| 1. |
- Ademuyiwa, Adesoji O., et al.
(författare)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 2. |
- Breitfeld, Jana, et al.
(författare)
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Genetic dissection of serum vaspin highlights its causal role in lipid metabolism
- 2023
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Ingår i: Obesity. - 1930-7381. ; 31:11, s. 2862-2874
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Vaspin (visceral adipose tissue derived serine protease inhibitor, SERPINA12) is associated with obesity-related metabolic traits, but its causative role is still elusive. The role of genetics in serum vaspin variability to establish its causal relationship with metabolically relevant traits was investigated. Methods: A meta-analysis of genome-wide association studies for serum vaspin from six independent cohorts (N = 7446) was conducted. Potential functional variants of vaspin were included in Mendelian randomization (MR) analyses to assess possible causal pathways between vaspin and homeostasis model assessment and lipid traits. To further validate the MR analyses, data from Genotype-Tissue Expression (GTEx) were analyzed, db/db mice were treated with vaspin, and serum lipids were measured. Results: A total of 468 genetic variants represented by five independent variants (rs7141073, rs1956709, rs4905216, rs61978267, rs73338689) within the vaspin locus were associated with serum vaspin (all p < 5×10−8, explained variance 16.8%). MR analyses revealed causal relationships between serum vaspin and triglycerides, low-density lipoprotein, and total cholesterol. Gene expression correlation analyses suggested that genes, highly correlated with vaspin expression in adipose tissue, are enriched in lipid metabolic processes. Finally, in vivo vaspin treatment reduced serum triglycerides in obese db/db mice. Conclusions: The data show that serum vaspin is strongly determined by genetic variants within vaspin, which further highlight vaspin's causal role in lipid metabolism.
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| 3. |
- Williamson, Alice, et al.
(författare)
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Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:6, s. 973-983
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Tidskriftsartikel (refereegranskat)abstract
- Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.
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| 4. |
- Aly, Markus
(författare)
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Prostate cancer diagnostics : complications and ways to reduce unnecessary biopsies
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Prostate cancer is the most common form of cancer among men in Sweden. There has been a rapid increase in the incidence rate of prostate cancer following the introduction of PSA testing and, today, more than 1800 men are diagnosed with the disease annually in Stockholm, Sweden. This increased testing has, however, not led to any significant reduction in the mortality of prostate cancer. There is no official screening programme for prostate cancer in Sweden, however, more than 60% of men above the age of 60 have undergone a PSA test in the last 5 years. What is less known is what proportion of men undergo a prostate biopsy after a PSA test and within what time frame. The majority of men undergoing a prostate biopsy are not diagnosed with a prostate cancer. In a setting where the PSA test had a better specificity these men would not have to undergo a prostate biopsy. To perform a prostate biopsy is not without risks. Serious infectious complications following prostate biopsies have been reported to be increasing in other parts of the world. The serious infectious complication rate in Stockholm, following a prostate biopsy, is not known. Aims: To investigate if genetic markers, SNPs, can be used as a complement to PSA to predict which men with a PSA <10 ng/mL need to undergo prostate biopsies. To explore the prostate biopsy rates and results in Stockholm and to investigate when PSA testing leads to prostate biopsies and to what extent these prostate biopsies cause side effects in terms of severe infections. Material and Methods: In Study I, 8088 men were identified who underwent at least one prostate biopsy in Stockholm between 2005 and 2007. Those alive and younger than 80 years of age, were invited to donate blood and fill out a questionnaire. 2542 men were included in the analysis when restricted to age less than 80, alive at time of invitation, valid PIN, and a PSA <10 ng/mL. In Study II, 860 men aged 50 to 69 years with a PSA of 1-3 ng/mL without a history of prostate cancer or previous prostate biopsies were invited to undergo a prostate biopsy. 