Stepwise Increase In Risk Research Articles

Cardiovascular-kidney-metabolic overlap in heart failure with preserved ejection fraction: Cardiac structure and function, clinical outcomes, and response to sacubitril/valsartan in PARAGON-HF.

Cardiovascular-kidney-metabolic (CKM) multimorbidity is prevalent among individuals with heart failure (HF), but whether cardiac structure and function, clinical outcomes, and treatment response to sacubitril/valsartan vary in relation to CKM status is unknown. In this PARAGON-HF post-hoc analysis, we evaluated the impact of CKM multimorbidity (atherosclerotic cardiovascular [CV] disease, chronic kidney disease, and type 2 diabetes) on cardiac structure and function, clinical outcomes, and treatment effects of sacubitril/valsartan versus valsartan. The primary outcome was a composite of total HF hospitalizations and CV death. Secondary outcomes included the individual components of the primary outcome and a composite kidney outcome (sustained estimated glomerular filtration rate reduction of ≥50%, end-stage kidney disease, or kidney-related death). At baseline, 35.2% had one CKM condition, 33.3% had two, 15.9% had three, and only 15.6% had HF alone. CKM multimorbidity was associated with higher septal and posterior wall thickness, lower global longitudinal strain, higher E/e', and worse right ventricular function. Total HF hospitalizations or CV death increased with greater CKM multimorbidity, with the highest relative risk observed with three CKM conditions (rate ratio 3.06, 95% confidence interval 2.33-4.03), compared with HF alone. Treatment effects of sacubitril/valsartan were consistent irrespective of the number of CKM conditions for the primary endpoint (pinteraction = 0.75), CV death (pinteraction = 0.82), total HF hospitalizations (pinteraction = 0.67), and the composite kidney endpoint (pinteraction = 0.99). Cardiovascular-kidney-metabolic multimorbidity was common in PARAGON-HF and associated with adverse changes in cardiac structure and function and with a stepwise increase in risk of clinical outcomes. Treatment effects of sacubitril/valsartan were consistent irrespective of CKM burden. ClinicalTrials.gov NCT01920711.

Population-Based Intraoperative Disease Severity Criteria for Pediatric Appendicitis

A standardized severity assessment approach is needed in children with appendicitis for postoperative adverse event estimation and severity adjustment for hospital-level comparative performance reporting. To examine the association between the presence and number of National Surgical Quality Improvement Program (NSQIP) Pediatric-defined intraoperative criteria for complicated appendicitis and outcomes in a population-based sample of children. This cohort study used data from the American College of Surgeons NSQIP Pediatric Appendectomy Procedure Targeted Participant Use Data File and General Participant Use Data File for children younger than 18 years who underwent appendectomy from January 1, 2019, through December 31, 2022, at 148 hospitals participating in NSQIP Pediatric. The presence of NSQIP Pediatric intraoperative criteria for complicated appendicitis (ie, visible perforation, intraperitoneal abscess, extraluminal fecalith, and diffuse fibrinopurulent exudate). Adverse event outcomes included postoperative rates of any surgical site infection (incisional or organ space), percutaneous drainage, sepsis, and reoperation. Resource use outcomes included operative duration and hospital length of stay, and rates of postoperative imaging, parenteral nutrition use, and revisits. Multivariable regression was used to explore the influence of individual and combinations of intraoperative criteria on outcomes after adjusting for patient characteristics. Of 82 950 patients included, 23 221 (27.9%) had at least 1 finding of complicated appendicitis. Compared with cases without any criteria present, the presence of each finding of complicated appendicitis was independently associated with higher rates of any adverse events; adjusted odds ratios (AORs) by finding were 5.57 (95% CI, 5.04-6.15) for visible hole, 4.83 (95% CI, 4.17-5.59) for diffuse fibrinopurulent exudate, 7.06 (95% CI, 5.77-8.63) for abscess, and 6.62 (95% CI, 4.78-9.15) for fecalith. An increasing number of criteria was associated with a stepwise increase in risk of any adverse events; AOR by number of criteria met were 5.55 (95% CI, 5.09-6.05) for 1 criterion, 8.86 (95% CI, 8.16-9.62) for 2 criteria, and 16.65 (95% CI, 15.10-18.35) for ≥3 criteria. Similar patterns in criteria-specific and cumulative implications for outcomes were observed with each individual adverse event and resource use measure. This cohort study found that postoperative complications and increased resource use are associated with the presence and number of NSQIP Pediatric criteria for complicated appendicitis. These criteria should be considered the gold standard, evidence-based severity assessment framework for estimating risk of adverse events and resource use in children with appendicitis.

Lipoprotein(a) and Risks of Peripheral Artery Disease, Abdominal Aortic Aneurysm, and Major Adverse LimbEvents.

