Risk Strata Research Articles

Therapies for Preventing Bone Loss with Glucocorticoid Treatment.

We aim to critically review recent recommendations regarding preventative strategies for glucocorticoid-induced osteoporosis and provide a summary of key evidence regarding available interventions. Lifestyle optimization remains the hallmark of bone health preservation. Early initiation of anti-osteoporotic agents in the setting of glucocorticoid exposure is essential, guided by appropriate risk stratification. Recommendations for calcium and vitamin D intake optimization are well-supported across all risk strata. Bisphosphonates are the mainstay of pharmacological therapy. Newer agents such as denosumab and teriparatide have demonstrated comparative benefit in terms of incident fracture risk reduction and bone mineral density preservation, with comparable adverse events. With due consideration to cost, resource availability, and patient values and preferences, these agents may warrant use as the first-line agents in this setting. Glucocorticoid-induced osteoporosis remains preventable and warrants early and targeted evidence-based therapy.

Development of a Prognostic Scoring System To Select Candidates for Irradiation Stent Implantation for Patients with Unresectable Biliary Tract Cancer

Background: Compared with conventional metal stent, irradiation stent can prolong the stent patency and the survival time of patients. We aimed to develop a predictive model to select appropriate candidates for irradiation stent implantation among patients with biliary obstruction caused by unresectable biliary tract cancer (BTC). Methods: The training cohort consisted of 130 patients from three centers, and an external independent center was allocated as the validation cohort with 43 patients. We constructed a prognostic nomogram and risk classification system to select appropriate patients with unresectable BTC for irradiation stent implantation. Findings: The C-index of the nomogram was 0·724 and 0·736 in the training cohort and validation cohort, respectively. The calibration curves showed good consistency of survival between the actual observation and nomogram prediction in both cohorts. A risk classification system was built to stratify patients into three risk strata. In the training cohort, the median survival of patients in the low-, intermediate-, and high-risk groups were 10·1 months (95% CI 9·1–11·1), 4·6 months (95% CI 3·6–5·6), and 1·5 months (95% CI 0·1–3·0), respectively. Interpretation: According to this newly developed predictive model, irradiation stents are highly recommended for patients in the low-risk group (score≤100) for long-term survival benefit but not recommended for those in the high-risk group (score≥166·5). Funding: This study was supported by the National Key Research and Development Project of China (2018YFA0704100), the National Natural Science Foundation of China (Major Scientific Research Instrument Development Program 81827805, 81441054, 81671796), Jiangsu Provincial Medical Youth Talent Program (ZDRCA2016078), the Key Research and Development Project of Jiangsu Province (BE2019750) and Innovation Platform of Jiangsu Provincial Medical Center (YXZXA2016005). Declaration of Interest: The authors have no conflicts of interest to declare. Ethical Approval: This multicenter retrospective study was approved by the institutional review boards at all participating centers. The requirement for written informed consent was waived due to the retrospective nature of the study.

Multimodality-Integrated Deep Survival Analysis of Hepatocellular Carcinoma After Transarterial Chemoembolization: A Two-Center Collaborative Study

Background & Aims: There is high heterogeneity in clinical outcome for patients with hepatocellular carcinoma (HCC) following transarterial chemoembolization (TACE) and the accurate survival prediction remains challenging. We aimed to develop and validate a deep survival approach for prognostic prediction in HCC with TACE. Methods: We built the survival models by integrating clinical variables, radiological identitifications, and an entire-volumetric radiomics signature in 200 training datasets using a series of survival analysis algorithms such as Cox extreme gradient boosting (Cox-XGBoost), Cox gradient boosting machine (Cox-GBM), deep Cox-Time, and stepwise Cox proportional hazard (Cox-PH) regression. Models were validated in two independent cohorts of 86 and 84 patients from two institutions, respectively. Concordance index (C-index) was used as the model performance metric. Results: A radiomics survival signature (Rad-S), constructed from 4,840 imaging features by Random survival forest and least absolute shrinkage and selection operator (LASSO) Cox analysis, demonstrated favorable prognostic performance with C-indexes of 0.610 to 0.663 in training and validation sets, respectively. Rad-S, modified Response Evaluation Criteria in Solid Tumors (mRECIST), and neutrophil to lymphocyte ratio (NLR) were selected as top variables. Among all survival analysis algorithms and existing prognostic systems, the Cox-GBM model achieved the best prediction performance, with C-indexes of 0.687 to 0.763 in training and validation cohort, respectively; it also gave two risk strata with significant different clinical outcome. Conclusions: The newly designed Rad-S can be a favorable prognostic predictor of HCC with TACE. The Cox-GBM model integrating multimodal data can enhance the prognostic prediction, thus help personalized clinical management. Funding: None to declare. Declaration of Interest: None to declare. Ethical Approval: Ethics committee approval was granted by the local institutional ethics review board (protocol 2018-SR-025), and the requirement of written informed consent was waived. All procedures involving human participants were performed in accordance with the 1975 Helsinki declaration and its later amendments.

