Preoperative beta blockers and other drugs in relation to anastomotic leakage after anterior resection for rectal cancer.

AIM: Previous research has indicated that preoperative beta blocker therapy is associated with a decreased risk of complications after surgery for rectal cancer. This is thought to arise because of the anti-inflammatory activity of the drug. These results need to be reproduced and analyses extended to other drugs with such properties, as this information might be useful in clinical decision-making. The main aim of this work was to replicate previous findings of beta blocker use as a prognostic marker for postoperative leakage. We also investigated whether drug exposure might induce anastomotic leaks. METHOD: This is a retrospective multicentre cohort study, comprising 1126 patients who underwent anterior resection for rectal cancer between 2014 and 2018. The use of any preoperative beta blocker was treated as the primary exposure, while anastomotic leakage within 12 months of surgery was the outcome. Secondary exposures comprised angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins and metformin. Using multivariable regression, we performed a replication analysis with a predictive aim for beta blockers only, while adjustment for confounding was done in more causally oriented analyses for all drugs. We estimated incidence rate ratio (IRR) and relative risk (RR) with 95% confidence intervals (CIs). RESULTS: Anastomotic leakage occurred in 20.6% of patients. Preoperative beta blockers were used by 22.7% of the cohort, while the leak distribution was almost identical between exposure groups. In the main replication analysis, no association could be detected (IRR 0.95, 95% CI 0.68-1.33). In the causally oriented analyses, only metformin affected the risk of leakage (RR 1.59, 95% Cl 1.31-1.92). CONCLUSION: While previous research has suggested that preoperative beta blocker use could be prognostic of anastomotic leakage, this study could not detect any such association. On the contrary, our results indicate that preoperative beta blocker use neither predicts nor causes anastomotic leakage after anterior resection for rectal cancer.

The modified Glasgow Prognostic Score indicates an increased risk of anastomotic leakage after anterior resection for rectal cancer.

BACKGROUND: Preoperative inflammation might cause and also be a marker for anastomotic leakage after anterior resection for rectal cancer. Available biomarker indices such as the modified Glasgow Prognostic Score (mGPS) or the C-reactive protein-to-albumin ratio (CAR) may be clinically useful for leakage assessment. METHODS: Patients who underwent anterior resection for rectal cancer during 2014-2018 from a multicentre retrospective cohort were included. Data from the Swedish Colorectal Cancer registry and chart review at each hospital were collected. In a subset of patients, preoperative laboratory assessments were available, constituting the exposures mGPS and CAR. Anastomotic leakage within 12 months was the outcome. Causally oriented analyses were conducted with adjustment for confounding, as well as predictive models. RESULTS: A total of 418 patients were eligible for analysis. Most patients had mGPS = 0 (84.7%), while mGPS = 1 (10.8%) and mGPS = 2 (4.5%) were less common. mGPS = 2 (OR: 4.11; 95% CI: 1.69-10.03) seemed to confer anastomotic leakage, while this was not seen for mGPS = 1 (OR 1.09; 95% CI: 0.53-2.25). A cut off point of CAR > 0.36 might be indicative of leakage (OR 2.25; 95% CI: 1.21-4.19). Predictive modelling using mGPS rendered an area-under-the-curve of 0.73 (95% CI: 0.67-0.79) at most. DISCUSSION: Preoperative inflammation seems to be involved in the development of anastomotic leakage after anterior resection for cancer. Inclusion into prediction models did not result in accurate leakage prediction, but high degrees of systemic inflammation might still be important in clinical decision-making.

Health and economic outcomes of a universal early intervention for parents and children from birth to age five: evaluation of the Salut Programme using a natural experiment.