Lp(a) (lipoprotein[a])-lowering therapy to reduce cardiovascular disease is under investigation in phase 3 clinical trials. High Lp(a) may be implicated in peripheral artery disease (PAD), abdominal aortic aneurysms (AAAs), and major adverse limb events (MALE). The authors investigated the association of high Lp(a) levels and corresponding LPA genotypes with risk of PAD, AAA, and MALE. The authors included 108,146 individuals from the Copenhagen General Population Study. During follow-up, 2,450 developed PAD, and 1,251 AAAs. Risk of MALE was assessed in individuals with PAD at baseline and replicated in the Copenhagen City Heart Study. Higher Lp(a) was associated with a stepwise increase in risk of PAD and AAA (P for trend<0.001). For individuals with Lp(a) levels≥99th (≥143mg/dL, ≥307nmol/L) vs<50th percentile (≤9mg/dL,≤17nmol/L), multivariable-adjusted HRs were 2.99 (95%CI: 2.09-4.30) for PAD and 2.22 (95%CI: 1.21-4.07) for AAA. For individuals with PAD, the corresponding incidence rate ratio for MALE was 3.04 (95%CI: 1.55-5.98). Per 50mg/dL (105nmol/L) genetically higher Lp(a) risk ratios were 1.39 (95%CI: 1.24-1.56) for PAD and 1.21 (95%CI: 1.01-1.44) for AAA, consistent with observational risk ratios of 1.33 (95%CI: 1.24-1.43) and 1.27 (95%CI: 1.15-1.41), respectively. In women smokers aged 70 to 79 years with Lp(a)<50th and≥99th percentile, absolute 10-year risks of PAD were 8% and 21%, and equivalent risks in men 11% and 29%, respectively. For AAA, corresponding risks were 2% and 4% in women, and 5% and 12% in men. High Lp(a) levels increased risk of PAD, AAA, and MALE by 2- to 3-fold in the general population, opening opportunities for prevention given future Lp(a)-lowering therapies.

Risk of subarachnoid haemorrhage reduces with blood pressure values below hypertensive thresholds.

Hypertension is a known risk factor for subarachnoid haemorrhage (SAH). The aim of this study was to describe the relationship between blood pressure and SAH using a large cohort study and perform a meta-analysis of the published literature. Participants in the UK Biobank were followed up via electronic records until 31 March 2017. Cox proportional hazards models were used to analyse the association between baseline blood pressure (systolic blood pressure [SBP], diastolic blood pressure [DBP] and MABP [mean arterial blood pressure]) and subsequent aneurysmal SAH. Linearity was assessed by comparing models including and excluding cubic splines. Electronic databases were searched from inception until 11 February 2022 for studies reporting on blood pressure and SAH. A total of 500,598 individuals were included with 539 (0.001%) suffering from aneurysmal SAH. Nonlinear models including cubic splines visually appeared linear between SBP of 110 and 180 mmHg and there was minimal difference in fit between linear and nonlinear models. When values were stratified, those with SBP 120-130 mmHg were at higher risk compared to those with SBP <120 mmHg (hazard ratio [HR] 1.41 [1.02, 1.95]). The meta-analysis demonstrated a similar increased risk of SAH in individuals with SBP 120-130 mmHg relative to those with <120 mmHg (HR 1.41 [1.17, 1.72]). A stepwise increase in risk was also seen at each subsequent threshold (130-140 mmHg: HR 1.85 [1.53, 2.24], 140-160 mmHg: HR 2.16 [1.57, 2.98], 160-180 mmHg: HR 2.81 [1.85, 4.29], >180 mmHg: HR 5.84 [1.94, 17.54]). The rate of SAH increases linearly with higher SBP in the general population and specifically appears lower in those with SBP <120 mmHg.

The impact of COVID-19 on opioid toxicity deaths for people who experience incarceration compared to the general population in Ontario: A whole population data linkage study.

To inform preparedness and population health action, we need to understand the effects of COVID-19 on health inequities. In this study, we assess the impact of COVID-19 on opioid toxicity deaths among people who experience incarceration compared to others in the general population in Ontario, Canada. We conducted a retrospective cohort study for the period of January 1, 2015 to December 31, 2020. We accessed and linked coronial data on all opioid toxicity deaths in Ontario with correctional data for people aged 18 years and older who were incarcerated in a provincial correctional facility. We used data from the Statistics Canada Census to calculate whole population rates. We used an interrupted time series design and segmented regression to assess for change in the level or rate of increase in deaths due to opioid toxicity coinciding with the COVID-19 pandemic. We compared the impact of COVID-19 on the opioid toxicity death rates for people exposed and not exposed to incarceration. Rates of opioid toxicity death increased with a linear positive slope in both persons exposed to incarceration and those not exposed over the study period. The start of COVID-19 measures coincided with a marked upward shift in the trend lines with modification of the effect of COVID-19 by both sex and exposure to incarceration. For persons exposed to incarceration, the risk ratio (RR) was 1.50 (95%CI 1.35-1.69) for males and 1.21 (95%CI 1.06-1.42) for females, and for persons not exposed to incarceration, the RR was 1.25 (95%CI 1.13-1.38) for males and not significant for females. COVID-19 substantially exacerbated the risk of opioid toxicity death, impacting males and females who experienced incarceration more than those who had not, with an immediate stepwise increase in risk but no change in the rate of increase of risk over time. Public health work, including pandemic preparedness, should consider the specific needs and circumstances of people who experience incarceration.

