Risk of kidney failure in patients with inflammatory bowel disease undergoing colectomy: a nationwide cohort study.

BACKGROUND: Inflammatory bowel disease (IBD) is frequently accompanied by kidney complications. Potential triggers or subpopulations at high-risk of kidney problems are not well elucidated. We hypothesized that surgical interventions, specifically colectomy, might in part explain this risk. METHODS: Nationwide Swedish cohort study comprising 82,051 individuals with biopsy-proven IBD diagnosed during 1965-2017, with follow-up until 2019. We investigated the association between incident colectomy (time-varying exposure) and future risk of acute kidney injury (AKI) and kidney failure (diagnosis of end-stage kidney disease or death due to chronic kidney disease) using Cox proportional hazard models. We also examined the impact of partial vs. total colectomy and the presence/duration of a stoma. Covariates included demographics, education level, and selected comorbidities. RESULTS: Over a median follow-up of 14 years, 16,479 individuals underwent colectomy, and 2,556 AKI and 1,146 kidney failure events occurred. Colectomy was associated with an increased relative risk of both AKI (adjusted hazard ratio [aHR] 2.37; 95%CI 2.17-2.58) and kidney failure (1.54; 1.34-1.76). Compared to pre-colectomy periods, undergoing total colectomy and colectomy with prolonged stoma showed higher risks of both kidney outcomes versus partial colectomy or colectomy with a temporary stoma, respectively. Subgroup analyses suggested higher risks in patients with ulcerative colitis. CONCLUSIONS: In people with IBD, rates of AKI and kidney failure are higher among those undergoing colectomy, particularly among those following total colectomy, or colectomy with a prolonged stoma. This study identifies a high-risk population that may benefit from established protocols for kidney function monitoring/surveillance and referral to nephrologist care.

Childhood and adolescence outcomes in offspring to parents with bipolar disorder: the impact of lifetime parental comorbidity, parental sex, and bipolar subtype.

BACKGROUND: Offspring of parents with bipolar disorder have increased risks of their own psychopathology. However, a large-scale survey of psychiatric, somatic, and adverse social outcomes up to adulthood, which could aid in prioritizing and tailoring prevention, is lacking. It also remains to clarify how risks are modified by other parental factors. METHODS: Swedish population registers were linked to compare offspring having (N = 24,788) and not having (N = 247,880) a parent with bipolar disorder with respect to psychiatric diagnoses and psychotropic medication, birth-related and somatic conditions, social outcomes, accidents, suicide attempts, and mortality. Individuals were followed until age 18. We estimated the influence of lifetime parental psychiatric comorbidity, bipolar disorder subtype, and sex on outcomes. RESULTS: Children of parents with bipolar disorder had 2-3 times higher risks of all psychiatric diagnoses, except for bipolar disorder, for which the risk was 11-fold. Significantly increased risks were also found for several somatic conditions, low school grades, criminal behavior, victimization, accidents, and suicidal behavior. Adjusting for lifetime parental psychiatric comorbidity attenuated most associations. Offspring of a parent with bipolar disorder type 2 had statistically significantly higher risks of attention deficit hyperactivity disorder, respiratory tract conditions, and accidents compared with offspring of a parent with bipolar disorder type 1. Offspring of mothers with bipolar disorder had higher risks of several psychiatric diagnoses, respiratory tract conditions, low school grades, and accidents compared with offspring of fathers with bipolar disorder. Having two parents with bipolar disorder entailed the highest risks of psychiatric outcomes in offspring. CONCLUSIONS: Early intervention and family support are particularly warranted for the offspring of a parent with bipolar disorder in the presence of lifetime parental psychiatric comorbidity, when the parent has bipolar disorder type 2, or when the mother or both parents have bipolar disorder.

Familial adversity: association with discontinuation of adjuvant hormone therapy and breast cancer prognosis.

