Relative Risk Of Adverse Events Research Articles

A noninferiority randomized open-label pilot study of 3- versus 7-day influenza postexposure prophylaxis with oseltamivir in hospitalized children

Short influenza postexposure prophylaxis (PEP) showed high efficacy in adults, but studies in children are lacking. This randomized open-label pilot trial aimed to verify noninferiority of a 3- versus 7-day prophylaxis with oral oseltamivir in hospitalized children. Influenza contacts were randomized to the 3- or 7-day group and efficacy, relative risk of adverse events (AEs), and the cumulative costs of drugs and AEs management were compared. The intention-to-treat (ITT) analysis included 59 children (n = 28 and n = 31 in the 3- and 7-day group, respectively). The efficacy was 100% (95% CI 87.7–100%) versus 93.6% (95% CI 78.6–99.2%) in the 3- and 7-day group; the differences were statistically insignificant. A per-protocol (PP) analysis including 56 patients (n = 27 and n = 29, respectively) showed 100% (95% CI 87.2–100%) and 93.1% (95% CI 77.2–99.2%) efficacy, respectively, without statistical significance. Differences were within the predefined noninferiority margin with an efficacy difference Δ = 6.45 percentage points (p.p.) with 1-sided 95% CI (− 2.8, − 1.31, p = 0.86; ITT) and Δ = 6.9 p.p. (1-sided 95% CI − 2.83, − 1.27, p = 0.85; PP). Adverse events did not differ significantly, while the cumulative costs of the prophylaxis and AEs management were higher in the 7-day group (median 10.5 euro vs. 4.5 euro, p < 0.01). This pilot study showed the noninferiority of the 3-day versus 7-day PEP, which was associated with lower costs.Trial registration number: NCT04297462, 5th March 2020, restrospectively registered.

Evaluation of time-to-onset and outcome of cardiac adverse events related to pembrolizumab using post-marketing surveillance in Japanese patients.

Pembrolizumab has been widely used in patients since its release, but information on cardiac Adverse Events (AEs) related to pembrolizumab remains lacking, particularly in Japanese populations. This study aims to evaluate time to onset, incidence rates, and outcomes for pembrolizumab-induced cardiac AEs in patients with cancer using the Japanese Adverse Drug Event Report database. We analysed data for the period from April 2004 to March 2022. Data on cardiac AEs were extracted and relative risks of AEs were estimated using the reporting odds ratio. We analysed 2,021,907 reports and identified 15,306 reports of AEs caused by pembrolizumab. Of these, 399 cardiac AEs were associated with pembrolizumab. Signals were detected for six cardiac AEs: myocarditis, immune-mediated myocarditis, pericardial effusion, cardiac tamponade, pericarditis, and pericarditis malignant. A histogram of median times to onset showed occurrence from 33 (21-97) days for immune-mediated myocarditis to 138 (67-168) days for pericarditis malignant, but some cases occurred even more than 1year after the start of administration. Among these, myocarditis was the most frequently reported (27.1%), with fatal cases also reported. This study focused on cardiac AEs caused by pembrolizumab as post-marketing AEs. Patients should be monitored not only at the time of administration, but also over time for signs of these AEs, especially myocarditis, as some patients may have serious outcomes.

Impact of pegaspargase dose capping on incidence of pegaspargase-related adverse events in adults.

Asparaginase derivatives are essential components of the treatment of acute lymphoblastic leukemia in adolescent and young adult patients. However, their associated toxicities limit wider use in older populations. This study seeks to determine if the practice of capping the pegaspargase dose at 3750 units reduces the risk of related adverse events in adults. Adverse event data were retrospectively collected 28 days following each administration of pegaspargase in a single center. Doses were categorized as either capped (≤3750 units) (n = 57, 47.5%) or non-capped (>3750 units) (n = 63, 52.5%). The primary endpoint of this study was the composite incidence of serious pegaspargase-related adverse events, defined as grade 3 or higher. Of the 120 doses administered, 47 (39.2%) were administered to patients > 39 years. For the primary endpoint, 26 doses (45.6%) in the dose capped group versus 22 doses (34.9%) in the non-dose capped group were associated with serious pegaspargase-related adverse events (p = 0.23). Isolated laboratory abnormalities accounted for all hepatotoxicity and pancreatic toxicity events, while venous thromboembolism and bleeding occurred after 8.3% and 13.3% of doses, respectively. Multivariate analysis of the primary outcome to adjust for differences in baseline characteristics found no difference between groups (OR 2.56 (0.84, 7.77, p = 0.098)). The incidence of serious clinical toxicities was low in this study, particularly pegaspargase-related venous thromboembolism. This suggests that the practice of capping pegaspargase doses at 3750 units, coupled with vigilant monitoring and prophylaxis for pegaspargase-related adverse events, can allow for the inclusion of this drug in the treatment of older individuals.

