Systemic inflammation and health outcomes in patients receiving treatment for atherosclerotic cardiovascular disease.

BACKGROUND AND AIMS: The burden and outcomes of inflammation in patients with atherosclerotic cardiovascular disease (ASCVD) are not well defined beyond the controlled settings of trials and research cohorts. METHODS: This was an observational study of ASCVD adults undergoing C-reactive protein testing in Stockholm's healthcare (2007-21). After excluding C-reactive protein tests associated with acute illness or medications/conditions that bias C-reactive protein interpretation, systemic inflammation was evaluated over a 3-month ascertainment window. Determinants of C-reactive protein ≥ 2 mg/L were explored with logistic regression. C-reactive protein categories were compared via negative-binomial/Cox regression for subsequent healthcare resource utilization and occurrence of major adverse cardiovascular events, heart failure hospitalization, and death. RESULTS: A total of 84 399 ASCVD adults were included (46% female, mean age 71 years, 59% with C-reactive protein ≥ 2 mg/L). Female sex, older age, lower kidney function, albuminuria, diabetes, hypertension, and recent anaemia were associated with higher odds of C-reactive protein ≥ 2 mg/L. The use of renin-angiotensin system inhibitors, antiplatelets, and lipid-lowering therapy was associated with lower odds. Over a median of 6.4 years, compared with C-reactive protein < 2 mg/L, patients with C-reactive protein ≥ 2 mg/L had higher rates of hospitalizations, days spent in hospital, outpatient consultations, and dispensed medications (P < .05 for all). They also had a higher rate of major adverse cardiovascular events [hazard ratio (HR) 1.30; 95% confidence interval (CI) 1.27-1.33], heart failure (HR 1.24; 95% CI 1.20-1.30), and death (HR 1.35; 95% CI 1.31-1.39). Results were consistent across subgroups and granular C-reactive protein categories and robust to the exclusion of extreme C-reactive protein values or early events. CONCLUSIONS: Three in five adults with ASCVD have systemic inflammation, which is associated with excess healthcare resource utilization and increased rates of cardiovascular events and death.

Poor recognition and undertreatment of anemia in patients with chronic kidney disease managed in primary care.

BACKGROUND: Anemia is a common complication of chronic kidney disease (CKD), but limited awareness and treatment options may hinder its management among CKD patients followed in primary care. METHODS: We evaluated adults with CKD stages 3-5 attending primary care in Stockholm, Sweden, 2012-2018. We assessed the incidence of anemia, clinical reactions, and association with subsequent major adverse cardiovascular events (MACE) and death. RESULTS: We identified 45,637 patients with CKD stages 3-5 free from anemia (mean age 78 years; 64% females; 79% CKD stage 3b). During a median follow-up of 2.4 years, 26% of patients developed anemia, and 10.4% developed severe anemia (hemoglobin <10 g/dL). Within 6 months from the anemia event, iron tests were infrequent; ferritin and transferrin saturation were tested in 27% and 11% of anemia cases, respectively, and 49% and 24% of severe anemia cases. Few patients were recognized with a clinical diagnosis (15% of anemia cases; 68% of severe anemias). Only 19% of patients with anemia received treatment, primarily iron (10%) and blood transfusions (7%); erythropoietin-stimulating agent use was anecdotal (∼1%). Treatment rates for severe anemia were higher, but 43% of patients still failed to receive treatment. Developing anemia was associated with a higher risk of MACE and death. CONCLUSION: Anemia was common and associated with adverse outcomes among patients with CKD stages 3-5 managed in primary care. Iron stores were infrequently tested, and a large proportion of patients with anemia remained untreated/under-recognized.

Discordances Between Creatinine- and Cystatin C-Based Estimated GFR and Adverse Clinical Outcomes in Routine Clinical Practice.