BACKGROUND: Many studies have examined patient-related factors affecting adjuvant hormone therapy adherence in breast cancer patients. Our study aimed to examine associations of family-related factors with adjuvant hormone therapy discontinuation and breast cancer-specific mortality. METHODS: By cross-linking seven Swedish health registers, we performed a cohort study including all breast cancer patients who initiated adjuvant hormone therapy during 2006-2019 in Sweden (N = 10,701). A group-based multi-trajectory model was used to identify familial adversity groups based on three dimensions: material deprivation, negative family dynamics, and loss or threat of loss. Cox proportional hazard models were used to investigate associations of familial adversity with hormone therapy discontinuation and breast cancer-specific mortality. RESULTS: We identified five distinctive familial adversity groups among the cohort participants. Compared to women with low familial adversity, higher risks to discontinue adjuvant hormone therapy were observed among women with material deprivation (hazard ratio (HR), 1.31; 95% CI, 1.20-1.43), negative family dynamics (HR, 1.16; 95% CI, 1.06-1.28), loss or threat to loss (HR, 1.15; 95% CI, 1.00-1.32), or high familial adversity (HR, 1.53; 95% CI, 1.40-1.68). Furthermore, women with material deprivation (HR, 1.37; 95% CI, 1.05-1.79), negative family dynamics (HR, 1.41; 95% CI, 1.01-1.97), or high adversity (HR, 1.67; 95% CI, 1.26-2.23) were at higher risks of dying from breast cancer. CONCLUSION: Familial adversity is associated with a higher risk of adjuvant hormone therapy discontinuation and breast cancer-specific mortality. Family-related factors identified in our study may help identify high-risk patients for interventions to prevent treatment discontinuation and subsequently improve breast cancer outcomes.

The bidirectional association between premenstrual disorders and perinatal depression: A nationwide register-based study from Sweden.

BACKGROUND: Premenstrual disorders (PMDs) and perinatal depression (PND) share symptomology and the timing of symptoms of both conditions coincide with natural hormonal fluctuations, which may indicate a shared etiology. Yet, there is a notable absence of prospective data on the potential bidirectional association between these conditions, which is crucial for guiding clinical management. Using the Swedish nationwide registers with prospectively collected data, we aimed to investigate the bidirectional association between PMDs and PND. METHODS AND FINDINGS: With 1,803,309 singleton pregnancies of 1,041,419 women recorded in the Swedish Medical Birth Register during 2001 to 2018, we conducted a nested case-control study to examine the risk of PND following PMDs, which is equivalent to a cohort study, and transitioned that design into a matched cohort study with onward follow-up to simulate a prospective study design and examine the risk of PMDs after PND (within the same study population). Incident PND and PMDs were identified through clinical diagnoses or prescribed medications. We randomly selected 10 pregnant women without PND, individually matched to each PND case on maternal age and calendar year using incidence density sampling (N: 84,949: 849,482). We (1) calculated odds ratio (OR) and 95% confidence intervals (CIs) of PMDs using conditional logistic regression in the nested case-control study. Demographic factors (country of birth, educational level, region of residency, and cohabitation status) were adjusted for. We (2) calculated the hazard ratio (HR) and 95% CIs of PMDs subsequent to PND using stratified Cox regression in the matched cohort study. Smoking, BMI, parity, and history of psychiatric disorders were further controlled for, in addition to demographic factors. Pregnancies from full sisters of PND cases were identified for sibling comparison, which contrasts the risk within each set of full sisters discordant on PND. In the nested case-control study, we identified 2,488 PMDs (2.9%) before pregnancy among women with PND and 5,199 (0.6%) among controls. PMDs were associated with a higher risk of subsequent PND (OR 4.76, 95% CI [4.52,5.01]; p < 0.001). In the matched cohort with a mean follow-up of 7.40 years, we identified 4,227 newly diagnosed PMDs among women with PND (incidence rate (IR) 7.6/1,000 person-years) and 21,326 among controls (IR 3.8). Compared to their matched controls, women with PND were at higher risk of subsequent PMDs (HR 1.81, 95% CI [1.74,1.88]; p < 0.001). The bidirectional association was noted for both prenatal and postnatal depression and was stronger among women without history of psychiatric disorders (p for interaction < 0.001). Sibling comparison showed somewhat attenuated, yet statistically significant, bidirectional associations. The main limitation of this study was that our findings, based on clinical diagnoses recorded in registers, may not generalize well to women with mild PMDs or PND. CONCLUSIONS: In this study, we observed a bidirectional association between PMDs and PND. These findings suggest that a history of PMDs can inform PND susceptibility and vice versa and lend support to the shared etiology between both disorders.