Evaluation of Time to Onset and Outcome of Cardiac Adverse Events Associated with Nilotinib using Post-Marketing Surveillance

Introduction: Cardiac adverse events (CAEs) have become a concern as serious adverse events (AEs) of nilotinib administration. No reports have described the incidence of CAEs associated with nilotinib in Japanese patients. Thus, we conducted this study to evaluate the risk of nilotinib-induced CAEs, time to onset, incidence rates, and post hoc outcomes using the Japanese Adverse Drug Event Report database. Methods: We analysed data for the period between April 2004 and March 2022. Data on CAEs were extracted, and relative risk of AEs was estimated using the reporting odds ratio. Results: We analysed 2,021,907 reports and identified 3,545 reports of AEs caused by nilotinib. Of these, 511 reports involved CAEs. Signals were detected for 19 CAEs. Of these, electrocardiogram QT prolonged was the most frequently reported (30.9%). Fatal outcomes were observed in eight AEs: cardiac failure, atrial fibrillation, acute myocardial infarction, pericardial effusion, myocardial infarction, cardiac arrest, pericarditis, and cardiac tamponade. Of these, acute myocardial infarction, myocardial infarction, pericarditis, and cardiac tamponade exhibited mortality rates >10%. A histogram of median times to onset showed nilotinib-associated AEs occurring 3–485 days after nilotinib administration. Conclusion: We focused on CAEs caused by nilotinib as post-marketing AEs. Some cases resulted in serious outcomes. Patients should be monitored for signs of onset of these AEs not only at the start of administration but for a long period of time.

Carvedilol Versus Other Nonselective Beta Blockers for Variceal Bleeding Prophylaxis and Death: A Network Meta-analysis.

We aimed to perform a network meta-analysis (NWM) to examine comparative effectiveness of non-selective beta blockers (NSBBs) on prophylaxis of gastroesophageal variceal bleeding (GVB) and mortality benefit. MEDLINE (OVID) and EMBASE databases were searched for eligible randomized clinical trials (RCTs) from inception to July 3, 2021. Outcomes of interest included primary/secondary prophylaxis of GVB, failure to achieve hepatic venous pressure gradient (HVPG) decremental response, liver-related and all-cause mortality. A Bayesian NWM was performed to derive relative risk (RR) with 95% credible intervals (CrIs). The ranking probability of each NSBB was assessed by surface under cumulative ranking curve (SUCRA). Thirty-three RCTs including 3,188 cirrhosis patients with gastroesophageal varices were included. Compared with placebo, nadolol ranked first for reducing variceal bleeding [RR:0.25, (95% CrI:0.11-0.51); SUCRA:0.898], followed by carvedilol [RR:0.33, (95% CrI: 0.11-0.88); SUCRA:0.692] and propranolol [RR:0.52, (95% CrI:0.37-0.75); SUCRA:0.405]. Carvedilol was more effective than propranolol in achieving HVPG decremental response [RR:0.43, (95% CrI: 0.26-0.69)]. Carvedilol ranked first for reducing all-cause mortality [RR: 0.32, (95% CrI:0.17-0.57); SUCRA:0.963), followed by nadolol [RR:0.48, (95% CI:0.29-0.77); SUCRA:0.688], and propranolol [RR:0.77, (95% CI:0.58-1.02); SUCRA: 0.337]. Similar findings were observed for liver-related mortality. Carvedilol ranked the safest. The RR of adverse events was 4.38, (95% CrI:0.33-161.4); SUCRA:0.530, followed by propranolol [RR: 7.54, (95% CrI:1.90-47.89); SUCRA:0.360], and nadolol [RR: 18.24, (95% CrI:91.51-390.90); SUCRA:0.158]. Carvedilol is the preferred NSBB with better survival benefit and lower occurrence of adverse events among patients with gastroesophageal varices.