Evaluation of the New American Urological Association Guidelines Risk Classification for Hematuria.

Microhematuria is a prevalent condition and the American Urological Association has developed a new risk-stratified approach for the evaluation of patients with microhematuria. Our objective was to provide the first evaluation of this important guideline. This multinational cohort study combines contemporary patients from 5 clinical trials and 2 prospective registries who underwent urological evaluation for hematuria. Patients were stratified into American Urological Association risk strata (low, intermediate or high risk) based on sex, age, degree of hematuria, and smoking history. The primary end point was the incidence of bladder cancer within each risk stratum. A total of 15,779 patients were included in the analysis. Overall, 727 patients (4.6%) were classified as low risk, 1,863 patients (11.8%) were classified as intermediate risk, and 13,189 patients (83.6%) were classified as high risk. The predominance of high risk patients was consistent across all cohorts. A total of 857 bladder cancers were diagnosed with a bladder cancer incidence of 5.4%. Bladder cancer was more prevalent in men, smokers, older patients and patients with gross hematuria. The cancer incidence for low, intermediate and high risk groups was 0.4% (3 patients), 1.0% (18 patients) and 6.3% (836 patients), respectively. The new risk stratification system separates hematuria patients into clinically meaningful categories with differing likelihoods of bladder cancer that would justify evaluating the low, intermediate and high risk groups with incremental intensity. Furthermore, it provides the relative incidence of bladder cancer in each risk group which should facilitate patient counseling regarding the risks and benefits of evaluation for bladder cancer.

Comparison of the effects of sibling and parental history of type 2 diabetes on metabolic syndrome

The aim of this study was to investigate the associations between sibling history, parental history and simultaneous sibling and parental history of diabetes, and the presence of the metabolic syndrome (MetS) and its components. Our study comprised 5000 participants from Taiwan Biobank until April, 2014. The participants were stratified into four groups according to sibling and/or parental family history (FH) of DM. MetS was defined as having 3 of the following 5 abnormalities based on the standard of the NCEP ATP III and modified criteria for Asians. The prevalence of MetS and its traits was estimated and compared among the four familial risk strata. Multivariate logistic regression analysis showed participants with sibling FH of DM [vs. no FH of DM; odds ratio (OR) 1.815; 95% confidence interval (CI) 1.293 to 2.548; p = 0.001], participants with parental FH of DM (vs. no FH of DM; OR 1.771; 95% CI 1.468 to 2.135; p < 0.001), and participants with simultaneous sibling and parental FH of DM (vs. no FH of DM; OR 2.961; 95% CI 2.108 to 4.161; p < 0.001) were significantly associated with MetS. A synergistic effect of sibling FH of DM and parental FH of DM on the association of MetS was also observed. In a nationally representative sample of Taiwan adults, a simultaneous sibling and parental history of diabetes shows a significant, independent association with MetS and its components, except for abdominal obesity. The association highlights the importance of obtaining stratified FH information in clinical practice and may help to identify individuals who should be targeted for screening and early prevention of MetS.

High-Risk Multiple Myeloma Patients Are Missed without Gene Expression Profiling

High-Risk Multiple Myeloma Patients Are Missed without Gene Expression Profiling

Clofarabine Significantly Increases Eradication of Minimal Residual Disease of B-Precursor ALL Compared to High-Dose Cytarabine in Randomized Trial Coall 08-09

