Confounding by indication of the safety of de-escalation in community-acquired pneumonia: a simulation study embedded in a prospective cohort

BackgroundObservational studies have demonstrated that de-escalation of antimicrobial therapy is independently associated with lower mortality. This most probably results from confounding by indication. Reaching clinical stability is associated with the decision to de-escalate and with survival. However, studies rarely adjust for this confounder. We quantified the potential confounding effect of clinical stability on the estimated impact of de-escalation on mortality in patients with community-acquired pneumonia.MethodsData were used from the Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA). The primary outcome was 30-day mortality. We performed Cox proportional-hazards regression with de-escalation as time-dependent variable and adjusted for baseline characteristics using propensity scores. The potential impact of unmeasured confounding was quantified through simulating a variable representing clinical stability on day three, using data on prevalence and associations with mortality from the literature.ResultsOf 1,536 included patients, 257 (16.7%) were de-escalated, 123 (8.0%) were escalated and in 1156 (75.3%) the antibiotic spectrum remained unchanged. The adjusted hazard ratio of de-escalation for 30-day mortality (compared to patients with unchanged coverage), without adjustment for clinical stability, was 0.36 (95%CI: 0.18-0.73). If 90% to 100% of de-escalated patients were clinically stable on day three, the fully adjusted hazard ratio would be 0.53 (95%CI: 0.26-1.08) to 0.90 (95%CI: 0.42-1.91), respectively. The simulated confounder was substantially stronger than any of the baseline confounders in our dataset.ConclusionsWith plausible, literature-based assumptions, clinical stability is a very strong confounder for the effects of de-escalation. Quantification of effects of de-escalation on patient outcomes without proper adjustment for clinical stability results in strong negative bias. As a result, the safety of de-escalation remains to be determined.

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Prognostic indicators of secondary progression in a paediatric-onset multiple sclerosis cohort in Kuwait

Multiple Sclerosis Journal ◽

10.1177/1352458515608960 ◽

2015 ◽

Vol 22 (8) ◽

pp. 1086-1093 ◽

Cited By ~ 4

Author(s):

Saeed Akhtar ◽

Raed Alroughani ◽

Samar F Ahmed ◽

Jasem Y Al-Hashel

Keyword(s):

Multiple Sclerosis ◽

Confidence Interval ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Cox Proportional Hazards Model ◽

Adjusted Hazard Ratio ◽

Secondary Progressive ◽

Hazards Model

Background: The frequency of paediatric-onset multiple sclerosis (POMS) and the precise risk of secondary progression of disease are largely unknown in the Middle East. This cross-sectional cohort study assessed the risk and examined prognostic factors for time to onset of secondary progressive multiple sclerosis (SPMS) in a cohort of POMS patients. Methods: The Kuwait National MS Registry database was used to identify a cohort of POMS cases (diagnosed at age <18 years) from 1994 to 2013. Data were abstracted from patients’ records. A Cox proportional hazards model was used to evaluate the prognostic significance of the variables considered. Results: Of 808 multiple sclerosis (MS) patients, 127 (15.7%) were POMS cases. The median age (years) at disease onset was 16.0 (range 6.5–17.9). Of 127 POMS cases, 20 (15.8%) developed SPMS. A multivariable Cox proportional hazards model showed that at MS onset, brainstem involvement (adjusted hazard ratio 5.71; 95% confidence interval 1.53–21.30; P=0.010), and POMS patient age at MS onset (adjusted hazard ratio 1.38; 95% confidence interval 1.01–1.88; P=0.042) were significantly associated with the increased risk of a secondary progressive disease course. Conclusions: This study showed that POMS patients with brainstem/cerebellar presentation and a relatively higher age at MS onset had disposition for SPMS and warrant an aggressive therapeutic approach.

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Metformin vs sulfonylurea use and risk of dementia in US veterans aged ≥65 years with diabetes

Neurology ◽

10.1212/wnl.0000000000004586 ◽

2017 ◽

Vol 89 (18) ◽

pp. 1877-1885 ◽

Cited By ~ 41

Author(s):

Ariela R. Orkaby ◽

Kelly Cho ◽

Jean Cormack ◽

David R. Gagnon ◽

Jane A. Driver

Keyword(s):

Lower Risk ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Confounding By Indication ◽

