Time-dependent Cox Proportional Hazards Research Articles

Association between Pentosan Polysulfate and Subsequent Maculopathy: Insights from a Nationwide Population-Based Study in Korea

PurposeTo determine the association between pentosan polysulfate (PPS) use and the subsequent development of maculopathy in Asian population. DesignA nationwide population-based retrospective cohort study using the Health Insurance Review and Assessment Service database. Participants103,553 individuals in the PPS user group and 205,792 individuals in the PPS non-user group, all newly diagnosed with cystitis between 2009 and 2020. MethodsThe association between PPS use and maculopathy was evaluated using a time dependent Cox proportional hazard model. Additionally, two sensitivity analyses were conducted by defining PPS users as individuals with an observation period over 6 months from the initial prescription or those with cumulative dose exceeding 9 g, employing the same analysis. Main Outcome MeasuresThe outcome measures included the hazard ratios (HR) representing the association between PPS use and maculopathy. ResultsPPS use was associated with an increased risk of subsequent maculopathy in univariate (HR, 1.7; 95% confidence intervals [CI], 1.66–1.75) and multivariate analysis (HR, 1.34; 95% CI, 1.31–1.38). These results were also confirmed in two sensitivity analyses. The mean cumulative dose of PPS for the cohort was 37.2 ± 76.7 g. ConclusionsIn this nationwide cohort study involving an Asian population, individuals with cystitis using PPS exhibit an increased risk of developing subsequent maculopathy.

Risk of Experiencing an Overdose Event for Patients Undergoing Treatment With Medication for Opioid Use Disorder.

Overdose risk during a course of treatment with medication for opioid use disorder (MOUD) has not been clearly delineated. The authors sought to address this gap by leveraging a new data set from three large pragmatic clinical trials of MOUD. Adverse event logs, including overdose events, from the three trials (N=2,199) were harmonized, and the overall risk of having an overdose event in the 24 weeks after randomization was compared for each study arm (one methadone, one naltrexone, and three buprenorphine groups), using survival analysis with time-dependent Cox proportional hazard models. By week 24, 39 participants had ≥1 overdose event. The observed frequency of having an overdose event was 15 (5.30%) among 283 patients assigned to naltrexone, eight (1.51%) among 529 patients assigned to methadone, and 16 (1.15%) among 1,387 patients assigned to buprenorphine. Notably, 27.9% of patients assigned to extended-release naltrexone never initiated the medication, and their overdose rate was 8.9% (7/79), compared with 3.9% (8/204) among those who initiated naltrexone. Controlling for sociodemographic and time-varying medication adherence variables and baseline substance use, a proportional hazard model did not show a significant effect of naltrexone assignment. Significantly higher probabilities of experiencing an overdose event were observed among patients with baseline benzodiazepine use (hazard ratio=3.36, 95% CI=1.76, 6.42) and those who either were never inducted on their assigned study medication (hazard ratio=6.64, 95% CI=2.12, 19.54) or stopped their medication after initial induction (hazard ratio=4.04, 95% CI=1.54, 10.65). Among patients with opioid use disorder seeking medication treatment, the risk of overdose events over the next 24 weeks is elevated among those who fail to initiate or discontinue medication and those who report benzodiazepine use at baseline.

Association between a priori and a posteriori dietary patterns and the risk of type 2 diabetes: a representative cohort study in Taiwan.