Prognostic significance of echocardiographic abnormalities in patients with heart failure with preserved ejection fraction

Abstract Funding Acknowledgements Type of funding sources: None. Background Heart failure with preserved ejection fraction (HFpEF) is recognised as a highly heterogenous condition (1). This extends to its echocardiographic phenotype, which according to the latest ESC diagnostic criteria, can include the presence of left ventricular hypertrophy (LVH), left atrial (LA) enlargement and elevated pulmonary artery systolic pressure (PASP) amongst others (2). The relative prognostic significance of these abnormalities however has not been well-described. Purpose The aim of this study was to evaluate the relative prognostic significance of echocardiographic abnormalities in a community-based cohort of patients with HFpEF and elevated NT-proBNP. Methods We analysed the echocardiograms of patients referred from the community with clinical signs of HF and elevated NTproBNP. We specifically evaluated the presence of LVH, LA enlargement and elevated PASP according to EACVI criteria. We excluded patients with NT-proBNP &amp;lt;125 pg/ml. The primary outcome was time to all-cause mortality or cardiovascular hospitalisation. Results The total cohort included 473 patients (mean age 78 years, 66% female, median NT-proBNP 587 pg/ml). Median follow-up was 27 months. 88 individuals had an occurrence of the primary outcome (18.6%). LA enlargement was the commonest abnormality (48.2%), then LVH (37.2%) and elevated PASP (18.4%). After adjustment for age, sex and NTproBNP, LA enlargement was significantly associated with the primary outcome in patients in sinus rhythm but not atrial fibrillation (sinus: hazard ratio 2.02, 95% CI 1.09–3.73, p = 0.025; AF: hazard ratio 0.68, 95% CI 0.31–1.48, p = 0.20; interaction p value 0.013). Neither elevated PASP (HR 1.50, 95% CI 0.94–2.39, p = 0.09) or LVH (HR 0.99, 95% CI 0.64–1.55, p = 0.98) were independently associated with the primary outcome. There did however appear to be a stepwise increase in risk based on the number of echocardiographic abnormalities present, with individuals with 2 or more abnormalities being significantly more likely to have an incidence of the primary outcome than those with fewer (Figure). Conclusion There may be differences in prognosis of HFpEF patients based on echocardiographic structural and functional parameters. These may therefore require different therapeutic approaches. The number of abnormalities appear to have a cumulative adverse effect on prognosis.

Systolic Blood Pressure and Cardiovascular Risk in Normotensive Adults

ObjectiveTo examine the association of systolic blood pressure (SBP) and cardiovascular risk in normotensive adults. Patients and MethodsThis study analyzed data from 7 prospective cohorts between September 29, 1948, and December 31, 2018. Complete information on history of hypertension and baseline blood pressure measurements were required for inclusion. We excluded individuals younger than 18 years old, those with a history of hypertension, and patients with baseline SBP measurements of less than 90 mm Hg or 140 mm Hg or higher. Cox proportional hazards regression and restricted cubic spline models were used to evaluate the hazards of cardiovascular outcomes. ResultsA total of 31,033 participants were included. The mean ± SD age was 45.3±14.8 years, 16,693 of the participants (53.8%) were female, and the mean ± SD SBP was 115.8±11.7. Over a median follow-up of 23.5 years, 7005 cardiovascular events occurred. Compared with those who had SBP levels of 90 to 99 mm Hg, participants with SBP levels of 100 to 109, 110 to 119, 120 to 129, and 130 to 139 mm Hg experienced 23% (hazard ratio [HR], 1.23; 95% CI, 1.07 to 1.42), 53% (HR, 1.53; 95% CI, 1.33 to 1.76), 87% (HR, 1.87; 95% CI, 1.62 to 2.16), and 117% (HR, 2.17; 95% CI, 1.87 to 2.52) increased risks of cardiovascular events, respectively. Compared with follow-up SBP of 90 to 99 mm Hg, the HRs for cardiovascular events were 1.25 (95% CI, 1.02 to 1.54), 1.93 (95% CI, 1.58 to 2.34), 2.55 (95% CI, 2.09 to 3.10), and 3.39 (95% CI, 2.78 to 4.14), respectively, for follow-up SBP levels of 100 to 109, 110 to 119, 120 to 129, and 130 to 139 mm Hg. ConclusionIn adults without hypertension, there is a stepwise increase in risk of cardiovascular events, with increasing SBP starting at levels as low as 90 mm Hg.

How a Family History of Allergic Diseases Influences Food Allergy in Children: The Japan Environment and Children's Study.