RATIONALE & OBJECTIVE: Cystatin C is recommended for measuring estimated glomerular filtration rate (eGFR) when estimates based on creatinine (eGFRcr) are not thought to be accurate enough for clinical decision making. While global adoption is slow, routine cystatin C testing in Sweden has been available for over a decade, providing real-world evidence about the magnitude of differences between eGFRcys and eGFRcr and their association with clinical outcomes. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 158,601 adults (48% women; mean age 62 years, eGFRcr 80, and eGFRcys 73mL/min/1.73/m2) undergoing testing for creatinine and cystatin C on the same day in connection with a health care encounter during 2010-2018 in Stockholm, Sweden. EXPOSURE: Percentage difference of eGFRcys minus eGFRcr (eGFRdiff). OUTCOME: Kidney failure with replacement therapy (KFRT), acute kidney injury (AKI), atherosclerotic cardiovascular disease (ASCVD), heart failure, and death. ANALYTICAL APPROACH: Multivariable Cox proportional hazards regression. RESULTS: Discordances between eGFRcr and eGFRcys were common, with eGFRcys being lower than eGFRcr (negative eGFRdiff) in most cases (65%). Patients with larger negative eGFRdiff were older, more often female, with higher eGFRcr and albuminuria, and more comorbid conditions. Compared with patients with similar eGFRcys and eGFRcr, the lowest quartile (eGFRcys > 27% lower than eGFRcr) had the higher HR of all study outcomes: AKI, 2.6 (95% CI, 2.4-2.9); KFRT, 1.4 (95% CI, 1.2-1.6); ASCVD, 1.4 (95% CI, 1.3-1.5); heart failure, 2.0 (95% CI, 1.9-2.2); and all-cause death, 2.6 (95% CI, 2.5-2.7). Conversely, patients in the highest quartile (positive eGFRdiff) were at lower risk. LIMITATIONS: Observational study, lack of information on indications for cystatin C testing. CONCLUSIONS: Cystatin C testing in routine care shows that many patients have a lower eGFRcys than eGFRcr, and these patients have a higher risk of multiple adverse outcomes. PLAIN-LANGUAGE SUMMARY: Clinicians require guidance when there are discrepancies between the estimated glomerular filtration rate based on creatinine (eGFRcr) and based on cystatin C (eGFRcys) in the same individual. Routine cystatin C testing in Sweden for over a decade permits exploration of how common and large these discrepancies are, and their associations with adverse clinical outcomes. In this observational study, we found that discordances between eGFRcys and eGFRcr are common, and 1 in 4 patients tested had an eGFRcys > 28% lower than their eGFRcr. We also show that an eGFRcys that is lower than the eGFRcr consistently identifies patients at higher risk of adverse outcomes, including cardiovascular events, kidney replacement therapy, acute kidney injury, and death.

Cardiorenal Outcomes Among Patients With Atrial Fibrillation Treated With Oral Anticoagulants.

RATIONALE & OBJECTIVE: Direct oral anticoagulants (DOACs) have progressively replaced vitamin K antagonists (VKAs) for stroke prevention in patients with nonvalvular atrial fibrillation (AF). DOACs cause fewer bleeding complications, but their other advantages, particularly related to kidney outcomes, remain inconclusive. We studied the risks of chronic kidney disease (CKD) progression and acute kidney injury (AKI) after DOAC and VKA administration for nonvalvular AF. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Cohort study of Swedish patients enrolled in the Stockholm Creatinine Measurements (SCREAM) project with a diagnosis of nonvalvular AF during 2011-2018. EXPOSURE: Initiation of DOAC or VKA treatment. OUTCOME: Primary outcomes were CKD progression (composite of >30% estimated glomerular filtration rate [eGFR] decline and kidney failure) and AKI (by diagnosis or KDIGO-defined transient creatinine elevations). Secondary outcomes were death, major bleeding, and the composite of stroke and systemic embolism. ANALYTICAL APPROACH: Propensity score weighted Cox regression was used to balance 50 baseline confounders. Sensitivity analyses included falsification end points, subgroups, and estimation of per-protocol effects. RESULTS: We included 32,699 patients (56% initiated DOAC) who were observed for a median of 3.8 years. Their median age was 75 years, 45% were women, and 27% had an eGFR <60mL/min/1.73m2. The adjusted HRs for DOAC versus VKA were 0.87 (95% CI, 0.78-0.98) for the risk of CKD progression and 0.88 (95% CI, 0.80-0.97) for AKI. HRs were 0.77 (95% CI, 0.67-0.89) for major bleeding, 0.93 (95% CI, 0.78-1.11) for the composite of stroke and systemic embolism, and 1.04 (95% CI, 0.95-1.14) for death. The results were similar across subgroups of age, sex, and baseline eGFR when restricting to patients at high risk for thromboembolic events and when censoring follow up at treatment discontinuation or change in type of anticoagulation. LIMITATIONS: Missing information on time in therapeutic range and treatment dosages. CONCLUSIONS: Among patients with nonvalvular AF treated in routine clinical practice compared with VKA use, DOAC use was associated with a lower risk of CKD progression, AKI, and major bleeding but a similar risk of the composite of stroke, systemic embolism, or death.

Quality of laboratory biomarker monitoring during treatment with lithium in patients with bipolar disorder.