The present study aimed to investigate the relationship between dietary patterns and the risk of type 2 diabetes mellitus (T2DM) among Taiwanese individuals. Data were collected using a nationwide cohort study (2001-15) from the Triple-High Database. Dietary intake was assessed using the twenty-group food frequency questionnaire and used to calculate alternate Mediterranean diet (aMED) and Dietary Approaches to Stop Hypertension (DASH) scores. Principal component analysis (PCA) and partial least-squares (PLS) regression were used to derive dietary patterns, with incident T2DM as the outcome. Multivariable-adjusted hazard ratios and 95 % confidence intervals were calculated using time-dependent Cox proportional hazards (Cox PH) regression analysis, and subgroup analyses were performed. A total of 4705 participants were enrolled in the study, and 995 had newly developed T2DM during the median 5⋅28-year follow-up period (30⋅7 per 1000 person-years). Six dietary patterns were extracted (PCA: Western, prudent, dairy and plant-based; PLS: health-conscious, fish-vegetable and fruit-seafood). The highest aMED score quartile had a 25 % (hazard ratio 0⋅75; 95 % CI 0⋅61, 0⋅92; P = 0⋅039) lower risk of T2DM than the lowest quartile. This association remained significant after adjustment (adjusted hazard ratio 0⋅74; 95 % CI 0⋅60, 0⋅91; P = 0⋅010), and no effect modifier was found for aMED. The DASH scores, PCA and PLS dietary patterns were not significant after adjustment. In conclusion, high adherence to a MED-type dietary pattern by Taiwanese foods was associated with a lower risk of T2DM in the Taiwanese population, regardless of unhealthy lifestyle habits.

Impact of Fluoroquinolone Prophylaxis on Neutropenic Fever, Infections, and Antimicrobial Resistance in Newly Diagnosed AML Patients.

Fluoroquinolone prophylaxis is recommended during induction chemotherapy for patients with acute myeloid leukemia (AML) to reduce risk of neutropenic fever and systemic bacterial infections. We evaluated the effectiveness of primary fluoroquinolone prophylaxis in an area with high fluoroquinolone resistance. We performed a retrospective chart review of newly diagnosed adult AML patients who received frontline therapy at Mount Sinai Hospital in New York, NY, between 2012 and 2019. Primary outcome was development of neutropenic fever. Secondary outcomes were development of systemic bacterial infections and infections with multidrug-resistant organisms and Clostridioides difficile. Infectious outcomes were collected through 6 months after therapy initiation. We estimated the effect of fluoroquinolone prophylaxis with a time-dependent Cox proportional hazards model. Of 121 included patients, 87 received antibiotic prophylaxis and 34 did not. There was no difference in baseline characteristics, although the prophylaxis group had longer neutropenia duration (median 30 vs. 23 days, P=.013). The prophylaxis group had a reduced risk of neutropenic fever (hazard ratio 0.59, P=.039). The prophylaxis group had fewer gram-positive (P=.043) and gram-negative (P=.049) bloodstream infections and fewer clinically documented infections during frontline therapy (P=.005) and follow-up (P=.026). There was no difference in incidence of C. difficile or infection with fluoroquinolone-resistant or multidrug-resistant organisms. There was no mortality difference between groups. In an area with high fluoroquinolone resistance, primary fluoroquinolone prophylaxis in newly diagnosed AML patients reduced the risk of neutropenic fever and systemic bacterial infections without increased antimicrobial resistance. Prospective, randomized studies are needed to confirm these observations.

High Mortality Rate in Oral Glucocorticoid Users: A Population-Based Matched Cohort Study.

ObjectiveThe aim of the study was to investigate all-cause and disease-specific mortality in a large population-based cohort of oral glucocorticoid (GC) users.MethodsThis was a retrospective, matched cohort study. Information on dispensed prescriptions was obtained from the Swedish Prescribed Drug Register. The cause of death was obtained from the Swedish Cause-of-Death Registry. Patients receiving prednisolone ≥5 mg/day (or equivalent dose of other GC) for ≥21 days between 2007-2014 were included. For each patient, one control subject matched for age and sex was included. The study period was divided into 3-month periods and patients were divided into groups according to a defined daily dose (DDD) of GC used per day. The groups were: Non-users (0 DDD per day), low-dose users (>0 but <0.5 DDD per day), medium-dose users (0.5-1.5 DDD per day) and high-dose users (>1.5 DDD per day). Hazard ratios (HRs), unadjusted and adjusted for age, sex and comorbidities, were calculated using a time-dependent Cox proportional hazard model.ResultsCases (n=223 211) had significantly higher all-cause mortality compared to controls (HR adjusted for age, sex and comorbidities 2.08, 95% confidence interval 2.04 to 2.13). After dividing the cases into subgroups, adjusted HR was 1.31 (1.28 to 1.34) in non-users, 3.64 (3.51 to 3.77) in low-dose users, 5.43 (5.27 to 5.60) in medium-dose users and, 5.12 (4.84 to 5.42) in high-dose users. The highest adjusted hazard ratio was observed in high-dose users for deaths from sepsis 6.71 (5.12 to 8.81) and pulmonary embolism 7.83 (5.71 to 10.74).ConclusionOral GC users have an increased mortality rate compared to the background population, even after adjustment for comorbidities. High-dose users have an increased risk of dying from sepsis, and pulmonary embolism compared to controls. Whether the relationship between GC exposure and the excess mortality is causal remains to be elucidated.