Effects from medications on functional biomarkers of aging in three longitudinal studies of aging in Sweden.

Antihypertensive, lipid-lowering, and blood glucose-lowering drugs have slowed down the aging process in animal models. In humans, studies are limited, have short follow-up times, and show mixed results. Therefore, this study aimed to estimate the effects of commonly used medications on functional aging, cognitive function, and frailty. We included information on individuals from three Swedish longitudinal population-based studies collected between 1986 and 2014. Our exposures were the 21 most used groups of medications among individuals aged 65 years and older in the Swedish population in 2022. Functional aging index (n = 1191), cognitive function (n = 1094), and frailty index (n = 1361) were the outcomes of interest. To estimate the medication effects, we used a self-controlled analysis, where each individual is his/her own control, thereby adjusting for all time-stable confounders. The analysis was additionally adjusted for time-varying confounders (chronological age, Charlson Comorbidity Index, smoking, body mass index, and the number of drugs). The participants were 65.5-82.8 years at the first in-person assessment. Adrenergics/inhalants (effect size = 0.089) and lipid-modifying agents/plain (effect size = 0.082) were associated with higher values of cognitive function (improvement), and selective calcium channel blockers with mainly vascular effects (effect size = -0.129) were associated with lower values of the functional aging index (improvement). No beneficial effects were found on the frailty index. Adrenergics/inhalants, lipid-modifying agents/plain, and selective calcium channel blockers with mainly vascular effects may benefit functional biomarkers of aging. More research is needed to investigate their clinical value in preventing adverse aging outcomes.

Combining Mendelian randomization with the sibling comparison design.

Mendelian randomization (MR) is a popular epidemiologic study design that uses genetic variants as instrumental variables (IVs) to estimate causal effects, while accounting for unmeasured confounding. The validity of the MR design hinges on certain IV assumptions, which may sometimes be violated due to dynastic effects, population stratification, or assortative mating. Since these mechanisms act through parental factors it was recently suggested that the bias resulting from violations of the IV assumptions can be reduced by combing the MR design with the sibling comparison design, which implicitly controls for all factors that are constant within families. In this article, we provide a formal discussion of this combined MR-sibling design. We derive conditions under which the MR-sibling design is unbiased, and we relate these to the corresponding conditions for the standard MR and sibling comparison designs. We proceed by considering scenarios where all three designs are biased to some extent, and discuss under which conditions the MR-sibling design can be expected to have less bias than the other two designs. We finally illustrate the theoretical results and conclusions with an application to real data, in a study of low-density lipoprotein and diastolic blood pressure using data from the Swedish Twin Registry.

Absolute and Relative Risks of Kidney and Urological Complications in Patients With Inflammatory Bowel Disease.

INTRODUCTION: The burden of kidney and urological complications in patients with inflammatory bowel disease (IBD) remains poorly characterized. METHODS: We analyzed association between developing IBD (as a time-varying exposure) and relative risks of receiving diagnoses of chronic kidney disease (CKD), acute kidney injury (AKI), or kidney stones, and experiencing a clinically-relevant decline in estimated glomerular filtration rate (eGFR) (CKD progression; composite of kidney failure or an eGFR decline ≥30%) in 1,682,795 individuals seeking healthcare in Stockholm, Sweden, during 2006-2018. We quantified 5- and 10-year absolute risks of these complications in a parallel matched cohort of IBD cases and random controls matched (1:5) on sex, age, and eGFR. RESULTS: During median 9 years, 10,117 participants developed IBD. Incident IBD was associated with higher risks of kidney-related complications compared with non-IBD periods: hazard ratio (HR) (95% confidence interval) was 1.24 (1.10-1.40) for receiving a CKD diagnosis and 1.11 (1.00-1.24) for CKD progression. For absolute risks, 11.8% IBD cases had a CKD event within 10-year. Of these, 6.4% received a CKD diagnosis, and 7.9% reached CKD progression. The risks of AKI (HR 1.97 [1.70-2.29]; 10-year absolute risk 3.6%) and kidney stones (HR 1.69 [1.48-1.93]; 10-year absolute risk 5.6%) were also elevated. Risks were similar in Crohn's disease and ulcerative colitis. DISCUSSION: More than 10% of patients with IBD developed CKD within 10-year from diagnosis, with many not being identified through diagnostic codes. This, together with their elevated AKI and kidney stone risks, highlights the need of established protocols for kidney function monitoring and referral to nephrological/urological care for patients with IBD.