BACKGROUND: Clinical guidelines recommend monitoring of creatinine and lithium throughout treatment with lithium. We here assessed the extent to which this occurs in healthcare in Sweden. METHODS: This is an observational study of all adults with bipolar disorder starting lithium therapy in Stockholm, Sweden, during 2007-2018. The main outcome was monitoring of blood lithium and creatinine at therapy initiation and/or once annually. The secondary outcome was monitoring of calcium and thyroid-stimulating hormone (TSH). Patients were followed up until therapy cessation, death, out-migration, or to the end of 2018. RESULTS: We identified 4428 adults with bipolar disorder who started lithium therapy and were followed up for up to 11 years. Their median age was 39 years, and 63% were women. The median duration on lithium therapy was 4.3 (IQR: 1.9-7.45) years, and the majority who discontinued therapy started another mood stabilizer soon after. Overall, 21% started lithium therapy without assessing the serum/plasma concentration of creatinine. The proportion of people who did not have both lithium and creatinine measured increased from 21% in the first year to 33% in the eleventh year. The proportion with annual testing for TSH or calcium was slightly lower. As few as 16% of patients had both lithium and creatinine tested once annually during their complete time on lithium. CONCLUSIONS: In a Swedish community sample, lithium and creatinine monitoring was inconsistent with guideline recommendations that call for measurement of annual biomarker levels.

Validation of risk scores for ischaemic stroke in atrial fibrillation across the spectrum of kidney function.

AIMS: The increasing prevalence of ischaemic stroke (IS) can partly be explained by the likewise growing number of patients with chronic kidney disease (CKD). Risk scores have been developed to identify high-risk patients, allowing for personalized anticoagulation therapy. However, predictive performance in CKD is unclear. The aim of this study is to validate six commonly used risk scores for IS in atrial fibrillation (AF) patients across the spectrum of kidney function. METHODS AND RESULTS: Overall, 36 004 subjects with newly diagnosed AF from SCREAM (Stockholm CREAtinine Measurements), a healthcare utilization cohort of Stockholm residents, were included. Predictive performance of the AFI, CHADS2, Modified CHADS2, CHA2DS2-VASc, ATRIA, and GARFIELD-AF risk scores was evaluated across three strata of kidney function: normal kidney function [estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2], mild CKD (eGFR 30-60 mL/min/1.73 m2), and advanced CKD (eGFR <30 mL/min/1.73 m2). Predictive performance was assessed by discrimination and calibration. During 1.9 years, 3069 (8.5%) patients suffered an IS. Discrimination was dependent on eGFR: the median c-statistic in normal eGFR was 0.75 (range 0.68-0.78), but decreased to 0.68 (0.58-0.73) and 0.68 (0.55-0.74) for mild and advanced CKD, respectively. Calibration was reasonable and largely independent of eGFR. The Modified CHADS2 score showed good performance across kidney function strata, both for discrimination [c-statistic: 0.78 (95% confidence interval 0.77-0.79), 0.73 (0.71-0.74) and 0.74 (0.69-0.79), respectively] and calibration. CONCLUSION: In the most clinically relevant stages of CKD, predictive performance of the majority of risk scores was poor, increasing the risk of misclassification and thus of over- or undertreatment. The Modified CHADS2 score performed good and consistently across all kidney function strata, and should therefore be preferred for risk estimation in AF patients.

CRISPR-Cas9 mediated genome editing of drought and salt tolerance (OsDST) gene in indica mega rice cultivar MTU1010.

Development of abiotic stress tolerant rice cultivars is necessary for sustainable rice production under the scenario of global climate change, dwindling fresh water resources and increase in salt affected areas. Several genes from rice have been functionally validated by using EMS mutants and transgenics. Often, many of these desirable alleles are not available indica rice which is mainly cultivated, and where available, introgression of these alleles into elite cultivars is a time and labour intensive process, in addition to the potential introgression of non-desirable genes due to linkage. CRISPR-Cas technology helps development of elite cultivars with desirable alleles by precision gene editing. Hence, this study was carried out to create mutant alleles of drought and salt tolerance (DST) gene by using CRISPR-Cas9 gene editing in indica rice cv. MTU1010. We used two different gRNAs to target regions of DST protein that might be involved in protein-protein interaction and successfully generated different mutant alleles of DST gene. We selected homozygous dst mutant with 366 bp deletion between the two gRNAs for phenotypic analysis. This 366 bp deletion led to the deletion of amino acid residues from 184 to 305 in frame, and hence the mutant was named as dst ∆184-305 . The dst ∆184-305 mutation induced by CRISPR-Cas9 method in DST gene in indica rice cv. MTU1010 phenocopied EMS-induced dst (N69D) mutation reported earlier in japonica cultivar. The dst ∆184-305 mutant produced leaves with broader width and reduced stomatal density, and thus enhanced leaf water retention under dehydration stress. Our study showed that the reduction in stomatal density in loss of function mutants of dst is, at least, in part due to downregulation of stomatal developmental genes SPCH1, MUTE and ICE1. The Cas9-free dst ∆184-305 mutant exhibited moderate level tolerance to osmotic stress and high level of salt stress in seedling stage. Thus, dst mutant alleles generated in this study will be useful for improving drought and salt tolerance and grain yield in indica rice cultivars.