Cardiovascular mortality and transportation noise: a prospective Swiss cohort study

Transportation noise from road, rail and air traffic can be detrimental to health and wellbeing. Previous studies, including our own, have shown death from specific cardiovascular diseases (CVD) to be associated with these exposures. Now, with 15 years of follow-up, integrated address history and noise exposure data for multiple years corresponding to census decades, we conducted an extended analysis of the Swiss National Cohort. Mean exposure in 5-year periods were calculated, and three virtual sub-cohorts were defined (2001-2006, etc.) in addition to the full cohort (2001-2015). Multi-pollutant (Lden_road, Lden_rail, Lden_air), time dependent Cox proportional hazards models were applied to 4.14 million adults and adjusted for potential confounders and PM2.5. During the 15-year follow-up, there were 277,506 CVD and 34,200 myocardial infarction (MI) deaths. In the full cohort, there was an increased risk of death for road traffic (1.029 [1.024−1.034] CVD; 1.043 [1.029−1.058] MI per 10dB), railway (1.013 [1.010−1.017] CVD; 1.020 [1.010−1.030] MI) and aircraft noise (1.040 [1.020−1.060] MI). For road traffic noise, Hazard ratios (HR) were higher in males vs. females and in younger vs. older age groups. HRs were also remarkably consistent with our previous analysis with follow-up until 2008, and were relatively similar across the three virtual sub-cohorts.

Baseline serum B-cell maturation antigen levels predict time to disease progression for patients with smoldering multiple myeloma.

Multiple myeloma (MM) patients with smoldering (S) disease are defined by a lack of CRAB/SLiM criteria but may transform into disease requiring treatment. The International Myeloma Working Group risk stratification model for SMM uses serum M-protein, serum-free light chain ratio, and bone marrow plasma cell percentage. We investigated whether baseline serum B-cell maturation antigen (sBCMA) levels are predictive of disease progression among 65 patients with SMM. A receiver operating characteristic curve was used to establish a definition for high-risk baseline sBCMA. Mantel Byar analysis was used to examine whether high-risk sBCMA was correlated with shorter time to transformation, and a time-dependent cox proportional hazard was used to determine whether it is independent of other risk factors. A z test for proportions was used to compare the percentage of patients that progressed among high-risk versus low-risk sBCMA patients. A baseline sBCMA level ≥137.5mg/ml was found to be the optimal cutoff between high- and low-risk SMM patients. Patients with high-risk sBCMA levels had a shorter time to transformation (P=.000332). sBCMA was also higher at the time of transformation than baseline levels (P=.0116). sBCMA was the only variable found to be significantly predictive of time to transformation and additionally was found to be independent of other risk factors. In this study, we have shown for the first time that sBCMA levels predict transformation of SMM to active disease and that these levels increase at the time of transformation. These results are consistent with other studies showing that active MM patients undergoing therapy with higher baseline sBCMA levels are more likely to progress early and its levels increase at the time of disease progression.

Microalbuminuria After Kidney Transplantation Predicts Cardiovascular Morbidity.