Background Since the FDA approval of clofarabine for the treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) at childhood, several studies have been launched which put clofarabine under scrutiny in combination with other cytostatic drugs as second or third line therapy. As a novel treatment-strategy we introduced the combination of clofarabine with pegylated asparaginase (PEG-ASP) in a randomized fashion in comparison to the standard consolidation course with high dose cytarabine (Hidac) combined with PEG-ASP into the frontline management of ALL within the CoALL 08-09 protocol. The primary objective of the study was to compare the MRD based assessment of the cytotoxic efficacy of the randomized courses in pediatric ALL. Patients and methods CoALL 08-09 was an open, interventional, multi-center, prospective, and randomized clinical trial for patients with newly diagnosed ALL. In March 2010 the trial had been opened for enrollment of patients under 18 years with confirmed diagnosis of acute B- or T-cell precursor leukemia. After a stratified phase I/II, in which patients with high-risk features and high post-induction MRD received the combination of clofarabine and PEG-ASP, the randomized trial started in November 2013. All patients with a measurable MRD at the end of induction (EOI), as measured by RQ-PCR according to EURO-MRD guidelines, were eligible for randomization to receive either the combination of clofarabine 5 x 40 mg/m2 or high dose cytarabine (HIDAC) 4 x 3g/m2 bothin combination with PEG-ASP 2.500 IU/m2 at the beginning of the consolidation phase. Until December 2019 303 study patients were randomized allocating 151 patients towards the clofarabine and 152 patients to the HIDAC arm. Patient characteristics and MRD burden prior to this treatment element were highly comparable. Results The reduction of minimal residual disease was significantly more profound after clofarabine compared to cytarabine (p(Cochran-Armitage)=.01 for BCP-ALL with 93 vs 79 patients reaching MRD negativity (Table 1). MRD status of BCP-ALL after the first randomized consolidation block (day 50) was of prognostic relevance with a statistically significant impact on EFS and relapse rate (Fig. 2a). However, no difference in outcome regarding the event-free and overall survival between the randomized arms was observed (5-year EFS: Clofarabine 85.7, SE=4.1 vs Hidac 84.8, SE=4.7 (p=.96) and OS: 95.7, SE=1.9 vs 92.2, SE=3.2(p=.59) Fig. 2b). This finding was recapitulated independent of gender, age, WBC count at diagnosis, ETV6-RUNX 1 translocation, immunophenotype or overall risk strata). Results for T-ALL patients are in the same range but because of small numbers not statistically significant. No differences in the incidence of severe or persistent toxicity btween randomized treatment elements as well as in the subsequent treatment realization were registered. Conclusion Clofarabine combined with PEG-asparaginase is highly effective and well tolerated in the frontline treatment of ALL. Although the prognostic impact of MRD is still discernible in early consolidation, the greater cytotoxic efficacy of clofarabine reflected by a more frequent eradication of MRD, did not translate into an apparent improvement of outcome likely due to a lack of power in the comparative analysis of randomized patients. Disclosures No relevant conflicts of interest to declare.

Relationship between AF-risk, ischemic stroke AF related, and cognitive dysfunction in population older than 65 years-old. MIND-COR study

Abstract Background The number of individuals with atrial fibrillation (AF) and cognitive impairment (CI) will increase 150% by 2050. Purpose The main objective of this study is to elucidate the relationship between AF-risk, the ischemic stroke, and the cognitive dysfunction. Methods Multicenter, longitudinal and retrospective community-based study of cohort ≥65 year-old without AF between 1/1/2013–31/12/2017 conducted by 11 Primary Care teams. Variables: sociodemographic; Charlson, CHA2DS2VASc score, Pfeiffer and NIHSS scores from records database (primary care, specialty clinics and hospitalizations). Kaplan-Meier to evaluate mortality. Descriptive analysis Cox regression to create an AF risk score was developed: Q1 (lowest AF-risk)-Q4 (highest AF-risk). Incidence density (ID) rate per 1000/people/years of AF and stroke; and CI prevalence were calculated by risk stratum. Approved by Ethics Committee of IDIAP Jordi Gol PP15/047. Results 46706 (women 49%) cases, aged 78.01±11.9 and average follow-up time 4.9±0.7 years. Q4 risk group (Q4) was characterized by women's (85.2%), highest age, AF, stroke, CI and mortality. 1244 AF were diagnosed (ID 10.5/1000/year's IC95% 9.9–11.2). Q3–4 levels included 53.8% of AF in men vs 84.2% in women. 214 strokes were diagnosed and 78.5% happened in Q3–4, especially among women (88.1%). The stroke and AF were diagnosed simultaneously in 9.8% (ID 5.8/1000/year CI95% 3.4–8.1) and showed higher severity (NIHSS 7.25±8.62 vs 4.55±5.74, p=0.002). The cognitive impairment increased from 2.6% (Q1) up to 16.4% (Q4) significantly higher in women (17.6% vs 12.1%) Conclusions Differences were found according to gender and risk groups. The risk-based screening could improve the effectiveness of AF screening in primary care. Funding Acknowledgement Type of funding source: None

Additional role of echocardiogram in pulmonary arterial hypertension risk stratification according to current ESC/ERS guidelines