Association Between Proton Pump Inhibitor Use and Risk of Progression of Chronic Kidney Disease.

BACKGROUND & AIMS: Proton pump inhibitors (PPI) have been associated with acute kidney injury and recent studies suggest that they may be associated with the risk of chronic kidney disease (CKD). METHODS: We performed a retrospective analysis using the Stockholm creatinine measurements database, which contains information on diagnoses, dispensation claims, and laboratory test results for all citizens in the Stockholm region from 2007 through 2010. We identified new users of PPIs (n = 105,305) and new users of H2 blockers (H2B; n = 9578); data on renal outcomes were collected for a median 2.7 years. The primary outcome was progression CKD, defined as doubling of creatinine or decrease in estimated glomerular filtration rate of 30% or more. Secondary outcomes were end-stage renal disease and acute kidney injury. Complete collection of repeated PPI and H2B dispensations at pharmacies in Sweden allowed modeling the time-dependent risk associated with cumulative PPI exposure. RESULTS: Users of PPIs, compared with users of H2Bs, had an increased risk for doubled levels of creatinine (1985 events; adjusted hazard ratio [HR], 1.26; 95% CI, 1.05-1.51) and decrease in estimated glomerular filtration rate of 30% or more (11,045 events; 1.26; 95% CI, 1.16-1.36). PPI use also associated with development of end-stage renal disease (HR, 2.40; 95% CI, 0.76-7.58) and acute kidney injury (HR, 1.30; 95% CI, 1.00-1.69). There was a graded association between cumulative exposure to PPIs and risk of CKD progression. This was not the case for cumulative H2B use. CONCLUSIONS: Initiation of PPI therapy and cumulative PPI exposure is associate with increased risk of CKD progression in a large, North European healthcare system. Although consistent, the association was modest in magnitude, and cannot exclude residual confounding.

Adherence and persistence to novel glucose-lowering medications in persons with type 2 diabetes mellitus undergoing routine care.

AIMS: To assess adherence and persistence to sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1-RA), and dipeptidyl peptidase-4 inhibitors (DPP4i) in routine care. METHODS: Using retrospective healthcare data from the Stockholm region, Sweden, we evaluated new-users of these agents during 2015-2020. We investigated adherence (≥80 % of days covered by an active supply), persistence (no treatment gap ≥ 60 days), and predictors for non-adherence and non-persistence. RESULTS: We identified 24,470 new-users of SGLT2i (10,743), GLP1-RA (10,315), and/or DPP4i (9,488). Over 2.8 years median follow-up, the proportion demonstrating adherence was higher for SGLT2i (57 %) than DPP4i (53 %, comparison p < 0.001), and for GLP1-RA than DPP4i (54 % vs 53 %, p < 0.001). Similarly, persistence was higher for both SGLT2i and GLP-RA than DPP4i (respectively, 50 % vs 44 %, p < 0.001; 49 % vs 44 %, p < 0.001). Overall adherence was better among users who were older, had a history of high blood pressure, used more non-diabetic medications, had lower Hba1c, had better kidney function, and had completed secondary schooling or university. Women had worse adherence to SGLT2i and GLP1-RA than DPP4i. CONCLUSIONS: We report adherence and persistence to SGLT2i, GLP1-RA and DPP4i in routine care, and identify prognostic factors that could inform implementation interventions to improve uptake of these important therapies.

Evaluation of the introduction of novel potassium binders in routine care; the Stockholm CREAtinine measurements (SCREAM) project.