The influence of family allergic history on food allergy in offspring in Japan is unknown. We analyzed data from a nationwide birth cohort study using logistic regression models to examine the associations of maternal, paternal, and both parental histories of allergic diseases (food allergy, atopic dermatitis, asthma, and rhinitis) with their child’s food allergy at 1.5 and 3 years of age. This analysis included 69,379 singleton full-term mothers and 37,179 fathers and their children. All parental histories of allergic diseases showed significant positive associations with their child’s food allergy. When both parents had a history of allergic diseases, the adjusted odds ratio (aOR) tended to be higher than when either parent had allergic diseases (p for trend < 0.0001). The highest aOR was detected when both parents had food allergy (2.60; 95% confidential interval, 1.58–4.27), and the aOR was 1.71 when either parent had food allergy (95% confidential interval, 1.54–1.91). The aORs were attenuated but still had significant positive associations after adjusting for the child’s atopic dermatitis, a risk factor for allergy development. In conclusion, all parental allergic diseases were significantly positively associated with their child’s food allergy. The effect of family history showed a stepwise increase in risk from either parent to both parents, and the highest risk of allergic disease was a parental history of food allergy.

Blood Pressure Classification Using the 2017 ACC/AHA Guideline and Heart Failure in Patients With Cancer.

Despite the growing recognition of the importance of hypertension in patients with cancer, little is known about whether high blood pressure (BP) among patients with cancer is associated with incident heart failure (HF) and other cardiovascular disease (CVD) events and what BP levels are linked to these events. We examined the association of BP classification on the basis of the 2017 American College of Cardiology/American Heart Association BP guideline with the risk of HF and CVD events in patients with cancer. We studied 33,991 patients with a history of breast, colorectal, or stomach cancer (median age, 53 years; 34.1% men). Patients receiving treatment with BP-lowering medications or having a history of CVD including HF were excluded. Using BP measurements at baseline, 33,991 participants were categorized as having normal BP (n = 17,444), elevated BP (n = 4,733), stage 1 hypertension (n = 7,502), or stage 2 hypertension (n = 4,312). The primary outcome was HF. Over a mean follow-up of 2.6 ± 2.2 years, 779 HF events were recorded. After multivariable adjustment, the hazard ratios (HRs) for HF were 1.15 (95% CI, 0.93 to 1.44) for elevated BP, 1.24 (95% CI, 1.03 to 1.49) for stage 1 hypertension, and 1.99 (95% CI, 1.63 to 2.43) for stage 2 hypertension. A stepwise increase in risk with BP categories was also observed in other CVD events. This association was observed even in patients undergoing active cancer treatment. The relationship between hypertension and the risk of developing HF in patients with cancer was confirmed in the Korean National Health Insurance Service database. Medication-naïve stage 1 and 2 hypertension was associated with a greater risk of HF and other CVD events in patients with cancer. Our results suggest the importance of multidisciplinary collaboration (eg, oncologists and cardiologists) to establish the optimal management strategy for hypertension in patients with cancer.

Incidence and Predictors of Early Death in Patients Undergoing Percutaneous LeftAtrial Appendage Closure.

Left atrial appendage closure (LAAC) aims to prevent ischemic events in patients with atrial fibrillation. As a preventive procedure, early death after LAAC could render the procedure futile. The authors sought to evaluate the incidence and factors associated with early death in LAAC recipients. This was a multicenter study including consecutive patients undergoing LAAC in a 10-year period (2009-2019). Death was considered early when occurring in the first year after LAAC. A total of 807 patients (mean age 76 ± 8 years, mean CHA₂DS₂-VASc score 4.5 ± 1.5) were included. Early death occurred in 125 patients (15.5%). In the multivariable analysis, factors associated with early death after LAAC were older age HR: 1.03; 95%CI: 1.01-1.06 per year; P=0.01), lower body mass index (HR: 0.92; 95%CI: 0.88-0.97 per 1kg/m² increase; P&lt; 0.001), diabetes (HR: 1.71; 95%CI: 1.19-2.47; P=0.002), prior heart failure (HR:1.74; 95%CI: 1.20-2.53; P=0.001), and lower estimated glomerular filtration rate (HR: 1.09; 95%CI: 1.05-1.13 per 5mL/min/1.73m² decrease; P&lt; 0.001). There was a stepwise increase in risk of early death within the first year of LAAC with the combination of different risk factors (up to 48.9% in the presence of &gt;3 risk factors). In this multicenter international registry, close to 1 in 6 patients died within the first year of LAAC. Older age, low body mass index, impaired estimated glomerular filtration rate, prior diabetes, and prior heart failure are independently associated with an increased risk. The risk of early death appeared to be prohibitive (∼50%) in the presence of &gt;3 of these risk factors.