BACKGROUND: The aim of this study was to investigate the health and economic outcomes of a universal early intervention for parents and children, the Salut Programme, from birth to when the child completed five years of age. METHODS: This study adopted a retrospective observational design using routinely collected linked register data with respect to both exposures and outcomes from Västerbotten county, in northern Sweden. Making use of a natural experiment, areas that received care-as-usual (non-Salut area) were compared to areas where the Programme was implemented after 2006 (Salut area) in terms of: (i) health outcomes, healthcare resource use and costs around pregnancy, delivery and birth, and (ii) healthcare resource use and related costs, as well as costs of care of sick child. We estimated total cumulative costs related to inpatient and specialised outpatient care for mothers and children, and financial benefits paid to mothers to stay home from work to care for a sick child. Two analyses were conducted: a matched difference-in difference analysis using the total sample and an analysis including a longitudinal subsample. RESULTS: The longitudinal analysis on mothers who gave birth in both pre- and post-measure periods showed that mothers exposed to the Programme had on average 6% (95% CI 3-9%) more full-term pregnancies and 2% (95% CI 0.03-3%) more babies with a birth weight ≥ 2500 g, compared to mothers who had care-as-usual. Savings were incurred in terms of outpatient care costs for children of mothers in the Salut area ($826). The difference-in-difference analysis using the total sample did not result in any significant differences in health outcomes or cumulative resource use over time. CONCLUSIONS: The Salut Programme achieved health gains, as a health promotion early intervention for children and parents, in terms of more full-term pregnancies and more babies with a birth weight ≥ 2500 g, at reasonable cost, and may lead to lower usage of outpatient care. Other indicators point towards positive effects, but the small sample size may have led to underestimation of true differences.

Oncological Impact of High Vascular Tie After Surgery for Rectal Cancer: A Nationwide Cohort Study.

OBJECTIVE: The purpose of this study was to investigate the impact of tie level on oncological outcomes in rectal cancer surgery. SUMMARY BACKGROUND DATA: Theoretically, a high tie of the inferior mesenteric artery could facilitate removal of apical node metastases and improve tumor staging accuracy. However, no appropriately sized randomized controlled trial exists and results from observational studies are not consistent. METHODS: All stage I-III rectal cancer patients who underwent abdominal surgery with curative intention in 2007 to 2014 were identified and followed, using the Swedish Colorectal Cancer Registry. Primary outcome was cancer-specific survival, whereas overall and relative survival, locoregional and distant recurrence, and lymph node harvest were secondary outcomes, with high tie as exposure. We used propensity score matching to emulate a randomized controlled trial, and then performed Cox regression analyses to estimate hazard ratios (HRs) with confidence intervals (CIs). RESULTS: Some 8287 patients remained for analysis, of which 37% had high tie surgery. After propensity score matching, the 5-year cancer-specific survival rate was overall 86% and we found no association between the level of tie and cancer-specific (HR 0.92, 95% CI 0.79-1.07) or overall (HR 0.98, 95% CI 0.89-1.08) survival, nor to locoregional (HR 0.85, 95% CI 0.59-1.23) or distant (HR 1.01, 95% CI 0.88-1.15) recurrence, nor to relative survival (HR 1.05, 95% CI 0.85-1.28). Stratification and sensitivity analyses were similarly insignificant, after adjustment for confounding. Total lymph node harvest was, however, increased after high tie surgery (P < 0.01), but no differences were seen regarding positive nodes (P = 0.72). CONCLUSION: In this nationwide cohort study, the level of tie did not influence any patient-oriented oncological outcome, neither overall nor in node-positive patients. This would allow the patient's anatomical configuration and the surgeon's preferences to determine the level of tie.

Defunctioning stomas may reduce chances of a stoma-free outcome after anterior resection for rectal cancer.