The management of incidental meningioma: An unresolved clinical conundrum.

The widespread availability and use of brain magnetic resonance imaging and computed tomography has led to an increase in the frequency of incidental meningioma diagnoses. Most incidental meningioma are small, demonstrate indolent behavior during follow-up, and do not require intervention. Occasionally, meningioma growth causes neurological deficits or seizures prompting surgical or radiation treatment. They may cause anxiety to the patient and present a management dilemma for the clinician. The questions for both patient and clinician are "will the meningioma grow and cause symptoms such that it will require treatment within my lifetime?" and "will deferment of treatment result in greater treatment-related risks and lower chance of cure?." International consensus guidelines recommend regular imaging and clinical follow-up, but the duration is not specified. Upfront treatment with surgery or stereotactic radiosurgery/radiotherapy may be recommended but this is potentially an overtreatment, and its benefits must be balanced against the risk of related adverse events. Ideally, treatment should be stratified based on patient and tumor characteristics, but this is presently hindered by low-quality supporting evidence. This review discusses risk factors for meningioma growth, proposed management strategies, and ongoing research in the field.

Evaluation of lung adverse events with nivolumab using the spontaneous reporting system in Japan

This study was conducted to examine times to onset, incidence rates, and outcomes of nivolumab-induced lung adverse events (AEs), using the Japanese Adverse Drug Event Report database. We analysed data for the period between April 2004 and March 2021. Data on lung AEs were extracted, and relative risks of AEs were estimated using the reporting odds ratio. We analysed 5,273,115 reports and found 18,721 reports of nivolumab-related AEs, including 3084 lung AEs. Signals were detected for nine lung AEs: interstitial lung disease; pneumonitis; lung disorder; organising pneumonia; pleural effusion; pneumonia aspiration; pneumonia bacterial; radiation pneumonitis; and infectious pleural effusion. Among these, interstitial lung disease was the most frequently reported (68.7%) and included some fatal cases. A histogram of median times to onset showed AEs occurring from 34 to 79 days after the first dose, but some cases occurred even more than one year after starting administration. In conclusion, we focused on lung AEs caused by nivolumab as post-marketing AEs. Some cases could potentially involve serious outcomes, particularly in interstitial lung disease. Patients should be monitored for signs of the development of these AEs not only at the start of administration, but also over an extended time.

Discontinuation rate of sulfasalazine, leflunomide and methotrexate due to adverse events in a real-life setting (NOR-DMARD).

MTX, LEF and SSZ are conventional synthetic DMARDs (csDMARDs) with a well-established role in the treatment of RA. We aimed to estimate and compare the relative risks for adverse events (AEs) and the discontinuation of these drugs owing to AEs. We included all 3339 patients from the NOR-DMARD study treated with MTX, LEF or SSZ in monotherapy. All reported AEs were compared between treatment groups using quasi-Poisson regression. In addition, drug retention rates were analysed using Kaplan-Meier estimates with Cox regression to control for possible confounders. We analysed drug retention rates and cumulative risk of discontinuation attributable to AEs using the Kaplan-Meier estimator. We assessed age, sex, baseline DAS in 28 joints with ESR (DAS28-ESR), seropositivity, prednisolone use, previous DMARD use, year of inclusion and co-morbidity as possible cofounders. We found that the discontinuation rate attributable to AEs was significantly higher for LEF and SSZ than for MTX. After the first year, it was 13.7% (95% CI 12.2, 15.2), 39.6% (95% CI 34.8, 44) and 43.4% (95% CI 38.2, 48.1) for MTX, SSZ and LEF, respectively. Similar results were found when adjusting for confounders. The overall AEs were comparable across the treatment groups. The AE profile was as expected for each drug. Our work has shown a similar AE profile of csDMARDs to previous data. However, higher discontinuation rates for SSZ and LEF cannot be explained easily from AE profiles.