Impact of malnutrition on outcomes following groin hernia repair: Insights from the ACS NSQIP

BackgroundThe present study examined the association of nutrition status, as defined by preoperative serum albumin, with postoperative outcomes and resource use after groin hernia repair. MethodsThe 2006 to 2019 American College of Surgeons National Surgical Quality Improvement Program database was queried for adults (≥18 years) undergoing open or laparoscopic repair of inguinal or femoral hernia. Patients were stratified based on the following preoperative serum albumin levels: <2.5 g/dL (severe hypoalbuminemia), 2.5 to <3.0 (moderate hypoalbuminemia), 3.0 to <3.5 (mild), and ≥3.5 (normal albumin). Multivariable regression models were developed to assess the association of hypoalbuminemia with outcomes of interest, including 30-day mortality, postoperative complications, length of stay, and 30-day readmission. ResultsOf the 261,052 patients meeting inclusion criteria, 0.3% had severe, 1.1% had moderate, and 7.4% had mild hypoalbuminemia, with 91.2% classified as normal albumin. After risk adjustment, mortality risk was greater for severe (5.8%, 95% confidence interval: 4.1–7.6), moderate (4.4%, 95% confidence interval: 3.4–5.3), and mild hypoalbuminemia (1.5%, 95% confidence interval: 1.2-1.8) relative to normal albumin (0.3%, 95% confidence interval: 0.2–0.3). Decreasing serum albumin levels were associated with a stepwise increase in risk of complications, length of stay, and 30-day readmission. ConclusionDecreased preoperative serum albumin is associated with increased mortality and morbidity after open and laparoscopic groin hernia repair. Serum albumin remains a relevant predictor of postsurgical outcomes and can thus be used in shared decision-making and optimization of malnourished patients in need of groin hernia repair.

Poster 114: Lower Extremity Injury Following Return to Sport from Concussion: A Systematic Review

Objectives:To examine the current body of research and determine whether there is an increased risk for LE musculoskeletal injury following a concussion and identify populations at an increased risk.Methods:A systematic review of the literature from January 1, 2000 to September 30, 2020 was performed using MEDLINE and PubMed databases. Key words included concussion, athlete, lower extremity injury, and return to sport. Inclusion criteria required original research articles written in English language examining the rate of LE injuries following a diagnosed concussion. Data extracted from each study included number of subjects, age, sex, sport played, level of play, odds ratio (OR) of injury, and number of concussions per athlete.Results:A total of 13 studies involving 4,349 athletes (88.1% male; mean age 19.8 years) met inclusion criteria. Athletes were classified as either high school (46.1%), collegiate (17.0%), or professional (36.9%). Four studies demonstrated an increased risk of LE injury within 90 days of a diagnosed concussion (OR 3.44, 95% CI 2.99-4.42) and 7 studies revealed an elevated risk of injury within one year of concussion (OR 1.85, 95% CI 1.73-2.84). Professional and college athletes demonstrated an increased risk (OR 2.49, 95% CI 2.40-2.72; OR 2.00, 95% CI 1.96-2.16, respectively) compared to high school athletes (OR 0.97, 95% CI 0.89-1.05). A stepwise increase in risk of sustaining a LE injury was observed with multiple concussions, with increasing risk observed from 2+ (OR 2.29, 95% CI 1.85-2.83) to 3+ career concussions (OR 2.86, 95% CI 2.36-3.48).Conclusions:An increased incidence of LE injuries was observed at 90-days and one year following the diagnosis of a concussion. Higher levels of competition, such as at the collegiate and professional level, resulted in an increased risk of sustaining a subsequent LE injury following a diagnosed concussion. These results suggest an at-risk population which may benefit from injury prevention methods following a concussion.Table 1.Study CharacteristicsTable 2.Odds ratio of suffering lower extremity injury within 90 days from a concussionTable 3.Odds ratio of suffering lower extremity injury within one year of concussionTable 5.Comparing lower extremity injury risk following concussion by level of competition

Validation of the prostate cancer comorbidity index in predicting cause-specific mortality in men undergoing radical prostatectomy.

Accurate prediction of competing risks of mortality remains a key component of prostate cancer treatment decision-making. We sought to validate the Prostate Cancer Comorbidity Index (PCCI) score for predicting other-cause mortality (OCM) and cancer outcomes in men undergoing radical prostatectomy (RP). We sampled 4857 men with prostate cancer treated with RP in the VA from 2000-2018. Risks of OCM, 90-day all-cause mortality (ACM), prostate cancer-specific mortality, metastasis, and biochemical recurrence by PCCI score were assessed using Cox proportional hazards and logistic regression. We compared prediction of 90-day ACM between PCCI and the American Society of Anesthesiology (ASA) score, a validated predictor of short-term mortality. Over median follow-up of 6.7 years (IQR 3.7-10.3), there was a stepwise increase in risk of OCM with higher PCCI score, with hazards (95%CI) of 1.53 (1.14-2.04), 2.11 (1.55-2.88), 2.36 (1.68-3.31), 3.61 (2.61-4.98), and 4.99 (3.58-6.96) for PCCI 1-2, 3-4, 5-6, 7-9, and 10 + (vs. 0), respectively. Projected 10-year cumulative incidence of OCM was 8%, 12%, 16%, 19%, 26%, and 32% for scores of 0, 1-2, 3-4, 5-6, 7-9, and 10+ , respectively. Men with PCCI 7+ had greater odds of 90-day ACM (OR 3.48, 95%CI 1.26-9.63) while men with higher ASA did not. Higher PCCI score was associated with worse cancer outcomes, with the highest categories driving the associations. The PCCI is a robust measure of short- and long-term OCM after RP, validated for use in clinical care and health services research focusing on surgical patient populations.