Intensity of and adherence to lipid-lowering therapy as predictors of goal attainment and major adverse cardiovascular events in primary prevention.

BACKGROUND: The effectiveness of lipid-lowering therapy (LLT) for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in routine care may depend on treatment intensity and adherence. METHODS: Observational study of adults with newly initiated LLT for primary prevention of ASCVD in Stockholm, Sweden, during 2017-2021. Study exposures were LLT adherence [proportion of days covered (PDC)], LLT intensity (expected reduction of LDL cholesterol), and the combined measure of adherence and intensity. At each LLT fill, adherence and intensity were calculated during the previous 12 months, and the patients estimated ASCVD risk was categorized. Study outcomes were major adverse cardiovascular events (MACE) and LDL-C goal attainment. RESULTS: Thirty-six thousand two hundred eighty-three individuals (mean age 63 years, 47% women, median follow-up 2 years), with a baseline low-moderate (40%), high (49%), and very-high (11%) ASCVD risk started LLT. Increases in LLT adherence, intensity, or adherence-adjusted intensity of 10% over 1 year were associated with lower risks of MACE (with hazard ratios of 0.95 [95% CI, 0.93-0.98]; 0.93 [0.86-1.00]; and 0.90 [0.85-0.95], respectively) and higher odds of attaining LDL goals. Patients with good adherence (≥80%) had similar risks of MACE and similar odds ratios for LDL-C goal attainment with low-moderate and high-intensity LLT. Treatment discontinuation was associated with increased MACE risk. The relative and absolute benefits of good adherence were greatest in patients with very high ASCVD risk. CONCLUSION: In routine-care primary prevention, better adherence to LLT was associated with a lower risk of MACE across all treatment intensities. Improving adherence is especially important among patients with very high ASCVD risk.

Inverse probability of treatment weighting with generalized linear outcome models for doubly robust estimation.

There are now many options for doubly robust estimation; however, there is a concerning trend in the applied literature to believe that the combination of a propensity score and an adjusted outcome model automatically results in a doubly robust estimator and/or to misuse more complex established doubly robust estimators. A simple alternative, canonical link generalized linear models (GLM) fit via inverse probability of treatment (propensity score) weighted maximum likelihood estimation followed by standardization (the g $$ g $$ -formula) for the average causal effect, is a doubly robust estimation method. Our aim is for the reader not just to be able to use this method, which we refer to as IPTW GLM, for doubly robust estimation, but to fully understand why it has the doubly robust property. For this reason, we define clearly, and in multiple ways, all concepts needed to understand the method and why it is doubly robust. In addition, we want to make very clear that the mere combination of propensity score weighting and an adjusted outcome model does not generally result in a doubly robust estimator. Finally, we hope to dispel the misconception that one can adjust for residual confounding remaining after propensity score weighting by adjusting in the outcome model for what remains 'unbalanced' even when using doubly robust estimators. We provide R code for our simulations and real open-source data examples that can be followed step-by-step to use and hopefully understand the IPTW GLM method. We also compare to a much better-known but still simple doubly robust estimator.

Association between cumulative psychosocial adversity in the family and ADHD and autism: a family-based cohort study.