Background: Microalbuminuria is a well-characterized marker of kidney malfunction, both in diabetic and non-diabetic populations, and is used as a prognostic marker for cardiovascular morbidity and mortality. A few studies implied that it has the same value in kidney transplanted patients, but the information relies on spot or dipstick urine protein evaluations, rather than the gold standard of timed urine collection.Methods: We revisited a cohort of 286 kidney transplanted patients, several years after completing a meticulously timed urine collection and assessed the prevalence of major cardiovascular adverse events (MACE) in relation to albuminuria.Results: During a median follow up of 8.3 years (IQR 6.4–9.1) 144 outcome events occurred in 101 patients. By Kaplan-Meier analysis microalbuminuria was associated with increased rate of CV outcome or death (p = 0.03), and this was still significant after stratification according to propensity score quartiles (p = 0.048). Time dependent Cox proportional hazard analysis showed independent association between microalbuminuria and CV outcomes 2 years following microalbuminuria detection (HR 1.83, 95% CI 1.07–2.96).Conclusions: Two years after documenting microalbuminuria in kidney transplanted patients, their CVD risk was increased. There is need for primary prevention strategies in this population and future studies should address the topic.

Association of spontaneous abortion with all cause and cause specific premature mortality: prospective cohort study

ObjectiveTo investigate the association of spontaneous abortion with the risk of all cause and cause specific premature mortality (death before the age of 70).DesignProspective cohort study.SettingThe Nurses’ Health Study II...

Transportation noise exposure and cardiovascular mortality: a 15-year analysis in Switzerland

Background: Transportation noise from road, rail and air traffic can be detrimental to health and wellbeing. Previous studies, including our own, have shown death from specific cardiovascular diseases (CVD) to be associated with these exposures. Now, with double the follow-up, integrated address history and transportation noise exposure data for multiple years corresponding to census decades, we conducted an extended analysis of the Swiss National Cohort. Methods: Mean noise exposure in 5-year periods was calculated, and three virtual sub-cohorts were defined (2000-2005, etc.) in addition to the full cohort (2000-2015). Multi-pollutant (Lden_road, Lden_rail, Lden_air), time dependent Cox proportional hazards models were applied to 3.8 mil adults (30-100 years old at 2000; age as timescale) and adjusted for sex, civil status, education, mother tongue, nationality, neighborhood socio-economic position and NO2 exposure. Results: During the 15-year follow-up, there were 249,000 CVD and 30,500 myocardial infarction deaths. In the full cohort, the relative risk for myocardial infarction mortality significantly increased by 4.1% [95% confidence interval: 2.6−5.6], 2.0% [0.9−3.1] and 3.2% [1.5−5.0] per 10 dB road traffic, railway and aircraft noise, respectively. CVD mortality was also significantly associated with road traffic noise (2.7% [2.2−3.2]) and railway noise (1.6% [1.2−2.0]) per 10 dB increase. Relative risks were remarkably consistent with our previous analyses with follow-up until 2008, and rather similar across the three virtual sub-cohorts indicating an absence of time trends for these associations. Conclusions: Cardiovascular effects of transportation noise may be modified by many factors such as building characteristics, window opening habits during the night and other lifestyle factors. For this reason, representative local data can be highly valuable for informing national noise limits aimed at protecting public health.

Evaluation of the Risk Factors for Acute Kidney Injury in Neonates Exposed to Antenatal Indomethacin.