AIM: To investigate the conflicting consequences of faecal diversion on stoma outcomes and anastomotic leakage in anterior resection for rectal cancer, including interaction effects determined by the extent of mesorectal excision. METHOD: Anterior resections between 2007 and 2016 were identified using the Swedish Colorectal Cancer Registry. National Patient Registry data were added to determine stoma outcome 2 years after surgery. Tumour distance from the anal verge constituted a proxy for extent of mesorectal excision [total mesorectal excision (TME): ≤10 cm; partial mesorectal excision (PME): 13-15 cm]. With confounder-adjusted probit regression, the total effect of defunctioning stoma on permanent stoma, and the interaction effect of extent of mesorectal excision, were estimated together with the indirect effect through anastomotic leakage. Baseline risks, risk differences (RDs) and relative risks (RRs) were reported. RESULTS: The main study cohort included 4529 patients. Defunctioning stomas influenced the absolute permanent stoma risk (TME: RD 0.11 [95% CI 0.09-0.13]; PME: RD 0.15 [95% CI 0.13-0.16]). The baseline risk was higher in TME, with a resulting greater RR in PME (2.23 [95% CI 1.43-3.02] vs 4.36 [95% CI 3.05-5.68]). The indirect reduction in permanent stoma rates, due to the alleviating effect of faecal diversion on anastomotic leakage, was small (TME: 0.89 [95% CI 0.81-0.96]; PME: 0.96 [95% CI 0.91-1.00]). CONCLUSION: In anterior resection for rectal cancer, defunctioning stomas may reduce chances of a stoma-free outcome. Considering leakage reduction benefits, consequences of routine diversion in TME might be fairly balanced, while this seems questionable in PME.

Prognostic Value of a Test of Central Auditory Function in Conversion from Mild Cognitive Impairment to Dementia.

BACKGROUND/OBJECTIVE: It has been suggested that central auditory processing dysfunction might precede the development of cognitive decline and Alzheimer's disease (AD). The Dichotic Digits Test (DDT) has been proposed as a test of central auditory function. Our objective was to evaluate the predictive capacity of the DDT in conversion from mild cognitive impairment (MCI) to dementia. METHODS: A total of 57 participants (26 females) with MCI were tested at baseline with pure tone audiometry, speech in quiet and in noise, and the DDT. The cognitive outcome was retrieved from medical files after 5 years. Groupwise comparisons of the baseline DDT scores were performed and the relative risk was calculated. RESULTS: Altogether 22 subjects developed any kind of dementia. Of the original 57 individuals within the MCI group, 15 developed AD and 7 developed other types of dementia. There was no significant difference in baseline DDT scores between the participants who converted to AD and those who did not. However, the group who developed other types of dementia (especially frontotemporal dementia) had lower DDT scores in the left ear than those participants who did not develop dementia. With a baseline DDT score below 50% correct responses, the participants diagnosed with MCI had a 2.49-times-higher risk of developing dementia than those with scores of 50% or better. CONCLUSION: The DDT as a central auditory test may be suitable when evaluating cognitive decline.

Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status.

Factors related to energy metabolism and the metabolic syndrome, such as higher body mass index (BMI), blood glucose, or blood lipids, and blood pressure, are associated with an increased risk of colorectal cancer (CRC). However, CRC is a heterogeneous disease, developing through distinct pathways with differences in molecular characteristics and prognosis, and possibly also in risk factors. For subtypes defined by KRAS and BRAF mutation status, BMI is the only metabolic factor previously studied, with inconsistent findings. We investigated whether associations between BMI, blood glucose, blood lipids, and blood pressure and CRC risk differed by tumor KRAS and BRAF mutation status in 117,687 participants from two population-based cohorts within the Northern Sweden Health and Disease Study (NSHDS). Hazard ratios (HRs) for overall CRC and CRC subtypes by metabolic factors were estimated with Cox proportional hazards regression, using multiple imputation to handle missing exposure and tumor data. During a median follow-up of 15.6 years, we acquired 1,250 prospective CRC cases, of which 766 cases had complete baseline and molecular tumor data. Consistent with previous evidence, higher BMI, total cholesterol, triglyceride levels, and blood pressure were associated with an increased risk of overall CRC (HRs per 1 standard deviation increase: 1.07 to 1.12). These associations were similar regardless of CRC subtype by KRAS and BRAF mutation status (all pheterogeneity > 0.05). The same was true for subtypes based on microsatellite instability status. Poor metabolic health may therefore be a universal mechanism for colorectal cancer, acting across multiple developmental pathways.