172 men were stratified into low-, intermediate- and high-risk groups according to their genetic score and then underwent a prostate biopsy. In Studies I and II, a genetic score, based on the known SNPs associated with a risk of prostate cancer at the time of the study in combination with PSA and other predictive factors, was created and used in a prediction model to enhance specificity in men with a PSA<10 ng/mL and sensitivity in men with a PSA of 1-3 ng/mL. In Study III, men who had undergone at least one prostate biopsy in Stockholm from 2003 to 2012 were included. Biopsies done in 2003 were acknowledged but not included in the analysis. Migration data was used for population analysis. Data from 38 800 biopsies was analysed. Main outcome in the study was time from PSA test to prostate biopsy. In Study IV, prostate biopsies (n=44 047) done from 2003 to 2012 were included and linked by the use of PIN to microbiological data resources to identify blood cultures taken and available biograms. The main variable studied for outcome was year of biopsy. Logistic regression and time to event were used to address associations. The net reclassification index was used to evaluate the predictive performance of the genetic risk score. In all the studies men were linked to several health registers, such as the Swedish Cancer Register, the National Prostate Cancer Register, the Swedish Cause of Death Register, the National Patient Register, and the Total Population Register. Results: In Study I, up to 23% of the prostate biopsies could have been avoided by using a genetic risk score in combination with age, family history, PSA and f/t PSA. The proportion of missed cancers would be between 5.8 and 12% depending on the risk cut-off used. The proportion of aggressive cancers missed would be between 3.3 and 8.3%. In Study II, the proportion of cancers diagnosed in the low-, intermediate- and high-risk groups was 18, 28 and 37 %, respectively (p<0.05). A borderline significant trend was seen between a higher genetic risk score and the risk of an aggressive prostate cancer. In Study III, 58 and 45% of men in aged 50-59 and 60-69 years of age, respectively, with a PSA between 4 and 10 ng/mL underwent a prostate biopsy within one year of the PSA test. For men with a PSA >10 ng/mL the proportion was 67 and 58% respectively. One out of eight men with an advanced prostate cancer had a first known PSA of >4 ng/mL more than 6 months prior to their diagnosis. In Study IV, the proportion of men with a positive blood culture within 30 days of the prostate biopsy in 2003 was 0.38 and 1.14% in 2012. Year of biopsy was highly significant as a risk factor for undergoing a blood culture and was robust both in the simple - and the adjusted analysis. Young age and low PSA values were associated with a risk of undergoing a blood culture. Men with a high Charlson Comorbidity Index had an increased risk of undergoing a blood culture. Bacteria resistant to common prophylactic antibiotics were more frequently found in blood cultures in the later years of the study than in the early years. Conclusion: A genetic risk score can be used to enhance the sensitivity and specificity of PSA in men undergoing an investigation for prostate cancer. By reducing the number of unnecessary biopsies the number of men suffering from severe infectious complications will be reduced as well as the number diagnosed with a low-risk prostate cancer. The proportion of relatively young men not undergoing a prostate biopsy within one year of the PSA test, although their result was pathological, was surprisingly high. One way to solve this problem would be to introduce a structured follow-up after PSA testing.
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| 5. |
- Björklund, Johan, et al.
(författare)
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The 90-day cause-specific mortality after radical prostatectomy : a nationwide population-based study.
- 2022
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Ingår i: BJU International. - : John Wiley & Sons. - 1464-4096 .- 1464-410X. ; 129:3, s. 318-324
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the cause-specific mortality in the postoperative period after radical prostatectomy (RP) for prostate cancer (PCa).METHODS: In the National Prostate Cancer Register of Sweden (NPCR), we identified all men who died within 90 days after RP performed 1998-2018 and we assessed cause of death in a chart review. We compared the adjudications of death from our medical record review with those in in the Swedish Cause of Death Registry (CDR).RESULTS: Out of 44 635, 58 (0.13%) men who had undergone RP from 1998 through 2018 died within 90 days after RP. Per medical record review the most common causes of death were cardiac disease (30%) and venous thromboembolic events (VTE; 21%). No men died of metastatic PCa as was first indicated in the CDR. After robot-assisted RP (RARP) or open retropubic RP (RRP), the postoperative mortality was 0.09% (19/21 520) and 0.19% (37/19 635), respectively. The effect off modality was confounded mainly by year of surgery, age at surgery, Charlson Comorbidity Index score and the concomitant pelvic lymph node dissection.CONCLUSION: The validated absolute 90-day mortality after RP was 1.3/1000 during the 21-year study period. Cardiovascular diseases were the most common causes of death after RP. Our validation of the CDR refuted the occurrence of postoperative deaths from metastatic PCa. There were differences in rates and type of mortality between RRP and RARP, but the RARP cohort was more recent than the RRP cohort, which likely explain the differences.
