Dose-dependent Increase In Risk Research Articles

African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1

Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant (rs3115534-G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations. GBA1 is a gene of high clinical and therapeutic interest. Damaging biallelic protein-coding variants cause Gaucher disease and monoallelic variants confer risk for PD and dementia with Lewy bodies, likely by reducing the function of glucocerebrosidase. Interestingly, the African ancestry-specific GBA1 risk variant is a noncoding variant, suggesting a different mechanism of action. Using full-length RNA transcript sequencing, we identified partial intron 8 expression in risk variant carriers (G) but not in nonvariant carriers (T). Antibodies targeting the N terminus of glucocerebrosidase showed that this intron-retained isoform is likely not protein coding and subsequent proteomics did not identify a shorter protein isoform, suggesting that the disease mechanism is RNA based. Clustered regularly interspaced short palindromic repeats editing of the reported index variant (rs3115534) revealed that this is the sequence alteration responsible for driving the production of these transcripts containing intron 8. Follow-up analysis of this variant showed that it is in a key intronic branchpoint sequence and, therefore, has important implications in splicing and disease. In addition, when measuring glucocerebrosidase activity, we identified a dose-dependent reduction in risk variant carriers. Overall, we report the functional effect of a GBA1 noncoding risk variant, which acts by interfering with the splicing of functional GBA1 transcripts, resulting in reduced protein levels and reduced glucocerebrosidase activity. This understanding reveals a potential therapeutic target in an underserved and underrepresented population.

Impact of Statin Therapy on Diabetes Incidence: Implications for Primary Prevention.

The present review aims to summarize current evidence, explore underlying mechanisms, and help guide clinicians regarding statin therapy and diabetes risk in primary prevention. The observational and genetic epidemiology, as well as evidence from randomized controlled trials and meta-analyses, illustrate a modest, dose-dependent increase in risk of diabetes from statin therapy. Risk of new onset diabetes from statins appears to be greatest in those near the diagnostic threshold for diabetes or with diabetes risk factors prior to statin initiation. The risk of incident diabetes is vastly offset by the cardiovascular protection offered from statin therapy and should not deter guideline recommended statin initiation in primary prevention.

Dose-dependent increase in risk of bleeding and bleeding complications in relation to SSRI use at delivery

IntroductionDepression during pregnancy is a severe state that increases the risk of suicide, as well as adverse newborn outcomes. Selective serotonin re-uptake inhibitors (SSRIs) are effective for the treatment of depression, but increase the risk of bleeding complications at delivery. Knowledge on the dose dependency of this association is lacking. MethodsA hospital-based cohort study of all women who gave birth at Karolinska University Hospital in Stockholm over the 5-year period from 2007 to 2011, with or without SSRI use, was undertaken. In total, 334 women who delivered vaginally and were exposed to SSRIs at delivery were identified. All other women who delivered vaginally formed the control group (n = 31,929). The electronic maternal health records of the 334 SSRI users were scrutinized, and the women were categorized into two groups: moderate (n = 246) or high (n = 88) SSRI dose at delivery. The main outcome was bleeding complications at delivery in relation to SSRI dose. ResultsA dose-dependent increase in the rate of postpartum haemorrhage (≥1000 ml) was found, affecting 8.4 %, 14.6 % and 23.9 % (p ≤ 0.001) of women in the control group, the moderate-dose group and the high-dose group, respectively. In addition, a dose-dependent increase in the rate of postpartum anaemia was found, affecting 7.0 %, 9.3 % and 15.9 % (p = 0.001) of women in the control group, the moderate-dose group and the high-dose group, respectively. Mean blood loss of 406 ml, 483 ml and 482 ml (p ≤ 0.001) was found in the control group, the moderate-dose group and the high-dose group, respectively. Women exposed to SSRIs delivered earlier, but did not have higher prevalence of pre-eclampsia compared with the control group. ConclusionsThe dose-dependent relationship between SSRIs and bleeding complications may be clinically useful in the management of this vulnerable group of women.

African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1.