One-carbon metabolite ratios as functional B-vitamin markers and in relation to colorectal cancer risk.

One-carbon metabolism biomarkers are easily measured in plasma, but analyzing them one at a time in relation to disease does not take into account the interdependence of the many factors involved. The relative dynamics of major one-carbon metabolism branches can be assessed by relating the functional B-vitamin marker total homocysteine (tHcy) to transsulfuration (total cysteine) and methylation (creatinine) outputs. We validated the ratios of tHcy to total cysteine (Hcy:Cys), tHcy to creatinine (Hcy:Cre) and tHcy to cysteine to creatinine (Hcy:Cys:Cre) as functional markers of B-vitamin status. We also calculated the associations of these ratios to colorectal cancer (CRC) risk. Furthermore, the relative contribution of potential confounders to the variance of the ratio-based B-vitamin markers was calculated by linear regression in a nested case-control study of 613 CRC cases and 1,190 matched controls. Total B-vitamin status was represented by a summary score comprising Z-standardized plasma concentrations of folate, cobalamin, betaine, pyridoxal 5'-phosphate and riboflavin. Associations with CRC risk were estimated using conditional logistic regression. We found that the ratio-based B-vitamin markers all outperformed tHcy as markers of total B-vitamin status, in both CRC cases and controls. In addition, associations with CRC risk were similar for the ratio-based B-vitamin markers and total B-vitamin status (approximately 25% lower risk for high vs. low B-vitamin status). In conclusion, ratio-based B-vitamin markers were good predictors of total B-vitamin status and displayed similar associations as total B-vitamin status with CRC risk. Since tHcy and creatinine are routinely clinically analyzed, Hcy:Cre could be easily implemented in clinical practice.

Data-driven confounder selection via Markov and Bayesian networks.

To unbiasedly estimate a causal effect on an outcome unconfoundedness is often assumed. If there is sufficient knowledge on the underlying causal structure then existing confounder selection criteria can be used to select subsets of the observed pretreatment covariates, X, sufficient for unconfoundedness, if such subsets exist. Here, estimation of these target subsets is considered when the underlying causal structure is unknown. The proposed method is to model the causal structure by a probabilistic graphical model, for example, a Markov or Bayesian network, estimate this graph from observed data and select the target subsets given the estimated graph. The approach is evaluated by simulation both in a high-dimensional setting where unconfoundedness holds given X and in a setting where unconfoundedness only holds given subsets of X. Several common target subsets are investigated and the selected subsets are compared with respect to accuracy in estimating the average causal effect. The proposed method is implemented with existing software that can easily handle high-dimensional data, in terms of large samples and large number of covariates. The results from the simulation study show that, if unconfoundedness holds given X, this approach is very successful in selecting the target subsets, outperforming alternative approaches based on random forests and LASSO, and that the subset estimating the target subset containing all causes of outcome yields smallest MSE in the average causal effect estimation.

Childhood family structure and women's adult overweight risk: A longitudinal study.

AIM: The aim of this study was to investigate whether women's adult overweight and obesity risk was associated with their childhood family structure, measured as their mothers' marital status history, during the women's first 18 years of life. METHODS: Using linked register data, we analyzed 30,584 primiparous women born in Sweden in 1975 who were between 19-35 years of age when their height and pre-pregnancy weight was recorded. The outcomes were women's overweight/obesity (body mass index (BMI) ≥ 25 kg/m2) and obesity (BMI ≥ 30 kg/m2) and the predictor was mothers' marital status history, which was summarized using sequence analysis. We carried out nested logistic regression models adjusting for women's age and maternal sociodemographic characteristics. RESULTS: Mothers' marital status history was summarized into six clusters: stable marriage, stable cohabitation, married then divorcing, cohabiting then separating, varied transitions, and not with father. In fully adjusted models and compared with women whose mothers belonged to the stable marriage cluster: (1) women whose mothers belonged to the other marital status clusters had higher odds of overweight/obesity (odds ratio (OR) ranging 1.15-1.19; p < 0.05); and (2) women whose mothers belonged to the stable cohabitation (OR = 1.31; 95% confidence interval (CI) = 1.14-1.52), cohabiting then separating (OR = 1.23; 95% CI = 1.01-1.49), varied transitions (OR = 1.24; 95% CI = 1.11-1.39), and not with father (OR = 1.24; 95% CI = 1.00-1.54) clusters had higher odds of obesity. CONCLUSIONS: Women whose mothers were not in stable marriage relationships had higher odds of being overweight or obese in adulthood. The finding that even women raised in the context of stable cohabitation had higher odds of being overweight or obese is intriguing as these relationships are socially accepted in Sweden.