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| 6. |
- Bonde, Tiago M., et al.
(författare)
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Time to castration-resistant prostate cancer and prostate cancer death according to PSA response in men with non-metastatic prostate cancer treated with gonadotropin releasing hormone agonists
- 2022
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Ingår i: Scandinavian journal of urology. - : Taylor & Francis Group. - 2168-1805 .- 2168-1813. ; 56:3, s. 169-175
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To predict castration-resistant prostate cancer (CRPC) and prostate cancer (Pca) death by use of clinical variables at Pca diagnosis and PSA levels after start of gonadotropin-releasing hormone agonists (GnRH) in men with non-metastatic castration sensitive prostate cancer (nmCSPC).Materials and Methods: PSA values for 1603 men with nmCSPC in the National Prostate Cancer Register of Sweden who received GnRH as primary treatment were retrieved from Uppsala-Örebro PSA Cohort and Stockholm PSA and Biopsy Register. All men had measured PSA before (pre-GnRH PSA) and 3–6 months after (post-GnRH PSA) date of start of GnRH. Unadjusted and adjusted Cox models were used to predict CRPC by PSA levels. PSA levels and ISUP grade were used to construct a risk score to stratify men by tertiles according to risk of CRPC and Pca death.Results: 788 (49%) men reached CRPC and 456 (28%) died of Pca during follow-up. Post-GnRH PSA predicted CRPC regardless of pre-GnRH PSA. CRPC risk increased with higher post-GnRH PSA, HR 4.7 (95% CI: 3.4–6.7) for PSA > 16 ng/mL vs 0–0.25 ng/mL and with ISUP grade, HR 3.7 (95%: 2.5–5.4) for ISUP 5 vs ISUP 1. Risk of Pca death in men above top vs bellow bottom tertile of post-GnRH PSA and ISUP grade was HR 4.1 (95% CI: 3.0–5.5).Conclusion: A risk score based on post-GnRH PSA and ISUP grade could be used for early identification of a target group for future clinical trials on additional therapy to GnRH.
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| 7. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 8. |
- Jäderling, Fredrik, et al.
(författare)
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Preoperative staging using magnetic resonance imaging and risk of positive surgical margins after prostate-cancer surgery
- 2019
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Ingår i: Prostate Cancer and Prostatic Diseases. - : Nature Publishing Group. - 1365-7852 .- 1476-5608. ; 22:3, s. 391-398
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is unclear whether preoperative staging using Magnetic Resonance Imaging (MRI) reduces the risk of positive margins in prostate cancer. We aimed to assess the effect on surgical margins and degree of nerve sparing of a pelvic MRI presented at a preoperative MRI conference. Methods: Single institution, observational cohort study including 1037 men that underwent robot assisted radical prostatectomy between October 2013 and June 2015. Of these, 557 underwent a preoperative MRI combined with a preoperative MRI conference and 410 did not. With whole-mount prostate specimen histopathology as gold standard we assessed the ability of MRI in finding the index tumor and the sensitivity and specificity for extra prostatic extension. We calculated relative risks for positive surgical margins and non-nerve sparing procedure, adjusting for preoperative risk factors using stabilized inverse-probability weighting. Results: MRI detected the index tumor in 80% of the cases. Non-organ confined disease (pT3) at histology was present in the MRI and the non-MRI group in 42% and 24%, respectively. Rate of positive surgical margins comparing the MRI and non-MRI groups was 26.7% and 33.7%, respectively, relative risk 0.79 [95% CI 0.65-0.96], weighted relative risk (wRR) 0.69 [95% CI 0.55-0.86]. The wRR of extensive positive surgical margins was 0.45 [95% CI 0.31-0.67]. Undergoing MRI was also associated with an increased risk of being operated with a non-nerve sparing technique (wRR, 1.84 [95% CI 1.11-3.03]). Conclusions: Our study suggests that preoperative prostate MRI in combination with a preoperative MRI conference affects the degree of nerve-sparing surgery and reduces positive surgical margins.