Recently, a novel African ancestry specific Parkinson's disease (PD) risk signal was identified at the gene encoding glucocerebrosidase ( GBA1 ). This variant (rs3115534-G) is carried by ∼50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups, but is almost absent in European and Asian ancestry populations. GBA1 is a gene of high clinical and therapeutic interest. Damaging bi-allelic protein-coding variants cause Gaucher disease and mono-allelic variants confer risk for PD and Dementia with Lewy Bodies, likely by reducing the function of glucocerebrosidase. Interestingly, the novel African ancestry specific GBA1 risk variant is a non-coding variant, suggesting a different mechanism of action. Using full length RNA transcript sequencing, we identified intron 8 expression in risk variant carriers (G) but not in non-variant carriers (T). Antibodies targeting the N-terminus of glucocerebrosidase showed that this intron-retained isoform is likely not protein coding and subsequent proteomics did not identify a shorter protein isoform, suggesting the disease mechanism is RNA-based. CRISPR editing of the reported index variant (rs3115534) revealed that this is the responsible sequence alteration driving production of these intron 8 containing transcripts. Follow-up analysis of this variant showed that it is in a key intronic branchpoint sequence and therefore has important implications in splicing and disease. In addition, when measuring glucocerebrosidase activity we identified a dose-dependent reduction in risk variant carriers (G). Overall, we report the functional effect of a GBA1 non-coding risk variant, which acts by interfering with the splicing of functional GBA1 transcripts, resulting in reduced protein levels and reduced glucocerebrosidase activity. This understanding reveals a novel therapeutic target in an underserved and underrepresented population.

Different operational definitions of polypharmacy and their association with the risk of all-cause hospitalization: A conceptual framework using administrative databases

Background: As in all pharmacoepidemiology studies, also in the cardiovascular field it is essential to take into account the clinical complexity of patients, which is very frequently estimated with polypharmacy. We aimed at describing the current heterogeneity of polypharmacy definition, and assessing the association of polypharmacy with clinical outcomes. Methods: Using administrative databases of the local health unit of Bergamo (Lombardy), all subjects aged ≥40 years with at least one reimbursed drug prescription during the year 2017 were identified. We selected from literature relevant operational definitions of polypharmacy. First, we applied World Health Organization (WHO) definition (at least ≥5 different medications, ATC 4th level code). Second, we excluded drug prescriptions associated with short-term treatment. Third, we considered only the prescriptions of drugs with a total annual defined daily doses (DDDs) ≥60. All the approaches were evaluated within one year, one quarter, and one month. A multivariate logistic regression model was performed to estimate odds ratios (OR) and 95% confidence intervals [95% CI] for the association between polypharmacy and the risk of hospitalization for all-causes. Results: Overall, 431,620 subjects were included in our cohort. The DDD-based definition led to estimates with little variability depending on the time windows (range 20.47%-21.16%), while the WHO definition determined the greatest variability (range 39.98%-31.24%). The DDD-based definition identified an older (mean age [SD], 72.6 [10.9]) and more complex cohort of patients (average number [SD] of previous hospitalizations 1.2 [1.7], average number of dispensed drugs 9.7 [3.5]). A dose-dependent increase in risk was observed as the number of the dispensed drugs increases regardless of definitions. Conclusions: Different definitions of polypharmacy led to different prevalence estimates. All definitions showed a dose-dependent association with hospitalization risk, with the definition based on DDDs being the least heterogeneous. However, only a patient-by-patient approach can determine whether or not polypharmacy is appropriate.

Measurable Residual FLT3-ITD before Allogeneic Transplant for Acute Myeloid Leukemia