Abstract Background Current pulmonary hypertension (PH) guidelines stratify the risk of patients with pulmonary arterial hypertension (PAH) using a multiparametric approach. A simplified risk table has been recently proposed and validated without including echocardiographic parameters. Purpose We evaluate the additional role of echocardiogram in PAH risk stratification using the recently proposed simplified risk table in patients with idiopathic/heritable (I/H) PAH and PAH associated with connective tissue disease (CTD) and congenital heart disease (CHD). Methods All patients with I/H-PAH, CTD-PAH and CHD-PAH referred to a single centre were included from 2003 to 2017. All patients were treated according to PH guidelines. The simplified risk assessment considered the following criteria: WHO functional class, 6-min walking distance, right atrial (RA) pressure or brain natriuretic peptide (BNP) plasma levels and cardiac index (CI) or mixed venous oxygen saturation (SvO2). For the last 2 criteria the worst parameter was chosen. Risk strata were defined as: Low risk= at least 3 low risk and no high-risk criteria; High risk= at least 2 high risk criteria including CI or SvO2; Intermediate risk= definitions of low or high risk not fulfilled. Then we performed a Cox analysis to evaluate the independent echocardiographic predictors of survival that were subsequently added to the simplified risk table to test their additional role in ameliorating risk stratification. Results 461 treatment-naïve patients were enrolled. Echocardiographic independent predictors of prognosis were the severity of tricuspid regurgitation [HR (95% CI) = 1.013 (1.006–1.021); p-value = 0.001], right atrial area [HR (95% CI) = 1.028 (1.012–1.045); p-value = 0.001] and the presence of pericardial effusion [HR (95% CI) = 1.533 (1.142–2.057); p-value= 0.004]. Only RA area significantly ameliorate the risk stratification power of the recently validated simplified PAH risk table (likelihood ratio chi2 increased from 63.8 to 68.1, likelihood ratio test = 0.039). Due to the significant correlation between RA area and both RA pressure (r=0.470; p&amp;lt;0.001) and BNP (r=0.372; p=0.004), we elaborate a second risk table in which RA area (utilizing the cut-offs proposed by the current PH guidelines) was considered together within the criteria including RA pressure and BNP (the worst parameter of the 3 was considered). Considering the second risk table including RA area the risk stratification power significantly improved (likelihood ratio chi2 increased from 63.8 to 72.7, AIC/BIC decreased from 1956/1964 to 1947/1955). Conclusions Echocardiographic RA area significantly improve the risk discrimination power of the recently proposed simplified risk table for patients with PAH. Funding Acknowledgement Type of funding source: None

A Novel Prostate SBRT vs HDR Comparison: A Disease Perspective

To compare current SBRT and HDR prostate treatment regimens from a disease perspective using the latest published dose-response functions We developed and validated a comprehensive software platform enabling in-silico growth of realistic prostate tumor-like volumes of random shape and morphology within prostate. Published probabilities of disease occurrence in various prostate zonal anatomies, for various disease stages were taken into account when tumorlets were generated. The model used the patient-specific segmented anatomy and dose distributions delivered for 10 patients. 4500 tumorlets, ranging from 0.1 to 10 cm3 were generated. Each tumorlet was overlapped with the dose distribution and the corresponding radiobiological integral parameters (EUBED, gBEUD) were computed. Data from 25 international radiotherapy outcome datasets, stratified by risk and use of ADT, were used to generate dose-response curves, fractionation sensitivity and repopulation. These values then enabled our model to convert integral metrics parameters into a probability of cure (PoC). A large range of radiobiological parameters, α/b = [1.5, 7.7] Gy and α = [0.04, 0.3] Gy-1 were explored in comparing currently accepted regimens (e.g. 7.25Gy x 5 and 13.5Gy x 2). SBRT plans were created using both RTOG 0938 and NRG GU005 criteria. A version of the plan was escalated from 36.25 to 40Gy. The two methods of integrating radio-biological dose effect (EUBED and gBEUD) handle dose inhomogeneity differently. SBRT plans display less dose inhomogeneity and consequently both formalisms produce very similar results. For HDR plans, which have more dose heterogeneity, the two formalisms produce slightly different results but for both, the PoC tends to decrease with the increased disease volume. Similar SBRT and HDR outcomes were observed for a very low α/b (1.5) and only low and intermediate risk disease. For higher α/b values, for all the dose-response curves examined, predictions showed that HDR provided a 5-30% increase in PoC, increasing with increased α/b and risk strata. The NRG plans, requiring higher dose coverage (98% vs 95%), produce, for the same prescription dose, a 1-5% PoC increase. The NRG 40Gy plans restore some of the PoC, when compared to HDR, particularly at large tumor volumes. We are presenting a novel perspective in comparing two treatment modalities or regimens. Our results show that using prescription dose alone in a BED-style equivalence, particularly when accounting for large degrees of variability in planning styles and delivery, has a limited value. The method we are proposing, looking at probabilities of cure at disease level –tumorlets- rather than physical peripheral prescription dose at gland level, has the potential to create a true equivalence between established and time-tested treatments (HDR) and newer modalities (SBRT), while accounting for all existent planning style variability.