Association of clonal hematopoiesis mutations with clinical outcomes: A systematic review and meta-analysis.

Clonal hematopoiesis (CH) mutations are common among individuals without known hematologic disease. CH mutations have been associated with numerous adverse clinical outcomes across many different studies. We systematically reviewed the available literature for clinical outcomes associated with CH mutations in patients without hematologic disease. We searched PubMed, EMBASE, and Scopus for eligible studies. Three investigators independently extracted the data, and each study was verified by a second author. Risk of bias was assessed using the Newcastle-Ottawa Scale. We identified 32 studies with 56 cohorts that examine the association between CH mutations and clinical outcomes. We conducted meta-analyses comparing outcomes among individuals with and without detectable CH mutations. We conducted meta-analyses for cardiovascular diseases (nine studies; HR = 1.61, 95% CI = 1.26–2.07, p = .0002), hematologic malignancies (seven studies; HR = 5.59, 95% CI = 3.31–9.45, p < .0001), therapy-related myeloid neoplasms (four studies; HR = 7.55, 95% CI = 4.3–13.57, p < .001), and death (nine studies; HR = 1.34, 95% CI = 1.2–1.5, p < .0001). The cardiovascular disease analysis was further stratified by variant allele fraction (VAF) and gene, which showed a statistically significant association only with a VAF of ≥ 10% (HR = 1.42, 95% CI = 1.24–1.62, p < .0001), as well as statistically significant associations for each gene examined with the largest magnitude of effect found for CH mutations in JAK2 (HR = 3.5, 95% CI = 1.84–6.68, p < .0001). Analysis of the association of CH mutations with hematologic malignancy demonstrated a numeric stepwise increase in risk with increasing VAF thresholds. This analysis strongly supports the association of CH mutations with a clinically meaningful increased risk of adverse clinical outcomes among individuals without hematologic disease, particularly with increasing VAF thresholds.

Lower Extremity Injury After Return to Sports From Concussion: A Systematic Review.

Background:Recent studies have suggested increased rates of lower extremity (LE) musculoskeletal injury after a diagnosed concussion, although significant heterogeneity exists.Purpose:To examine the current body of research and determine whether there is an increased risk for LE musculoskeletal injury after a concussion and to identify populations at an increased risk.Study Design:Systematic review; Level of evidence, 3.Methods:A systematic review of current literature using MEDLINE and PubMed databases was performed. Keywords included concussion, athlete, lower extremity injury, and return to sport. Inclusion criteria required original research articles written in the English language examining the rate of LE injuries after a diagnosed concussion.Results:A total of 13 studies involving 4349 athletes (88.1% male and 11.9% female; mean age, 19.8 years) met inclusion criteria. Athletes were classified as high school (46.1%), collegiate (17.0%), or professional (36.9%). Of the 13 studies, 4 demonstrated an increased risk of LE injury within 90 days of a diagnosed concussion (odds ratio [OR], 3.44; 95% CI, 2.99-4.42), and 6 revealed an elevated risk of injury within 1 year of concussion (OR, 1.85; 95% CI, 1.73-2.84). Increased risk was seen in professional (OR, 2.49; 95% CI, 2.40-2.72) and collegiate (OR, 2.00; 95% CI, 1.96-2.16) athletes compared with high school athletes (OR, 0.97; 95% CI, 0.89-1.05). A stepwise increase in risk of sustaining an LE injury was observed with multiple concussions, with increasing risk observed from ≥2 (OR, 2.29; 95% CI, 1.85-2.83) to ≥3 (OR, 2.86; 95% CI, 2.36-3.48) career concussions.Conclusion:An increased incidence of LE injuries was observed at 90 days and 1 year after the diagnosis of a concussion. Higher levels of competition, such as at the collegiate and professional levels, resulted in an increased risk of sustaining a subsequent LE injury after a diagnosed concussion. These results suggest an at-risk population who may benefit from injury prevention methods after a concussion. Future studies should focus on identifying which injuries are most common, during what time period athletes are most vulnerable, and methods to prevent injury after return to sports.

Joint Associations of Multiple Lifestyle Factors With Risk of Active Tuberculosis in the Population: The Singapore Chinese Health Study.