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| 9. |
- Khoshkar, Yashar, et al.
(författare)
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Mortality in men with castration‐resistant prostate cancer—A long‐term follow‐up of a population‐based real‐world cohort
- 2022
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Ingår i: BJUI Compass. - : John Wiley & Sons. - 2688-4526. ; 3:2, s. 173-183
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The objective of this study is to find clinical variables that predict the prognosis for men with castration-resistant prostate cancer (CRPC) in a Swedish real-life CRPC cohort, including a risk group classification to clarify the risk of succumbing to prostate cancer. This is a natural history cohort representing the premodern drug era before the introduction of novel hormonal drug therapies.Methods PSA tests from the clinical chemistry laboratories serving health care in six regions of Sweden were retrieved and cross-linked to the National Prostate Cancer Registry (NPCR) to identify men with a prostate cancer diagnosis. Through further cross-linking with data sources at the Swedish Board of Health and Welfare, we retrieved other relevant information such as prescribed drugs, hospitalizations, and cause of death. Men entered the CRPC cohort at the first date of doubling of their PSA nadir value with the last value being >2 ng/ml, or an absolute increase of >5 ng/ml or more, whilst on 3 months of medical castration or if they had been surgically castrated (n = 4098). By combining the two variables with the largest C-statistics, “PSA at time of CRPC” and “PSA doubling time,” a risk group classification was created.Rsults PSA-DT and PSA at date of CRPC are the strongest variables associated with PC specific survival. At the end of follow-up, the proportion of men who died due to PC was 57%, 71%, 81%, 86%, and 89% for risk categories one through five, respectively. The median overall survival in our cohort of men with CRPC was 1.86 years (95% CI: 1.79–1.97).Conclusion For a man with castration-resistant prostate cancer, there is a high probability that this will be the main cause contributing to his death. However, there is a significant difference in mortality that varies in relation to tumor burden assessed as PSA doubling time and PSA at time of CRCP. This information could be used in a clinical setting when deciding when to treat more or less aggressively once entering the CRPC phase of the disease.
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| 10. |
- Lophatananon, Artitaya, et al.
(författare)
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Height, selected genetic markers and prostate cancer risk : results from the PRACTICAL consortium.
- 2017
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 117:5, s. 734-743
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a possible role for its association with the risk of aggressive prostate cancer.METHODS: We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and 6016 controls and a subset of high grade cases (2480 cases). We explored height, polymorphisms in genes related to growth processes as main effects and their possible interactions.RESULTS: The results suggest that height is associated with high-grade prostate cancer risk. Men with height >180 cm are at a 22% increased risk as compared to men with height <173 cm (OR 1.22, 95% CI 1.01-1.48). Genetic variants in the growth pathway gene showed an association with prostate cancer risk. The aggregate scores of the selected variants identified a significantly increased risk of overall prostate cancer and high-grade prostate cancer by 13% and 15%, respectively, in the highest score group as compared to lowest score group.CONCLUSIONS: There was no evidence of gene-environment interaction between height and the selected candidate SNPs.Our findings suggest a role of height in high-grade prostate cancer. The effect of genetic variants in the genes related to growth is seen in all cases and high-grade prostate cancer. There is no interaction between these two exposures.
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