Components of One-carbon Metabolism Other than Folate and Colorectal Cancer Risk.

BACKGROUND: Despite extensive study, the role of folate in colorectal cancer remains unclear. Research has therefore begun to address the role of other elements of the folate-methionine metabolic cycles. This study investigated factors other than folate involved in one-carbon metabolism, i.e., choline, betaine, dimethylglycine, sarcosine, and methionine and relevant polymorphisms, in relation to the risk of colorectal cancer in a population with low intakes and circulating levels of folate. METHODS: This was a prospective case-control study of 613 case subjects and 1,190 matched control subjects nested within the population-based Northern Sweden Health and Disease Study. We estimated odds ratios (OR) by conditional logistic regression, and marginal risk differences with weighted maximum likelihood estimation using incidence data from the study cohort. RESULTS: Higher plasma concentrations of methionine and betaine were associated with modest colorectal cancer risk reductions (OR [95% confidence interval {CI}] for highest versus lowest tertile: 0.76 [0.57, 0.99] and 0.72 [0.55, 0.94], respectively). Estimated marginal risk differences corresponded to approximately 200 fewer colorectal cancer cases per 100,000 individuals on average. We observed no clear associations between choline, dimethylglycine, or sarcosine and colorectal cancer risk. The inverse association of methionine was modified by plasma folate concentrations (OR [95% CI] for highest/lowest versus lowest/lowest tertile of plasma methionine/folate concentrations 0.39 [0.24, 0.64], Pinteraction = 0.06). CONCLUSIONS: In this population-based, nested case-control study with a long follow-up time from baseline to diagnosis (median: 8.2 years), higher plasma concentrations of methionine and betaine were associated with lower colorectal cancer risk.See Video Abstract at http://links.lww.com/EDE/B83.

Regional inequalities in pre-pregnancy overweight and obesity in Sweden, 1992, 2000, and 2010.

AIMS: To investigate regional differences and time trends in women's overweight and obesity in Sweden. METHODS: Using data from the Swedish Medical Birth Register (women aged ⩾18 years, first pregnancy only) and the Total Population Register accessed through the Umeå SIMSAM Lab, age-standardized prevalence of pre-pregnancy overweight/obesity (BMI ⩾ 25 kg/m(2)) and obesity (BMI ⩾ 30 kg/m(2)) were estimated by county for the years 1992, 2000, and 2010. Maps were created using ArcMap v10.2.2 to display regional variations over time and logistic regression analyses were used to assess if the observed trends were significant. RESULTS: The prevalence of pre-pregnancy overweight/obesity and obesity increased significantly in all Swedish counties between 1992, and 2010. In 2010, Södermanland and Gotland exhibited the highest age-standardized overweight/obesity (39.7%) and obesity (15.1%) prevalence, respectively. The sharpest increases between 1992 and 2010 were observed in Västerbotten for overweight/obesity (75% increase) and in Gotland for obesity (233% increase). Across the years, Stockholm had the lowest prevalence of overweight/obesity (26.3% in 2010) and obesity (7.3% in 2010) and one of the least steep increases in prevalence of both between 1992 and 2010. CONCLUSIONS: Substantial regional differences in pre-pregnancy overweight and obesity prevalence are apparent in Sweden. Further research should elucidate the mechanisms causing these differences.

Potential upstream regulators of cannabinoid receptor 1 signaling in prostate cancer: a Bayesian network analysis of data from a tissue microarray.