Cumulative exposure to psychosocial adversity at an early age has been shown to be a risk factor for attention-deficit hyperactivity disorder (ADHD) and autism that often co-occur. However, it is not clear if this association reflects a causal effect or familial confounding. We aimed to assess whether cumulative psychosocial adversity in the family increases the risk for ADHD and autism in offspring while accounting for unmeasured familial confounding. We used a population-based cohort of 1,877,901 individuals born in Sweden between 1990 and 2009. Participants were followed from the age of 3 until 2013, with a median follow up time of 13.8 years. We created a cumulative index based on 7 psychosocial adversity factors. We used Cox regression to estimate the hazard ratios (HRs) relating neurodevelopmental conditions to cumulative psychosocial adversity. To address familial confounding, the analyses were repeated in groups of relatives of different kinship: siblings and half-siblings and cousins. A dose-response relationship was observed between cumulative exposure to psychosocial adversity and ADHD at a general population level (covariate adjusted HRs (aHRs) with 95% confidence intervals ranged from 1.55 [one adversity; 1.53-1.58] to 2.65 [ ≥ 4 adversities; 1.98-3.54]). No clear dose-response relation was seen for autism (aHRs ranged from 1.04 [.59-1.84] to 1.37 [1.30-1.45]). HRs of ADHD and autism decreased with increasing level of kinship in the analysis of relatives. Cumulative exposure to psychosocial adversity was associated with both ADHD and autism in the general population, these associations were partly explained by unmeasured familial confounding between relatives. This highlights the need for using family-based designs in studies of psychosocial adversity and ADHD and autism.

Absolute and Relative Risks of Kidney Outcomes Associated With Lithium vs Valproate Use in Sweden.

Importance: Among patients with bipolar disorder, discordant findings have been published on the nephrotoxic effects of lithium therapy. Objective: To quantify absolute and relative risks of chronic kidney disease (CKD) progression and acute kidney injury (AKI) in people who initiated lithium compared with valproate therapy and to investigate the association between cumulative use and elevated lithium levels and kidney outcomes. Design, Setting, and Participants: This cohort study had a new-user active-comparator design and used inverse probability of treatment weights to minimize confounding. Included patients initiated therapy with lithium or valproate from January 1, 2007, to December 31, 2018, and had a median follow-up of 4.5 years (IQR, 1.9-8.0 years). Data analysis began in September 2021, using routine health care data from the period 2006 to 2019 from the Stockholm Creatinine Measurements project, a recurrent health care use cohort of all adult residents in Stockholm, Sweden. Exposures: New use of lithium vs new use of valproate and high (>1.0 mmol/L) vs low serum lithium levels. Main Outcomes and Measures: Progression of CKD (composite of >30% decrease relative to baseline estimated glomerular filtration rate [eGFR] and kidney failure), AKI (by diagnosis or transient creatinine elevations), new albuminuria, and annual eGFR decrease. Outcomes by attained lithium levels were also compared in lithium users. Results: The study included 10 946 people (median [IQR] age, 45 [32-59] years; 6227 female [56.9%]), of whom 5308 initiated lithium therapy and 5638 valproate therapy. During follow-up, 421 CKD progression events and 770 AKI events were identified. Compared with patients who received valproate, those who received lithium did not have increased risk of CKD (hazard ratio [HR], 1.11 [95% CI, 0.86-1.45]) or AKI (HR, 0.88 [95% CI, 0.70-1.10]). Absolute 10-year CKD risks were low and similar: 8.4% in the lithium group and 8.2% in the valproate group. No difference in the risk of developing albuminuria or the annual rate of eGFR decrease was found between groups. Among more than 35 000 routine lithium tests, only 3% of results were in the toxic range (>1.0 mmol/L). Lithium values greater than 1.0 mmol/L, compared with lithium values of 1.0 mmol/L or less, were associated with increased risk of CKD progression (HR, 2.86; 95% CI, 0.97-8.45) and AKI (HR, 3.51; 95% CI, 1.41-8.76). Conclusions and Relevance: In this cohort study, compared with new use of valproate, new use of lithium was meaningfully associated with adverse kidney outcomes, with low absolute risks that did not differ between therapies. However, elevated serum lithium levels were associated with future kidney risks, particularly AKI, emphasizing the need for close monitoring and lithium dose adjustment.

Sensitivity analysis of G-estimators to invalid instrumental variables.

