Objective
We previously showed that maternal under‐nutrition during gestation is associated with increased metabolic and cardiovascular disease in the offspring. Also, we found increased neonatal ...adiposity among the grandchildren of women who had been undernourished during pregnancy. In the present study we investigated whether these transgenerational effects have led to altered body composition and poorer health in adulthood in the grandchildren.
Design
Historical cohort study.
Setting
Web‐based questionnaire.
Population
The adult offspring (F2) of a cohort of men and women (F1) born around the time of the 1944–45 Dutch famine.
Methods
We approached the F2 adults through their parents. Participating F2 adults (n = 360, mean age 37 years) completed an online questionnaire.
Main outcome measures
Weight, body mass index (BMI), and health in F2 adults, according to F1 prenatal famine exposure.
Results
Adult offspring (F2) of prenatally exposed F1 fathers had higher weights and BMIs than offspring of prenatally unexposed F1 fathers (+4.9 kg, P = 0.03; +1.6 kg/m², P = 0.006). No such effect was found for the F2 offspring of prenatally exposed F1 mothers. We observed no differences in adult health between the F2 generation groups.
Conclusions
Offspring of prenatally undernourished fathers, but not mothers, were heavier and more obese than offspring of fathers and mothers who had not been undernourished prenatally. We found no evidence of transgenerational effects of grandmaternal under‐nutrition during gestation on the health of this relatively young group, but the increased adiposity in the offspring of prenatally undernourished fathers may lead to increased chronic disease rates in the future.
There is limited evidence whether being on fludrocortisone prevents vasovagal syncope.
The authors sought to determine whether treatment with fludrocortisone reduces the proportion of patients with ...recurrent vasovagal syncope by at least 40%, representing a pre-specified minimal clinically important relative risk reduction.
The multicenter POST 2 (Prevention of Syncope Trial 2) was a randomized, placebo-controlled, double-blind trial that assessed the effects of fludrocortisone in vasovagal syncope over a 1-year treatment period. All patients had >2 syncopal spells and a Calgary Syncope Symptom Score >-3. Patients received either fludrocortisone or matching placebo at highest tolerated doses from 0.05 mg to 0.2 mg daily. The main outcome measure was the first recurrence of syncope.
The authors randomized 210 patients (71% female, median age 30 years) with a median 15 syncopal spells over a median of 9 years equally to fludrocortisone or placebo. Of these, 96 patients had ≥1 syncope recurrences, and only 14 patients were lost to follow-up before syncope recurrence. There was a marginally nonsignificant reduction in syncope in the fludrocortisone group (hazard ratio HR: 0.69: 95% confidence interval CI: 0.46 to 1.03; p = 0.069). In a multivariable model, fludrocortisone significantly reduced the likelihood of syncope (HR: 0.63; 95% CI: 0.42 to 0.94; p = 0.024). When the analysis was restricted to outcomes after 2 weeks of dose stabilization, there was a significant benefit due to fludrocortisone (HR: 0.51; 95% CI: 0.28 to 0.89; p = 0.019).
The study did not meet its primary objective of demonstrating that fludrocortisone reduced the likelihood of vasovagal syncope by the specified risk reduction of 40%. The study demonstrated a significant effect after dose stabilization, and there were significant findings in post hoc multivariable and on-treatment analyses. (A randomised clinical trial of fludrocortisone for the prevention of vasovagal syncope; ISRCTN51802652; Prevention of Syncope Trial 2 POST 2; NCT00118482).
Background and aims
Clinicopathological characteristics of gastric cancer (GC) are changing, especially in the West with a decreasing incidence of distal, intestinal-type tumours and the ...corresponding increasing proportion of tumours with Laurén diffuse or WHO poorly cohesive (PC) including signet ring cell (SRC) histology. To accurately assess the behaviour and the prognosis of these GC subtypes, the standardization of pathological definitions is needed.
Methods
A multidisciplinary expert team belonging to the European Chapter of International Gastric Cancer Association (IGCA) identified 11 topics on pathological classifications used for PC and SRC GC. The topics were debated during a dedicated Workshop held in Verona in March 2017. Then, through a Delphi method, consensus statements for each topic were elaborated.