Safety implications of concomitant administration of antidepressants and opioid analgesics in surgical patients

ABSTRACT Background Commonly prescribed antidepressants (paroxetine, fluoxetine, duloxetine, bupropion) inhibit bioconversion of several prodrug opioid medications to their active metabolite, potentially decreasing analgesic effect. There is a paucity of studies assessing the risk-benefit of concomitant administration of antidepressants and opioids. Research design and methods Observational study of adult patients taking antidepressants prior to scheduled surgery using 2017–2019 electronic medical record data to assess perioperative use of opioids and to determine the incidence and risk factors for developing postoperative delirium. We conducted a generalized linear regression with the Gamma log-link to assess the association between use of antidepressants and opioids and a logistic regression to assess the association between antidepressants use and the likelihood of developing postoperative delirium. Results After controlling for patient demographic and clinical characteristics, and postoperative pain, use of inhibiting antidepressants was associated with 1.67 times greater use of opioids per hospitalization day (p = 0.00154), a two-fold increase in the risk for developing postoperative delirium (p = 0.0224), and an estimated average of four additional days of hospitalization (p < 0.00001) compared to use of non-inhibiting antidepressants. Conclusions Careful consideration to drug-drug interactions and risk of related adverse events remains critical in the safe and optimal management of postoperative pain in patients taking concomitantly antidepressants.

Efficacy and safety of frontline systemic therapy for advanced HCC: A network meta-analysis of landmark phase III trials

Direct comparisons across first-line regimens for advanced hepatocellular carcinoma are not available. We performed a network metanalysis of phase III of trials to compare first-line systemic treatments for hepatocellular carcinoma in terms of overall survival (OS), progression-free survival (PFS), objective response rate, disease control rate, and incidence of adverse events (AEs). After performing a literature review from January 2008 to September 2022, we screened 6,329 studies and reviewed 3,009 studies, leading to identification of 15 phase III trials for analysis. We extracted odds ratios for objective response rate and disease control rate, relative risks for AEs, and hazard ratios (HRs) with 95% CIs for OS and PFS, and used a frequentist network metanalysis, with fixed-effect multivariable meta-regression models to estimate the indirect pooled HRs, odds ratios, relative risks, and corresponding 95% CIs, considering sorafenib as reference. Of 10,820 included patients, 10,444 received active treatment and 376 placebo. Sintilimab+ IBI350, camrelizumab+ rivoceranib, and atezolizumab+ bevacizumab provided the greatest reduction in the risk of death compared with sorafenib, with HRs of 0.57 (95% CI 0.43-0.75), 0.62 (95% CI 0.49-0.79), and 0.66 (95% CI 0.52-0.84), respectively. Considering PFS, camrelizumab+ rivoceranib and pembrolizumab+ lenvatinib were associated with the greatest reduction in the risk of PFS events compared with sorafenib, with HRs of 0.52 (95% CI 0.41-0.65) and 0.52 (95% CI 0.35-0.77), respectively. Immune checkpoint inhibitor (ICI) monotherapies carried the lowest risk for all-grade and grade ≥3 AEs. The combinations of ICI+ anti-vascular endothelial growth factor, and double ICIs lead to the greatest OS benefit compared with sorafenib, whereas ICI+ kinase inhibitor regimens are associated with greater PFS benefit at the cost of higher toxicity rates. In the last few years, many different therapies have been studied for patients with primary liver cancer that cannot be treated with surgery. In these cases, anticancer drugs (alone or in combination) are given with the intent to keep the cancer at bay and, ultimately, to prolong survival. Among all the therapies that have been investigated, the combination of immunotherapy (drugs that boost the immune system against the cancer) and anti-angiogenic agents (drugs that act on tumoural vessels) has appeared the best to improve survival. Similarly, the combination of two types of immunotherapies that activate the immune system at different levels has also shown positive results. PROSPERO CRD42022366330.

Evaluation of Cardiac Adverse Events with Nivolumab Using a Japanese Real-World Database.