Little is known about the joint associations of multiple lifestyle risk factors including smoking, low body mass index, physical inactivity, alcohol consumption, and low diet quality with risk of active tuberculosis. We analyzed data from the Singapore Chinese Health Study, a prospective cohort study of 63257 Chinese adults aged 45-74 years enrolled between 1993 and 1998. Incident cases of active tuberculosis were identified via linkage with the National TB Registry through 31 December 2016. Cox proportional hazards regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) of tuberculosis risk in relation to the combined scores of lifestyle risk factors. Compared with participants with none of the risk factors, the adjusted HRs (95% CI) of active tuberculosis for participants with 1, 2, 3, 4, and 5 risk factors were 1.24 (1.02-1.51), 1.84 (1.51-2.23), 2.52 (2.03-3.14), 4.07 (3.07-5.41), and 9.04 (5.44-15.02), respectively (Ptrend<.0001). The HR for those with 5 factors was ~1.5 times the product of individual risk estimates from the 5 factors on a multiplicative scale. The stepwise increase in risk of active tuberculosis with increasing number of lifestyle risk factors was significantly stronger in participants with diabetes than their counterparts without diabetes at recruitment (Pinteraction=.01). Multiple lifestyle risk factors were associated with risk of active tuberculosis in a synergistic manner. Our findings highlight the importance of public health programs and interventions targeting these factors simultaneously to reduce the tuberculosis burden among the general population.

P075 Urgency and its Association with Quality of Life and Clinical Outcomes in Ulcerative Colitis Patients.

Urgency, the immediate need to defecate, is common in ulcerative colitis (UC). The frequently used patient reported outcome (PRO)-2 for UC includes only rectal bleeding and stool frequency. We sought to investigate the association of urgency in UC patients with 1) quality of life (QoL) domains and 2) future UC hospitalizations, steroid prescriptions, and colectomy. We conducted a cross-sectional and then a subsequent longitudinal study within IBD Partners, a patient-powered research network. We described associations of levels of urgency in UC patients with PROMIS QoL domains (depression, anxiety, social satisfaction, fatigue, sleep, and pain). Next, a longitudinal cohort determined associations between baseline urgency and subsequent clinical outcomes including UC hospitalization, steroid prescription, or colectomy within 12 months. We used bivariate statistics and logistic regression models to describe independent associations. A total of 632 UC patients were included in the cross-sectional study. After adjusting for clinical variables, rectal bleeding, and stool frequency, "hurry", "immediately" and "incontinence" increased the odds of social impairment by 2.05 [1.24-3.4] (p = 0.005), 2.76 [1.1-6.74] (p = 0.028), and 7.7 [1.66-38.3] (p = 0.009) respectively compared to "no hurry". Urgency also significantly increased the odds of depression, anxiety, and fatigue. In the multivariate pooled logistic regression of the longitudinal cohort, Urgency was associated with a significant stepwise increase in risk of hospitalizations, steroids, and colectomy. "Hurry", "immediately" and "incontinence" increased the odds of colectomy within 12 months by 1.41 [1.15-1.72] (p < 0001), and 3.29 [2.13-5.09] (p < 0001). We demonstrate that urgency is a PRO independently associated with compromised QoL in patients with UC. Urgency is associated with future risk of hospitalizations, steroid prescription, and colectomy. Our findings support the consideration of urgency as a UC-specific PRO and its use as an outcome in clinical trials to capture QoL and risk of clinical decompensation.

Risk Stratification of Elderly Patients Undergoing Spinal Surgery Using the Modified Frailty Index.

Retrospective cohort. To validate the 11-item modified Frailty Index (mFI) as a perioperative risk stratification tool in elderly patients undergoing spine surgery. All consecutive cases of spine surgery in patients aged 65 years or older between July 2016 and June 2018 at a state-wide trauma center were retrospectively reviewed. The primary outcome was post-operative major complication rate (Clavien-Dindo Classification ≥ III). Secondary outcome measures included the rate of all complications, 6-month mortality and surgical site infection. A total of 348 cases were identified. The major complication rate was significantly lower in patients with an mFI of 0 compared to ≥ 0.45 (18.3% versus 42.5%, P = .049). As the mFI increased from 0 to ≥ 0.45 there was a stepwise increase in risk of major complications (P < .001). Additionally, 6-month mortality rate was considerably lower when the mFI was 0 rather than ≥ 0.27 (4.2% versus 20.4%, P = .007). Multivariate analysis demonstrated an mFI ≥ 0.27 was significantly associated with an increased incidence of major complication (OR 2.80, 95% CI 1.46-5.35, P = .002), all complication (OR 2.93, 95% CI 1.70-15.11, P < .001), 6-month mortality (OR 7.39, 95% CI 2.55-21.43, P < .001) and surgical site infection (OR 4.43, 95% CI 1.71-11.51, P = .002). The American Society of Anesthesiologists' (ASA) index did not share a stepwise relationship with any outcome. The mFI is significantly associated in a gradated fashion with increased morbidity and mortality. Patients with an mFI ≥ 0.27 are at greater risk of major complications, all-complications, 6-monthy mortality, and surgical site infection.

