Risk Of Serious Adverse Events Research Articles

Dose reduction and discontinuation due to the combination of CDK4/6 inhibitors and endocrine drugs: a systematic review and meta-analysis.

With the widespread use of CDK4/6 inhibitors, the number of discontinuations and reductions due to adverse events is increasing. Therefore, we examined the risk of dose reduction, discontinuation, and occurrence of serious adverse events and death due to adverse events when CDK4/6 inhibitors are combined with endocrine drugs. We searched English-language articles published up to February 10, 2024, using RR values (risk ratio) to indicate the risk of discontinuation, dose reduction, death, and the risk of serious adverse events. When CDK4/6 inhibitors were used in combination with endocrine drugs, abemaciclib resulted in the highest risk of discontinuation, dose reduction, and serious adverse events. Ribociclib caused the highest risk of death. When using CDK4/6 inhibitors in the clinical setting, a comprehensive evaluation should be performed to avoid dosage reductions and discontinuations and to choose the most appropriate treatment regimen.

A novel antigen biomarker for detection of high-level of Loa loa microfilaremia.

Loiasis is a disease caused by the nematode Loa loa. Serious adverse events sometimes occur in people with heavy L. loa microfilaremia after ivermectin treatment. In regions of Central Africa where loiasis is endemic, this significantly impedes global elimination programs for lymphatic filariasis and onchocerciasis that use mass distribution of ivermectin. Improved diagnostic tests to identify individuals at increased risk of serious adverse events could facilitate efforts to eliminate lymphatic filariasis and onchocerciasis in this region. We previously identified the L. loa protein Ll-Bhp-1 in loiasis patient sera. Here, we further characterize Ll-Bhp-1 and report development of an antigen capture ELISA to detect this antigen. This assay detected Ll-Bhp-1 in 74 of 116 (63.8%) loiasis patient sera. Ll-Bhp-1 levels were significantly correlated with L. loa microfilarial counts, and the sensitivity of the assay was highest for samples from people with high counts, (94% and 100% in people with ≥20,000 and ≥50,000 microfilaria per milliliter of blood, respectively). The antigen was not detected in 112 sera from people with other filarial infections, or in 34 control sera from the USA. This Ll-Bhp-1 antigen assay is specific for loiasis, and highly sensitive for identifying people with high L. loa microfilarial counts who are at increased risk for serious adverse events after ivermectin treatment. L. loa antigen detection has the potential to facilitate loiasis mapping efforts and programs to eliminate lymphatic filariasis and onchocerciasis in Central Africa.

Improvements in daytime sleepiness and disrupted nighttime sleep with once-nightly sodium oxybate in people with narcolepsy type 1 and type 2: a plain language summary.

This is a plain language summary of a published article in the journal Sleep. Narcolepsy is a sleep condition that has 2 different subtypes: narcolepsy type 1 and narcolepsy type 2. These are called NT1 and NT2 for short. Sodium oxybate (SXB) is approved to treat excessive daytime sleepiness (EDS) and cataplexy. People with NT1 and NT2 both have EDS, but cataplexy is only present in people with NT1. Limited information is available about how SXB works in people with NT2. This is because previous trials have included only people with NT1 or people with unspecified narcolepsy. For more than 20years, the only available formulation of this medicine had to be given twice during the night. Many people with narcolepsy find that chronically waking up in the middle of the night for a second dose of SXB is disruptive to themselves or others in their household. People have also reported sleeping through alarm clocks, missing their second dose, and feeling worse the next day. Some people have accidentally taken the second dose too early, putting them at risk for serious adverse effects. These adverse effects may include slow breathing, low blood pressure, or sedation. The US Food and Drug Administration (FDA) approved a medicine called LUMRYZ™ (sodium oxybate) for extended-release oral suspension in May 2023. LUMRYZ is a once-nightly formulation of SXB (ON-SXB for short) and is taken as a single dose before bedtime. This medicine treats EDS and muscle weakness (also known as cataplexy) in people with narcolepsy. A clinical trial called REST-ON studied ON-SXB to find out if it was better at treating narcolepsy symptoms than a medicine with no active ingredients (placebo). This summary describes a study that tested whether ON-SXB was better than placebo at treating narcolepsy symptoms in people with NT1 or NT2. This study showed that compared to people who took placebo, people who took ON-SXB were able to stay awake longer during the day, felt less sleepy during the daytime, had less cataplexy, and had more improvements in their symptoms overall than people who took placebo. ON-SXB has been proven effective for people with NT1 or NT2. Unlike prior formulations of SXB, ON-SXB is taken once at bedtime, without requiring waking up in the middle of the night for a second dose.