Nivolumab has been used for the treatment of various types of cancers and has achieved improvements in overall survival. However, nivolumab can cause a variety of adverse events (AEs). Among these, cardiac-specific AEs have received little attention in clinical trials, despite their life-threatening potential. The present study aimed to determine the risk of nivolumab-induced cardiac AEs, time to onset, incidence rates, and post hoc outcomes using the Japanese Adverse Drug Event Report database. We analyzed data for the period between April 2004 and March 2021. Data on cardiac AEs were extracted and relative risk of AEs was estimated using the reporting odds ratio (ROR). We analyzed 1,772,494 reports and identified 18,721 reports of AEs caused by nivolumab. Of these, 409 reports involved cardiac AEs. Signals were detected for four cardiac AEs: myocarditis; pericardial effusion; pericarditis; and immune-mediated myocarditis. Among these, myocarditis was the most frequently reported (35.0%) and included fatal cases. A histogram of times to onset showed nivolumab-associated AEs occurring 41-127days after starting administration, with outlier cases of myocarditis or pericardial effusion occurring after more than one year, both with catastrophic consequences. This study focused on cardiac AEs caused by nivolumab as post-marketing AEs. Myocarditis and pericardial effusion have been associated with some fatal cases after administration of nivolumab. Patients should be monitored for signs of onset for these AEs, not only at the start of administration, but also over an extended period after nivolumab administration.

Evaluation of lung adverse events with trastuzumab using the Japanese pharmacovigilance database.

The present study aimed to determine the risk of trastuzumab-induced lung toxicity, time to onset, and post hoc outcomes using the Japanese Adverse Drug Event Report database. We analyzed data for the period between April 2004 and March 2021. Data on lung toxicities were extracted, and relative risk of adverse events (AEs) was estimated using the reporting odds ratio. We analyzed 1,772,494 reports and identified 4362 reports of AEs caused by trastuzumab. Of these, 693 lung toxicities were reportedly associated with trastuzumab. Signals were detected for seven lung toxicities: interstitial lung disease, pulmonary edema, pleural effusion, lung disorder, acute pulmonary edema, pulmonary fibrosis, and radiation pneumonitis. Among these, interstitial lung disease was the most frequently reported (61.8%). A histogram of times to onset showed occurrence from 1 to 105days, but some cases of interstitial lung disease occurred even more than one year after the start of administration. The AEs showing the highest fatality rates were interstitial lung disease, pulmonary fibrosis, and radiation pneumonitis. This study focused on lung toxicities caused by trastuzumab as post-marketing AEs. Some cases could potentially involve serious outcomes; therefore, patients should be monitored for signs of the onset of these AEs not only at the start of administration, but also over an extended period, especially for interstitial lung disease.

Evaluation of lung toxicity with bevacizumab using the spontaneous reporting database

This study was undertaken to determine the risk of bevacizumab-induced lung toxicity, time to onset, and post hoc outcomes using the Japanese Adverse Drug Event Report database. We analysed data for the period between April 2004 and March 2021. Data on lung toxicities were extracted, and relative risk of adverse events (AEs) was estimated using the reporting odds ratio. We analysed 5,273,115 reports and identified 20,399 reports of AEs caused by bevacizumab. Of these, 1679 lung toxicities were reportedly associated with bevacizumab. Signals were detected for nine lung toxicities. A histogram of times to onset showed occurrence from 35 to 238 days, but some cases occurred even more than one year after the start of administration. Approximately 20% of AEs were thromboembolic events. Among these, pulmonary embolism was the most frequently reported and fatal cases were also reported. The AEs showing the highest fatality rates were pulmonary haemorrhage, pulmonary infarction, and pulmonary thrombosis. In conclusion, we focused on lung toxicities caused by bevacizumab as post-marketing AEs. Some cases could potentially result in serious outcomes, patients should be monitored for signs of onset of AEs not only at the start of administration, but also over a longer period of time.

