The genetics of incontinence: A scoping review.

The genetic causes underlying incontinence in both children and adults have begun to be unravelled during the last decades. The aim of this scoping review is to synthesize current knowledge on the genetics of childhood and adult urinary and faecal incontinence, identify similarities between different incontinence subgroups, and identify knowledge gaps to aid future research. PRISMA-ScR was used, and 76 studies were included. Early epidemiological family and twin studies suggest high heritability of incontinence. Linkage studies provide evidence for the existence of rare genetic variants; however, these variants have not been identified. Later candidate gene association studies and recent genome-wide association studies provide the first preliminary evidence that common risk variants also play a role. The genetics of incontinence in children and adults has predominantly been studied separately, but this review identifies for the first time the endothelin system as a potential common pathophysiological pathway. Overall, these findings strengthen the hypothesis that genetic variants play a prominent role in the pathogenesis of incontinence. Future research should include hypothesis-free studies of rare and common variants in large well-characterized cohorts with incontinence. Studies should include different age groups and ethnicities and both sexes to fully reveal the genetics of incontinence.

Impaired phosphate transport in SLC34A2 variants in patients with pulmonary alveolar microlithiasis.

BACKGROUND: Variants in SLC34A2 encoding the sodium-dependent phosphate transport protein 2b (NaPi-IIb) cause the rare lung disease pulmonary alveolar microlithiasis (PAM). PAM is characterised by the deposition of calcium-phosphate concretions in the alveoli usually progressing over time. No effective treatment is available. So far, 30 allelic variants in patients have been reported but only a few have been functionally characterised. This study aimed to determine the impact of selected SLC34A2 variants on transporter expression and phosphate uptake in cellular studies. METHODS: Two nonsense variants (c.910A > T and c.1456C > T), one frameshift (c.1328delT), and one in-frame deletion (c.1402_1404delACC) previously reported in patients with PAM were selected for investigation. Wild-type and mutant c-Myc-tagged human NaPi-IIb constructs were expressed in Xenopus laevis oocytes. The transport function was investigated with a 32Pi uptake assay. NaPi-IIb protein expression and localisation were determined with immunoblotting and immunohistochemistry, respectively. RESULTS: Oocytes injected with the wild-type human NaPi-IIb construct had significant 32Pi transport compared to water-injected oocytes. In addition, the protein had a molecular weight as expected for the glycosylated form, and it was readily detectable in the oocyte membrane. Although the protein from the Thr468del construct was synthesised and expressed in the oocyte membrane, phosphate transport was similar to non-injected control oocytes. All other mutants were non-functional and not expressed in the membrane, consistent with the expected impact of the truncations caused by premature stop codons. CONCLUSIONS: Of four analysed SLC34A2 variants, only the Thr468del showed similar protein expression as the wild-type cotransporter in the oocyte membrane. All mutant transporters were non-functional, supporting that dysfunction of NaPi-IIb underlies the pathology of PAM.

Differences in the urinary metabolome and proteome between wet and dry nights in children with monosymptomatic nocturnal enuresis and nocturnal polyuria.

BACKGROUND: Nocturnal enuresis (NE) is a common disease with multiple pathogenic mechanisms. This study aimed to compare levels of metabolites and proteins between wet and dry nights in urine samples from children with monosymptomatic NE (MNE). METHODS: Ten boys with MNE and nocturnal polyuria (age: 7.6 ± 1.3 years) collected their total nighttime urine production during a wet and a dry night. Untargeted metabolomics and proteomics were performed on the urine samples by liquid chromatography coupled with high-mass accuracy tandem mass spectrometry (LC-MS/MS). RESULTS: On wet nights, we found reduced urine osmolality (P = 0.025) and increased excretion of urinary potassium and sodium by a factor of, respectively, 2.1 (P = 0.038) and 1.9 (P = 0.19) compared with dry nights. LC-MS identified 59 metabolites and 84 proteins with significantly different levels between wet and dry nights (fold change (FC) < 0.67 or > 1.5, P < 0.05). Some compounds were validated by different methodologies. During wet nights, levels of compounds related to oxidative stress and blood pressure, including adrenalin, were increased. We found reduced levels of aquaporin-2 on wet nights. The FCs in the 59 metabolites were positively correlated to the FCs in the same metabolites identified in urine samples obtained during the evening preceding wet and dry nights. CONCLUSIONS: Oxidative stress, which in the literature has been associated with nocturia and disturbances in sleep, might be increased during wet nights in children with MNE. We further found evidence of increased sympathetic activity. The mechanisms related to having wet nights in children with MNE seem complex, and both free water and solute handling appear to be important. A higher resolution version of the Graphical abstract is available as Supplementary information.