Background: In the past year, multiple studies have demonstrated the drastically increased risk of relapse and death in patients with Acute Myeloid Leukemia (AML) who have persistent FLT3 internal tandem duplication (ITD) mutations detectable in clinical remission by next generation sequencing (NGS). Translating this evidence into a change in clinical practice requires both widely available testing and a clear understanding of the clinical implications of FLT3-ITD detection at defined threshold levels. In the largest of the recent studies (Pre-MEASURE, PMID: 36881031), we performed FLT3-ITD MRD detection in blood DNA collected from 608 patients at the time of first remission (CR1) prior to allogeneic hematopoietic cell transplant (alloHCT). To evaluate cross-assay comparability and the impact of residual disease burden levels, we performed analysis on this cohort using a commercially available FLT3-ITD MRD NGS assay. Methods: Of the 608 patients aged 18 or older from the Pre-MEASURE study who received an alloHCT for FLT3-ITD mutated AML during CR1 at a CIBMTR reporting site in the USA between the years of 2013-2019, patients not experiencing non-relapse mortality and with sufficient DNA from pretransplant blood available were included in this analysis. A commercially available testing kit (IVS, Invivoscribe, San Diego, CA), which can detect FLT3-ITD MRD by NGS for up to 21 patients on one Illumina MiSeq flow cell, was used to establish a workflow following clinical testing standards and validated to detect ITDs down to a variant allele fraction (VAF) of at least 0.005%. Results were compared to those previously reported using an anchored multiplex PCR-based (AMP) targeted NGS assay. Overall survival (OS) and cumulative incidence of relapse were estimated with the day of transplant as time 0 using Kaplan-Meier estimation (log-rank tests) and Cox proportional hazards models. Results: A total of 451 patients were included in this study, of which 173 (38%) experienced relapse (median: 5.2 months; range 0.7-52.1) and 133 (29%) died (median: 10.7 months; range 2-53.8) post-alloHCT. The IVS assay identified 232 FLT3-ITD variants with a median VAF of 0.005% (range 0.0002-44%) and length of 51bp (range 5-228). IVS positive patients had a median of 1 FLT3-ITD variant (range 1-15) and median maximum VAF of 0.01% (range 0.0003-44%). Utilizing the same VAF cutoff of 0.01% for MRD positivity for the IVS test as used in the Pre-MEASURE study, patients testing positive prior to alloHCT exhibited higher rates of relapse (79% vs 31%, p<0.0001) and decreased survival (29% vs 77%, p<0.0001) at 3 years compared to testing negative. These results closely align with those previously reported using the AMP assay (Figure A). The IVS test has a superior limit of detection compared with the AMP test, allowing investigation of alternative VAF thresholds. In total, 151 patients (33.5%) were FLT3-ITD MRD positive by IVS of which only 75 (17%) had VAF ≥0.01%. A threshold-free approach for the IVS test improved the ability to identify patients at risk of relapse, predicting 63% of relapses within 6 months of transplant compared to 43% with the 0.01% cutoff, but resulted in decreased specificity as 42% of all positive patients relapsed within 6 months vs. 57% with the 0.01% VAF cutoff. In multivariable analysis, IVS FLT3-ITD MRD status was associated with both relapse and overall survival (Figure B). Additionally, stratifying patients by their level of residual FLT3-ITD disease burden prior to alloHCT revealed a dose-dependent increase in risk for death (Figure B) and relapse. Any detectable level of residual FLT3-ITD over 0.001% VAF exhibited increased risk, with VAFs ≥0.01% being the highest. Conclusions: In this analysis of patients with AML from the Pre-MEASURE study, we show cross-assay evidence that the detection of residual FLT3-ITD variants in pre-transplant blood during CR1 is associated with significantly increased risk of relapse and death after alloHCT. The highly sensitive assay used in this study could identify ~2/3 of patients who relapsed within 6 months and demonstrated that a dose-dependent correlation between residual FLT3-ITD level and adverse clinical outcomes exists, with VAF ≥0.01% representing the highest risk. This evidence provides strong justification for NGS-based AML MRD clinical testing for persistent FLT3-ITD prior to alloHCT to identify patients at high risk of post-transplant relapse and death.

Risk Stratification Models Overestimate Progression Risk in Contemporary Patients with Smoldering Multiple Myeloma (SMM)

