and forecast analyses indicated that the GL-T2D relation tended to have reached stability and to have been underestimated. The relation was apparent at all doses of GL investigated, although it was statistically significant only at >95 g GL/2000 kcal. CONCLUSION: After we accounted for several sources of heterogeneity, findings from prospective cohort studies that related the GL to T2D appear robust and consistently indicate strong and significantly lower T2D risk in persons who consume lower-GL diets. This review was registered at http://www.crd.york.ac.uk/PROSPERO as CRD42011001810.