Brain charts for the human lifespan Anderson, K M; Adamson, C; Adler, S ...
Nature (London),
04/2022, Letnik:
604, Številka:
7906
Journal Article
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Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual ...differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight
. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories
of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones
, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
Osteoporosis constitutes a major public health problem through its association with age-related fractures, most notably those of the proximal femur. Substantial geographic variation has been noted in ...the incidence of hip fracture throughout the world, and estimates of recent incidence trends have varied widely. Studies in the published literature have reported an increase, plateau, and decrease in age-adjusted incidence rates for hip fracture among both men and women. Accurate characterisation of these temporal trends is important in predicting the health care burden attributable to hip fracture in future decades. We therefore conducted a review of studies worldwide, addressing secular trends in the incidence of hip and other fractures. Studies in western populations, whether in North America, Europe or Oceania, have generally reported increases in hip fracture incidence through the second half of the last century, but those continuing to follow trends over the last two decades have found that rates stabilise with age-adjusted decreases being observed in certain centres. In contrast, some studies suggest that the rate is rising in Asia. This synthesis of temporal trends in the published literature will provide an important resource for preventing fractures. Understanding the reasons for the recent declines in rates of hip fracture may help understand ways to reduce rates of hip fracture worldwide.
Introduction
Rheumatoid arthritis (RA) is a common systemic autoimmune disease of unknown cause, characterized by a chronic, symmetric, and progressive inflammatory polyarthritis. One of the most ...deleterious effects induced by the chronic inflammation of RA is bone loss. During the last 15 years, the better knowledge of the cytokine network involved in RA allowed the development of potent inhibitors of the inflammatory process classified as biological DMARDs. These new drugs are very effective in the inhibition of inflammation, but there are only few studies regarding their role in bone protection. The principal aim of this review was to show the evidence of the principal biologic therapies and bone loss in RA, focusing on their effects on bone mineral density, bone turnover markers, and fragility fractures.
Methods
Using the PICOST methodology, two coauthors (PC, LM-S) conducted the search using the following MESH terms: rheumatoid arthritis, osteoporosis, clinical trials, TNF- antagonists, infliximab, adalimumab, etanercept, certolizumab, golimumab, IL-6 antagonists, IL-1 antagonists, abatacept, tocilizumab, rituximab, bone mineral density, bone markers, and fractures. The search was conducted electronically and manually from the following databases: Medline and Science Direct. The search period included articles from 2003 to 2015. The selection included only original adult human research written in English. Titles were retrieved and the same two authors independently selected the relevant studies for a full text. The retrieved selected studies were also reviewed completing the search for relevant articles. The first search included 904 titles from which 253 titles were selected. The agreement on the selection among researchers resulted in a Kappa statistic of 0.95 (p < 0.000). Only 248 abstracts evaluated were included in the acronym PICOST. The final selection included only 28 studies, derived from the systematic search. Additionally, a manual search in the bibliography of the selected articles was made and included into the text and into the section of “small molecules of new agents.”
Conclusion
Treatment with biologic drugs is associated with the decrease in bone loss. Studies with anti-TNF blocking agents show preservation or increase in spine and hip BMD and also a better profile of bone markers. Most of these studies were performed with infliximab. Only three epidemiological studies analyzed the effect on fractures after anti-TNF blocking agent’s treatment. IL-6 blocking agents also showed improvement in localized bone loss not seen with anti-TNF agents. There are a few studies with rituximab and abatacept. Although several studies reported favorable actions of biologic therapies on bone protection, there are still unmet needs for studies regarding their actions on the risk of bone fractures.
Background
Studies comparing upfront surgery with neoadjuvant treatment in pancreatic cancer may report only patients who underwent resection and so survival will be skewed. The aim of this study was ...to report survival by intention to treat in a comparison of upfront surgery versus neoadjuvant treatment in resectable or borderline resectable pancreatic cancer.
Methods
MEDLINE, Embase and the Cochrane Library were searched for studies reporting median overall survival by intention to treat in patients with resectable or borderline resectable pancreatic cancer treated with or without neoadjuvant treatment. Secondary outcomes included overall and R0 resection rate, pathological lymph node rate, reasons for unresectability and toxicity of neoadjuvant treatment.
Results
In total, 38 studies were included with 3484 patients, of whom 1738 (49·9 per cent) had neoadjuvant treatment. The weighted median overall survival by intention to treat was 18·8 months for neoadjuvant treatment and 14·8 months for upfront surgery; the difference was larger among patients whose tumours were resected (26·1 versus 15·0 months respectively). The overall resection rate was lower with neoadjuvant treatment than with upfront surgery (66·0 versus 81·3 per cent; P < 0·001), but the R0 rate was higher (86·8 (95 per cent c.i. 84·6 to 88·7) versus 66·9 (64·2 to 69·6) per cent; P < 0·001). Reported by intention to treat, the R0 rates were 58·0 and 54·9 per cent respectively (P = 0·088). The pathological lymph node rate was 43·8 per cent after neoadjuvant therapy and 64·8 per cent in the upfront surgery group (P < 0·001). Toxicity of at least grade III was reported in up to 64 per cent of the patients.