Introduction: SMM is an asymptomatic precursor of multiple myeloma (MM), affecting ~1 in 200 people aged >40 years. Historically, risk of progression from SMM to MM was 10% per year in the first 5 years. However, since then, the definition and characteristics of the SMM patient population have changed substantially. First, IMWG diagnostic criteria for MM in 2014 changed to include biomarker-only myeloma (SLiM), reclassifying asymptomatic patients previously considered SMM. Second, incorporation of advanced imaging (CT, PET/CT, MRI) identified bone disease with greater sensitivity. Hence, we hypothesized that in the contemporary era, the risk of progression from SMM to MM would be markedly lower than historically. Methods: We performed a retrospective cohort study of consecutive patients with SMM at Columbia University Irving Medical Center from 2014-2022 and observed without therapeutic intervention. Our primary objective was to measure cumulative incidence of progression to MM and to characterize progression events. We also calculated predicted 2-year risk of progression by different risk-stratification models (Mayo 20/2/20, PANGEA, IMWG SMM model) in our cohort. Results: 102 consecutive patients with SMM were included. Median year of diagnosis was 2019 (range, 2014-2022). Baseline clinical and demographic characteristics of the cohort are shown in Table 1. The three most common scenarios that led to SMM diagnosis were workup of anemia/cytopenias(s) (n=22; 21.8%), incidental protein gap or elevated immunoglobulin level (n=20; 19.8%), and renal dysfunction (n=16; 15.8%). The racial/ethnic makeup of our study cohort was 38% Hispanic/Latino, 38% Non-Hispanic White, 19% Black/African-American, and 5% Asian. Bone disease was ruled out by advanced imaging (whole body CT, PET/CT, WB-MRI, and/or MRI spine+ pelvis) in 81.2% of patients. The most common abnormality on FISH was hyperdiploidy (39.2%), followed by t(11;14) (22.1%), with ≥1 high-risk cytogenetic abnormality (HRCA) in 35% of patients. Median follow-up was 45 months (95% CI, 34-52). 22/102 patients (21.6%) progressed to symptomatic plasma cell dyscrasia: CRAB myeloma in 18, SLiM myeloma in 1, systemic AL amyloidosis in 3 patients. The cumulative incidence of progression to MM (CRAB/SLiM) at 1, 2, 3, and 4 years from SMM diagnosis was 3.1% (95% CI, 0.99-9.1), 7.7% (95% CI, 3.7-15.3), 13.9% (95% CI, 8.1-23.1), and 17.1% (95% CI, 10.3-27.1) respectively [Figure 1]. Notably, presence of HRCA by FISH had a dose-dependent increase in risk of progression, with the 2-year risk being 75% (95% CI, 24-97%) in patients with ≥2 HRCA vs 13.0% (95% CI, 5.9-26.3) in those with 0-1 HRCA respectively ( p=0.0049). Among 18 patients who progressed to CRAB myeloma, the myeloma-defining event/s (MDEs) were anemia in 11, anemia + bone disease in 4, and bone disease in 3 patients. Among patients with a bone disease MDE, 4/7 had >1 lytic lesions on imaging and 3 had vertebral compression fracture(s). No patient had renal insufficiency or hypercalcemia as MDE. The sole patient with SLiM had a serum free light chain ratio>100 as the only MDE. 13/102 patients (12.75%) died, with 4/13 deaths attributed to myeloma after disease progression. The predicted median 2-year risk of progression to MM with different risk-stratification models were as follows: PANGEA with Bone Marrow (BM): 5.75% (range, 1.2-42); PANGEA without BM: 4.6% (0.7-26.6); Mayo 20/2/20: 9.7% (9.7-47.4); IMWG SMM: 26% (3.8-73). Figure 2 shows Sankey diagram of predicted risk tertiles for patients at SMM diagnosis by different models. Notably, a substantial proportion of high-risk patients by 20/2/20, who are currently considered for therapeutic intervention, were re-assigned to intermediate risk (2-year risk of progression 8.1-20%) by PANGEA-BM. Conclusion: The risk of progression to MM among this cohort of contemporary patients with SMM is <5% per year for the 1 st 4 years, which is substantially lower than the historical rate of 10% per year. Morbid progression such as renal failure or fractures are very infrequent, with anemia being the most common MDE. Prospective studies testing active surveillance strategies are needed in contemporary SMM cohorts to determine the optimal approach to these patients and ensure balancing of potential risks and benefits of treatment.

Late Health Outcomes Among Survivors of Wilms Tumor Diagnosed Over Three Decades: A Report From the Childhood Cancer Survivor Study.

To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens. Cumulative incidence of late mortality (≥ 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of ≥ 4 chemotherapy agents. Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5; 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5; rate ratio [RR] compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0; 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5; 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4; 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity. With approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortality/morbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.

Use of Inhaled Corticosteroids and Risk of Acquiring Haemophilus influenzae in Patients with Chronic Obstructive Pulmonary Disease.

Background: Inhaled corticosteroids (ICS) are widely used in chronic obstructive pulmonary disease (COPD), despite the known risk of severe adverse effects including pulmonary infections. Research Question: Our study investigates the risk of acquiring a positive Haemophilus influenzae airway culture with use of ICS in outpatients with COPD. Study Design and Methods: We conducted an epidemiological cohort study using data from 1 January 2010 to 19 February 2018, including 21,218 outpatients with COPD in Denmark. ICS use 365 days prior to cohort entry was categorised into low, moderate, and high, based on cumulated ICS dose extracted from a national registry on reimbursed prescriptions. A Cox proportional hazards regression model was used to assess the future risk of acquiring H. Influenzae within 365 days from cohort entry, and sensitivity analyses were performed using propensity score matched models. Results: In total, 801 (3.8%) patients acquired H. Influenzae during follow-up. Use of ICS was associated with a dose-dependent increased risk of acquiring H. Influenzae with hazard ratio (HR) 1.2 (95% confidence interval (CI) 0.9–1.5, p value = 0.1) for low-dose ICS; HR 1.7 (95% CI 1.3–2.1, p value < 0.0001) for moderate dose; and HR 1.9 (95% CI 1.5–2.4, p value < 0.0001) for high-dose ICS compared to no ICS use. Results were confirmed in the propensity-matched model using the same categories. Conclusions: ICS use in outpatients with COPD was associated with a dose-dependent increase in risk of isolating H. Influenzae. This observation supports that high dose ICS should be used with caution.