Cox Proportional Hazards Models ◽

Incident Dementia ◽

Us Veterans

Objective:To determine whether metformin is associated with a lower incidence of dementia than sulfonylureas.Methods:This was a retrospective cohort study of US veterans ≥65 years of age with type 2 diabetes who were new users of metformin or a sulfonylurea and had no dementia. Follow-up began after 2 years of therapy. To account for confounding by indication, we developed a propensity score (PS) and used inverse probability of treatment weighting (IPTW) methods. Cox proportional hazards models estimated the hazard ratio (HR) of incident dementia.Results:We identified 17,200 new users of metformin and 11,440 new users of sulfonylureas. Mean age was 73.5 years and mean HbA1c was 6.8%. Over an average follow-up of 5 years, 4,906 cases of dementia were diagnosed. Due to effect modification by age, all analyses were conducted using a piecewise model for age. Crude hazard ratio [HR] for any dementia in metformin vs sulfonylurea users was 0.67 (95% confidence interval [CI] 0.61–0.73) and 0.78 (95% CI 0.72–0.83) for those <75 years of age and ≥75 years of age, respectively. After PS IPTW adjustment, results remained significant in veterans <75 years of age (HR 0.89; 95% CI 0.79–0.99), but not for those ≥75 years of age (HR 0.96; 95% CI 0.87–1.05). A lower risk of dementia was also seen in the subset of younger veterans who had HbA1C values ≥7% (HR 0.76; 95% CI 0.63–0.91), had good renal function (HR 0.86; 95% CI 0.76–0.97), and were white (HR 0.87; 95% CI 0.77–0.99).Conclusions:After accounting for confounding by indication, metformin was associated with a lower risk of subsequent dementia than sulfonylurea use in veterans <75 years of age. Further work is needed to identify which patients may benefit from metformin for the prevention of dementia.

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Prognostic value of leukemia inhibitory factor and its receptor in pancreatic adenocarcinoma

Future Oncology ◽

10.2217/fon-2019-0684 ◽

2020 ◽

Vol 16 (3) ◽

pp. 4461-4473 ◽

Cited By ~ 3

Author(s):

Dong Wang ◽

Kun Liu ◽

Yingchi Yang ◽

Tingting Wang ◽

Quan Rao ◽

...

Keyword(s):

Overall Survival ◽

Pancreatic Adenocarcinoma ◽

Leukemia Inhibitory Factor ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Adjusted Hazard Ratio ◽

Inhibitory Factor ◽

Normal Tissues ◽

Kaplan Meier

Currently, the prognostic effects of leukemia inhibitory factor (LIF) and LIF receptor (LIFR) in pancreatic adenocarcinoma (PAAD) are not clear. In the present study, we utilized the large datasets from four public databases to investigate the expression of LIF and LIFR and their clinical significance in PAAD. Eight cohorts containing 1278 cases with PAAD were identified and the analysis results suggested that LIF was highly expressed while LIFR was lowly expressed in PAAD tissues compared with adjacent or normal tissues. Kaplan–Meier plot curves and univariate and multivariate Cox proportional hazards regression analyses indicated high LIF expression was associated with shorter overall survival (adjusted hazard ratio = 1.641, 95% CI: 1.399–1.925, p < 0.001) whereas high LIFR expression was associated with longer overall survival (adjusted hazard ratio = 0.653, 95% CI: 0.517–0.826, p < 0.001).

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IGF-Binding Proteins, Adiponectin, and Survival in Metastatic Colorectal Cancer: Results From CALGB (Alliance)/SWOG 80405

JNCI Cancer Spectrum ◽

10.1093/jncics/pkaa074 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Brendan J Guercio ◽

Sui Zhang ◽

Fang-Shu Ou ◽

Alan P Venook ◽

Donna Niedzwiecki ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Adjusted Hazard Ratio ◽

Igf Binding Proteins ◽

C Peptide ◽

Igf Binding ◽

Igfbp 3

Abstract Background Energy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study. Methods Baseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute–sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). P values are 2-sided. Results Median follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; Pnonlinearity < .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; Ptrend = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; Ptrend < .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; Ptrend < .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS (Pnonlinearity = .03). Conclusions Among patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.

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Association between sinusitis and relapse and changes in the myeloperoxidase–antineutrophil cytoplasmic antibody in microscopic polyangiitis

PLoS ONE ◽

10.1371/journal.pone.0243572 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0243572

Author(s):

Hiroya Tanaka ◽

Makoto Yamaguchi ◽

Takayuki Katsuno ◽

Hirokazu Sugiyama ◽

Shiho Iwagaitsu ◽

...