Psychotropic medication among children who experience parental death to cancer.

The psychological consequences of losing a parent to cancer are unclear. We investigated whether experiencing parental death to cancer before 18 years of age increases the risk of psychotropic medication. We used register data of all children born in Denmark between 1 January 1987 and 31 December 2016 (N = 1,488,846). We assessed rate ratios (RRs) with 95% confidence intervals (CIs) for first redeemed prescription of antidepressants, anxiolytics and hypnotics according to parental death status using Poisson multi-state models. We further examined whether the associations differed according to the gender of the deceased parent, child's age at the time of death or the parental length of illness. Cancer-bereaved children had a significantly increased risk of first prescription of psychotropic medication (rate ratio, RR 1.22, 95% confidence interval, CI 1.10-1.34 for males; RR 1.18, 95% CI 1.09-1.28 for females). Associations were strongest if the parent had the same sex as the child and if the parent died within one year of diagnosis. The risk was highest during the first six months after the loss (RR 2.35, 95% confidence interval, CI 1.48-3.73 for males; RR 1.81, 95% CI 1.17-2.80 for females). Children who lose a parent to cancer, particularly in cases when the disease progressed quickly, may need extra psychological support, especially during the first six months after the death.

Bilateral oophorectomy and rate of colorectal cancer: A prospective cohort study.

Worldwide, colorectal cancer is the second most common cancer and third cause of cancer death in women. Estrogen exposure has been inversely associated with colorectal cancer. Oophorectomy reduces circulating estrogen, but the effect on colorectal cancer remains uncertain. The aim of this study was to examine the association between unilateral and bilateral oophorectomy and subsequent risk of colorectal cancer, and whether this association varied by menopausal status at time of oophorectomy, use of hormone replacement therapy (HRT) at baseline, hysterectomy and baseline body mass index (BMI). The study included 25 698 female nurses (aged ≥45 years) participating in the Danish Nurse Cohort. Nurses were followed from baseline until date of colorectal cancer, death, emigration or end of follow-up at December 31, 2018, whichever came first. We examined the association between oophorectomy and colorectal cancer (all ages and stratified by menopausal status). The potential modifying effects of hysterectomy, HRT use at baseline and BMI were investigated. During 542 140 person-years of follow-up, 863 (3.4%) nurses were diagnosed with colorectal cancer. Bilateral oophorectomy was associated with a 79% increased colorectal cancer rate, adjusted rate ratio (aRR) (95% confidence interval [CI]): 1.79 (1.33-2.42). Effect estimates following unilateral oophorectomy also showed higher rate of colorectal cancer, although less pronounced and nonstatistically significant (aRR) (95% CI): 1.25 (0.86-1.82). Similar results were seen when stratifying by menopausal status. The association was not modified by baseline HRT use, hysterectomy or BMI. Oophorectomy was associated with increased rate of colorectal cancer, with highest rates among women with bilateral oophorectomy.

Understanding quality data correctly: a randomized comparison of presentation formats among cancer patients and relatives.