Results
A consensus was reached on the need to classify gastric carcinoma according to the most recent edition of the WHO classification which is currently WHO 2010. Moreover, to standardize the definition of SRC carcinomas, the proposal that only WHO PC carcinomas with more than 90% poorly cohesive cells having signet ring cell morphology have to be classified as SRC carcinomas was made. All other PC non-SRC types have to be further subdivided into PC carcinomas with SRC component (< 90% but > 10% SRCs) and PC carcinomas not otherwise specified (< 10% SRCs).
Conclusion
The reported statements clarify some debated topics on pathological classifications used for PC and SRC GC. As such, this consensus classification would allow the generation of evidence on biological and prognostic differences between these GC subtypes.
In a randomized, delayed-start trial of levodopa in Parkinson’s disease, with one group receiving the drug for 80 weeks and the other starting at 40 weeks, the difference between the groups in the ...progression of symptoms was not significant.
Obtaining spectroscopic observations of the progenitors of core-collapse supernovae is often unfeasible, due to an inherent lack of knowledge as to what stars experience supernovae and when they will ...explode. In this Letter we present photometric and spectroscopic observations of the progenitor activity of SN 2023fyq before the He-rich progenitor explodes as a Type Ibn supernova. The progenitor of SN 2023fyq shows an exponential rise in flux prior to core collapse. Complex He I emission line features are observed in the progenitor spectra, with a P Cygni-like profile, as well as an evolving broad base with velocities of the order of 10 000 km s −1 . The luminosity and evolution of SN 2023fyq is consistent with a Type Ibn, reaching a peak r -band magnitude of −18.8 mag, although there is some uncertainty regarding the distance to the host, NGC 4388, which is located in the Virgo cluster. We present additional evidence of asymmetric He-rich material being present both prior to and after the explosion of SN 2023fyq, which suggests that this material survived the ejecta interaction. Broad O I , C I , and the Ca II triplet lines are observed at late phases, confirming that SN 2023fyq was a genuine supernova, rather than a non-terminal interacting transient. SN 2023fyq provides insight into the final moments of a massive star’s life, demonstrating that the progenitor is likely highly unstable before core collapse.
Background
The literature on the prognostic relevance of signet-ring cell (SRC) histology in gastric cancer (GC) is controversial which is most likely related to inconsistent SRC classification based ...on haematoxylin–eosin staining. We hypothesised that mucin stains can consistently identify SRC-GC and predict GC patient outcome.
Methods
We performed a comprehensive literature review on mucin stains in SRC-GC and characterised the mucin expression in 851 Caucasian GC and 410 Asian GC using Alcian Blue (AB)-Periodic Acid-Schiff (PAS), MUC2 (intestinal-type mucin), and MUC5AC (gastric-type mucin). The relationship between mucin expression and histological phenotype poorly cohesive (PC) including proportion of SRCs, non-poorly cohesive (non-PC), or mucinous (MC), clinicopathological variables, and patient outcome was analysed.
Results
Depending on mucin expression and cut-offs, the positivity rates of SRC-GC reported in the literature varied from 6 to 100%. Patients with MUC2 positive SRC-GC or SRC-GC with (gastro)intestinal phenotype had poorest outcome.
In our cohort study, PC with ≥ 10% SRCs expressed more frequently MUC2, MUC5AC, and ABPAS (
p
< 0.001,
p
= 0.004 and
p
< 0.001, respectively). Caucasians with AB positive GC or combined ABPAS-MUC2 positive and MUC5AC negative had poorest outcome (all
p
= 0.002). This association was not seen in Asian patients.
Conclusions
This is the first study to suggest that mucin stains do not help to differentiate between SRC-GC and non-SRC-GC. However, mucin stains appear to be able to identify GC patients with different outcome. To our surprise, the relationship between outcome and mucin expression seems to differ between Caucasian and Asian GC patients which warrants further investigations.
Colorectal, endometrial and upper urinary tract tumours are characteristic for Lynch syndrome (hereditary non-polyposis colon carcinoma, HNPCC). The aim of the present study was to establish whether ...carriers of mutations in mismatch repair genes MLH1, MSH2 or MSH6 are at increased risk of urinary bladder cancer.