Keyword(s):

Proportional Hazards ◽

Microscopic Polyangiitis ◽

Antineutrophil Cytoplasmic Antibody ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Adjusted Hazard Ratio ◽

University Hospital ◽

Cox Proportional Hazards Models ◽

Medical University ◽

Risk Of Relapse

Previous studies have evaluated the risk factors for relapse of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and the biomarkers of AAV for predicting relapse. However, little is known about the association between the presence of sinusitis and relapse and changes in the ANCA levels in AAV. This single-center, retrospective cohort study included 104 consecutive patients who were newly diagnosed with myeloperoxidase (MPO)-ANCA-positive microscopic polyangiitis (MPA) between 2006 and 2018 and were treated at the Aichi Medical University Hospital in Japan. The relationships between sinusitis and relapse of vasculitis and elevated MPO-ANCA levels were assessed using multivariate Cox proportional hazards models that were adjusted for clinically relevant factors. During the entire follow-up period (median, 24 months; interquartile range, 7–54 months), 93 (89.4%) patients achieved remission. After achieving remission, 38 (40.9%) patients experienced at least one relapse (13 [65.0%] in the sinusitis group; 25 [34.3%] in the non-sinusitis group). Sinusitis was identified as a significant predictor of relapse (adjusted hazard ratio: 2.41, 95% confidence interval [CI]: 1.19–4.88; P = 0.015). Furthermore, sinusitis was more likely to be associated with elevated MPO-ANCA levels (adjusted hazard ratio: 2.59, 95% CI: 1.14–5.92; P = 0.024). In conclusion, sinusitis was associated with a higher risk of relapse and elevated MPO-ANCA levels in MPA patients, suggesting that careful management may be required to reduce the risk of relapse in patients with sinusitis. Further studies are needed to elucidate the optimal treatment strategy for these patients.

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Statins Are Associated With Reduced Mortality in Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2016.68.3482 ◽

2016 ◽

Vol 34 (33) ◽

pp. 4008-4014 ◽

Cited By ~ 26

Author(s):

Kristen Marie Sanfilippo ◽

Jesse Keller ◽

Brian F. Gage ◽

Suhong Luo ◽

Tzu-Fei Wang ◽

...

Keyword(s):

Multiple Myeloma ◽

Statin Therapy ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Adjusted Hazard Ratio ◽

Sensitivity Analyses ◽

Reductase Inhibitors ◽

Specific Mortality ◽

Statin Use

Purpose The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) have activity in one of the pathways influenced by nitrogen-containing bisphosphonates, which are associated with improved survival in multiple myeloma (MM). To understand the benefit of statins in MM, we evaluated the association between statin use and mortality in a large cohort of patients with MM. Patients and Methods From the Veterans Administration Central Cancer Registry, we identified patients diagnosed with MM between 1999 and 2013. We defined statin use as the presence of any prescription for a statin within 3 months before or any time after MM diagnosis. Cox proportional hazards regression assessed the association of statin use with mortality, while controlling for known MM prognostic factors. Results We identified a cohort of 4,957 patients, of whom 2,294 received statin therapy. Statin use was associated with a 21% decrease in all-cause mortality (adjusted hazard ratio, 0.79; 95% CI, 0.73 to 0.86; P < .001) as well as a 24% decrease in MM-specific mortality (adjusted hazard ratio, 0.76; 95% CI, 0.67 to 0.86; P < .001). This association remained significant across all sensitivity analyses. In addition to reductions in mortality, statin use was associated with a 31% decreased risk of developing a skeletal-related event. Conclusion In this cohort study of US veterans with MM, statin therapy was associated with a reduced risk of both all-cause and MM-specific mortality. Our findings suggest a potential role for statin therapy in patients with MM. The putative benefit of statin therapy in MM should be corroborated in prospective studies.

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Early Changes in Serum Albumin Predict Clinical and Endoscopic Outcomes in Patients With Ulcerative Colitis Starting Anti-TNF Treatment

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa309 ◽

2020 ◽

Author(s):

Sun-Ho Lee ◽

Margaret Walshe ◽

Eun Hye Oh ◽

Sung Wook Hwang ◽

Sang Hyoung Park ◽

...