BACKGROUND: The pharmacological management of hyperkalemia traditionally considered calcium or sodium polystyrene sulfonate and, since recently, the novel binders patiromer and sodium zirconium cyclosilicate. We evaluated their patterns of use, duration of treatment and relative effectiveness/safety in Swedish routine care. METHODS: Observational study of adults initiating therapy with sodium polystyrene sulfonate or a novel binder (sodium zirconium cyclosilicate or patiromer) in Stockholm 2019-2021. We quantified treatment duration by repeated dispensations, compared mean achieved potassium concentration within 60 days, and potential adverse events between treatments. RESULTS: A total of 1879 adults started treatment with sodium polystyrene sulfonate, and 147 with novel binders (n = 41 patiromer and n = 106 sodium zirconium cyclosilicate). Potassium at baseline for all treatments was 5.7 mmol/L. Sodium polystyrene sulfonate patients stayed on treatment a mean of 61 days (14% filled ≥3 consecutive prescriptions) compared to 109 days on treatment (49% filled ≥3 prescriptions) for novel binders. After 15 days of treatment, potassium similarly decreased to 4.6 (SD 0.6) and 4.8 (SD 0.6) mmol/L in the sodium polystyrene sulfonate and novel binder groups, respectively, and was maintained over the 60 days post-treatment. In multivariable regression, the odds ratio for novel binders (vs sodium polystyrene sulfonate) in reaching potassium ≤ 5.0 mmol/L after 15 days was 0.65 (95% CI 0.38-1.10) and after 60 days 0.89 (95% CI 0.45-1.76). Hypocalcemia, hypokalemia, and initiation of anti-diarrheal/constipation medications were the most-commonly detected adverse events. In multivariable analyses, the OR for these events did not differ between groups. CONCLUSION: We observed similar short-term effectiveness and safety for all potassium binders. However, treatment duration was longer for novel binders than for sodium polystyrene sulfonate.

N-terminal pro-B-type natriuretic peptide concentrations, testing and associations with worsening heart failure events.

AIMS: In patients with heart failure (HF), we aimed to assess (i) the time trends in N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing; (ii) patient characteristics associated with NT-proBNP testing; (iii) distribution of NT-proBNP levels, focusing on the subgroups with (WHFE) vs. without (NWHFE) a worsening HF event, defined as an HF hospitalization; and (iv) changes of NT-proBNP levels over time. METHODS AND RESULTS: NT-proBNP testing and levels were investigated in HF patients enrolled in the Swedish Heart Failure Registry (SwedeHF) linked with the Stockholm CREAtinine Measurements project from January 2011 to December 2018. Index date was the first registration in SwedeHF. Patterns of change in NT-proBNP levels before (in the previous 6 ± 3 months) and after (in the following 6 ± 3 months) the index date were categorized as follows: (i) <3000 ng/L at both measurements = stable low; (ii) <3000 ng/L at the first measurement and ≥3000 ng/L at the second measurement = increased; (iii) ≥3000 ng/L at the first measurement and <3000 ng/L at the second measurement = decreased; and (iv) ≥3000 ng/L at both measurements = stable high. Univariable and multivariable logistic regression models, expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs), were performed to assess the associations between (i) clinical characteristics and NT-proBNP testing and (ii) changes in NT-proBNP from 6 months prior to the index date and the index date and a WHFE. Consistency analyses were performed in HF with reduced ejection fraction (HFrEF) alone. A total of 4424 HF patients were included (median age 74 years, women 34%, HFrEF 53%), 33% with a WHFE. NT-proBNP testing increased over time, up to 55% in 2018, and was almost two-fold as frequent, and time to testing was less than half, in patients with WHFE vs. NWHFE. Independent predictors of testing were WHFE, higher heart rate, diuretic use, and preserved ejection fraction. Median NT-proBNP was 3070 ng/L (Q1-Q3: 1220-7395), approximately three-fold higher in WHFE vs. NWHFE. Compared with stable low NT-proBNP levels, increased (OR 4.27, 95% CI 2.47-7.37) and stable high levels (OR 2.48, 95% CI 1.58-3.88) were independently associated with a higher risk of WHFE. Results were consistent in the HFrEF population. CONCLUSIONS: NT-proBNP testing increased over time but still was only performed in half of the patients. Testing was associated with a WHFE, with features of more severe HF and for differential diagnosis purposes. Increased and stable high levels were associated with a WHFE. Overall, our data highlight the potential benefits of carrying further implementation of NT-proBNP testing in clinical practice.

Designing eHealth interventions for children with complex care needs requires continuous stakeholder collaboration and co-creation.

