Summary
The associations between body fatness at a young age (childhood, adolescence and young adulthood; age ≤ 30 years) and diffuse large B‐cell lymphoma (DLBCL), oesophageal adenocarcinoma, ...gastric cardia cancer, hepatocellular carcinoma, multiple myeloma, pancreatic cancer, renal cell cancer and thyroid cancer remain inconclusive. We performed a comprehensive systematic literature review and meta‐analysis of observational studies to clarify the associations between body fatness at a young age and the risks of these cancers. PubMed and Web of Science databases were searched for relevant observational studies. Fifty‐six articles yielded data on 27,559 cancer cases, including 3,170 DLBCL, 1,491 oesophageal adenocarcinoma, 1,103 gastric cardia cancer, 1,067 hepatocellular carcinoma, 3,090 multiple myeloma, 7,220 pancreatic cancer, 6,212 renal cell cancer and 4,206 thyroid cancer cases. Each 5 kg m−2 increase in body mass index at a young age was positively associated with DLBCL (relative risk RR 1.21, 95% confidence interval CI 1.09, 1.35), oesophageal adenocarcinoma (RR 1.88, 95% CI 1.37, 2.57), gastric cardia cancer (RR 1.59, 95% CI 1.15, 2.21), hepatocellular carcinoma (RR 1.31, 95% CI 1.13, 1.51), multiple myeloma (RR 1.23, 95% CI 1.15, 1.30), pancreatic cancer (RR 1.17, 95% CI 1.11, 1.24), renal cell cancer (RR 1.22, 95% CI 1.16, 1.28) and thyroid cancer (RR 1.12, 95% CI 1.07, 1.17). In summary, higher body fatness at a young age increases the risks of developing various types of cancer later in life. Prevention of overweight and obesity in children, adolescents and young adults should therefore be emphasized to reverse the obesity epidemic and thereby avoid further increases in the burden of cancer attributed to excess body fatness.
Summary
In the present meta-analysis, reductions in the risk of hip fracture with milk consumption were only observed among American adults, but not among Scandinavian adults, possibly because milk ...products are more commonly fortified with vitamin D in the former population than in Scandinavian countries. The reduction in the risk of hip fracture was also observed with yogurt consumption, which is often associated with healthy lifestyles and dietary patterns that contribute to improved bone health.
Introduction
Although dairy products contain bone-beneficial nutrients, the association between dairy consumption and the risk of hip fracture remains equivocal. Fueling this uncertainty, the elevated risk of hip fracture in association with milk consumption was observed in a cohort of Swedish women. A systematic review and meta-analysis of prospective cohort studies was performed to critically evaluate the association, or lack thereof, between dairy consumption (milk, yogurt, and cheese) and the risk of hip fracture.
Methods
A random effects model was used to generate the summary relative risks (RRs) with their 95% confidence intervals (CIs) for the associations of interest.
Results
In the meta-analysis of the highest versus lowest category of consumption, higher consumption of yogurt (RR 0.78, 95% CI 0.68, 0.90), but not milk (RR 0.86, 95% CI 0.73, 1.02) or cheese (RR 0.85, 95% CI 0.66, 1.08), was associated with a lower risk of hip fracture. For milk, the reduced risk of fracture with higher milk consumption was observed in the USA (RR 0.75, 95% CI 0.65, 0.87), but not in Scandinavian countries (RR 1.00, 95% CI 0.85, 1.17). These findings were further supported by the fact that American studies (RR 0.93, 95% CI 0.88, 0.98; per 1 glass/day), but not Scandinavian studies (RR 1.01, 95% CI 0.95, 1.07; per 1 glass/day), demonstrated a linear association between milk consumption and the risk of hip fracture.
Conclusions
The cumulative evidence from prospective cohort studies reassuringly suggests that the risk of hip fracture may not be elevated among people who consume milk, yogurt, and cheese, and that a greater consumption of milk or yogurt may even be associated with a lower risk of hip fracture depending on the factors that may differ across the population of interest.
Summary
In the present meta-analysis based on real-world data, the use of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1ra), or sodium-glucose ...cotransporter-2 inhibitors (SGLT2i) was not associated with the risk of fracture.