A prospective evaluation of the Flacker-Kiely One Year Mortality Score and the added value of NT-proBNP

Objective: Several mortality indices have been constructed to aid clinical decision making in older adults. We aimed to prospectively validate the Flacker-Kiely (FK) mortality index in a Norwegian nursing home cohort, which has not been done before, and explore whether NT-ProBNP could improve its discriminatory power.Methods: We performed a cohort/mortality study. From November 2017 to July 2018, physicians in all public long-term nursing homes in Bergen, Norway, scored residents according to the original Flacker Kiely index. Mortality data were derived from the Norwegian Cause of Death Registry and NT-ProBNP values were obtained from routinely collected blood chemistry. An alternative FK index using the NT-ProBNP-value as a marker for the presence of heart failure was constructed (FK NT-ProBNP index). The ProBNP cut-off value was selected based on a Cox regression model (“dead/alive 1 year”/” NT-ProBNP (Ng/l)”, where the value with the highest Youden index was identified. We judged index performance by using c-statistics.Results: Both the original FK index and the constructed FK NT-ProBNP index discriminated between risk strata. The FK NT-ProBNP index yielded a C-index of 0.66 compared to 0.62 for the original FK index. Optimal discriminatory power was shown with a NT-ProBNP cut-off value of 1,595 Ng/l as heart failure criterion, and FK NT-ProBNP score 6.6.Conclusions: The prospective mortality estimation ability of the FK-index was comparable to previous retrospective studies. The inclusion of NT-ProBNP as a heart failure criterion strengthen the discriminatory power and utility of the index, both in clinic and administration.

Impact of inhaled treprostinil on risk stratification with noninvasive parameters: a post hoc analysis of the TRIUMPH and BEAT studies.

The 2015 European Society of Cardiology/European Respiratory Society treatment guidelines recommend frequent risk assessment in pulmonary arterial hypertension utilizing risk variables. Our objectives were: (1) to investigate the impact of inhaled treprostinil on risk stratification using the French noninvasive approach and REVEAL 2.0, and (2) to analyze the prognostic utility of both risk stratification methods in the predominantly New York Heart Association/World Health Organization functional class III/IV cohorts of TRIUMPH and BEAT. A post hoc analysis was performed to assess risk at baseline and follow-up at Week 12 in the TRIUMPH cohort (n = 148) and at Week 16, 21, and 30 in the inhaled treprostinil naïve placebo BEAT cohort (n = 73). Overall survival, clinical worsening-free survival, and pulmonary arterial hypertension-related hospitalization-free survival were all assessed in the pooled TRIUMPH and inhaled treprostinil naïve placebo BEAT cohorts based on risk group/strata at Week 12/16 follow-up. Inhaled treprostinil improved REVEAL 2.0 risk stratum (OR: 2.38, 95% CI: 1.09–5.19, p = 0.0298) and REVEAL 2.0 score (p = 0.0008) compared to placebo in the TRIUMPH cohort at Week 12. REVEAL 2.0 risk stratum and the number of low-risk criteria by the French approach improved at Weeks 16, 21, and 30 in the inhaled treprostinil naïve placebo BEAT cohort. Combining cohorts, REVEAL 2.0 risk stratification at follow-up was prognostic for clinical worsening-free, pulmonary arterial hypertension hospitalization-free, and overall survival, whereas the number of low-risk criteria was not. These post-hoc pooled analyses suggest inhaled treprostinil improves risk status and indicates that the REVEAL 2.0 calculator may be more suitable than the French noninvasive method for evaluating short-term clinical change in the New York Heart Association/World Health Organization functional class III/IV population.

Genome-Wide Polygenic Score, Clinical Risk Factors, and Long-Term Trajectories of Coronary Artery Disease.

To determine the relationship of a genome-wide polygenic score for coronary artery disease (GPSCAD) with lifetime trajectories of CAD risk, directly compare its predictive capacity to traditional risk factors, and assess its interplay with the Pooled Cohort Equations (PCE) clinical risk estimator. Approach and Results: We studied GPSCAD in 28 556 middle-aged participants of the Malmö Diet and Cancer Study, of whom 4122 (14.4%) developed CAD over a median follow-up of 21.3 years. A pronounced gradient in lifetime risk of CAD was observed-16% for those in the lowest GPSCAD decile to 48% in the highest. We evaluated the discriminative capacity of the GPSCAD-as assessed by change in the C-statistic from a baseline model including age and sex-among 5685 individuals with PCE risk estimates available. The increment for the GPSCAD (+0.045, P<0.001) was higher than for any of 11 traditional risk factors (range +0.007 to +0.032). Minimal correlation was observed between GPSCAD and 10-year risk defined by the PCE (r=0.03), and addition of GPSCAD improved the C-statistic of the PCE model by 0.026. A significant gradient in lifetime risk was observed for the GPSCAD, even among individuals within a given PCE clinical risk stratum. We replicated key findings-noting strikingly consistent results-in 325 003 participants of the UK Biobank. GPSCAD-a risk estimator available from birth-stratifies individuals into varying trajectories of clinical risk for CAD. Implementation of GPSCAD may enable identification of high-risk individuals early in life, decades in advance of manifest risk factors or disease.