Psoriasis and Cardiometabolic Diseases: The Impact of Inflammation on Vascular Health.

Psoriasis is a common chronic inflammatory condition associated with a higher risk of cardiovascular disease. Psoriasis confers a dose-dependent increase in risk for the metabolic syndrome and its components. The metabolic syndrome and its components have been associated with higher coronary atherosclerosis in psoriasis and cardiovascular events in the general population. In this review, we discuss the role of inflammation and psoriasis in cardiometabolic diseases with a focus on the metabolic syndrome and its components. We highlight the relationship between psoriasis and important cardiovascular risk factors encompassed by obesity, dyslipidemia, insulin resistance and hypertension. Furthermore, we briefly highlight literature on anti-inflammatory therapies and their impact on the components of the metabolic syndrome as well as directly quantified coronary atherosclerosis burden.

The familial risk of infection-related hospitalization in children: A population-based sibling study.

To assess the risk of severe childhood infections within families, we conducted a sibling analysis in a population-based cohort study with genealogical linkage. We investigated the sibling risk of hospitalization with common infections, a marker of severity. We hypothesized that having siblings hospitalized for infection would increase the proband's risk of admission with infection. We used population data on Western Australian live-born singletons and their siblings between 1980 and 2014. Measures of infection were infection-related hospitalizations from discharge diagnostic codes. Exposure was having a sibling who had an infection-related hospitalization. Outcomes were infection-related hospitalizations in the child/proband. Probands were followed until an infection-related hospitalization admission (up to the first three), death, 18th birthday, or end of 2014, whichever occurred first. Infection risks were estimated by adjusted Cox proportional hazard models for multiple events. Of 512,279 probands, 142,915 (27.9%) had infection-related hospitalizations; 133,322 (26.0%) had a sibling with a previous infection-related hospitalization (i.e. exposed). Median interval between sibling and proband infection-related hospitalizations was 1.4 years (inter-quartile range 0.5-3.7). Probands had a dose-dependent increase in risk if sibling/s had 1, 2, or 3+ infection-related hospitalizations (adjusted hazard ratio, aHR 1.41, 95% CI 1.39-1.43; aHR 1.65, 1.61-1.69; aHR 1.83, 1.77-1.90, respectively). Among siblings with the same clinical infection type, highest sibling risks were for genitourinary (aHR 2.06, 1.68-2.53), gastrointestinal (aHR 2.07, 1.94-2.19), and skin/soft tissue infections (aHR 2.34, 2.15-2.54). Overall risk of infection-related hospitalization was higher in children with more siblings and with older siblings. In this population-based study, we observed an increased risk of infection-related hospitalization in children whose siblings were previously hospitalized for infection. Public health interventions may be particularly relevant in families of children hospitalized with infection.

Diabetes, glycaemic control, and risk of COVID-19 hospitalisation: Population-based, prospective cohort study

ObjectiveWe aimed to examine the prospective association of diabetes and glycaemic control with COVID-19 hospitalisation in a large community-based cohort study. Methods and study designParticipants (N = 337,802, aged 56.4 ± 8.1 yr; 55.1% women) underwent biomedical assessments at baseline as part of the UK Biobank prospective cohort study. The outcome was cases of COVID-19 serious enough to warrant a hospital admission from 16-March-2020 to 26-April-2020. ResultsAt follow up, 649 cases COVID-19 were recorded. In multivariable adjusted analyses, risk of COVID-19 was elevated in people with undiagnosed diabetes at baseline (A1C ≥ 6.5%) (risk ratio = 2.68; 95% confidence interval: 1.66, 4.33) and poorly controlled (A1C ≥ 8.6%) diagnosed diabetes (1.91;1.04, 3.52). There was a dose-dependent increase in risk of COVID-19 with increasing A1C, that persisted in multivariable adjusted models (per SD [0.9%]: 1.07; 1.03, 1.11; p[trend] < 0.001). ConclusionIn this large community-based sample, higher levels of A1C within the normal range were a risk factor for COVID-19. Glucose regulation may play a key role in immune responses to this infection. Undiagnosed cases of diabetes in the general community may present a particularly high risk.