Development and validation of a disease risk stratification system for patients with haematological malignancies: a retrospective cohort study of the European Society for Blood and Marrow Transplantation registry

Diagnosis and remission status at the time of allogeneic haematopoietic stem-cell transplantation (HSCT) are the principal determinants of overall survival following transplantation. We sought to develop a contemporary disease-risk stratification system (DRSS) that accounts for heterogeneous transplantation indications. In this retrospective cohort study we included 55 histology and remission status combinations across haematological malignancies, including acute leukaemia, lymphoma, multiple myeloma, and myeloproliferative and myelodysplastic disorders. A total of 47 265 adult patients (aged ≥18 years) who received an allogeneic HSCT between Jan 1, 2012, and Dec 31, 2016, and were reported to the European Society for Blood and Marrow Transplantation registry were included. We divided EBMT patients into derivation (n=25 534), tuning (n=18 365), and geographical validation (n=3366) cohorts. Disease combinations were ranked in a multivariable Cox regression for overall survival in the derivation cohort, cutoff for risk groups were evaluated for the tuning cohort, and the selected system was tested on the geographical validation cohort. An independent single-centre US cohort of 660 patients transplanted between Jan 1, 2010, and Dec 31, 2015 was used to externally validate the results. The DRSS model stratified patients in the derivation cohort (median follow-up was 2·1 years [IQR 1·0-3·2]) into five risk groups with increasing mortality risk: low risk (reference group), intermediate-1 (hazard ratio for overall survival 1·26 [95% CI 1·17-1·36], p<0·0001), intermediate-2 (1·53 [1·42-1·66], p<0·0001), high (2·03 [1·86-2·22], p<0·0001), and very high (2·87 [2·63-3·13], p<0·0001). DRSS levels were also associated with a stepwise increase in risk across the tuning and geographical validation cohort. In the external validation cohort (median follow-up was 5·7 years [IQR 4·5-7·1]), the DRSS scheme separated patients into 4 risk groups associated with increasing risk of mortality: intermediate-2 risk (hazard ratio [HR] 1·34 [95% CI 1·04-1·74], p=0·025), high risk (HR 2·03 [95% CI 1·39-2·95], p=0·00023) and very-high risk (HR 2·26 [95% CI 1·62-3·15], p<0·0001) patients compared with the low risk and intermediate-1 risk group (reference group). Across all cohorts, between 64% and 65% of patients were categorised as having intermediate-risk disease by a previous prognostic system (ie, the disease-risk index [DRI]). The DRSS reclassified these intermediate-risk DRI patients, with 855 (6%) low risk, 7111 (51%) intermediate-1 risk, 5700 (41%) intermediate-2 risk, and 375 (3%) high risk or very high risk of 14 041 patients in a subanalysis combining the tuning and internal geographic validation cohorts. The DRI projected 2-year overall survival was 62·1% (95% CI 61·2-62·9) for these 14 041 patients, while the DRSS reclassified them into finer prognostic groups with overall survival ranging from 45·7% (37·4-54·0; very high risk patients) to 73·1% (70·1-76·2; low risk patients). The DRSS is a novel risk stratification tool including disease features related to histology, genetic profile, and treatment response. The model should serve as a benchmark for future studies. This system facilitates the interpretation and analysis of studies with heterogeneous cohorts, promoting trial-design with more inclusive populations. The Varda and Boaz Dotan Research Center for Hemato-Oncology Research, Tel Aviv University.

Body mass index and risk of obesity-related conditions in a cohort of 2.9 million people: Evidence from a UK primary care database.

ObjectiveObesity rates in the United Kingdom are some of the highest in Western Europe, with considerable clinical and societal impacts. Obesity is associated with type 2 diabetes (T2D), osteoarthritis, cardiovascular disease, and increased mortality; however, relatively few studies have examined the occurrence of multiple obesity‐related outcomes in the same patient population. This study was designed to examine the associations between body mass index (BMI) and a broad range of obesity‐related conditions in the same large cohort from a UK‐representative primary care database.MethodsDemographic data and diagnosis codes were extracted from the Clinical Practice Research Datalink GOLD database in January 2019. Adults registered for ≥ 3 years were grouped by BMI, with BMI 18.5–24.9 kg/m2 as reference group. Associations between BMI and 12 obesity‐related outcomes were estimated using Cox proportional hazard models, adjusted for age, sex, and smoking.ResultsMore than 2.9 million individuals were included in the analyses and were followed up for occurrence of relevant outcomes for a median of 11.4 years during the study period. Generally, there was a stepwise increase in risk of all outcomes with higher BMI. Individuals with BMI 40.0–45.0 kg/m2 were at particularly high risk of sleep apnea (hazard ratio [95% confidence interval] vs. reference group: 19.8 [18.9–20.8]), T2D (12.4 [12.1–12.7]), heart failure (3.46 [3.35–3.57]), and hypertension (3.21 [3.15–3.26]).ConclusionsThis study substantiates evidence linking higher BMI to higher risk of a range of serious health conditions, in a large, representative UK cohort. By focusing on obesity‐related conditions, this demonstrates the wider clinical impact and the healthcare burden of obesity, and highlights the vital importance of management, treatment approaches, and public health programs to mitigate the impact of this disease.