Introduction
Cumulative evidence from randomized control trials (RCTs) with limited fracture events showed that the use of DPP-4i, GLP-1ra, or SGLT2i may not affect the risk of fracture. However, additional insights from large population-based studies with routinely collected data on fracture events and an adequate amount of fracture events are necessary to draw firm conclusions. To refine and complement the results from RCTs, a systematic review and meta-analysis of observational studies were performed to investigate the association between the use of DPP-4i, GLP-1ra, or SGLT2i and the risk of fracture in real-world settings.
Methods
The PubMed and Web of Science databases were searched to identify relevant observational studies. A random-effect model was used to estimate the summary relative risks (RRs).
Results
The use of DPP-4i (RR 0.83, 95% CI confidence interval 0.60, 1.14;
n
= 11), GLP-1ra (RR 0.65, 95% CI 0.24, 1.74;
n
= 4), or SGLT2i (RR 1.02, 95% CI 0.91, 1.16;
n
= 4) was not associated with the risk of fracture. In general, there was a consistent lack of association between the use of DPP-4i or GLP-1ra and the risk of fracture across nearly all subgroups, except for a significantly reduced risk of hip fracture with the use of GLP-1ra (RR 0.21, 95% CI 0.04, 0.98).
Conclusions
Cumulative real-world evidence does not support an association between the use of DPP-4i, GLP-1ra, or SGLT2i and the risk of fracture. Our findings, together with the cumulative evidence from RCTs, should reassure policy makers and medical practitioners that the use of these medications is unlikely to increase the risk of fracture among type 2 diabetes mellitus patients in general. Further studies need to investigate the long-term impact of these drugs on the fracture risk, particularly in high-risk populations.
Individuals with diabetes mellitus (DM) have an increased risk of fracture. Glycemic control is crucial to the management of DM, but there are concerns pertaining to hypoglycemia development in the ...course of glycemic control target achievement. The extent to which glycemic control may affect the risk of fracture remains less defined. Hypoglycemia-induced falls have been suggested to contribute to an elevated risk of fracture in DM patients. In this meta-analysis of observational studies, we aimed to investigate the relative contribution of glycemic control, as measured by glycated hemoglobin (HbA1c), and hypoglycemia to the risk of fracture in DM. The PubMed and Web of Science databases were searched for relevant studies. A random-effects model was used to generate summary relative risks (RRs) and 95% confidence intervals (CIs). Both increased HbA1c levels (RR
per 1% increase
1.08, 95% CI 1.03, 1.14;
n
studies
= 10) and hypoglycemia (RR 1.52, 95% CI 1.23, 1.88;
n
studies
= 8) were associated with an increased risk of fracture. The association between HbA1c levels and the risk of fracture was somewhat nonlinear, with a noticeably increased risk observed at an HbA1c level ≥ 8%. The positive associations of HbA1c levels and hypoglycemia with the risk of fracture did not reach statistical significance in the studies that adjusted for insulin use, hypoglycemia, or falls for the former and in those that adjusted for falls for the latter. In summary, both increased HbA1c levels and hypoglycemia may increase the risk of fracture in patients with DM. The positive association between HbA1c levels and the risk of fracture appears to be, in part, explained by hypoglycemia-induced falls, possibly due to insulin use. The avoidance of hypoglycemia in the course of achieving good glycemic control through the careful selection of glucose-lowering medications may contribute to fracture prevention by reducing the risk of falls related to treatment-induced hypoglycemia.
Epileptic encephalopathies are severe epilepsy disorders with strong genetic bases. We performed targeted next‐generation sequencing (NGS) in 70 patients with epileptic encephalopathies. The likely ...pathogenicity of variants in candidate genes was evaluated by American College of Medical Genetics and Genomics (ACMG) scoring taken together with the accepted clinical presentation. Thirty‐three candidate variants were detected after population filtration and computational prediction. According to ACMG, 21 candidate variants, including 18 de novo variants, were assessed to be pathogenic/likely pathogenic with clinical concordance. Twelve variants were initially assessed as uncertain significance by ACMG, among which 3 were considered causative and 3 others were considered possibly causative after analysis of clinical concordance. In total, 24 variants were identified as putatively causative, among which 19 were novel findings. SCN1A mutations were identified in 50% of patients with Dravet syndrome. TSC1/TSC2 mutations were detected in 66.7% of patients with tuberous sclerosis. STXBP1 mutations were the main findings in patients with West syndrome. Mutations in SCN2A, KCNT1, KCNQ2 and CLCN4 were identified in patients with epileptic infantile with migrating focal seizures; among them, KCNQ2 and CLCN4 were first identified as potential causative genes. Only one CHD2 mutation was detected in patients with Lennox‐Gastaut syndrome. This study highlighted the utility of targeted NGS in genetic diagnoses of epileptic encephalopathies and a comprehensive evaluation of the pathogenicity of variants based on ACMG scoring and assessment of clinical concordance. Epileptic encephalopathies differ in genetic causes, and the genotype‐phenotype correlations would provide insights into the underlying pathogenic mechanisms.