Background: Patient representatives are increasingly engaged in quality in health care, and even though quality data are publicly available, correct interpretation may be challenging. We designed a randomized study with the primary aim to examine the association between preferred data presentation format and the interpretation of quality data among cancer patients and relatives.Material and methods: Surveys were distributed to the Danish Cancer Society Citizens' Panel between 31 March and 14 April 2019 and 55% completed the survey (N = 464) including six storyboards that presented authentic quality data in table format, league table and point estimates. The storyboards were randomized to expose participants to the data in the three different formats and in varying presentation order. Logistic regression models were used to calculate Odds Ratios (ORs) and 95% confidence intervals (CIs) for the association between preferred presentation format, health literacy, education and cohabitation status as exposures and interpretation of quality data as outcome.Results: The majority of participants (97%) had high literacy and 57% had a medium or long higher education. A total of 60% found the questions difficult or very difficult and 33% were not able to correctly interpret at least one format. Correct interpretation was associated with preferred league table (OR = 1.62; 95% CI = 1.04-5.52) and if the data was presented in the preferred format. Medium and long education were associated with correct interpretation of at least one format (OR = 1.93; 95% CI = 1.16-3.21 and OR = 3.89; 95% CI = 1.90-7.95, respectively) while health literacy and cohabitation status were not.Conclusions: More than one third of the participants were not able to correctly interpret the data and the understanding of quality data improved with longer education and if the data was presented in the preferred format. Decision-makers should carefully consider displaying quality data according to preferred presentation format and to guide interpretation for individuals with short education.

Breast cancer rate after oophorectomy: A Prospective Danish Cohort Study.

The association between oophorectomy and risk of breast cancer in the general population is uncertain. The aim of our study was to determine the breast cancer rate in women from the general population after oophorectomy (performed before/after menopause), and whether this varies by use of hormone replacement therapy (HRT), hysterectomy, body mass index (BMI) and shift work. The study included 24 409 female nurses (aged ≥45 years) participating in the Danish Nurse Cohort. Nurses were followed from cohort entry until date of breast cancer, death, emigration or end of follow-up at 31 December 2018, whichever came first. Poisson regression with log-transformed person-years as the offset examined the association between oophorectomy and breast cancer (all ages and stratified by menopausal status at time of oophorectomy). The potential modifying effect of HRT use, hysterectomy, BMI and shift work on the associations was estimated. During 502 463 person-years of follow-up, 1975 (8.1%) nurses were diagnosed with breast cancer. Bilateral oophorectomy was associated with a reduced breast cancer rate compared to nurses with preserved ovaries, adjusted rate ratio (95% confidence interval): 0.79 (0.64; 0.99). Similar associations (magnitude and direction) were detected for unilateral oophorectomy and when stratifying according to menopausal status at time of oophorectomy, but without statistical significance. Unilateral and bilateral oophorectomy is associated with a reduced breast cancer rate in women from the general population. This association is not modified by use of HRT, hysterectomy, BMI or shift work.

Prediction of the postoperative 90-day mortality after acute colorectal cancer surgery: development and temporal validation of the ACORCA model.

PURPOSE: The aim of this study was to develop and validate a model to predict 90-day mortality after acute colorectal cancer surgery. METHODS: The model was developed in all patients undergoing acute colorectal cancer surgery in 2014-2016 and validated in a patient group operated in 2017 in Denmark. The outcome was 90-day mortality. Tested predictor variables were age, sex, performance status, BMI, smoking, alcohol, education level, cohabitation status, tumour localization and primary surgical procedure. Variables were selected according to the smallest Akaike information criterion. The model was shrunken by bootstrapping. Discrimination was evaluated with a receiver operated characteristic curve, calibration with a calibration slope and the accuracy with a Brier score. RESULTS: A total of 1450 patients were included for development of the model and 451 patients for validation. The 90-day mortality rate was 19% and 20%, respectively. Age, performance status, alcohol, smoking and primary surgical procedure were the final variables included in the model. Discrimination (AUC = 0.79), calibration (slope = 1.04, intercept = 0.04) and accuracy (brier score = 0.13) were good in the developed model. In the temporal validation, discrimination (AUC = 0.80) and accuracy (brier score = 0.13) were good, and calibration was acceptable (slope = 1.19, intercept = 0.52). CONCLUSION: We developed prediction model for 90-day mortality after acute colorectal cancer surgery that may be a promising tool for surgeons to identify patients at risk of postoperative mortality.

Eight novel variants in the SLC34A2 gene in pulmonary alveolar microlithiasis.