Efficacy and safety profile of antivascular endothelial growth factor receptor tyrosine kinase inhibitors (avRTKIs) in patients (Pts) with neuroendocrine tumors(NETs): A systematic review and meta-analysis (SRMA).

e16216 Background: Vascular endothelial growth factor mediated signaling is central to NETs. As such, multiple avRTKIs have been tested in NETs over the last 2 decades, mostly in small phase II studies. In fact, there have been no randomized phase III trials conducted in United States apart from the one leading to approval of sunitinib in pancreatic (p) NETs. Several other avRTKIs have demonstrated clinical promise including surufatinib in phase III trials conducted in China; this drug is currently under FDA review for potential approval. In the current SRMA, we aim to address this deficiency by benchmarking efficacy and safety profiles of avRTKIs. Methods: A literature search was done to identify all phase II and phase III studies of avRTKIs in pts with NETs published between 1/1/2000–7/31/2021. Data abstraction was performed by one author and validated by another. Efficacy was assessed by aggregating progression-free survival (PFS) and overall response rate (ORR) data. PFS and ORR were assessed using a random effects model separately for pts with pNETs and extra-pancreatic (ep) NETs. Toxicity was assessed by calculating the relative risk (RR) compared to control arm and incidence of adverse events (AEs) of interest. Results: Of 92 identified studies, 17 (with 8 individual avRTKIs) were included in the meta-analysis after excluding redundant studies; baseline study characteristics are listed in the Table.A total of 1611 pts (853 men, 758 women) were available for the analysis; 1194 received avRTKIs. The ORR in pNETs was 18% (95% confidence interval (CI) 13-25%) while the ORR in pts with epNETs was 8% (95% CI 5-12%); test for differences between pNETs and epNETs (x12 = 8.47, p &lt; .01). The median PFS in pNETs was 13.9 months (95% CI 11.43-16.38 months) while median PFS in epNETs was 12.71 months (95% CI 9.37-16.05 months); test for differences between pNETs and epNETs (x12 = .32, p = .57). The incidence (and RR compared to control) of most common ≥ grade 3/4 AEs were hypertension 22.4% (4.48, p &lt; .001), diarrhea 6.4% (RR 3.03, p = .005), neutropenia 5.2% (20.4, p = .036) and proteinuria 4.6% (27.25, p = .001). Incidence (and RR compared to control) of rare but serious complications included non-central nervous system bleeding 8.7% (2.17, p &lt; .001) and cardiac dysfunction 6.4% (2.52, p = .01). Conclusions: Among pts tx with avRTKIs, pts with pNETs demonstrated improved ORR but not PFS compared to these outcomes in pts with epNETs. In addition, this study also benchmarks the incidence and RR of AEs in pts with NETs treated with avRTKIs who are often on therapy longer than other pts.[Table: see text]

Time to Onset of Bendamustine-associated Skin Damage Using the Spontaneous Reporting System.

Bendamustine-associated skin damage occurs frequently in Japan and can have a profound impact on health-related quality of life. To our knowledge, there are no reports on the timing of skin damage caused by bendamustine. This study assessed trends in and the time to onset of skin damage caused by bendamustine using the Japanese Adverse Drug Reaction Reporting Database (JADER). Data related to skin damage with more than five reported cases from April 2004 to March 2021 were extracted from JADER, and the relative risk of adverse events was estimated using the reporting odds ratio and 95% confidence interval. The data were analyzed for time to onset of skin damage. JADER included a total of 2,450 reports of adverse drug reactions from bendamustine. Of these, 170 skin ailments of 10 types were reported to be associated with bendamustine. Significant associations for skin damage were found for rash, herpes zoster, and infusion-related reactions. The reporting odds ratios (with 95% confidence interval) for rash, herpes zoster, and infusion-related reaction were 1.63 (1.19-2.21), 3.25 (2.20-4.78), and 7.25 (4.84-10.85), respectively. The median onset (interquartile range) of rash, herpes zoster, and infusion-related reactions caused by bendamustine were 13 (10-28), 60 (28-107), and 6 (1-28) days, respectively. A comprehensive study using a pharmacovigilance approach enabled us to identify that a rash or infusion-related reaction may be expected within 2 weeks of treatment with bendamustine and that the onset of herpes zoster occurs at a median of 2 months after treatment with bendamustine.

Clinical Characteristics and Risk Factors for Pulmonary Infection in Emergency ICU Patients.