Evidence is limited about important maternal and neonatal risk factors that affect neonatal renal function. The incidence of acute kidney injury (AKI) and identification of associated risk factors in neonates exposed to antenatal indomethacin was studied. A retrospective cohort of neonates exposed to antenatal indomethacin within 1 week of delivery was analyzed for development of AKI up to 15 days of life. Adjusted hazard ratios (HRs) and 95% CIs for AKI risk were calculated in time-dependent Cox proportional hazards models. Among 143 neonates with mean gestational age of 28.3 ± 2.4 weeks, AKI occurred in 62 (43.3%), lasting a median duration of 144 hours (IQR, 72-216 hours). Neonates with AKI had greater exposure to postnatal NSAIDs (48.4% vs 9.9%, p < 0.001) and inotropes (37.1% vs 3.7%, p < 0.001) compared with neonates without AKI. In multivariable-adjusted models, increased AKI risk was observed with antenatal indomethacin doses received within 24 to 48 hours (HR, 1.6; 95% CI, 1.28-1.94; p = 0.036) and <24 hours (HR, 2.33; 95% CI, 1.17-4.64; p = 0.016) prior to delivery. Further, postnatal NSAIDs (HR, 2.8; 95% CI, 1.03-7.61; p = 0.044), patent ductus arteriosus (HR, 4.04; 95% CI, 1.27-12.89; p = 0.018), and bloodstream infection (HR, 3.01; 95% CI, 1.37-6.60; p = 0.006) were associated significantly with increased risk of AKI following antenatal indomethacin. Neonates with AKI experienced more bloodstream infection, severe intraventricular hemorrhage, patent ductus arteriosus, respiratory distress syndrome, and longer hospitalization. Extended risk of AKI with antenatal indomethacin deserves clinical attention among this population at an already increased AKI risk.

Relationship between time-varying status of reflux esophagitis and Helicobacter pylori and progression to long-segment Barrett\u2019s esophagus: time-dependent Cox proportional-hazards analysis

BackgroundReflux esophagitis (RE) and absence of Helicobacter pylori (non-H. pylori) are considered to be associated with the progression to long-segment Barrett’s esophagus (LSBE). However, it is difficult to assess this association because RE and H. pylori status can change during follow-up. Additionally, the association between H. pylori eradication and LSBE remains unclear.MethodsA total of 11,493 asymptomatic Japanese subjects who underwent medical check-ups and were endoscopically diagnosed with short-segment Barrett’s esophagus (SSBE) between May 2006 and December 2015 were enrolled. The hazards of progression to LSBE were compared between time-varying RE and H. pylori infection/eradication by time-dependent multivariable Cox proportional hazards models.ResultsA total of 7637 subjects who underwent additional medical check-ups after being diagnosed with endoscopic SSBE were analyzed. Subjects with RE and without current/past H. pylori infection were strongly associated with a higher rate of progression to LSBE (adjusted hazard ratio [HR]: 7.17, 95% confidence interval [CI]: 2.48–20.73, p < 0.001 for RE and non-H. pylori vs. non-RE and H. pylori groups). Subjects with H. pylori had a lower rate of progression to LSBE (adjusted HR: 0.48, 95% CI: 0.22–1.07, p = 0.07 for H. pylori vs. non-H. pylori). Hazards of progression to LSBE were still lower in the H. pylori eradication group than that of the non-H. pylori group (adjusted HR: 0.51, 95% CI: 0.18–1.46, p = 0.21).ConclusionsRE and non-H. pylori were associated with the progression to LSBE, considering the changes in exposures. H. pylori infection was associated with the prevention of the development of LSBE irrespective of RE. The environment preventive of the development of LSBE persists for at least a few years after H. pylori eradication.

Changes in Plant Based Diets and Subsequent Risk of Type 2 Diabetes: Results from 3 Large US Cohorts