Increased risk of new persistent opioid use in pediatric and young adult patients with kidney stones.

Adolescents and young adults are a vulnerable patient population for development of substance use disorder. However, the long-term impact of opioid prescribing in young adult patients with renal colic is not known. Our objective was to describe rates of opioid prescription and identify risk factors for persistent opioid use in patients age 25 years or younger with renal colic from kidney stones. Using previously validated, linked administrative databases, we performed a population-based, retrospective cohort study of opioid-naive patients age 25 years or younger with renal colic between July 1, 2013 and September 30, 2017 in Ontario. All family practitioner, urgent care, and specialist visits in the province were captured. Our primary outcome was persistent opioid use, defined as filling a prescription for an opioid between 91 and 180 days after initial visit. Ontario uses a narcotic monitoring system, which captures all opioids dispensed in the province. Of the 6962 patients identified, 56% were prescribed an opioid at presentation and 34% of those were dispensed more than 200 oral morphine equivalents. There was persistent opioid use in 313 (8.1%) patients who filled an initial opioid prescription. In adjusted analysis, those prescribed an opioid initially had a significantly higher risk of persistent opioid use (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.50-2.29) and opioid overdose (OR 3.45; 1.08-11.04). There was a dose-dependent increase in risk of persistent opioid use with escalating initial opioid dose. History of mental illness (OR 1.32; 1.02-1.71) and need for surgery (OR 1.71; 1.24-2.34) were also associated with persistent opioid use. Among patients with kidney stones age 25 years or younger, filling an opioid prescription after presentation is associated with an increased risk of persistent opioid use 3-6 months later and a higher risk of serious long-term complications, such as opioid overdose.

Lifestyle risk factors, inflammatory mechanisms, and COVID-19 hospitalization: A community-based cohort study of 387,109 adults in UK

We conducted the first large-scale general population study on lifestyle risk factors (smoking, physical inactivity, obesity, and excessive alcohol intake) for COVID-19 using prospective cohort data with national registry linkage to hospitalisation. Participants were 387,109 men and women (56.4 ± 8.8 yr; 55.1% women) residing in England from UK Biobank study. Physical activity, smoking, and alcohol intake, were assessed by questionnaire at baseline (2006–2010). Body mass index, from measured height and weight, was used as an indicator of overall obesity. Outcome was cases of COVID-19 serious enough to warrant a hospital admission from 16-March-2020 to 26-April-2020. There were 760 COVID-19 cases. After adjustment for age, sex and mutually for each lifestyle factor, physical inactivity (Relative risk, 1.32, 95% confidence interval, 1.10, 1.58), smoking (1.42;1.12, 1.79) and obesity (2.05 ;1.68, 2.49) but not heavy alcohol consumption (1.12; 0.93, 1.35) were all related to COVID-19. We also found a dose-dependent increase in risk of COVID-19 with less favourable lifestyle scores, such that participants in the most adverse category had 4-fold higher risk (4.41; 2.52–7.71) compared to people with the most optimal lifestyle. C-reactive protein levels were associated with elevated risk of COVID-19 in a dose-dependent manner, and partly (10–16%) explained associations between adverse lifestyle and COVID-19. Based on UK risk factor prevalence estimates, unhealthy behaviours in combination accounted for up to 51% of the population attributable fraction of severe COVID-19. Our findings suggest that an unhealthy lifestyle synonymous with an elevated risk of non-communicable disease is also a risk factor for COVID-19 hospital admission, which might be partly explained by low grade inflammation. Adopting simple lifestyle changes could lower the risk of severe infection.