Instrumental variables regression is a tool that is commonly used in the analysis of observational data. The instrumental variables are used to make causal inference about the effect of a certain exposure in the presence of unmeasured confounders. A valid instrumental variable is a variable that is associated with the exposure, affects the outcome only through the exposure (exclusion), and is not confounded with the outcome (exogeneity). Unlike the first assumption, the other two are generally untestable and rely on subject-matter knowledge. Therefore, a sensitivity analysis is desirable to assess the impact of assumptions' violation on the estimated parameters. In this paper, we propose and demonstrate a new method of sensitivity analysis for G-estimators in causal linear and non-linear models. We introduce two novel aspects of sensitivity analysis in instrumental variables studies. The first is a single sensitivity parameter that captures violations of exclusion and exogeneity assumptions. The second is an application of the method to non-linear models. The introduced framework is theoretically justified and is illustrated via a simulation study. Finally, we illustrate the method by application to real-world data and provide guidelines on conducting sensitivity analysis.

Concomitant Discontinuation of Cardiovascular Therapy and Adjuvant Hormone Therapy Among Patients With Breast Cancer.

Importance: A large proportion of patients with breast cancer concomitantly use adjuvant hormone therapy and cardiovascular therapy. Objective: To examine the relative risk of discontinuing cardiovascular therapy during the periods before and after discontinuation of adjuvant hormone therapy. Design, Setting, and Participants: This population-based cohort study included all women aged 40 to 74 years in Stockholm, Sweden, who were diagnosed with breast cancer and concomitantly using adjuvant hormone therapy and cardiovascular therapy. Patients were enrolled from July 1, 2005, to August 31, 2020, with a median follow-up of 7.2 years. Data were analyzed from November 3, 2021, to May 12, 2022. Exposure: Discontinuation of adjuvant hormone therapy. Main Outcomes and Measures: The main outcome was discontinuation of cardiovascular therapy (cardiovascular drugs, statins, or aspirin) within 1 year before and after discontinuation of adjuvant hormone therapy. Incidence rate ratios with 95% CIs were estimated using Poisson regression. Furthermore, hazard ratios (HRs) with 95% CIs for cause-specific mortality were estimated using Cox proportional hazards regression models, comparing those who discontinued and continued adjuvant hormone therapy. Results: A total of 5493 patients with breast cancer who concomitantly used cardiovascular therapy were identified; 1811 who discontinued adjuvant hormone therapy were individually matched to 1 patient each who continued therapy by year of breast cancer diagnosis, age at diagnosis, and use of the same cardiovascular therapy. Most patients (4070 [74.1%]) were aged 60 years or older at diagnosis. At the time when patients discontinued adjuvant hormone therapy, 248 (12.2%) concomitantly discontinued their cardiovascular therapy. During follow-up, a higher discontinuation rate of cardiovascular therapy was also observed among those who discontinued adjuvant hormone therapy. Consistently, adjuvant hormone therapy discontinuation was associated with an increased risk of death not only due to breast cancer (HR, 1.43; 95 CI%, 1.01-2.01) but also cardiovascular disease (HR, 1.79; 95 CI%, 1.15-2.81). Stratifying the analyses on baseline type of adjuvant hormone therapy yielded consistent results. Conclusions and Relevance: In this cohort study of data from population-based registers in Sweden, patients who discontinued adjuvant hormone therapy were also more likely to discontinue cardiovascular therapy, especially at the time when they discontinued adjuvant hormone therapy. These findings suggest that clinicians should shift from single- to multiple-disease focus to prevent discontinuation of therapies for other diseases among patients with breast cancer.

Long-term Visit-to-Visit Variability in Hemoglobin A1c and Kidney-Related Outcomes in Persons With Diabetes.