Objective: Hospital-to-home (H2H) transitions challenge families of children with medical complexity (CMC) and healthcare professionals (HCP). This study aimed to gain deeper insights into the H2H transition process and to work towards eHealth interventions for its improvement, by applying an iterative methodology involving both CMC families and HCP as end-users. Methods: For 20-weeks, the Dutch Transitional Care Unit consortium collaborated with the Amsterdam University of Applied Sciences, HCP, and CMC families. The agile SCREAM approach was used, merging Design Thinking methods into five iterative sprints to stimulate creativity, ideation, and design. Continuous communication allowed rapid adaptation to new information and the refinement of solutions for subsequent sprints. Results: This iterative process revealed three domains of care - care coordination, social wellbeing, and emotional support - that were important to all stakeholders. These domains informed the development of our final prototype, 'Our Care Team', an application tailored to meet the H2H transition needs for CMC families and HCP. Conclusion: Complex processes like the H2H transition for CMC families require adaptive interventions that empower all stakeholders in their respective roles, to promote transitional care that is anticipatory, rather than reactive. Innovation: A collaborative methodology is needed, that optimizes existing resources and knowledge, fosters innovation through collaboration while using creative digital design principles. This way, we might be able to design eHealth solutions with end-users, not just for them.

Novel glucose-lowering drugs and the risk of acute kidney injury in routine care; the Stockholm CREAtinine Measurements (SCREAM) project.

INTRODUCTION: Little is known about the comparative effects of sodium glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1-RA), or dipeptidyl peptidase-4 inhibitors (DPP-4i) on the risk of acute kidney injury (AKI) in routine care, which may differ from the controlled setting of trials. METHODS: Observational study comparing risks of AKI among new users of SGLT2i, GLP1-RA or DPP-4i in the region of Stockholm, Sweden, during 2008-2018. AKI was defined by ICD-10 codes and creatinine-based KDIGO criteria. We used inverse probability of treatment weighting (IPTW) to adjust for 60 potential confounders, weighted Kaplan-Meier curves and Cox regression to estimate hazard ratios and absolute risks. RESULTS: We included 17,407 participants who newly initiated DPP-4i (N = 10,605), GLP1-RA (N = 4448) or SGLT2i (N = 2354). Mean age was 63 years (39% women) and median (IQR) eGFR was 89 (73-100) ml/min/1.73 m2. During a median follow-up of 2.5 years, 1411 participants experienced AKI. SGLT2i users had the lowest incidence rate of AKI, 18.3 [CI 95% 14.1-23.4] per 1000 person years, followed by GLP1-RA (22.5; 19.9-25.3) and DPP-4i (26.6; 25-28.2). The weighted 3-year absolute risk for AKI was 5.79% [3.63-8.52] in the SGLT2i group, compared with 7.03% [5.69-8.69] and 7.00% [6.43-7.58] in the GLP1-RA and DPP-4i groups, respectively. The adjusted hazard ratio was 0.73 [CI 95% 0.45-1.16] for SGLT2i vs. DPP-4i, and 0.98 [CI 95% 0.82-1.18] for GLP1-RA vs. DPP-4i. CONCLUSION: This study of routine care patients initiating novel glucose-lowering drugs showed similar occurrence of AKI between therapies, and suggests lower risk for SGLT2i.

Albuminuria and the risk of cancer: the Stockholm CREAtinine Measurements (SCREAM) project.

Background: Studies investigating the association of chronic kidney disease and cancer have focused on estimated glomerular filtration (eGFR) rather than on albuminuria. This study aimed to examine whether albuminuria is associated with cancer incidence, and whether this association is independent of eGFR. Methods: We included subjects of the Stockholm Creatinine Measurements (SCREAM) project without a history of cancer-250 768 subjects with at least one urine albumin-creatinine ratio (ACR) test (primary cohort) and 433 850 subjects with at least one dipstick albuminuria test (secondary cohort). Albuminuria was quantified as KDIGO albuminuria stages. The primary outcome was overall cancer incidence. Secondary outcomes were site-specific cancer incidence rates. Multivariable Cox proportional hazards regression models adjusted for confounders including eGFR to calculate hazard ratios and 95% confidence intervals (HRs, 95% CIs). Results: During a median follow-up of 4.3 (interquartile range 2.0-8.2) years, 21 901 subjects of the ACR cohort developed de novo cancer. In multivariable analyses, adjusting among others for eGFR, subjects with an ACR of 30-299 mg/g or ≥300 mg/g had a 23% (HR 1.23; 95% CI 1.19-1.28) and 40% (HR 1.40; 95% CI 1.31-1.50) higher risk of developing cancer, respectively, when compared with subjects with an ACR <30 mg/g. This graded, independent association was also observed for urinary tract, gastrointestinal tract, lung and hematological cancer incidence (all P < .05). Results were similar in the dipstick albuminuria cohort. Conclusions: Albuminuria was associated with the risk of cancer independent of eGFR. This association was primarily driven by a higher risk of urinary tract, gastrointestinal tract, lung and hematological cancers.

Scream Sound-induced Chronic Psychological Stress Results in Diminished Ovarian Reserve in Adult Female Rat.

