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 now over a decade ago that a published meta-analysis used a predefined standard to identify valid studies. Considering valid studies only, and using random effects dose–response meta-analysis (DRM) while withdrawing spurious results (p < 0.05), we ascertained whether these relations would 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). The combined T2D–GI RR was 1.27 (1.15–1.40) (p < 0.001, n = 10 studies) per 10 units GI, while that for the 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 2000 kcal diet, respectively. In conclusion, among adults initially in good health, diets higher in GI or GL were robustly associated with incident T2D. Together with mechanistic and other data, this supports 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 GL are substantial food markers predicting the development of T2D worldwide, for persons of European ancestry and of East Asian ancestry.

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.

ObjectiveTo 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.MethodsWe 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.ResultsEligible 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 (I2≤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) (I2=0); for GI (47-82 U), 2.71 (95% CI, 1.47-4.40) (I2=0); and for the CHD-carbohydrate dependence on GI (50-80 U), 4.57 (95% CI, 1.86-11.4) (I2=16%). Bradford-Hill criteria indicated that these relations were probably causal.ConclusionStrong 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 RegistrationPROSPERO Identifier: CRD42013004504

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.

In their sensitive account of suffering in end-of-life decisionmaking, 1 Professor Isaacs and Ms Preisz are right to assert that children do not exist in isolation, but rather that the positive value in their lives is derived from the web of relations they exist within. Despite this network of relations being a fundamental source of value for the individual, the individual remains the fundamental unit to which rights may accrue. In their prudent reluctance to overrule parents in life and death decisions about children's suffering, the authors give undue weight to the parents' own suffering arising from their children's ongoing illness and survival.Consider John and Jane, two children with the same illness. After careful consideration, a small majority of physicians argue for ongoing treatment and therefore survival for both John and Jane, but the burdens of ongoing treatment and survival are considered significantly more onerous by John's parents than Jane's parents. Per the authors' reasoning, where the parent's perceptions of the burdens of treatment and survival are taken into account as one of a number of variables in the burdens versus benefits calculus, it is conceivable that the decision to ultimately terminate John's ongoing treatment may turn on the burdensomeness to his parents of his treatment and survival. If we assume that John and Jane have an otherwise equal claim to continued existence, then it would seem a perverse outcome that John's claim is overruled by his having, through no fault of his own, parents for whom the burdens of his own ongoing illness and survival are more onerous.Furthermore, just as the burdens of intensive care may be ameliorated by for example analgesia, sedation, and other nonpharmacological means of mitigating suffering, so may the burdens of the child's ongoing illness and survival on their family be ameliorated. The particular family unit in which we imagine a child might benefit from love and affection is itself historically contingent. Children may thrive in other arrangements, for example, living with extended family or kinship networks, or in foster-care or adoption arrangements. We can also imagine a society where the almost superhuman expectations placed on parents of children with profound neuro-disability are recognised for what they are, and new models of care, appropriately resourced, are directed towards these families to ease the burdens of care, and tip the balance of this tragic calculus in favour of survival.

ConclusionsMebeverine and mefenamic acid are effective in relieving symptoms of dysmenorrhoea.

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.

Cyclin D2 (CCND2) stabilisation 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 p.Arg60Gln variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased levels of CCND2 through increased transcription, and not stabilisation of CCND2. We show the purified b-HLH-LZ domain of MAXR60Q (Max*R60Q) 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 patients 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 MAXR60Q patients, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.