RATIONALE & OBJECTIVE: To characterize associations between long-term visit-to-visit variability of hemoglobin A1c (HbA1c) and risk of adverse kidney outcomes in patients with diabetes. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 93,598 adults with diabetes undergoing routine care in Stockholm, Sweden. EXPOSURES AND PREDICTORS: Categories of baseline and time-varying HbA1c variability score (HVS, the percentage of total HbA1c measures that vary by>0.5% [5.5mmol/mol] during a 3-year window): 0-20%, 21%-40%, 41%-60%, 61%-80%, and 81%-100%, with 0-20% as the reference group. OUTCOME: Chronic kidney disease (CKD) progression (composite of>50% estimated glomerular filtration rate [eGFR] decline and kidney failure), acute kidney disease (AKI by clinical diagnosis or transient creatinine elevations according to KDIGO criteria), and worsening of albuminuria. ANALYTICAL APPROACH: Multivariable Cox proportional hazards regression. RESULTS: Compared with persons showing low HbA1c variability (HVS 0-20%), any increase in variability was associated with a higher risk of adverse kidney outcomes beyond mean HbA1c. For example, for patients with a baseline HbA1c variability of 81%-100%, the adjusted HR was 1.6 (95% CI, 1.47-1.74) for CKD progression, 1.23 [1.16-1.3] for AKI, and 1.28 [1.21-1.36] for worsening of albuminuria. The results were consistent across subgroups (diabetes subtypes, baseline eGFR, or albuminuria categories), in time-varying analyses and in sensitivity analyses including time-weighted average HbA1c or alternative metrics of variability. LIMITATIONS: Observational study, limitations of claims data, lack of information on diet, body mass index, medication changes, and diabetes duration. CONCLUSIONS: Higher long-term visit-to-visit HbA1c variability is consistently associated with the risks of CKD progression, AKI, and worsening of albuminuria. PLAIN-LANGUAGE SUMMARY: The evidence for current guideline recommendations derives from clinical trials that focus on a single HbA1c as the definitive measure of efficacy of an intervention. However, long-term visit-to-visit fluctuations of HbA1c may provide additional value in the prediction of future kidney complications. We evaluated the long-term fluctuations in glycemic control in almost 100,000 persons with diabetes undergoing routine care in Stockholm, Sweden. We observed that higher long-term HbA1c fluctuation is consistently associated with the risks of chronic kidney disease progression, worsening of albuminuria and acute kidney injury. This finding supports a role for long-term glycemic variability in the development of kidney complications and illustrates the potential usefulness of this metric for risk stratification at the bedside beyond a single HbA1c test.

Longitudinal associations between use of antihypertensive, antidiabetic, and lipid-lowering medications and biological aging.

Aging is a major risk factor for many chronic diseases. This study aimed to examine the effects of antihypertensive, lipid-lowering, and antidiabetic drugs on biological aging. We included 672 participants and 2746 repeated measurements from the Swedish Adoption/Twin Study of Aging. Self-reported medicine uses were categorized into antidiabetic, antihypertensive, and lipid-lowering drugs. A total of 12 biomarkers for biological aging (BA biomarkers) were included as outcomes. Conditional generalized estimating equations were applied conditioning on individuals to estimate the drug effect on BA biomarker level within the same person when using or not using the drug. Chronological age, body mass index, smoking status, number of multiple medication uses, blood pressure, blood glucose level, and apoB/apoA ratio were adjusted for as covariates in the model. Overall, using antihypertensive drugs was associated with a decrease in one DNA-methylation age (PCGrimAge: beta = - 0.39, 95%CI = - 0.67 to - 0.12). When looking into drug subcategories, calcium channel blockers (CCBs) were associated with a decrease in several DNA-methylation ages (PCHorvathAge beta = - 1.28, 95%CI = - 2.34 to - 0.21; PCSkin&bloodAge beta = - 1.34, 95%CI = - 2.61 to - 0.07; PCPhenoAge beta = - 1.74, 95%CI = - 2.58 to - 0.89; PCGrimAge beta = - 0.57, 95%CI = - 0.96 to - 0.17) and in functional biological ages (functional age index beta = - 2.18, 95%CI = - 3.65 to - 0.71; frailty index beta = - 1.31, 95%CI = - 2.43 to - 0.18). However, the results within other drug subcategories were inconsistent. Calcium channel blockers may decrease biological aging captured by the BA biomarkers measured at epigenetic and functional level. Future studies are warranted to confirm these effects and understand the underlying biological mechanisms.

Target parameters and bias in non-causal change-score analyses with measurement errors.