BACKGROUND: The endocannabinoid system regulates cancer cell proliferation, and in prostate cancer a high cannabinoid CB1 receptor expression is associated with a poor prognosis. Down-stream mediators of CB1 receptor signaling in prostate cancer are known, but information on potential upstream regulators is lacking. RESULTS: Data from a well-characterized tumor tissue microarray were used for a Bayesian network analysis using the max-min hill-climbing method. In non-malignant tissue samples, a directionality of pEGFR (the phosphorylated form of the epidermal growth factor receptor) → CB1 receptors were found regardless as to whether the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) was included as a parameter. A similar result was found in the tumor tissue, but only when FAAH was included in the analysis. A second regulatory pathway, from the growth factor receptor ErbB2 → FAAH was also identified in the tumor samples. Transfection of AT1 prostate cancer cells with CB1 receptors induced a sensitivity to the growth-inhibiting effects of the CB receptor agonist CP55,940. The sensitivity was not dependent upon the level of receptor expression. Thus a high CB1 receptor expression alone does not drive the cells towards a survival phenotype in the presence of a CB receptor agonist. CONCLUSIONS: The data identify two potential regulators of the endocannabinoid system in prostate cancer and allow the construction of a model of a dysregulated endocannabinoid signaling network in this tumor. Further studies should be designed to test the veracity of the predictions of the network analysis in prostate cancer and other solid tumors.

Developing machine learning models to predict multi-class functional outcomes and death three months after stroke in Sweden.

Globally, stroke is the third-leading cause of mortality and disability combined, and one of the costliest diseases in society. More accurate predictions of stroke outcomes can guide healthcare organizations in allocating appropriate resources to improve care and reduce both the economic and social burden of the disease. We aim to develop and evaluate the performance and explainability of three supervised machine learning models and the traditional multinomial logistic regression (mLR) in predicting functional dependence and death three months after stroke, using routinely-collected data. This prognostic study included adult patients, registered in the Swedish Stroke Registry (Riksstroke) from 2015 to 2020. Riksstroke contains information on stroke care and outcomes among patients treated in hospitals in Sweden. Prognostic factors (features) included demographic characteristics, pre-stroke functional status, cardiovascular risk factors, medications, acute care, stroke type, and severity. The outcome was measured using the modified Rankin Scale at three months after stroke (a scale of 0-2 indicates independent, 3-5 dependent, and 6 dead). Outcome prediction models included support vector machines, artificial neural networks (ANN), eXtreme Gradient Boosting (XGBoost), and mLR. The models were trained and evaluated on 75% and 25% of the dataset, respectively. Model predictions were explained using SHAP values. The study included 102,135 patients (85.8% ischemic stroke, 53.3% male, mean age 75.8 years, and median NIHSS of 3). All models demonstrated similar overall accuracy (69%-70%). The ANN and XGBoost models performed significantly better than the mLR in classifying dependence with F1-scores of 0.603 (95% CI; 0.594-0.611) and 0.577 (95% CI; 0.568-0.586), versus 0.544 (95% CI; 0.545-0.563) for the mLR model. The factors that contributed most to the predictions were expectedly similar in the models, based on clinical knowledge. Our ANN and XGBoost models showed a modest improvement in prediction performance and explainability compared to mLR using routinely-collected data. Their improved ability to predict functional dependence may be of particular importance for the planning and organization of acute stroke care and rehabilitation.

Management and outcome in foreign-born vs native-born patients with myocardial infarction in Sweden.