Use of Proton Pump Inhibitors Increases Risk of Incident Kidney Stones

Proton pump inhibitors (PPIs) are widely prescribed and have effects on gut ion absorption and urinary ion concentrations. PPIs might therefore protect against or contribute to development of kidney stones. We investigated the association between PPI use and kidney stones. We performed a retrospective study using data from the Women's Veteran's Cohort Study, which comprised men and women, from October 1, 1999 through September 30, 2017. We collected data from 465,891 patients on PPI usage over time, demographics, laboratory results, comorbidities, and medication usage. Time-varying Cox proportional hazards and propensity matching analyses determined risk of PPI use and incident development of kidney stones. Use of histamine-2 receptor antagonists (H2RAs) was measured and levothyroxine use was a negative control exposure. PPI use was associated with kidney stones in the unadjusted analysis, with PPI use as a time-varying variable (hazard ratio [HR], 1.74; 95% CI, 1.67-1.82), and persisted in the adjusted analysis (HR, 1.46; CI, 1.38-1.55). The association was maintained in a propensity score-matched subset of PPI users and nonusers (adjusted HR, 1.25; CI 1.19-1.33). Increased dosage of PPI was associated with increased risk of kidney stones (HR, 1.11; CI, 1.09-1.14 for each increase in 30 defined daily doses over a 3-month period). H2RAs were also associated with increased risk (adjusted HR, 1.47; CI 1.31-1.64). We found no association, in adjusted analysis, of levothyroxine use with kidney stones (adjusted HR, 1.06; CI 0.94-1.21). In a large cohort study of veterans, we found PPI use to be associated with a dose-dependent increase in risk of kidney stones. H2RA use also has an association with risk of kidney stones, so acid suppression might be an involved mechanism. The effect is small and should not change prescribing for most patients.

The burden of adverse obstetric and perinatal outcomes from maternal smoking in an Australian cohort.

Maternal smoking is associated with a number of adverse outcomes with a dose-dependent increase in risk. The aim of this study was to evaluate the obstetric and perinatal outcomes in women who smoked during pregnancy. This was a retrospective cohort study of women who smoked during pregnancy and birthed at a major perinatal centre in Australia between January 2000 and April 2017. The study cohort was compared to a cohort of women who did not smoke in pregnancy. Smoking status was ascertained on history and included all types of smoking. Demographic characteristics and obstetric, intrapartum and perinatal outcomes were compared between the two groups. The study cohort included 20477 (14.6%) women who smoked during pregnancy and 119396 controls. Women who smoked tended to be younger, of higher body mass index (BMI), Caucasian and Indigenous ethnicity. Smokers were less likely to be nulliparous, but more likely to be hypertensive and have a lower socioeconomic status compared to non-smokers. Women who smoked were more likely to have a caesarean section for non-reassuring fetal status (adjusted odds ratio (aOR) 1.16, 95%CI 1.07-1.26, P<0.001). The infants of women who smoked were more likely to be born preterm, have a lower median birth weight and birth weights <10th (aOR 1.76, 95%CI 1.66-1.86, P<0.001) and <5th centile (aOR 2.00, 95%CI 1.86-2.16, P<0.001). Neonatal outcomes in the smoking cohort were worse with an increase in neonatal intensive care unit admission (aOR 1.34, 95%CI 1.27-1.43, P<0.001), severe acidosis (aOR 1.41, 95%CI 1.27-1.43, P<0.001) and a composite of severe neonatal outcomes (18.0% vs 12.0%, aOR 1.35, 95%CI 1.28-1.43, P<0.001). Women who smoke in pregnancy have worse obstetric and perinatal outcomes compared to controls and should be managed as high risk.

Dose⁻Response Relationships between Second-Hand Smoke Exposure and Depressive Symptoms among Adolescents in Guangzhou, China.

There has been little focus on the possible association between second-hand smoke (SHS) exposure and depressive symptoms among adolescents. Thus, this study aimed to explore the dose–response relationships between SHS exposure and depressive symptoms among adolescents and differentiate these associations in setting-specific exposure and severity-specific outcomes. A cross-sectional study was conducted using a stratified cluster sampling method to obtain a representative sample of high school students in Guangzhou, China. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale. Univariable and multivariable logistic regression models were used to explore the potential associations between SHS exposure and depressive symptoms. Among 3575 nonsmoking students, 29.6% were classified as having probable depressive symptoms and 9.6% had severe depressive symptoms. There were monotonically increasing dose–response relationships between setting-specific (public places, homes, or indoor/outdoor campuses) SHS exposure and severity-specific (probable or severe) depressive symptoms. When examining these relations by source of exposure, we also observed similar dose–response relationships for SHS exposure in campuses from smoking teachers and from smoking classmates. Our findings suggest that regular SHS exposure is associated with a significant, dose-dependent increase in risk of depressive symptoms among adolescents, and highlight the need for smoke-free environments to protect the health of adolescents.

Frequency–risk relationships between second-hand smoke exposure and respiratory symptoms among adolescents: a cross-sectional study in South China

ObjectivesAlthough previous studies have suggested an association between second-hand smoke (SHS) exposure and respiratory symptoms, current evidence is inconsistent. Additionally, it remains unclear whether there are frequency–risk relationships between SHS...