Conclusion
Neoadjuvant treatment appears to improve overall survival by intention to treat, despite lower overall resection rates for resectable or borderline resectable pancreatic cancer.
PROSPERO registration number: CRD42016049374.
Improved survival with neoadjuvant treatment
To determine an effective and tolerable dose of a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, for the acute treatment of migraine.
Randomized, double-blind, ...parallel-group, clinical trial with a two-stage, adaptive, dose-ranging design. Patients were allocated to treat a moderate or severe migraine attack with MK-0974 (25, 50, 100, 200, 300, 400, or 600 mg), rizatriptan 10 mg, or placebo taken orally. The primary endpoint was pain relief (reduction to mild or none) 2 hours after dosing. Secondary endpoints included pain freedom at 2 hours and sustained pain relief at 24 hours. A prespecified, blinded, automated interim analysis was used to discontinue randomization to less effective doses.
Per the adaptive study design, the four lowest MK-0974 groups (25, 50, 100, 200 mg) were discontinued due to insufficient efficacy. For the remaining treatment groups, the estimated pain relief proportions at 2 hours were 300 mg (n = 38) 68.1%, 400 mg (n = 45) 48.2%, 600 mg (n = 40) 67.5%, rizatriptan 10 mg (n = 34) 69.5%, and placebo (n = 115) 46.3%. The prespecified primary efficacy hypothesis test, which compared the average 2-hour pain relief response proportion of the combined 300, 400, and 600 mg MK-0974 groups to placebo, was significant (P = 0.015). A generally similar efficacy pattern was seen for other endpoints. MK-0974 was generally well tolerated and there did not appear to be an increase in adverse events with increasing dose.
The novel, orally administered calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, was effective and generally well tolerated for the acute treatment of migraine.
There is limited evidence regarding the prognostic effects of pathologic lymph node (LN) regression after neoadjuvant chemotherapy for esophageal adenocarcinoma, and a definition of LN response is ...lacking. This study aimed to evaluate how LN regression influences survival after surgery for esophageal adenocarcinoma.
Multicenter cohort study of patients with esophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgical resection at five high-volume centers in the United Kingdom. LNs retrieved at esophagectomy were examined for chemotherapy response and given a LN regression score (LNRS)-LNRS 1, complete response; 2, <10% residual tumor; 3, 10%-50% residual tumor; 4, >50% residual tumor; and 5, no response. Survival analysis was performed using Cox regression adjusting for confounders including primary tumor regression. The discriminatory ability of different LN response classifications to predict survival was evaluated using Akaike information criterion and Harrell C-index.
In total, 17,930 LNs from 763 patients were examined. LN response classified as
(LNRS 1 ≥1 LN, no residual tumor in any LN; n = 62, 8.1%),
(LNRS 1-3 ≥1 LN, residual tumor ≥1 LN; n = 155, 20.3%),
(LNRS 4-5; n = 303, 39.7%), or
(no tumor/regression; n = 243, 31.8%) demonstrated superior discriminatory ability. Mortality was reduced in patients with complete LN response (hazard ratio HR, 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR, 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR, 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%).
Pathologic LN regression after neoadjuvant chemotherapy was a strong prognostic factor and provides important information beyond pathologic TNM staging and primary tumor regression grading. LN regression should be included as standard in the pathologic reporting of esophagectomy specimens.
Despite promising evidence that laparoscopic fundoplication provides better short-term relief of gastro-oesophageal reflux disease (GORD) than continued medical management, uncertainty remains about ...whether benefits are sustained and outweigh risks.
To evaluate the long-term clinical effectiveness, cost-effectiveness and safety of laparoscopic surgery among people with GORD requiring long-term medication and suitable for both surgical and medical management.
Five-year follow-up of a randomised trial (with parallel non-randomised preference groups) comparing a laparoscopic surgery-based policy with a continued medical management policy. Cost-effectiveness was assessed alongside the trial using a NHS perspective for costs and expressing health outcomes in terms of quality-adjusted life-years (QALYs).
Follow-up was by annual postal questionnaire and selective hospital case notes review; initial recruitment in 21 UK hospitals.
Questionnaire responders among the 810 original participants. At entry, all had documented evidence of GORD and symptoms for > 12 months. Questionnaire response rates (years 1-5) were from 89.5% to 68.9%.
Three hundred and fifty-seven participants were recruited to the randomised comparison (178 randomised to surgical management and 179 randomised to continued medical management) and 453 to the preference groups (261 surgical management and 192 medical management). The surgeon chose the type of fundoplication.