It is well established that chronic psychological stress (PS) induces female reproductive dysfunction. However, the studies on the consequences of chronic PS exposure precisely targeting ovarian reserve are lacking. In the present study, we employed a chronic scream sound-induced PS model to investigate the potential effect of pure psychosocial stressors on ovary reserve. Female rats were subjected to scream sound stress, white noise, or background for 3 weeks. Animals were euthanized by cervical dislocation after stress for collection of blood or ovaries. Sex hormones were analyzed by enzyme-linked immunosorbent assay. The follicle number was examined by histopathology. Granulosa cell apoptosis of the ovaries was examined by in situ cell death detection kit. Finally, rats were mated with proven fertile male rats to study fertility parameters. Female rats exposed to scream sound were presented with reduced weight gain and sucrose preference, while immobility time in forced swim test and serum corticosterone concentration were significantly increased. Scream sound stress sequentially decreased plasma anti-Müllerian hormone and estradiol concentration, induced primordial and preantral follicles loss, augmented granulosa cell apoptosis in ovarian growing follicles, and eventually decreased litter sizes. Based on these results, we suggest that chronic PS induced loss of ovarian reserve by accelerated primordial follicle activation and destruction of growing follicles, which results in follicle depletion and decreased fertility.

Humans read emotional arousal in monkey vocalizations: evidence for evolutionary continuities in communication.

Humans and other mammalian species communicate emotions in ways that reflect evolutionary conservation and continuity, an observation first made by Darwin. One approach to testing this hypothesis has been to assess the capacity to perceive the emotional content of the vocalizations of other species. Using a binary forced choice task, we tested perception of the emotional intensity represented in coos and screams of infant and juvenile female rhesus macaques (Macaca mulatta) by 113 human listeners without, and 12 listeners with, experience (as researchers or care technicians) with this species. Each stimulus pair contained one high- and one low-arousal vocalization, as measured at the time of recording by stress hormone levels for coos and the degree of intensity of aggression for screams. For coos as well as screams, both inexperienced and experienced participants accurately identified the high-arousal vocalization at significantly above-chance rates. Experience was associated with significantly greater accuracy with scream stimuli but not coo stimuli, and with a tendency to indicate screams as reflecting greater emotional intensity than coos. Neither measures of empathy, human emotion recognition, nor attitudes toward animal welfare showed any relationship with responses. Participants were sensitive to the fundamental frequency, noisiness, and duration of vocalizations; some of these tendencies likely facilitated accurate perceptions, perhaps due to evolutionary homologies in the physiology of arousal and vocal production between humans and macaques. Overall, our findings support a view of evolutionary continuity in emotional vocal communication. We discuss hypotheses about how distinctive dimensions of human nonverbal communication, like the expansion of scream usage across a range of contexts, might influence perceptions of other species' vocalizations.

Secondary hyperparathyroidism and adverse health outcomes in adults with chronic kidney disease.

BACKGROUND: Secondary hyperparathyroidism (sHPT) develops frequently in patients with chronic kidney disease (CKD). However, the burden and long-term impact of sHPT on the risk of adverse health outcomes are not well studied. METHODS: We evaluated all adults receiving nephrologist care in Stockholm during 2006-11 who were not undergoing kidney replacement therapy and had not developed sHPT. Incident sHPT was identified by using clinical diagnoses, initiated medications or two consecutive parathyroid hormone (PTH) measurements ≥130 pg/mL. We characterized sHPT incidence by estimated glomerular filtration rate (eGFR) strata, evaluated clinical predictors and quantified the association between incident sHPT (time-varying exposure) and the risk of fractures, CKD progression, major adverse cardiovascular events (MACEs) and death. RESULTS: We identified 2556 adults with CKD Stages 1-5 (mean age 66 years, 38% women), of whom 784 developed sHPT during follow-up. The incidence of sHPT increased with advancing CKD: from 57 cases/1000 person-years in CKD Stage G3 to 230 cases/1000 person-years in Stage G5. In multivariable analyses, low eGFR was the strongest sHPT predictor, followed by young age, male sex and diabetes. Incident sHPT was associated with a 1.3-fold (95% confidence interval 1.1-1.8) increased risk of death, a 2.2-fold (1.42-3.28) higher risk of MACEs, a 5.0-fold (3.5-7.2) higher risk of CKD progression and a 1.3-fold (1.5-2.2) higher risk of fractures. Results were consistent in stratified analyses and after excluding early events. CONCLUSIONS: Our findings illustrate the burden of sHPT in advanced CKD and highlight the susceptibility for adverse outcomes of patients developing sHPT. This may inform clinical decisions regarding pre-sHPT risk stratification, PTH monitoring and risk-prevention strategies post-sHPT development.