BACKGROUND: Pulmonary alveolar microlithiasis (PAM) is caused by genetic variants in the SLC34A2 gene, which encodes the sodium-dependent phosphate transport protein 2B (NaPi-2b). PAM is characterised by deposition of calcium phosphate concretions (microliths) in the alveoli leading to pulmonary dysfunction. The variant spectrum of SLC34A2 has not been well investigated and it is not yet known whether a genotype-phenotype correlation exists. METHODS: We collected DNA from 14 patients with PAM and four relatives, and analysed the coding regions of SLC34A2 by direct DNA sequencing. To determine the phenotype characteristics, clinical data were collected and a severity score was created for each variant, based on type and localisation within the protein. RESULTS: We identified eight novel allelic variants of SLC34A2 in 14 patients with PAM. Four of these were nonsense variants, three were missense and one was a splice site variant. One patient was heterozygous for two different variants and all other patients were homozygous. Four patients were asymptomatic and 10 patients were symptomatic. The severity of the disease was associated with the variant severity. CONCLUSIONS: Our findings support a significant role for SLC34A2 in PAM and expand the variant spectrum of the disease. Thus, SLC34A2 variants were detected in all patients and eight novel allelic variants were discovered. An association between disease severity and the severity of the variants was found; however, this needs to be investigated in larger patient populations.

Comorbidity and early death in Danish stage I lung cancer patients - an individualised approach.

Background: Comorbidity is an important prognostic marker and a treatment indicator for lung cancer patients. Register-based studies often describe the burden of comorbidity by the Charlson comorbidity index (CCI) based on hospital discharge data. We assessed the association between somatic and psychiatric comorbidity and death within one year in early lung cancer and, furthermore, the burden of comorbidity according to treatment type.Material and methods: We conducted a population-based matched case-control study of stage I lung cancer identifying all treated patients who died (all-cause) within one year after diagnosis (early death group, cases). On the basis of data from the Danish Lung Cancer Registry these patients were then matched with two controls who survived more than one year (survivors). Through a review of the medical records, we validated inclusion criteria and collected data on somatic and psychiatric comorbidity. We assessed the association between comorbidity and early death with multivariate conditional logistic regression.Results: We included 221 cases and 410 controls. The mean CCI score in the early death group was 2.3 vs. 1.3 in the survivor group (p < .001). Still, 22% vs. 30% had a CCI score of zero (p = .04) with an average number of comorbidities among these patients of 1.63 vs. 1.06 respectively (p = .006). Among women, 23% in the early death group had depression vs. 13% in the survivor group, corresponding to an unadjusted odds ratio (OR) of 2.0 (CI 95% 1.0-3.7). However, in an adjusted analysis (incl. somatic comorbidities) the OR was 1.7 (CI 95% 0.8-3.5). Patients undergoing oncological therapy were older and tended to have more somatic comorbidities than the surgically treated patients.Conclusion: Comorbidity remains a significant prognostic marker even for stage I lung cancer patients with a CCI score of zero. The suggested association between early death and depression among women needs to be studied further.

Agreement between the Danish Cancer Registry and the Danish Colorectal Cancer Group Database.

Background: The Danish Cancer Registry (DCR) and the Danish Colorectal Cancer Group (DCCG) database are population-based registries collecting information on Danish patients with colorectal cancer (CRC). DCR registers all patients with incident CRC whereas DCCG records patients with first time CRC. The registries use different inclusion criteria. The consequencenses of this are unknown and not previously evaluated. The aim of this study was to examine the agreement between patients registered in DCR and DCCG and to evaluate its influence on estimated survival and mortality.Material and methods: Patients registered in DCR and DCCG with CRC in 2014-2015 were included. Because of different inclusion criteria, DCCG's inclusion criteria were applied to DCR. Descriptive statistics were used for comparisons. One-year relative survival (1-year RS) was calculated, and the Cox proportional hazard model used for calculating 1-year mortality rate ratios (1-year MRR).Results: In 2014-2015, DCR registered 9678 Danish residents with CRC that fulfilled DCCG's inclusion criteria, while DCCG registered 10,312 Danish residents with CRC. Allowing ±180 days between dates of diagnosis, 10,688 patients were registered with CRC in the merger of the two registries. Of these, 86% were included in both registers, 4% only in DCR, and 10% only in DCCG. No difference was found in 1-year RS between patients in DCR 86% (95% CI: 85-87) and DCCG 85% (95% CI: 84-86). However, patients registered in DCCG had a 1-year MRR of 1.09 (95% CI: 1.01-1.17) compared to DCR.Conclusion: An agreement of 86% of patients was found between the two registries. The discrepancy did not influence 1-year RS. DCCG registered more patients than DCR, and 1-year MRR of patients in DCCG was increased compared to patients in DCR. Regular linkage of the registries is recommended to improve data quality of both registries.