Carriers and first degree relatives of 95 families with a germline mutation in the MLH1 (n=26), MSH2 (n=43), or MSH6 (n=26) gene were systematically questioned about the occurrence of carcinoma. The cumulative risk of cancer occurring before the age of 70 years (CR70) was compared to the CR70 of the general Dutch population. Microsatellite instability (MSI) testing and/or immunohistochemistry (IHC) for mismatch repair proteins was performed on bladder tumour tissue.
Bladder cancer was diagnosed in 21 patients (90% men) from 19 Lynch syndrome families (2 MLH1, 15 MSH2, and 4 MSH6). CR70 for bladder cancer was 7.5% (95% CI 3.1% to 11.9%) for men and 1.0% (95% CI 0% to 2.4%) for women, resulting in relative risks for mutation carriers and first degree relatives of 4.2 (95% CI 2.2 to 7.2) for men and 2.2 (95% CI 0.3 to 8.0) for women. Men carrying an MSH2 mutation and their first degree relatives were at highest risks: CR70 for bladder and upper urinary tract cancer being 12.3% (95% CI 4.3% to 20.3%) and 5.9% (95% CI 0.7% to 11.1%). Bladder cancer tissue was MSI positive in 6/7 tumours and loss of IHC staining was found in 14/17 tumours, indicating Lynch syndrome aetiology.
Patients with Lynch syndrome carrying an MSH2 mutation are at increased risk of urinary tract cancer including bladder cancer. In these cases surveillance should be considered.
We present the discovery of PS18kh, a tidal disruption event discovered at the center of SDSS J075654.53+341543.6 (d 322 Mpc) by the Pan-STARRS Survey for Transients. Our data set includes ...pre-discovery survey data from Pan-STARRS, the All-sky Automated Survey for Supernovae, and the Asteroid Terrestrial-impact Last Alert System as well as high-cadence, multiwavelength follow-up data from ground-based telescopes and Swift, spanning from 56 days before peak light until 75 days after. The optical/UV emission from PS18kh is well-fit as a blackbody with temperatures ranging from T 12,000 K to T 25,000 K and it peaked at a luminosity of L 8.8 × 1043 erg s−1. PS18kh radiated E = (3.45 0.22) × 1050 erg over the period of observation, with (1.42 0.20) × 1050 erg being released during the rise to peak. Spectra of PS18kh show a changing, boxy/double-peaked H emission feature, which becomes more prominent over time. We use models of non-axisymmetric accretion disks to describe the profile of the H line and its evolution. We find that at early times the high accretion rate leads the disk to emit a wind which modifies the shape of the line profile and makes it bell-shaped. At late times, the wind becomes optically thin, allowing the non-axisymmetric perturbations to show up in the line profile. The line-emitting portion of the disk extends from rin ∼ 60rg to an outer radius of rout ∼ 1400rg and the perturbations can be represented either as an eccentricity in the outer rings of the disk or as a spiral arm in the inner disk.
The aim of this study was to develop and validate a clinical prediction model to predict overall survival in patients with nonmetastatic, resected gallbladder cancer (GBC).
Although several tools are ...available, no optimal method has been identified to assess survival in patients with resected GBC.
Data from a Dutch, nation-wide cohort of patients with resected GBC was used to develop a prediction model for overall survival. The model was internally validated and a cohort of Australian GBC patients who underwent resection was used for external validation. The performance of the American Joint Committee on Cancer (AJCC) staging system and the present model were compared.
In total, 446 patients were included; 380 patients in the development cohort and 66 patients in the validation cohort. In the development cohort median survival was 22 months (median follow-up 75 months). Age, T/N classification, resection margin, differentiation grade, and vascular invasion were independent predictors of survival. The externally validated C-index was 0.75 (95%CI: 0.69-0.80), implying good discriminatory capacity. The discriminative ability of the present model after internal validation was superior to the ability of the AJCC staging system (Harrell C-index 0.71, 95%CI: 0.69-0.72) vs. 0.59 (95% CI: 0.57-0.60).
The proposed model for the prediction of overall survival in patients with resected GBC demonstrates good discriminatory capacity, reasonable calibration and outperforms the authoritative AJCC staging system. This model can be a useful tool for physicians and patients to obtain information about survival after resection and is available from https:// gallbladderresearch.shinyapps.io/Predict_GBC_survival/.
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