Stress Related Disorders and the Risk of Kidney Disease.

INTRODUCTION: Stress related disorders (SRDs, i.e., psychiatric disorders induced by significant life stressors) increase vulnerability to health problems. Whether SRDs associate with risk of acute kidney injury (AKI) and chronic kidney disease (CKD) is unknown. METHODS: A population-matched cohort study in Sweden included 30,998 patients receiving a SRDs diagnosis and 116,677 unexposed patients matched by age, sex and estimated glomerular filtration rates (eGFR). The primary outcome was CKD progression, defined as a sustained relative decline in eGFR of more than 40% or commencement of kidney replacement therapy. The secondary outcome was AKI, defined by death or hospitalization attributed to AKI or rapid creatinine changes (increase ≥ 0.3 mg/d over 48 hours or 1.5x over 7 days). Cox models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: During a medium follow-up of 3.2 years, compared to the unexposed, patients with SRDs (median age 45 years, 71% women), were at increased risk of CKD progression (HR 1.23, 95% CI 1.10-1.37) and AKI (HR 1.22, 95% CI 1.04-1.42). While the HR of CKD progression remained similarly elevated during the entire follow-up period, the association with AKI was only observed during the first year after SRDs diagnosis. Results were consistent in stratified analyses, when only considering AKI-hospitalizations/death, and when disregarding eGFR measurements close to index date. CONCLUSIONS: A diagnosis of SRDs is associated with subsequent risk of AKI and CKD progression. While studies should confirm this observation and characterize underlying mechanisms, close monitoring of kidney function following SRDs diagnosis may be indicated.

Heteronuclear cross-relaxation effect modulated by the dynamics of N-functional groups in the solid state under 15N DP-MAS DNP.

In a typical magic-angle spinning (MAS) dynamic nuclear polarization (DNP) nuclear magnetic resonance (NMR) experiment, several mechanisms are simultaneously involved when transferring much larger polarization of electron spins to NMR active nuclei of interest. Recently, specific cross-relaxation enhancement by active motions under DNP (SCREAM-DNP) [Daube et al. JACS 2016] has been reported as one of these mechanisms. Thereby 13C enhancement with inverted sign was observed in a direct polarization (DP) MAS DNP experiment, caused by reorientation dynamics of methyl that was not frozen out at 100 K. Here, we report on the spontaneous polarization transfer from hyperpolarized 1H to both primary amine and ammonium nitrogens, resulting in an additional positive signal enhancement in the 15N NMR spectra during 15N DP-MAS DNP. The cross-relaxation induced signal enhancement (CRE) for 15N is of opposite sign compared to that observed for 13C due to the negative sign of the gyromagnetic ratio of 15N. The influence on CRE efficiency caused by variation of the radical solution composition and by temperature was also investigated.

Detecting Screams From Home Audio Recordings to Identify Tantrums: Exploratory Study Using Transfer Machine Learning.

BACKGROUND: Qualitative self- or parent-reports used in assessing children's behavioral disorders are often inconvenient to collect and can be misleading due to missing information, rater biases, and limited validity. A data-driven approach to quantify behavioral disorders could alleviate these concerns. This study proposes a machine learning approach to identify screams in voice recordings that avoids the need to gather large amounts of clinical data for model training. OBJECTIVE: The goal of this study is to evaluate if a machine learning model trained only on publicly available audio data sets could be used to detect screaming sounds in audio streams captured in an at-home setting. METHODS: Two sets of audio samples were prepared to evaluate the model: a subset of the publicly available AudioSet data set and a set of audio data extracted from the TV show Supernanny, which was chosen for its similarity to clinical data. Scream events were manually annotated for the Supernanny data, and existing annotations were refined for the AudioSet data. Audio feature extraction was performed with a convolutional neural network pretrained on AudioSet. A gradient-boosted tree model was trained and cross-validated for scream classification on the AudioSet data and then validated independently on the Supernanny audio. RESULTS: On the held-out AudioSet clips, the model achieved a receiver operating characteristic (ROC)-area under the curve (AUC) of 0.86. The same model applied to three full episodes of Supernanny audio achieved an ROC-AUC of 0.95 and an average precision (positive predictive value) of 42% despite screams only making up 1.3% (n=92/7166 seconds) of the total run time. CONCLUSIONS: These results suggest that a scream-detection model trained with publicly available data could be valuable for monitoring clinical recordings and identifying tantrums as opposed to depending on collecting costly privacy-protected clinical data for model training.