We identified 24 causative mutations (19 novel) in a cohort of 70 EE patients and delineated new phenotype associated with CLCN4 and KCNQ2.
Summary
We conducted a meta-analysis of observational study to clarify the association between sex hormone-binding globulin (SHBG) levels and the risk of fracture in older adults. We found that ...higher SHBG levels were associated with an increased risk of fracture in older adults.
Introduction
The association between SHBG levels and the risk of fracture in older adults remains elusive. We aim to clarify this association by conducting a meta-analysis of observational studies.
Methods
PubMed and Web of Science databases were searched for relevant observational studies investigating the association between SHBG levels and the risk of fracture in older adults. The relative risks (RRs) with 95% confidence intervals (CIs) from each study were transformed into a continuous variable for each 1 μg/dL increase in SHBG and were pooled under a random-effects model.
Results
A total of 16 observational studies were included in the present meta-analysis. The summary RR of fracture risk associated with each 1 μg/dL increase in SHBG was 1.18 (95% CI 1.11, 1.26); no statistically significant heterogeneity was observed across studies (
I
2
= 0%,
P
= 0.67). The positive association was also evident in men (RR 1.22, 95% CI 1.12, 1.33) and women (RR 1.15, 95% CI, 1.05, 1.26). By site of fracture, higher SHBG levels were positively associated with higher risks of hip fracture (RR 1.43, 95% CI 1.23, 1.65), vertebral fracture (RR 1.31, 95% CI 1.12, 1.54), and non-vertebral fracture (RR 1.21, 95% CI 1.06, 1.38).
Conclusions
The present meta-analysis suggests that higher SHBG levels predict an increased risk of fracture in older adults. Further studies should aim to elucidate the complex biological mechanisms by which SHBG may affect fracture risk.
Summary
Higher body fatness in adulthood has been consistently associated with an increased risk of postmenopausal breast cancer, as well as a tendency towards a lower risk of premenopausal breast ...cancer. However, the association between body fatness at a young age (≤30 years), body fatness gain and the risk of breast cancer is less defined. PubMed and Web of Science databases were searched to identify relevant publications. Risk estimates with 95% confidence intervals from each study were transformed into a continuous variable for each 5 kg m−2 increase in body mass index (BMI) and were pooled under a random‐effects model. Each 5 kg m−2 increase in BMI was significantly associated with a 14%, 12% and 17% lower risk of breast cancer later in life among all women, premenopausal women and postmenopausal women, respectively. Significant heterogeneity and publication bias were observed. The results remained unchanged after the trim and fill method was applied to correct the bias. Each 5 kg m−2 increase in BMI from a young age until cohort entry was significantly associated with a 13% and 14% higher risk of breast cancer in all women and postmenopausal women, respectively. In summary, higher body fatness at a young age may have a protective role in the later development of breast cancer in both premenopausal and postmenopausal women. However, this potential benefit should not be overemphasized, as our findings suggest that increased body fatness gain from a young age is positively associated with postmenopausal breast cancer risk. These findings further justify the need to maintain a steady weight throughout life.
It has recently been proposed that combining chirality with topological band theory results in a totally new class of fermions. Understanding how these unconventional quasiparticles propagate and ...interact remains largely unexplored so far. Here, we use scanning tunneling microscopy to visualize the electronic properties of the prototypical chiral topological semimetal PdGa. We reveal chiral quantum interference patterns of opposite spiraling directions for the two PdGa enantiomers, a direct manifestation of the change of sign of their Chern number. Additionally, we demonstrate that PdGa remains topologically non-trivial over a large energy range, experimentally detecting Fermi arcs in an energy window of more than 1.6 eV that is symmetrically centered around the Fermi level. These results are a consequence of the deep connection between chirality in real and reciprocal space in this class of materials, and, thereby, establish PdGa as an ideal topological chiral semimetal.