Survival analysis using a 5-step stratified testing and amalgamation routine (5-STAR) in randomized clinical trials.

Randomized clinical trials are often designed to assess whether a test treatment prolongs survival relative to a control treatment. Increased patient heterogeneity, while desirable for generalizability of results, can weaken the ability of common statistical approaches to detect treatment differences, potentially hampering the regulatory approval of safe and efficacious therapies. A novel solution to this problem is proposed. A list of baseline covariates that have the potential to be prognostic for survival under either treatment is pre-specified in the analysis plan. At the analysis stage, using all observed survival times but blinded to patient-level treatment assignment, "noise" covariates are removed with elastic net Cox regression. The shortened covariate list is used by a conditional inference tree algorithm to segment the heterogeneous trial population into subpopulations of prognostically homogeneous patients (risk strata). After patient-level treatment unblinding, a treatment comparison is done within each formed risk stratum and stratum-level results are combined for overall statistical inference. The impressive power-boosting performance of our proposed 5-step stratified testing and amalgamation routine (5-STAR), relative to that of the logrank test and other common approaches that do not leverage inherently structured patient heterogeneity, is illustrated using a hypothetical and two real datasets along with simulation results. Furthermore, the importance of reporting stratum-level comparative treatment effects (time ratios from accelerated failure time model fits in conjunction with model averaging and, as needed, hazard ratios from Cox proportional hazard model fits) is highlighted as a potential enabler of personalized medicine. An R package is available at https://github.com/rmarceauwest/fiveSTAR.

Safety, immunogenicity, and efficacy of a Clostridioides difficile toxoid vaccine candidate: a phase 3 multicentre, observer-blind, randomised, controlled trial

In the absence of a licensed vaccine, Clostridioides (formerly Clostridium) difficile infection represents a substantial health burden. The aim of this study was to evaluate the efficacy, immunogenicity, and safety of a toxoid vaccine candidate. We did a phase 3 multicentre, observer-blind, randomised, controlled trial at 326 hospitals, clinics, and clinical research centres in 27 countries in the USA, Canada, Latin America, Europe, and the Asia-Pacific region. We included adults aged 50 years or older who were considered to be at an increased risk of C difficile infection because they had previously had two hospital stays (each ≥24 h in duration) and had received systemic antibiotics in the previous 12 months (risk stratum 1), or because they were anticipating being admitted to hospital for 72 h or more for elective surgery within 60 days of enrolment (risk stratum 2). Eligible participants were stratified by geographical region and the two risk strata, and randomly assigned (2:1), with a fixed block size of three, to receive either a C difficile toxoid vaccine candidate, containing toxoids A and B (C difficile vaccine candidate group), or a placebo vaccine (placebo group). Participants, investigators, and personnel responsible for collecting safety data and analysing blood and stool samples were masked to group assignment. Personnel responsible for study product preparation and administration were not masked to group assignment. One dose (0·5 mL) of C difficile vaccine candidate or placebo vaccine was administered intramuscularly on days 0, 7, and 30. The primary outcome was the efficacy of the vaccine in preventing symptomatic C difficile infection, defined as having three or more loose stools in a period of 24 h or less, loose stools for 24 h or more, and a PCR-positive test for C difficile toxin B in a loose stool sample, within 3 years after the final vaccine dose. The primary outcome was measured in the modified intention-to-treat population (ie, all participants who received at least one injection of the assigned vaccine). The safety of the vaccine was assessed in the safety analysis set (ie, all participants who had received at least one injection, analysed according to the product received). This study is registered with WHO/ICTRP, number U111-1127-7162, and ClinicalTrials.gov, number NCT01887912, and has been terminated. Between July 30, 2013, and Nov 17, 2017, we enrolled and randomly assigned 9302 participants to the C difficile vaccine candidate group (n=6201) or to the placebo group (n=3101). 6173 (99·5%) participants in the C difficile vaccine candidate group and 3085 (99·5%) participants in the placebo group received at least one dose of the vaccine. The study was terminated after the first planned interim analysis because of futility. In the C difficile vaccine candidate group, 34 C difficile infections were reported over 11 697·2 person-years at risk (0·29 infections per 100 person-years [95% CI 0·20-0·41]) compared with 16 C difficile infections over 5789·4 person-years at risk in the placebo group (0·28 infections per 100 person-years [0·16-0·45]), indicating a vaccine efficacy of -5·2% (95% CI -104·1 to 43·5). In the C difficile vaccine candidate group, 2847 (46·6%) of 6113 participants reported an adverse event within 30 days of injection compared with 1282 (41·9%) of 3057 participants in the placebo group. The proportion of participants who had an adverse event leading to study discontinuation was 4·8% in both groups (296 participants in the C difficile vaccine candidate group and 146 participants in the placebo group). 1662 (27·2%) participants in the C difficile vaccine candidate group reported at least one serious adverse event compared with 851 (27·8%) participants in the placebo group. In adults at risk for C difficile infection, a bivalent C difficile toxoid vaccine did not prevent C difficile infection. Since the C difficile vaccine candidate met the criteria for futility, the study was terminated and clinical development of this vaccine candidate was stopped. Sanofi Pasteur.