Abstract Objectives Plant-based diets may lower type 2 diabetes (T2D) risk. Whether changes in adherence to plant-based diets are associated with subsequent T2D risk remains unknown. We aimed to evaluate the associations between 4 year changes in plant based diets and subsequent 4 year risk of T2D. Methods We prospectively followed 76,530 women in the Nurses’ Health Study (NHS, 1986–2012), 81,586 women in NHS II (1991–2017), and 34,468 men in the Health Professionals’ Follow-up Study (1986–2016). Diet was assessed every 4 years using validated food-frequency questionnaires. Adherence to plant-based diets was assessed using previously developed indices – the overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI). Self reported T2D cases were validated by supplementary questionnaires. We used multivariable time dependent Cox proportional hazards models to estimate hazard ratios (HR) and 95% CIs for T2D associated with 4 year changes in adherence to plant based diets. Results of the three cohorts were pooled using an inverse variance-weighted meta-analysis. Results We documented 12,016 cases of T2D during 2818,485 person-years of follow-up. After adjustment for initial BMI, initial and 4-year changes in lifestyle and other factors, compared with participants whose indices remained relatively stable (±3%), participants with the largest 4-year decrease (&amp;gt;10%) in PDI and hPDI had a 12%-23% higher T2D risk in the subsequent 4 years (HR for PDI, 1.12 (95% CI 1.05, 1.20), HR for hPDI, 1.23 (1.16, 1.31)). Conversely, each 10% incremental increase in PDI and hPDI over 4 years was associated with a 7%–9% lower T2D risk in subsequent 4 years (HR for PDI, 0.93 (0.90, 0.95), HR for hPDI, 0.91 (0.87, 0.95)). Changes in uPDI were not associated with T2D risk. Further adjustment for concurrent changes in body weight, a potential mediator, modestly attenuated the associations but results remained significant. We estimated that body weight changes explained 6.0%–36% of the associations between 4 year changes in PDI and hPDI and subsequent T2D risk. Conclusions Improving adherence to overall and healthful plant based diets over a 4 year period was associated with a lower T2D risk, whereas decreased adherence to overall and healthful plant based diets was associated with a higher T2D risk. Funding Sources Nutricia Research Foundation/NIH.

Investigation of factors associated with spontaneous preterm birth in pregnant women living with HIV.

To investigate factors contributing to preterm birth (PTB), including cART use and clinical and social determinants of health, in women living with HIV (WLWH) from British Columbia, Canada. Retrospective observational cohort. We investigated the effect of cART use and other clinical and demographic factors on spontaneous PTB (sPTB) rates (<37 weeks gestational age) among 631 singleton pregnancies between 1997 and 2018. Exposure to cART was modelled in comparison to no exposure, exposure in the first trimester, and between regimens. Differences in sPTB risk were estimated using time-dependent Cox's proportional hazards models. Overall, the sPTB rate was 16%. Cumulative cART use was associated with lower risk of PTB (Wald test P = 0.02; hazard ratio = 0.98, 95% CI = 0.96-0.99) and specific cART regimens were not associated with increased risk of sPTB. Exposure in the first trimester was not associated with sPTB and for each week of cART exposure, the risk of sPTB decreased by 2%. In a multivariable model, HIV viral load and substance use remained associated with risk of sPTB, but not cART exposure. The sPTB rate among pregnant WLWH was more than three times higher than in the general population. However, sPTB was not related specifically to use of cART; in fact, cART appeared to reduce the risk of sPTB. Uncontrolled HIV replication and substance use were associated with increased risk of sPTB among pregnant WLWH. This emphasizes the important role of prenatal care, access to cART, and smoking cessation and harm reduction to reduce the risk of sPTB in WLWH.

Association between thiopurine exposure and depression in patients with inflammatory bowel disease and rheumatoid arthritis.

Ras-related C3 botulinum substrate 1 (Rac1) is a member of the small molecule family Rho guanosine triphosphate (GTP)ases. Recent findings reveal epigenetic downregulation of Rac1 is a mechanism of depression. The purpose of this study was to evaluate Rac1 as a therapeutic target for depression we examine the association between thiopurines, which inhibit Rac1, and the risk of depression among US veterans. This study uses data spanning January 2000-May 2019, comparing thiopurine exposure (no exposure, less than one year, 1-2.9 years, 3-5 years, and greater than five years) in two separate cohorts, a rheumatoid arthritis cohort and inflammatory bowel disease cohort. We estimate the hazard of depression using a time dependent cox proportional hazards model. A total of 76,763 rheumatoid arthritis and 46,787 inflammatory bowel disease patients met all inclusion criteria. Patients exposed to thiopurines less than one year have a 27% (hazard ratio=1.272; 95% confidence interval=(1.038-1.559)) and 67% (hazard ratio=1.667 95% confidence interval=(1.501-1.850)) higher risk of depression in the rheumatoid arthritis and inflammatory bowel disease cohorts, respectively. In the inflammatory bowel disease cohort, we find the risk of depression is increased for up to five years of thiopurine exposure. These results provide evidence that Rac1 regulation is a viable therapeutic target for depression. Further research into therapeutics targeting Rac1 for the treatment of depression is warranted.