AIMS: Previous studies on disparities in healthcare and outcomes have shown conflicting results. The aim of this study was to assess differences in baseline characteristics, management, and outcomes in myocardial infarction (MI) patients, by country of birth. METHODS AND RESULTS: In total, 194 259 MI patients (64% male, 15% foreign-born) from the nationwide SWEDEHEART (The Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) registry were included and compared by geographic region of birth. The primary outcome was 1-year major adverse cardiovascular events (MACEs) including all-cause death, MI, and stroke. Secondary outcomes were long-term MACE (up to 12 years), the individual components of MACE, 30-day mortality, management, and risk factors. Logistic regression, Cox proportional hazard models, and propensity score match (PSM), accounting for baseline differences, were used. Foreign-born patients were younger, often male, and had a higher cardiovascular (CV) risk factor burden, including smoking, diabetes, and hypertension. In PSM analyses, Asia-born patients had higher likelihood of revascularization [odds ratio 1.16, 95% confidence interval (CI) 1.04-1.30], statins and beta-blocker prescription at discharge, and a 34% lower risk of 30-day mortality. Furthermore, no statistically significant differences were found in primary outcomes except for Asia-born patients having lower risk of 1-year MACE [hazard ratio (HR) 0.85, 95% CI 0.73-0.98], driven by lower mortality (HR 0.72, 95% CI 0.57-0.91). The results persisted over the long-term follow-up. CONCLUSION: This study shows that in a system with universal healthcare coverage in which acute and secondary preventive treatments do not differ by country of birth, foreign-born patients, despite higher CV risk factor burden, will do at least as well as native-born patients.

Performance of modeling and balancing approach methods when using weights to estimate treatment effects in observational time-to-event settings.

In observational studies weighting techniques are often used to overcome bias due to confounding. Modeling approaches, such as inverse propensity score weighting, are popular, but often rely on the correct specification of a parametric model wherein neither balance nor stability are targeted. More recently, balancing approach methods that directly target covariate imbalances have been proposed, and these allow the researcher to explicitly set the desired balance constraints. In this study, we evaluate the finite sample properties of different modeling and balancing approach methods, when estimating the marginal hazard ratio, through Monte Carlo simulations. The use of the different methods is also illustrated by analyzing data from the Swedish stroke register to estimate the effect of prescribing oral anticoagulants on time to recurrent stroke or death in stroke patients with atrial fibrillation. In simulated scenarios with good overlap and low or no model misspecification the balancing approach methods performed similarly to the modeling approach methods. In scenarios with bad overlap and model misspecification, the modeling approach method incorporating variable selection performed better than the other methods. The results indicate that it is valuable to use methods that target covariate balance when estimating marginal hazard ratios, but this does not in itself guarantee good performance in situations with, e.g., poor overlap, high censoring, or misspecified models/balance constraints.

Defunctioning loop ileostomy in anterior resection for rectal cancer and subsequent renal failure: nationwide population-based study.

BACKGROUND: Electrolyte disturbances and dehydration are common after anterior resection for rectal cancer with a defunctioning loop ileostomy. High-quality population-based studies on the impact of a defunctioning loop ileostomy on renal failure are lacking. METHODS: This was a nationwide observational study, based on the Swedish Colorectal Cancer Registry of patients undergoing anterior resection for rectal cancer between 2008 and 2016, with follow-up until 2017. Patients with severe co-morbidity, with age greater than 80 years, and with pre-existing renal failure were excluded. Loop ileostomy at index surgery constituted exposure, while a diagnosis of renal failure was the outcome. Acute and chronic events were analysed separately. Inverse probability weighting with adjustment for confounding derived from a causal diagram was employed. Hazards ratios (HRs) with 95 per cent c.i. are reported. RESULTS: A total of 5355 patients were eligible for analysis. At 5-year follow-up, all renal failure events (acute and chronic) were 7.2 per cent and 3.3 per cent in the defunctioning stoma and no stoma groups respectively. In the weighted analysis, a HR of 11.59 (95 per cent c.i. 5.68 to 23.65) for renal failure in ostomates was detected at 1 year, with the largest effect from acute renal failure (HR 24.04 (95 per cent c.i. 8.38 to 68.93)). Later follow-up demonstrated a similar pattern, but with smaller effect sizes. CONCLUSION: Patients having a loop ileostomy in combination with anterior resection for rectal cancer are more likely to have renal failure, especially early after surgery. Strategies are needed, such as careful fluid management protocols, and further research into alternative stoma types or reduction in stoma formation.