Surgical treatment and survival from colorectal cancer in Denmark, England, Norway, and Sweden: a population-based study.

BACKGROUND: Survival from colorectal cancer has been shown to be lower in Denmark and England than in comparable high-income countries. We used data from national colorectal cancer registries to assess whether differences in the proportion of patients receiving resectional surgery could contribute to international differences in colorectal cancer survival. METHODS: In this population-based study, we collected data from all patients aged 18-99 years diagnosed with primary, invasive, colorectal adenocarcinoma from Jan 1, 2010, to Dec 31, 2012, in Denmark, England, Norway, and Sweden, from national colorectal cancer registries. We estimated age-standardised net survival using multivariable modelling, and we compared the proportion of patients receiving resectional surgery by stage and age. We used logistic regression to predict the resectional surgery status patients would have had if they had been treated as in the best performing country, given their individual characteristics. FINDINGS: We extracted registry data for 139 457 adult patients with invasive colorectal adenocarcinoma: 12 958 patients in Denmark, 97 466 in England, 11 450 in Norway, and 17 583 in Sweden. 3-year colon cancer survival was lower in England (63·9%, 95% CI 63·5-64·3) and Denmark (65·7%, 64·7-66·8) than in Norway (69·5%, 68·4-70·5) and Sweden (72·1%, 71·2-73·0). Rectal cancer survival was lower in England (69·7%, 69·1-70·3) than in the other three countries (Denmark 72·5%, 71·1-74·0; Sweden 74·1%, 72·7-75·4; and Norway 75·0%, 73·1-76·8). We found no significant differences in survival for patients with stage I disease in any of the four countries. 3-year survival after stage II or III rectal cancer and stage IV colon cancer was consistently lower in England (stage II rectal cancer 86·4%, 95% CI 85·0-87·6; stage III rectal cancer 75·5%, 74·2-76·7; and stage IV colon cancer 20·5%, 19·9-21·1) than in Norway (94·1%, 91·5-96·0; 83·4%, 80·1-86·1; and 33·0%, 31·0-35·1) and Sweden (92·9%, 90·8-94·6; 80·6%, 78·2-82·7; and 23·7%, 22·0-25·3). 3-year survival after stage II rectal cancer and stage IV colon cancer was also lower in England than in Denmark (stage II rectal cancer 91·2%, 88·8-93·1; and stage IV colon cancer 23·5%, 21·9-25·1). The total proportion of patients treated with resectional surgery ranged from 47 803 (68·4%) of 69 867 patients in England to 9582 (81·3%) of 11 786 in Sweden for colon cancer, and from 16 544 (59·9%) of 27 599 in England to 4106 (70·8%) of 5797 in Sweden for rectal cancer. This range was widest for patients older than 75 years (colon cancer 19 078 [59·7%] of 31 946 patients in England to 4429 [80·9%] of 5474 in Sweden; rectal cancer 4663 [45·7%] of 10 195 in England to 1342 [61·9%] of 2169 in Sweden), and the proportion of patients treated with resectional surgery was consistently lowest in England. The age gradient of the decline in the proportion of patients treated with resectional surgery was steeper in England than in the other three countries in all stage categories. In the hypothetical scenario where all patients were treated as in Sweden, given their age, sex, and disease stage, the largest increase in resectional surgery would be for patients with stage III rectal cancer in England (increasing from 70·3% to 88·2%). INTERPRETATION: Survival from colon cancer and rectal cancer in England and colon cancer in Denmark was lower than in Norway and Sweden. Survival paralleled the relative provision of resectional surgery in these countries. Differences in patient selection for surgery, especially in patients older than 75 years or individuals with advanced disease, might partly explain these differences in international colorectal cancer survival. FUNDING: Early Diagnosis Policy Research Grant from Cancer Research UK (C7923/A18348).