In studies where the outcome is a change-score, it is often debated whether or not the analysis should adjust for the baseline score. When the aim is to make causal inference, it has been argued that the two analyses (adjusted vs. unadjusted) target different causal parameters, which may both be relevant. However, these arguments are not applicable when the aim is to make predictions rather than to estimate causal effects. When the scores are measured with error, there have been attempts to quantify the bias resulting from adjustment for the (mis-)measured baseline score or lack thereof. However, these bias results have been derived under an unrealistically simple model, and assuming that the target parameter is the unadjusted (for the true baseline score) association, thus dismissing the adjusted association as a possibly relevant target parameter. In this paper we address these limitations. We argue that, even if the aim is to make predictions, there are two possibly relevant target parameters; one adjusted for the baseline score and one unadjusted. We consider both the simple case when there are no measurement errors, and the more complex case when the scores are measured with error. For the latter case, we consider a more realistic model than previous authors. Under this model we derive analytic expressions for the biases that arise when adjusting or not adjusting for the (mis-)measured baseline score, with respect to the two possible target parameters. Finally, we use these expressions to discuss when adjustment is warranted in change-score analyses.

Invasive cervical cancer, precancerous lesions, and cervical screening participation among women with mental illness in Sweden: a population-based observational study.

BACKGROUND: WHO aims to eliminate cervical cancer. Whether women with mental illness constitute a group at high-risk and require targeted prevention initiatives remains unknown. We aimed to assess whether women with severe mental illness, psychiatric or neurodevelopmental disorders, have an increased risk of invasive cervical cancer, and an increased risk of precancerous lesions and a lower degree of participation in cervical screening compared with women without severe mental illness. METHODS: In this population-based observational study, 4 112 598 women from 1973 to 2018 in Sweden were included to compare the risk of invasive cervical cancer, high-grade precancerous cervical lesions (CIN2+), and degree of participation in cervical screening (defined as the proportion of time covered by screening during a period when cervical screening is recommended) between women with and without mental illness. We focused on severe mental illness (ie, diagnosed in specialised psychiatric care) and also investigated milder mental illness (ie, use of psychotropic medications prescribed in primary care without specialist diagnosis) as secondary exposure. In two nested case-control studies, we defined the cases as women who have a diagnosis of invasive cervical cancer or CIN2+, and randomly selected individually matched controls from women who did not have these diagnoses. FINDINGS: Women with a specialist diagnosis of mental illness had a higher risk of invasive cervical cancer (hazard ratio 2·39, 95% CI 2·22-2·57) and CIN2+ (2·22, 2·18-2·26) and a 5·0% (4·8-5·2) lower cervical screening participation compared with matched controls. The risk increment of invasive cervical cancer and CIN2+ was greatest for substance misuse, whereas the screening reduction was greatest for intellectual disability and autism. In contrast, women who used prescribed psychotropic medications without specialist diagnosis had slightly higher screening participation and higher risk of CIN2+ but lower risk of invasive cervical cancer than women with neither specialist diagnosis nor medication use. INTERPRETATION: Women with severe mental illness participate less in screening and experience a higher risk of cervical neoplasia. Refined approaches are needed to better target these women in the elimination agenda of cervical cancer. FUNDING: Swedish Cancer Society.

ß2-Adrenoreceptor Agonists, Montelukast, and Parkinson Disease Risk.

OBJECTIVE: This study was undertaken to examine the association between montelukast use, ß2-adrenoreceptor (ß2AR) agonist use, and later Parkinson disease (PD). METHODS: We ascertained use of ß2AR agonists (430,885 individuals) and montelukast (23,315 individuals) from July 1, 2005 to June 30, 2007, and followed 5,186,886 PD-free individuals from July 1, 2007 to December 31, 2013 for incident PD diagnosis. We estimated hazard ratios and 95% confidence intervals using Cox regressions. RESULTS: We observed 16,383 PD cases during on average 6.1 years of follow-up. Overall, use of ß2AR agonists and montelukast were not related to PD incidence. A 38% lower PD incidence was noted among high-dose montelukast users when restricted to PD registered as the primary diagnosis. INTERPRETATION: Overall, our data do not support inverse associations between ß2AR agonists, montelukast, and PD. The prospect of lower PD incidence with high-dose montelukast exposure warrants further investigation, especially with adjustment for high-quality data on smoking. ANN NEUROL 2023;93:1023-1028.