Statin adherence and persistence on secondary prevention of cardiovascular disease in Taiwan

BackgroundEvidence and treatment guidelines support the use of statins in patients with established atherosclerotic cardiovascular disease (ASCVD) for secondary prevention of subsequent cardiovascular (CV) event. However, treatment adherence and persistence...

The impact of a musculoskeletal training program on residents\u2019 recognition and treatment of osteoporosis

BackgroundOsteoporosis is inadequately treated in primary care settings. Under-recognition of the condition among male Veterans may contribute to this problem. In order to improve understanding of bone health in older male patients, we developed the “Musculoskeletal (MSK) Education Week”, a multidisciplinary clinical training initiative within a primary care ambulatory rotation for internal medicine (IM) residents at the Salt Lake City VA Medical Center. The objective of this study was to evaluate the impact of this program on trainees’ recognition of osteoporosis or treatment of this condition following the training experience.MethodsWe examined several clinical behaviors of post-graduate year 1 (PGY-1) IM trainees following their participation in the MSK Education Week between July 1–April 30, 2014. To determine the prevalence of these clinical behaviors, we conducted an observational study of patients age 50 and older enrolled at the Salt Lake City VA Healthcare System from July 1, 2013 to May 31, 2014. We used time-dependent multivariable Cox proportional hazard models to evaluate the impact of the training program on 4 osteoporosis-related outcomes: (1) completion of dual energy X-ray absorptiometry (DXA) scan, (2) diagnosis of osteopenia, (3) diagnosis of osteoporosis, and (4) initiation of osteoporosis medications.ResultsTwenty-six PGY-1 IM residents participated in the MSK Education Week, and 43,678 Veterans were identified over these periods of observation. In the Veterans cohort, 1154 had an encounter with a provider who had completed the training (and were therefore “exposed” to the training) and 42,524 Veterans did not. After adjusting for confounders, the effect of the provider training program was significant for DXA (HR = 1.78, 95% CI: 1.11, 2.87), osteoporosis diagnosis (HR = 3.90, 95% CI: 2.09, 7.29), and initiation of medications (HR = 2.87, 95% CI: 2.02, 4.09) outcomes.ConclusionsWe have shown that IM residents’ participation in the MSK Education Week was associated with significantly improvements in their completion of DXA scans, diagnosis of osteoporosis, and initiation of fracture-reducing medications in a population of US Veterans. Long-term follow up is needed to determine whether these initial results are followed by actual reductions in osteoporotic fractures.

Excessive remifentanil during total intravenous anesthesia is associated with increased risk of pain after robotic thyroid surgery.

The widespread use of remifentanil during total intravenous anesthesia (TIVA) has raised concerns about the risk of postoperative remifentanil-associated pain. Although a recent meta-analysis suggests that remifentanil-associated pain is unlikely to occur in patients with TIVA because of the protective effect of co-administered propofol, the evidence is not conclusive. We retrospectively assessed 635 patients who received robotic thyroid surgery under TIVA to evaluate the risk of remifentanil-associated pain. Postoperative pain was evaluated using 11-point numeric rating scale (NRS). Time dependent Cox proportional hazards regression analysis was used to determine the risk factors of treatment-requiring pain (NRS > 4) during the first 48 postoperative hours. Postoperative pain rapidly decreased, and treatment-requiring pain remained in 12.8% (81 out of 635) of patients at 48 hours postoperatively. After adjusting for the time-dependent analgesic consumption, intraoperative use of remifentanil > 0.2 mcg/kg/min was a positive predictor of postoperative pain with a hazard ratio of 1.296 (95% C.I., 1.014–1.656, P = 0.039) during 48 hours after surgery. In conclusion, excessive use of remifentanil during TIVA was associated with increased risk of pain after robotic thyroid surgery. Prospective trials are required to confirm these results and determine whether decreasing remifentanil consumption below the threshold can reduce postoperative pain.