Digital auscultation in PERCH: Associations with chest radiography and pneumonia mortality in children

BackgroundWhether digitally recorded lung sounds are associated with radiographic pneumonia or clinical outcomes among children in low‐income and middle‐income countries is unknown. We sought to address these knowledge gaps.MethodsWe enrolled 1 to 59monthold children hospitalized with pneumonia at eight African and Asian Pneumonia Etiology Research for Child Health sites in six countries, recorded digital stethoscope lung sounds, obtained chest radiographs, and collected clinical outcomes. Recordings were processed and classified into binary categories positive or negative for adventitial lung sounds. Listening and reading panels classified recordings and radiographs. Recording classification associations with chest radiographs with World Health Organization (WHO)‐defined primary endpoint pneumonia (radiographic pneumonia) or mortality were evaluated. We also examined case fatality among risk strata.ResultsAmong children without WHO danger signs, wheezing (without crackles) had a lower adjusted odds ratio (aOR) for radiographic pneumonia (0.35, 95% confidence interval (CI): 0.15, 0.82), compared to children with normal recordings. Neither crackle only (no wheeze) (aOR: 2.13, 95% CI: 0.91, 4.96) or any wheeze (with or without crackle) (aOR: 0.63, 95% CI: 0.34, 1.15) were associated with radiographic pneumonia. Among children with WHO danger signs no lung recording classification was independently associated with radiographic pneumonia, although trends toward greater odds of radiographic pneumonia were observed among children classified with crackle only (no wheeze) or any wheeze (with or without crackle). Among children without WHO danger signs, those with recorded wheezing had a lower case fatality than those without wheezing (3.8% vs. 9.1%, p = .03).ConclusionsAmong lower risk children without WHO danger signs digitally recorded wheezing is associated with a lower odds for radiographic pneumonia and with lower mortality. Although further research is needed, these data indicate that with further development digital auscultation may eventually contribute to child pneumonia care.

Tailoring integrated care services for high-risk patients with multiple chronic conditions: a risk stratification approach using cluster analysis

BackgroundThe purpose of this study was to produce a risk stratification within a population of high-risk patients with multiple chronic conditions who are currently treated under a case management program and to explore the existence of different risk subgroups. Different care strategies were then suggested for healthcare reform according to the characteristics of each subgroup.MethodsAll high-risk multimorbid patients from a case management program in the Navarra region of Spain were included in the study (n = 885). A 1-year mortality risk score was estimated for each patient by logistic regression. The population was then divided into subgroups according to the patients’ estimated risk scores. We used cluster analysis to produce the stratification with Ward’s linkage hierarchical algorithm. The characteristics of the resulting subgroups were analyzed, and post hoc pairwise tests were performed.ResultsThree distinct risk strata were found, containing 45, 38 and 17% of patients. Age increased from cluster to cluster, and functional status, clinical severity, nursing needs and nutritional values deteriorated. Patients in cluster 1 had lower renal deterioration values, and patients in cluster 3 had higher rates of pressure skin ulcers, higher rates of cerebrovascular disease and dementia, and lower prevalence rates of chronic obstructive pulmonary disease.ConclusionsThis study demonstrates the existence of distinct subgroups within a population of high-risk patients with multiple chronic conditions. Current case management integrated care programs use a uniform treatment strategy for patients who have diverse needs. Alternative treatment strategies should be considered to fit the needs of each patient subgroup.

Revisiting Risk-stratified Whiplash-exposed Patients 12 to 14 Years After Injury.

Objective:The objective of this study was to evaluate the long-term predictive value of the Danish Whiplash Group Risk Assessment Score (DWGRAS) with 7 risk strata.Design:E-questionnaire-based follow-up study (n=927) combining 2 cohorts of whiplash-injured patients, 1 observational (n=187) and 1 interventional randomized controlled trial (n=740).Methods:Nine hundred twenty-seven previously healthy persons exposed to acute whiplash injury during motor vehicle collision were sent letter by postal service asking the addressee if they would respond to an E-questionnaire. Outcome measures were: whiplash-related disability, pain, use of medication/nonmedical treatment, work capacity.Results:The response rate was 37%. Fifty-five percent reported whiplash-related disability. Fourteen percent reported daily symptoms. A strong relationship was found between risk strata and impact of event and between risk strata and disabling symptoms.Conclusions:Internal and long-term validation of DWGRAS was performed, but a low response rate indicates that results should be interpreted with caution. Furthermore, external validation needs to be done in long-term studies. An receiver operating characteristics curve of 0.73 (95% confidence interval 0.67; 0.79) predicting daily or weekly whiplash-related disability after 12 to 14 years was found using the DWGRAS risk score.