Background Pulmonary infection in the emergency ICUs increases patient morbidity, hospital stay, treatment costs, and the risk of related adverse events. Methods This study included 695 patients admitted to our emergency ICU between December 2019 and March 2021. Medical records of emergency ICU patients were reviewed to collect their clinical data, including antibiotic use, history of tracheostomy, history of mechanical ventilation, presence or absence of underlying disease, history of smoking, alcohol consumption, age, gender, and history of shock. Bacterial cultures were performed. The incidence, main clinical features, main pathogens, and risk factors of pulmonary infection in emergency ICU were analyzed. Results In this study, 69 of the 695 emergency ICU patients (9.93%) developed pulmonary infection. The main clinical features of patients with pulmonary infection included cough and expectoration (97.10%), shortness of breath and chest tightness (95.65%), leukocyte elevation (69.57%), confusion (31.88%), drowsiness (28.99%), persistent fever (27.54%), and nausea and vomiting (10.14%). The main pathogenic bacteria in those with pulmonary infection included Klebsiella pneumoniae (62.32%), Pseudomonas aeruginosa (49.28%), Streptococcus pneumoniae (21.74%), Staphylococcus aureus (39.13%), Candida albicans (7.25%), Pneumococcus pneumoniae (15.95%), Pseudomonas aeruginosa (24.64%), and lung diplococcus inflammatory (13.04%). Univariate analysis showed that there were no significant differences in the occurrence of pulmonary infection with regard to sex, smoking, and alcohol consumption, but there were significant differences with regard to age, basic disease, invasive surgery, and shock. Logistic regression analysis confirmed that age ≥ 80 years, invasive surgery, shock, and basic diseases ≥ 2 were important risk factors for pulmonary infection in emergency ICU patients. Conclusion Considering the clinical features and risk factors for pulmonary infection in the emergency ICU, preventive and control measures are required to minimize its occurrence and ensure good outcomes.

Prior-Preconditioned Conjugate Gradient Method for Accelerated Gibbs Sampling in “Large n, Large p” Bayesian Sparse Regression

In a modern observational study based on healthcare databases, the number of observations and of predictors typically range in the order of 105–106 and of 104–105. Despite the large sample size, data rarely provide sufficient information to reliably estimate such a large number of parameters. Sparse regression techniques provide potential solutions, one notable approach being the Bayesian method based on shrinkage priors. In the “large n and large p” setting, however, the required posterior computation encounters a bottleneck at repeated sampling from a high-dimensional Gaussian distribution, whose precision matrix Φ is expensive to compute and factorize. In this article, we present a novel algorithm to speed up this bottleneck based on the following observation: We can cheaply generate a random vector b such that the solution to the linear system Φ β = b has the desired Gaussian distribution. We can then solve the linear system by the conjugate gradient (CG) algorithm through matrix-vector multiplications by Φ ; this involves no explicit factorization or calculation of Φ itself. Rapid convergence of CG in this context is guaranteed by the theory of prior-preconditioning we develop. We apply our algorithm to a clinically relevant large-scale observational study with n = 72 , 489 patients and p = 22 , 175 clinical covariates, designed to assess the relative risk of adverse events from two alternative blood anti-coagulants. Our algorithm demonstrates an order of magnitude speed-up in posterior inference, in our case cutting the computation time from two weeks to less than a day. Supplementary materials for this article are available online.

Drug Treatment of Hypercholesterolemia in Older Adults: Focus on Newer Agents.

There is increasing research interest in cholesterol-lowering therapy in older patients. The newer lipid-lowering agents (the proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors evolocumab and alirocumab; the PCSK9 synthesis inhibitor inclisiran, and the adenosine triphosphate–citrate lyase inhibitor bempedoic acid) might also provide more options for the future treatment of older patients. Data analyses of the phase III outcome trials of the PCSK9 inhibitors suggest that their clinical benefits are maintained at older ages and that there is no increased relative risk of adverse events in older patients; however, data from patients aged ≥ 75 years and particularly aged ≥ 85 years are limited, and the trials did not collect information on the frailty status of patients. Frailty is a predictor of adverse outcomes, including mortality, and might help guide therapy decisions. To date, no outcome data are available for cardiovascular endpoints for the low-density lipoprotein cholesterol-lowering drugs inclisiran and bempedoic acid. Except for the risk of gout and tendon rupture with bempedoic acid, which remains to be further characterized in larger populations, the safety profile of the novel lipid-lowering agents in older patients seems favorable. The newer lipid-lowering agents could be added to other lipid-lowering medication or used as an alternative treatment in older patients with documented statin intolerance (as is already recommended in guidelines for the PCSK9 inhibitors), such as myopathy. Especially in older patients needing high-intensity therapy despite polypharmacy or certain comedications, the absence of clinically relevant drug–drug interactions with the PCSK9 inhibitors and inclisiran might be an advantage.