Markers for Increased Thrombotic Risk within the Complete Blood Count

IntroductionThe complete blood count is one of the most frequently ordered patient blood test. It provides the most basic hematological measurements including hematocrit (Hct), white blood cell count (WBC), and platelet count (PLT). An increase in some of these markers have been shown to be associated an increased thrombotic risk. Most notablyHctfor patients with polycythemiaveraand WBC and PLT in cancer patients. Some population studies have shown an increased propensity of thrombosis among healthy individuals with elevatedHct. However these studies have not included sufficient clinical data to account for potential confounders. The aim of this study is to assess whether elevation of these hematological markers are risk factors for thrombosis in the general population.MethodsComplete blood count and baseline characteristics were obtained from participants in the Reykjavik-AGES study at enrollment in 2002. The Reykjavik-AGES study, a nationwide screening study of 5755 elderly individuals, includes thorough medical history, physical examination, and blood measurements. Lifetime incidents of thrombotic events were recorded up to 2015 in the Icelandic National Health Service and cross-linked to the participants of the study through the National Registry of the total Population. Primary outcomes of arterial and venous thrombosis were considered separately 10 years before and after enrollment. Hct, WBC, and PLT were used to determine exposure and stratified into five quintiles in four respective analyses. The second quintile was used as a reference group. Cox proportional hazard regression was used to determine hazard ratios and confidence intervals. We then adjusted for age, gender, body mass index, diabetes mellitus, cigarette smoking (in pack years), hypertension and statin use. For arterial thrombosis we also adjusted for family history of arterial thrombosis and for venous thrombosis we censored at diagnosis of malignant neoplasm. In the analysis of WBC we also adjusted for C-reactive protein, an acute phase protein. Individuals with abnormal values of these parameters were excluded from the study (PLT < 150x109/L, WBC > 13x109/L or < 2.0,Hct < 35% were excluded)ResultsCrude analyses ofHctrevealed a dose dependent increased risk of arterial (hazard ratio (HR) 1.2, 95% confidence interval (CI) 1.08-1.33, p<0.001) and venous (HR 1.2, 95% CI 1.80-1.34, p=0.001) thrombosis with increasing values. However, after adjusting for confounders there was no association (Table). There was no association between higher levels of PLT and increased risk of thrombosis (Table). Analysis of WBC showed a dose dependent increase in risk for arterial thrombosis (HR 1.31, 95% CI 1.18-1.45, p<0.001) after adjusting for confounders. A similar but weaker effect was found for venous thrombosis (HR 1.16, 95% CI1.02-1.32, p=0.027).ConclusionIn this large population-based prospective cohort study including detailed clinical information on 5755 elderly individuals, we observed no association of elevatedHctor PLT with risk of arterial or venous thrombosis after adjusting for confounders. However, we found a clear increase in the thrombotic risk associated with higher WBC, especially for arterial thrombosis. We speculate this may be due to a higher baseline of leukocyte activation and a low-grade inflammatory state. These factors have been shown to play a part in thrombotic pathways. We therefore conclude WBC to be a marker for thrombotic risk within the general population. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Dose–response relations between second-hand smoke exposure and depressive symptoms among middle-aged women

A growing body of evidence indicates a strong association between smoking and depression. However, little is known about the possible effects of second-hand smoke (SHS) exposure on depression. This study aimed to examine the potential dose–response relation between SHS exposure and depressive symptoms among non-smoking middle-aged women. A cross-sectional survey was conducted using a stratified three-stage sampling method. Depressive symptoms were measured by the Center for Epidemiologic Studies Depression Scale with a cut-off point of 16. Self-reported SHS exposure was defined as non-smokers׳ inhalation of the smoke exhaled from smokers on at least one day a week. The multivariable logistic regression analysis was completed with adjustment for potential confounders. Among 1280 middle-aged women, 19.4% were classified as having depressive symptoms. There was a 104% increased odds of depressive symptoms corresponding to SHS exposure in general (OR=2.04, 95% CI 1.48–2.79) using no exposure as reference. There were significant positive relations between SHS exposure in general and depressive symptoms in a dose–response manner. These significant trends were observed consistently whether SHS exposure occurred in homes or workplaces. Our findings suggest that long-term and regular SHS exposure is associated with a significant, dose-dependent increase in risk of depressive symptoms.