Brain proteome changes in female Brd1+/- mice unmask dendritic spine pathology and show enrichment for schizophrenia risk.

Genetic and molecular studies have implicated the Bromodomain containing 1 (BRD1) gene in the pathogenesis of schizophrenia and bipolar disorder. Accordingly, mice heterozygous for a targeted deletion of Brd1 (Brd1+/- mice) show behavioral phenotypes with broad translational relevance to psychiatric disorders. BRD1 encodes a scaffold protein that affects the expression of many genes through modulation of histone acetylation. BRD1 target genes have been identified in cell lines; however the impact of reduced Brd1 levels on the brain proteome is largely unknown. In this study, we applied label-based quantitative mass spectrometry to profile the frontal cortex, hippocampus and striatum proteome and synaptosomal proteome of female Brd1+/- mice. We successfully quantified between 1537 and 2196 proteins and show widespread changes in protein abundancies and compartmentalization. By integrative analysis of human genetic data, we find that the differentially abundant proteins in frontal cortex and hippocampus are enriched for schizophrenia risk further linking the actions of BRD1 to psychiatric disorders. Affected proteins were further enriched for proteins involved in processes known to influence neuronal and dendritic spine morphology e.g. regulation of cytoskeleton dynamics and mitochondrial function. Directly prompted in these findings, we investigated dendritic spine morphology of pyramidal neurons in anterior cingulate cortex and found them significantly altered, including reduced size of small dendritic spines and decreased number of the mature mushroom type. Collectively, our study describes known as well as new mechanisms related to BRD1 dysfunction and its role in psychiatric disorders, and provides evidence for the molecular and cellular dysfunctions underlying altered neurosignalling and cognition in Brd1+/- mice.

The effect of hypoxia on ZEB1 expression in a mimetic system of the blood-brain barrier.

The blood-brain barrier consists of a tightly sealed monolayer of endothelial cells being vital in maintaining a stable intracerebral microenvironment. The barrier is receptive to leakage upon exposure to environmental factors, like hypoxia, and its disruption has been suggested as a constituent in the pathophysiology of both neurological and psychiatric disorders. The schizophrenia associated ZEB1 gene encodes a transcription factor susceptible to transcriptional control by a hypoxia induced factor, HIF1A, known to be implicated in blood-brain barrier dysfunction. However, whether ZEB1 is also implicated in maintaining blood-brain barrier integrity upon hypoxia is unknown. Here we assessed Hif1a, Zo1 and Zeb1 mRNA expression and ZO1 protein abundancy in a mimetic system of the in vivo blood-brain barrier comprising mouse brain endothelial cells subjected to the norm- and proven hypoxic conditions. Despite that, Hif1a mRNA expression was significantly increased, clearly indicating that the oxygen-deprived environment introduced a hypoxia response in the cells, we found no hypoxia-induced changes in neither ZO1 abundancy nor in the expression of Zo1 and Zeb1 mRNA. However, independent of hypoxia status, we found that Zeb1 and Zo1 mRNA expression is highly correlated. Further studies are warranted that investigate the implication of the ZEB1/ZO1 axis in blood-brain barrier maintenance under different physiological conditions.

Do people improve health behavior after their partner is diagnosed with cancer? A prospective study in the Danish diet, Cancer and Health Cohort.

Background: The cancer diagnosis is regarded as a stressful life event that is thought to trigger a teachable moment to induce health behavior changes among cancer patients. However, this may also hold true for their partners. We assessed if partners of cancer patients make more health behavior changes compared to persons whose partner remained cancer-free. Methods: Lifestyles was assessed in the prospective Danish Diet, Cancer and Health study. Logistic regression analyses were used to assess health behavior change among partners of cancer patients (n = 672) compared to partners of persons who remained cancer-free (n = 5534). Additionally, associations in two subgroups were assessed: bereaved partners and partners of patients who remained alive after cancer. Results: Partners of cancer patients were more likely to decrease their alcohol intake compared to partners of persons who remained cancer free. This finding could mainly be attributed to bereaved partners. Moreover, bereaved partners were also more likely to decrease their BMI. In contrast to our hypothesis, bereaved partners were more likely to decrease fruit intake and increase sugared beverages compared to partners of persons who remained cancer free. In general, men tended to improve their physical activity, while women tended to worsen their physical activity following the cancer diagnosis of their partner. Conclusions: A cancer diagnosis in the partner does seem to improve health behavior change only for alcohol intake. Bereaved partners tend to worsen dietary behaviors after the patient's death.