Summary
What is known and objectives
Tacrolimus (TAC) is widely used as part of immunosuppressive regimens. There is great interindividual variation on the disposition of TAC. The aim of this study ...was to develop a population pharmacokinetic (PPK) model for Chinese liver transplant patients and evaluate genetic polymorphism and other possible factors on the PK parameters. The exposure of TAC is to be estimated through Bayesian modelling.
Methods
A total of 47 sets of rich‐time PK and 1234 conventional therapeutic drug monitoring (TDM) data were collected from 125 Chinese liver transplant patients. The pathophysiological data of these patients were recorded. CYP3A5*3 and ABCB1 genotypes were determined for each patient. The PPK model for TAC was established by nonlinear mixed‐effects modelling (nonmem). The impact of pathophysiology and genotype on PPK parameters was evaluated. Bayesian estimators for the area under concentration‐time curve (AUC) of TAC were validated.
Results
A two‐compartment model with lag time was found to be the most suitable model for the pooled full PK and TDM data for Chinese liver transplant patients. The CL/F, V2/F, Q/F, V3/F, Ka and lag time were 17.4±0.81 L/h, 165±44.1 L, 54.9±25.8L/h, 594±87.5 L, 0.51±0.095 L/h and 1.57±0.34 h. Post‐operative day (POD), creatinine clearance (CLcr) and ABCB1 C3435T genotypes were found to have significant influences on CL/F (P<.01). ABCB1 C3435T genotypes showed a significant correlation with V2/F (P<.01). C0–C2 and C0–C2–C4 were shown to be suitable for the estimation of AUC in Chinese liver transplant patients.
What is new and conclusion
A PPK model for TAC was established successfully in Chinese liver transplant patients. POD, CLcr and ABCB1 C3435T genotypes were shown to have significant effects on CL/F. The AUC of TAC in Chinese liver transplant patients could be estimated through Bayesian modelling, based on which individualized immunosuppressive regimens can be designed.
Visual predictive check based on the final model in patients with ABCB1 CC (A), CT (B) and TT (C) genotypes. A population pharmacokinetic (PPK) model for tacrolimus (TAC) was established successfully based on 47 sets of rich time PK and 1234 conventional therapeutic drug monitoring (TDM) data Chinese liver transplant patients. ABCB1 C3435T genotypes were shown to have significant effects on CL/F. The area under concentration‐time curve (AUC) of TAC in Chinese liver‐transplant patients could be estimated through Bayesian modelling, based on which individualized immunosuppressive regimens can be designed.
Signaling abnormalities in immune responses in the small intestine can trigger chronic type 2 inflammation involving interaction of multiple immune cell types. To systematically characterize this ...response, we analyzed 58,067 immune cells from the mouse small intestine by single-cell RNA sequencing (scRNA-seq) at steady state and after induction of a type 2 inflammatory reaction to ovalbumin (OVA). Computational analysis revealed broad shifts in both cell-type composition and cell programs in response to the inflammation, especially in group 2 innate lymphoid cells (ILC2s). Inflammation induced the expression of exon 5 of Calca, which encodes the alpha-calcitonin gene-related peptide (α-CGRP), in intestinal KLRG1+ ILC2s. α-CGRP antagonized KLRG1+ ILC2s proliferation but promoted IL-5 expression. Genetic perturbation of α-CGRP increased the proportion of intestinal KLRG1+ ILC2s. Our work highlights a model where α-CGRP-mediated neuronal signaling is critical for suppressing ILC2 expansion and maintaining homeostasis of the type 2 immune machinery.
Display omitted
•scRNA-seq reveals intestinal immune cell programs in allergic inflammation•Intestinal KLRG1+ ILC2s express α-CGRP and its receptors•α-CGRP regulates type 2 cytokine production of KLRG1+ ILC2s•α-CGRP maintains KLRG1+ ILC2 homeostasis and the type 2 immune machinery
Allergic inflammation involves the interaction of multiple immune cell types, as well as their crosstalk with other physiological systems, such as neurons. By establishing intestinal immune cell atlas at different states, Xu et al. identify that neuropeptide α-CGRP modulates group 2 innate lymphoid cell responses and the allergic reaction.
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