Primary: disease-specific outcome measure (the REFLUX questionnaire); secondary: Short Form questionnaire-36 items (SF-36), European Quality of Life-5 Dimensions (EQ-5D), NHS resource use, reflux medication, complications.
The randomised groups were well balanced. By 5 years, 63% in the randomised surgical group and 13% in the randomised medical management group had received a total or partial wrap fundoplication (85% and 3% in the preference groups), with few perioperative complications and no associated deaths. At 1 year (and 5 years) after surgery, 36% (41%) in the randomised surgical group - 15% (26%) of those who had surgery - were taking proton pump inhibitor medication compared with 87% (82%) in the randomised medical group. At each year, differences in the REFLUX score significantly favoured the randomised surgical group (a third of a SD; p< 0.01 at 5 years). SF-36 and EQ-5D scores also favoured surgery, but differences attenuated over time and were generally not statistically significant at 5 years. The worse the symptoms at trial entry, the larger the benefit observed after surgery. Those randomised to medical management who subsequently had surgery had low baseline scores that markedly improved after surgery. Following fundoplication, 3% had surgical treatment for a complication and 4% had subsequent reflux-related operations - most often revision of the wrap. Dysphagia, flatulence and inability to vomit were similar in the two randomised groups. The economic analysis indicated that surgery was the more cost-effective option for this patient group. The incremental cost-effectiveness ratio for surgery in the base case was £7028 per additional QALY; these findings were robust to changes in approaches and assumptions. The probability of surgery being cost-effective at a threshold of £20,000 per additional QALY was > 0.80 for all analyses.
After 5 years, laparoscopic fundoplication continues to provide better relief of GORD symptoms with associated improved health-related quality of life. Complications of surgery were uncommon. Despite being initially more costly, a surgical policy is highly likely to be cost-effective.
Current Controlled Trials ISRCTN15517081.
This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 22. See the HTA programme website for further project information.
Carcinogenicity of night shift work Ward, Elizabeth M; Germolec, Dori; Kogevinas, Manolis ...
The lancet oncology,
08/2019, Letnik:
20, Številka:
8
Journal Article
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The Nurses' Health Study II, a large cohort study that evaluated breast cancer risk across a broad age range, found an elevated risk of breast cancer in long-duration night workers,3 which was also ...seen in a Swedish cohort study. The largest case-control study,4 including more than 6000 breast cancer cases and corresponding controls from five countries, incorporated an extensive exposure assessment protocol and evaluated detailed exposure metrics on both duration and intensity of exposure (eg, number of night shifts per week). Several studies found positive associations between night shift work and prostate cancer risk, particularly in association with longer duration of exposures, but in others there was no, or a very small, increased risk when examining ever versus never exposure to night shift work.5,6 Several informative studies found some evidence of positive associations between colorectal cancer risk and duration of night shift work. Increased incidences of hepatocellular carcinoma were seen in all three strains in comparison with control mice maintained at a stable 12-h light and 12-h dark schedule.8 In another study, exposure to constant light for a lifetime increased the incidences of lung adenocarcinoma, malignant melanoma, and total tumours in female wild-type CBA mice in comparison with control mice maintained at a 12-h light and 12-h dark schedule.9 The evaluation was further supported by positive results in other studies in rodents exposed to shifts in the light–dark schedule or continuous light using carcinogen-induced or transplantable tumour models.
Vitamin D insufficiency is common in women of childbearing age and increasing evidence suggests that the risk of osteoporotic fracture in adulthood could be determined partly by environmental factors ...during intrauterine and early postnatal life. We investigated the effect of maternal vitamin D status during pregnancy on childhood skeletal growth.
In a longitudinal study, we studied 198 children born in 1991–92 in a hospital in Southampton, UK; the body build, nutrition, and vitamin D status of their mothers had been characterised during pregnancy. The children were followed up at age 9 years to relate these maternal characteristics to their body size and bone mass.
49 (31%) mothers had insufficient and 28 (18%) had deficient circulating concentrations of 25(OH)-vitamin D during late pregnancy. Reduced concentration of 25(OH)-vitamin D in mothers during late pregnancy was associated with reduced whole-body (
r=0·21, p=0·0088) and lumbar-spine (
r=0·17, p=0·03) bone-mineral content in children at age 9 years. Both the estimated exposure to ultraviolet B radiation during late pregnancy and the maternal use of vitamin D supplements predicted maternal 25(OH)-vitamin D concentration (p<0·0001 and p=0·0110, respectively) and childhood bone mass (p=0·0267). Reduced concentration of umbilical-venous calcium also predicted reduced childhood bone mass (p=0·0286).
Maternal vitamin D insufficiency is common during pregnancy and is associated with reduced bone-mineral accrual in the offspring during childhood; this association is mediated partly through the concentration of umbilical venous calcium. Vitamin D supplementation of pregnant women, especially during winter months, could lead to longlasting reductions in the risk of osteoporotic fracture in their offspring.
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