Mortality after emergency treatment of colorectal cancer and associated risk factors-a nationwide cohort study.

PURPOSE: The aim of this study was to investigate if postoperative mortality after acute surgical treatment of colorectal cancer has decreased in Denmark during this period and to investigate risk factors associated with early death. METHODS: This is a nationwide and population-based cohort study. From the Danish Colorectal Cancer Group database and National Patient Registry, we collected data on all patients operated with bowel resection, diverting stoma only, or placement of an endoscopic stent from 2005 to 2015. Year of surgery was the main exposure variable and 90-day postoperative mortality the primary outcome. RESULTS: We included 6147 patients. The incidence of patients per year was stable during 2005-2015. The 90-day mortality decreased from 31% in 2005 to 24% in 2015 with a significant time trend (p < 0.0001). Other factors associated with postoperative mortality were increasing age, presence of comorbidity (measured as Charlson comorbidity index score ≥ 1), and stage IV disease. Insertion of self-expanding metallic stent was protective for 90-day postoperative mortality compared with other surgical procedures. CONCLUSION: Ninety-day postoperative mortality from acute colorectal surgery has improved in Denmark from 2005 to 2015. Nevertheless, almost one out of four patients undergoing acute surgery for colorectal cancer dies within 90 days.

Pre-diagnostic changes in body mass index and mortality among breast cancer patients.

PURPOSE: We investigated whether changes in body mass index (BMI) before a breast cancer diagnosis affected mortality and whether trajectories more accurately predict overall mortality compared to a single measure of BMI. METHODS: Our prospective cohort comprised 2012 women with breast cancer who reported their weight in each decade from 20 to 50-64 years of age. We used trajectory analysis to identify groups with similar development patterns in BMI and Cox proportional hazards models to examine the association between trajectory groups and mortality, and interactions with oestrogen receptor status and smoking. We used c-index statistics to compare the trajectory model with the single measure model of BMI. RESULTS: We identified three distinct trajectory groups, with a mean BMI at age 20 of 19, 22 and 24 increasing to 23 (normal-to-normal), 29 (normal-to-overweight) and 37 (normal-to-obese) at 50-64 years of age, respectively. Women in the normal-to-obese trajectory group experienced significantly higher overall mortality than those in the normal-to-normal trajectory group (HR 1.76, 95% CI 1.21‒2.56). The association declined to a non-significant level after adjustments for clinical prognostic factors. Although not significant, the same tendency was seen for breast cancer-specific mortality. The association was strongest in women with oestrogen receptor-negative tumours. Weight changes over time were not significantly different from a single BMI measure before diagnosis to predict survival. CONCLUSION: Weight gain affects overall mortality after breast cancer but clinical prognostic factors largely eliminate the association. Using trajectories of weight changes did not improve the predictive value compared to a single measure of BMI.

The Novel Ser18del AVP Variant Causes Inherited Neurohypophyseal Diabetes Insipidus by Mechanisms Shared with Other Signal Peptide Variants.