Keyword(s):

Ulcerative Colitis ◽

Serum Albumin ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Interquartile Range ◽

Adjusted Hazard Ratio ◽

Protein Levels ◽

Patient Status ◽

Timely Access

Abstract Background Up to 60% of patients with ulcerative colitis (UC) ultimately fail anti-tumor necrosis factor (TNF) treatment. We aimed to investigate early predictive markers of clinical and endoscopic outcomes in patients with UC who were anti-TNF-naïve commencing anti-TNF treatment, with particular focus on changes in albumin and C-reactive protein levels in the first 2 weeks of treatment. Methods We retrospectively investigated 210 patients with UC who started infliximab or adalimumab between 2009 and 2016 (male, 62.4%; median age at diagnosis, 37.9 years [interquartile range, 25.5–48.9 years]; median follow-up duration, 3.3 years [1.9–5.0 years]). Logistic and Cox proportional-hazards regressions were performed to identify variables associated with primary nonresponse (PNR), endoscopic outcomes, time-to-colectomy, and anti-TNF failure. Results Forty-one patients (19.5%) experienced PNR; week 0/week 2 ratio serum albumin was associated with PNR (adjusted odds ratio [aOR], 1.8; 95% confidence interval [CI], 1.1–2.9, per interquartile range increase). Week 0/week 2 ratio albumin was also associated with endoscopic response (aOR, 0.28; 95% CI, 0.31–0.82) and endoscopic remission (aOR, 0.61; 95% CI, 0.39–0.96) at weeks 8 to 14, time-to-colectomy (adjusted hazard ratio, 2.12; 95% CI, 1.29–3.49) and time-to-anti-TNF failure (adjusted hazard ratio, 1.54; 95% CI, 1.22–1.96), regardless of age, disease severity, or in-patient status. Association with time-to-colectomy and anti-TNF failure was externally validated in an independent cohort of inpatients with UC starting infliximab. Conclusions Change in serum albumin within the first 2 weeks of anti-TNF treatment is predictive of PNR, endoscopic outcomes, time-to-colectomy, and anti-TNF failure in patients with UC. Timely access to this biomarker enables early identification of patients with UC at risk of anti-TNF failure and may guide early optimization of anti-TNF treatment to improve disease outcomes.

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Prognostic Value of Maternal Cardiovascular Hemodynamics in Women With Gestational Hypertension and Chronic Hypertension in Pregnancy

Hypertension ◽

10.1161/hypertensionaha.120.14982 ◽

2020 ◽

Vol 76 (2) ◽

pp. 506-513

Author(s):

Erkan Kalafat ◽

Helen Perry ◽

Sophie Bowe ◽

Basky Thilaganathan ◽

Asma Khalil

Keyword(s):

Cardiac Output ◽

Prognostic Value ◽

Proportional Hazards ◽

Gestational Hypertension ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Adjusted Hazard Ratio ◽

Chronic Hypertension ◽

Increased Risk ◽

Cardiovascular Assessment

This study aimed to assess the prognostic value of cardiovascular assessment in women with gestational hypertension or chronic hypertension for the risk of preeclampsia and need for closer antenatal surveillance. This was a prospective study of pregnancies complicated by gestational hypertension or chronic hypertension presenting to St George’s Hospital, between January 2015 and May 2018. A noninvasive ultrasonic cardiac output monitor was used to obtain cardiovascular variables of cardiac output (CO) and systemic vascular resistance (SVR) and weight-adjusted indices. The primary outcome was the time to development of preeclampsia in women with gestational hypertension or chronic hypertension. In women with gestational hypertension or chronic hypertension (n=149), cox-proportional hazards analysis showed that mean arterial pressure ( P =0.006), Afro-Caribbean ethnicity ( P =0.045), and gestational age at the time of diagnosis above 34 weeks ( P <0.001) were significantly associated with increased risk of earlier preeclampsia. Women with high SVR and normal CO (adjusted hazard ratio, 2.32 [95% CI, 1.06–5.08]; P =0.035) and high SVR and low CO (adjusted hazard ratio, 7.79 [95% CI, 1.94–31.24]; P =0.003) cardiovascular profiles had significantly higher risk of earlier preeclampsia compared with women with normal SVR and normal CO. The findings of this study demonstrate that hypertensive women with increased SVR and low CO had a higher risk of developing preeclampsia sooner.

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Effectiveness of first-line treatments in metastatic squamous non-small-cell lung cancer

Current Oncology ◽

10.3747/co.26.4485 ◽

2019 ◽

Vol 26 (3) ◽

Cited By ~ 1

Author(s):

B. P. Levy ◽

J. E. Signorovitch ◽

H. Yang ◽

O. Patterson-Lomba ◽

C. Q. Xiang ◽

...