ASCCP Risk-Based Colposcopy Recommendations Applied in Thai Women With Atypical Squamous Cells of Undetermined Significance or Low-Grade Squamous Intraepithelial Lesion Cytology.

To compare the proportion of cervical intraepithelial neoplasia (CIN) 2 or worse pathology among different risk strata according to the ASCCP when applied in women who had atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion (LSIL) cervical cytology; to assess performance of colposcopy; and to assess the independent predictors for detected CIN 2 or worse pathology. This is a secondary analysis of a previous prospective study, which included Thai women with ASC-US or LSIL cytology who underwent high-risk human papillomavirus (HPV) testing and subsequent colposcopy with directed biopsy. Patients were classified as lowest-risk, intermediate-risk, or highest-risk based on cervical cytology, high-risk HPV testing, and colposcopic impression. The proportion of CIN 2 or worse pathology and associated prognostic factors were analyzed. Of 697 women, 103 (14.8%), 573 (82.2%) and 21 (3%) were classified into lowest-risk, intermediate-risk, and highest-risk groups, respectively. The proportion of CIN 2 or worse pathology was 1%, 11.2%, and 61.9% in those same groups, respectively (P<.001). Colposcopy to detect CIN 2 or worse pathology had a sensitivity, specificity, positive predictive value, and negative predictive value of 98.7%, 18%, 13.2%, and 99.1%, respectively. Independent predictors for detecting CIN 2 or worse pathology were positive high-risk HPV, HPV 16/18 positivity, and high-grade colposcopic impression. This study supports a no biopsy with follow-up strategy in the lowest-risk group, inconsistent with ASCCP recommendations, but is in alignment with a strategy of multiple targeted biopsies in the intermediate-risk and highest-risk groups.

MENTAL HEALTH AND SUBSTANCE USE

Research ObjectiveNational health care efforts have been focused on ensuring patients have access to safe and effective chronic pain treatment while reducing the risk of opioid use disorder, overdose, and death. Within Veterans Health Administration (VHA), recent policy has sought to improve targeting of clinical interventions for patients with high‐dose opioid prescriptions. The Stratification Tool for Opioid Risk Management (STORM) is a safety initiative implemented by VHA to help clinicians evaluate and mitigate opioid‐related risks among their patients. STORM’s predictive model and web‐based dashboard help clinicians identify patients with an opioid prescription who are at high risk of serious adverse events (SAEs) (such as overdose, overdose death, or suicide) and may benefit from clinical interventions to mitigate that risk.We examine the extent to which VHA clinicians effectively target patients for risk mitigation prior to and following implementation of the STORM dashboard. Additionally, we analyze the extent to which implementation of STORM is associated with increased rates of mitigation within each patient risk strata.Study DesignThis study leverages a national observational study of VHA prescription, inpatient, outpatient, and mortality data to categorize patients based on risk profiling. We identify clinical treatment activity across thirteen distinct risk mitigation strategies (such as psychosocial assessments) for a high‐risk patient population prior to and after implementation of STORM.Population StudiedSince early 2018, the STORM algorithm has calculated a daily risk score for SAEs for each Veteran receiving an outpatient opioid prescription, based upon demographic information, previous SAEs, substance use, and mental health history from electronic medical records. This study focuses on high‐risk patients, defined as those at or above the 95th percentile of risk score, and further stratifies within this group of patients to examine comparative rates of risk mitigation.Principal FindingsPrior to implementation of the STORM dashboard and mandated use of the associated scoring algorithm to target clinical interventions, VHA providers were already providing risk mitigation interventions at higher rates for higher risk patients than for lower risk patients. Specifically, patients in the top 1% of risk were observed to receive statistically significantly higher rates of risk mitigation than patients at lower risk levels including timely drug screening, psychological assessment, and safety planning.Following the nationwide implementation of STORM, higher rates of risk mitigation strategies were observed within each strata of high‐risk patients. For example, the rate of psychosocial assessments and use of safety plans were observed to statistically significantly increase by 6‐34% across each risk strata following implementation.ConclusionsEvidence from the pre‐STORM period suggests that VHA clinicians judge inherent risk when managing patients with opioid prescriptions and making clinical treatment decisions. VHA opioid patients at the highest risk for SAEs are more likely to receive risk mitigation than patients with lower risk. Inclusion of high‐risk patients in STORM is associated with even higher rates of mitigation strategies across all risk strata.Implications for Policy or PracticePolicy initiatives that help clinicians identify high‐risk patients may enhance targeting and use of risk mitigation strategies among vulnerable patient populations.Primary Funding SourceDepartment of Veterans Affairs.