High baseline neutrophil-to-lymphocyte ratio predicts worse outcome in patients with metastatic BRAF-positive melanoma treated with BRAF and MEK inhibitors.

Neutrophil-to-lymphocyte ratio (NLR) has been shown to be prognostic in several solid malignancies. There are limited data regarding its value during novel therapies in patients with melanoma. The aim of the study was to assess the practical utility of this ratio in patients with BRAF-mutant melanoma treated with a combination of BRAF and MEK inhibitors (BRAFi/MEKi). We included 215 patients with inoperable or metastatic melanoma who underwent BRAFi/MEKi treatment between October 2015 and June 2017. Baseline NLR and other complete blood count-derived inflammatory markers were tested for association with overall survival and progression-free survival in univariate and multivariate models. On-treatment NLR was also assessed for relationship with these outcomes using the time-dependent Cox's proportional hazard model. Prognostic model based on NLR and lactate dehydrogenase (LDH) levels was also developed. Patients with NLR values more than four had poorer progression-free survival (P<0.001, 1-year rates 51.6 vs. 26.7%) and overall survival (P<0.001, 1-year rates 77.3 vs. 53.1%). In a multivariate model adjusted for LDH levels, metastatic sites and age baseline NLR ratio and delay in starting MEKi were deemed statistically significant (hazard ratio: 1.81; 95% confidence interval: 1.16-2.85; P=0.009 and hazard ratio: 2.06; 95% confidence interval: 1.24-3.44, P=0.005 respectively). In a model based on NLR and LDH, 1-year survival rates were 57, 40 and 23%, respectively if zero, one or both factors were elevated. Our results demonstrate the usefulness of NLR and a predictive model based on combinations of NLR and LDH as a prognostic markers during BRAFi/MEKi treatment. Our real-world data confirm the efficacy of BRAFi/MEKi therapy showed in the clinical trials.

Chronic obstructive pulmonary disease and the development of atrial fibrillation

BackgroundChronic obstructive pulmonary disease (COPD) has been associated with atrial fibrillation (AF). More insight into the epidemiology and underlying mechanisms is required to optimize management. MethodsThe Rotterdam Study is a large, population-based cohort study with long-term follow-up. Time dependent Cox proportional hazard models were constructed to study the effect of COPD on incident AF, adjusted for age, sex and pack years of cigarette smoking, and additionally stratified according to exacerbation frequency, left atrial size and baseline systemic inflammatory levels. Results1369 of 10,943 subjects had COPD, of whom 804 developed AF. The AF incidence rate was 14 per 1000 person years in COPD and 8 per 1000 person years in subjects without COPD. The adjusted hazard ratio (HR) for COPD subjects to develop AF as compared to subjects without COPD was 1.28 (95%CI [1.04, 1.57]). COPD subjects with frequent exacerbations had a twofold increased AF risk (HR 1.99 [1.42, 2.79]) and COPD subjects with a left atrial size ≥40 mm also had an elevated AF risk (HR 1.77 [1.07, 2.94]). COPD subjects with baseline systemic inflammatory levels above the median had significantly increased AF risks (hsCRP≥1.83 mg/L: HR 1.51 [1.13, 2.03] and IL6 ≥ 1.91 ng/L: HR 2.49 [1.18, 5.28]), whereas COPD subjects below the median had in both analyses no significantly increased AF risk. ConclusionsCOPD subjects had a 28% increased AF risk, which further increased with frequent exacerbations and an enlarged left atrium. The risk was driven by COPD subjects having elevated systemic inflammatory levels.