Efficacy and safety of belimumab in the treatment of systemic lupus erythematosus: A meta‑analysis

The present meta‑analysis aimed to systematically review the efficacy and safety of belimumab (BLM) therapy for patients with active and autoantibody‑positive systemic lupus erythematosus (SLE) treated with standard of care (SOC). To evaluate the efficacy and safety of BLM plus SOC treatment in patients with active SLE, eligible studies were retrieved from the Web of Science, The Cochrane Library, PubMed and Embase online databases up to July, 2021. Review Manager (version 5.3) and STATA 16.0 software were used to analyze the extracted data from the included studies. A total of seven randomized controlled trials (RCTs) and 19 case series, with 4,235 and 2,597 patients with SLE, respectively were analyzed. In the RCTs, there were more SLE responder index (SRI‑4) responders in the BLM group compared with the control group [52.8 vs. 41.6%; relative risk (RR), 1.27; 95% confidence interval (95% CI), 1.18‑1.37); P&lt;0.00001]. In addition, compared with the placebo group, more patients in the BLM group achieved a ≥4‑point reduction in the Safety of Estrogens in Lupus National Assessment‑Systemic Lupus Erythematosus Disease Activity Index score (RR, 1.26; 95% CI, 1.15‑1.38; P&lt;0.00001). Furthermore, treatment with BLM was found to significantly decrease the risk of severe disease exacerbations (flares) compared with the control group (RR, 0.72; 95% CI, 0.63‑0.81; P&lt;0.00001). Additionally, the corticosteroid dosage was reduced by ≥25 or 50% to ≤7.5 mg/day during weeks 40‑52 in more patients in the BLM group compared with the control group (RR, 1.44; 95% CI, 1.17‑1.76; P=0.0005). However, no differences were observed in the RR of adverse events (AEs) and severe AEs between both groups (RR, 1.00; 95% CI, 0.97‑1.02; P=0.84; and RR, 0.80; 95% CI, 0.62‑1.03; P=0.08, respectively). In the case series studies, the total remission rate was 60.5% (95% CI, 52.1‑68.3%; P=0.015). In addition, treatment with BLM significantly decreased the use of corticosteroids (mean deviation, ‑8.73; 95% CI, ‑11.07 to ‑6.39; P&lt;0.00001). Overall, the results of the present meta‑analysis demonstrated that BLM therapy provided significant clinical efficacy and it was well‑tolerated by patients with active SLE. More importantly, treatment with BLM may reduce the use of glucocorticoids.

Novel Therapies in Takayasu Arteritis.

Takayasu Arteritis (TAK) is a large-vessel vasculitis that preferentially involves the aorta and its primary branches. Cardiac involvement is frequent in TAK and is a major determinant of the patient's outcome. Glucocorticoids (GC) are the mainstay of therapy for TAK, with high doses of GC effective to induce remission. However, relapses are common and lead to repeated and prolonged GC treatments with high risk of related adverse events. Potential GC toxicity is a major concern, especially because patients with TAK are young and need to be treated for several years, often for the whole life. Conventional immunosuppressive drugs are used in patients with severe manifestations but present some limitations. New therapeutic approaches are needed for patients with refractory disease or contraindications to conventional therapies. Fortunately, major progress has been made in understanding TAK pathogenesis, leading to the development of targeted biotherapies. In particular, IL-6 and TNF-α pathways seems to be the most promising therapeutic targets, with emerging data on Tocilizumab and TNF inhibitors. On the other hand, new insights on JAK-Inhibitors, Rituximab, Ustekinumab and Abatacept have been explored in recent studies. This review summarizes the emerging therapies used in TAK, focusing on the most recent studies on biologics and analyzing their efficacy and safety.