BACKGROUND/AIM: Variability in the severity and age at onset of autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) may be associated with certain types of variants in the arginine vasopressin (AVP) gene. In this study, we aimed to describe a large family with an apparent predominant female occurrence of polyuria and polydipsia and to determine the underlying cause. METHODS: The family members reported their family demography and symptoms. Two subjects were diagnosed by fluid deprivation and dDAVP challenge tests. Eight subjects were tested genetically. The identified variant along with 3 previously identified variants in the AVP gene were investigated by heterologous expression in a human neuronal cell line (SH-SY5Y). RESULTS: Both subjects investigated clinically had a partial neurohypophyseal diabetes insipidus phenotype. A g.276_278delTCC variant in the AVP gene causing a Ser18del deletion in the signal peptide (SP) of the AVP preprohormone was perfectly co-segregating with the disease. When expressed in SH-SY5Y cells, the Ser18del variant along with 3 other SP variants (g.227G>A, Ser17Phe, and Ala19Thr) resulted in reduced AVP mRNA, impaired AVP secretion, and partial AVP prohormone degradation and retention in the endoplasmic reticulum. Impaired SP cleavage was demonstrated directly in cells expressing the Ser18del, g.227G>A, and Ala19Thr variants, using state-of-the-art mass spectrometry. CONCLUSION: Variants affecting the SP of the AVP preprohormone cause adFNDI with variable phenotypes by a mechanism that may involve impaired SP cleavage combined with effects at the mRNA, protein, and cellular level.

A Novel Synonymous Variant in the AVP Gene Associated with Autosomal Dominant Familial Neurohypophyseal Diabetes Insipidus Causes Partial RNA Missplicing.

OBJECTIVE: Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is characterized by severe polyuria and polydipsia and is caused by variations in the gene encoding the AVP prohormone. This study aimed to ascertain a correct diagnosis, to identify the underlying genetic cause of adFNDI in a Swedish family, and to test the hypothesis that the identified synonymous exonic variant in the AVP gene (c.324G>A) causes missplicing and endoplasmic reticulum (ER) retention of the prohormone. DESIGN/PATIENTS: Three affected family members were admitted for fluid deprivation test and dDAVP (1-deamino-8-d-arginine-vasopressin) challenge test. Direct sequencing of the AVP gene was performed in the affected subjects, and genotyping of the identified variant was performed in family members. The variant was examined by expression of AVP minigenes containing the entire coding regions as well as intron 2 of AVP. METHODS/RESULTS: Clinical tests revealed significant phenotypical variation with both complete and partial adFNDI phenotype. DNA analysis revealed a synonymous c.324G>A substitution in one allele of the AVP gene in affected family members only. Cellular studies revealed both normally spliced and misspliced pre-mRNA in cells transfected with the AVP c.324G>A minigene. Confocal laser scanning microscopy showed collective localization of the variant prohormone to ER and vesicular structures at the tip of cellular processes. CONCLUSION: We identified a synonymous variant affecting the second nucleotide of exon 3 in the AVP gene (c.324G>A) in a family in which adFNDI segregates. Notably, we showed that this variant causes partial missplicing of pre-mRNA, resulting in accumulation of the variant prohormone in ER. Our study suggests that even a small amount of aberrant mRNA might be sufficient to disturb cellular function, resulting in adFNDI.

Assessing the pattern of recurrence in Danish stage I lung cancer patients in relation to the follow-up program: are we failing to identify patients with cerebral recurrence?

BACKGROUND: There is paucity of evidence regarding the optimal follow-up (FU) regimen for lung cancer. Consequently, FU is organized differently across countries. The Danish FU regimen has short FU intervals with a computed tomography (CT) scan of the chest and upper abdomen every three months in the early phase (first 2 years), then every six months in the late phase of FU (3rd, 5th year). Characterizing recurrences missed by the FU program in terms of site, tumor histology, department, and phase of FU, could improve the FU program. MATERIAL AND METHOD: A case-control study of curatively treated stage I lung cancer patients who attended the Danish FU-program and had recurrence identified through the follow-up program (controls, FU group) or outside FU program (cases, symptomatic group). RESULTS: Of 233 included patients with recurrence, the FU group constituted 85% (n = 197). Among the 15% (n = 36) in the symptomatic group, 53% had involvement of the central nervous system compared with 3% in the FU group. The unadjusted odds ratio (OR) for having an isolated brain recurrence (IBR) in the symptomatic group was 52.3 (95%CI: 15.1-181.4) as compared with the FU group. The OR for having a symptomatic recurrence in the early phase of FU was 2.5 (95%CI: 0.7-8.7) compared with the late phase. CONCLUSIONS: The FU program did not identify the majority of patients with IBR. Including cerebral imaging in the FU program may result in an earlier detection of brain metastases. These matters should be studied in a prospective setting.