Keyword(s):

Lung Cancer ◽

Cell Lung Cancer ◽

Medical Records ◽

Proportional Hazards ◽

Progression Free Survival ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Adjusted Hazard Ratio ◽

First Line ◽

Kaplan Meier

Background Commonly used first-line (1L) chemotherapies for patients with advanced squamous-cell lung cancer (scc) include gemcitabine–platinum (gp), nab-paclitaxel–carboplatin (nabpc), and sb-paclitaxel–carboplatin (sbpc) regimens. However, no head-to-head trials have compared those treatments. In the present study, we compared the efficacy of 1L gp, nabpc, and sbpc in patients with scc and in patients with scc who subsequently received secondline (2L) immunotherapy.Methods Medical records of patients who initiated the 1L treatments of interest between June 2014 and October 2015 were reviewed by 132 participating physicians. Kaplan–Meier curves were used to evaluate overall survival (os), progression-free survival (pfs), and treatment discontinuation (td), and then Cox proportional hazards regression was used to compare the results between the cohorts.Results Medical records of 458 patients with scc receiving gp (n = 139), nabpc (n = 159), or sbpc (n = 160) as 1L therapy were reviewed. Median os was longer with nabpc (23.9 months) than with gp (16.9 months; adjusted hazard ratio vs. nabpc: 1.55; p < 0.05) and with sbpc (18.3 months; adjusted hazard ratio: 1.42; p = 0.10). No differences were observed in pfs (median pfs: 8.8, 8.0, and 7.6 months for gp, nabpc, and sbpc respectively; log-rank p = 0.76) or in td (median td: 5.5, 5.7, and 4.6 months respectively; p = 0.65). For patients who subsequently received 2L immunotherapy, no differences in os were observed (median os: 27.3, 25.0, and 23.0 months respectively; p = 0.59).Conclusions In a nationwide sample of scc patients, longer median os was associated with 1L nabpc than with gp and sbpc. Median os for all 1L agents considered was similar in the subgroup of patients who sequenced to a 2L immunotherapy.

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Factors that contribute to urban–rural gradients in risk of schizophrenia: Comparing Danish and Western Australian registers

Australian & New Zealand Journal of Psychiatry ◽

10.1177/00048674211009615 ◽

2021 ◽

pp. 000486742110096

Author(s):

Oleguer Plana-Ripoll ◽

Patsy Di Prinzio ◽

John J McGrath ◽

Preben B Mortensen ◽

Vera A Morgan

Keyword(s):

Confidence Interval ◽

Western Australia ◽

Urban Areas ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Indigenous Status ◽

Increased Risk ◽

The Relationship ◽

Western Australian

Introduction: An association between schizophrenia and urbanicity has long been observed, with studies in many countries, including several from Denmark, reporting that individuals born/raised in densely populated urban settings have an increased risk of developing schizophrenia compared to those born/raised in rural settings. However, these findings have not been replicated in all studies. In particular, a Western Australian study showed a gradient in the opposite direction which disappeared after adjustment for covariates. Given the different findings for Denmark and Western Australia, our aim was to investigate the relationship between schizophrenia and urbanicity in these two regions to determine which factors may be influencing the relationship. Methods: We used population-based cohorts of children born alive between 1980 and 2001 in Western Australia ( N = 428,784) and Denmark ( N = 1,357,874). Children were categorised according to the level of urbanicity of their mother’s residence at time of birth and followed-up through to 30 June 2015. Linkage to State-based registers provided information on schizophrenia diagnosis and a range of covariates. Rates of being diagnosed with schizophrenia for each category of urbanicity were estimated using Cox proportional hazards models adjusted for covariates. Results: During follow-up, 1618 (0.4%) children in Western Australia and 11,875 (0.9%) children in Denmark were diagnosed with schizophrenia. In Western Australia, those born in the most remote areas did not experience lower rates of schizophrenia than those born in the most urban areas (hazard ratio = 1.02 [95% confidence interval: 0.81, 1.29]), unlike their Danish counterparts (hazard ratio = 0.62 [95% confidence interval: 0.58, 0.66]). However, when the Western Australian cohort was restricted to children of non-Aboriginal Indigenous status, results were consistent with Danish findings (hazard ratio = 0.46 [95% confidence interval: 0.29, 0.72]). Discussion: Our study highlights the potential for disadvantaged subgroups to mask the contribution of urban-related risk factors to risk of schizophrenia and the importance of stratified analysis in such cases.

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