Safety and Efficacy of the Novel RNA Interference Therapies for Hypertriglyceridemia and Mixed Hyperlipidemia Management: A Systematic Review and Meta-analysis

BackgroundNo meta-analysis has holistically analyzed and summarized the safety and therapeutic efficacy of the newer RNA interference (RNAi) therapies, olezarsen, plozasiran, and zodasiran, in managing conditions associated with hypertriglyceridemia (HTG). MethodsRandomized controlled trials (RCTs) involving patients with HTG or mixed hyperlipidemia (MHL) receiving either olezarsen, plozasiran, or zodasiran in the intervention arm and a placebo in the control arm were searched through electronic databases. The primary outcome was the safety profile of the drugs studied; secondary outcomes included the percent change from baseline (CFB) in the lipid levels, including triglyceride (TG). ResultsSix RCTs with 334 participants were evaluated. Olezarsen, plozasiran, and zodasiran were well-tolerated with no higher risk of serious adverse events or injection-site reactions. After 24 weeks, plozasiran increased alanine aminotransferase and HbA1c more than placebo, although the difference was insignificant at 48 weeks. Plozasiran and zodasiran had little effect on hyperglycemia worsening. Olezarsen increased the likelihood of mild platelet count decreases without clinical harm. At their longest clinical trial follow-up, the highest doses of olezarsen, plozasiran, and zodasiran lowered TG by 55.2%, 50.57%, and 51.2% of baseline levels. All three drugs decreased non-HDL-C and remnant cholesterol. Olezarsen and plozasiran lowered ApoC-III and increased HDL-C, whereas zodasiran reduced HDL-C. Zodasiran decreased LDL-C, whereas olezarsen and plozasiran had no effects on LDL-C. Plozasiran and zodasiran lowered apolipoprotein B, but not olezarsen. ConclusionThe newer RNA interference (RNAi) therapies appear safe and have excellent TG-lowering efficacy in patients with HTG and MHL.

Efficacy and safety of therapeutic vaccines for the treatment of chronic hepatitis B: A systematic review and meta-analysis of randomized controlled trials update.

Most people diagnosed with chronic hepatitis B (CHB) need treatment to help reduce the risk of liver disease and limit disease transmission. Therapeutic vaccine (TV) candidates have been under study for their clinical effects on inducing HBV-specific host immune responses. This review aimed to systematically synthesize updated evidence on the efficacy and safety of TVs in patients with CHB. This systematic review was performed by searching different databases from January to February 2021. Completed randomized controlled trials that reported TVs' efficacy and/or safety for treating CHB compared with the standard of care (SOC) or placebo were included. Efficacy and safety estimates were reported as the logarithm of the odds ratio and risk differences, respectively. I2 > 50% was considered significant heterogeneity. Significant publication bias was considered when Egger's test P value < .10. The risk of bias was assessed using the Cochrane Risk of Bias tool. The GRADE methodology was used to assess the certainty of the evidence for each outcome. Twenty-four articles with 2889 pooled samples were included. TVs made a significant difference in hepatitis B envelope antigen (HBeAg) SC (log OR = 0.76, P = .01) and (log OR = 0.40, P = .03) compared to placebo and combination therapy, respectively. HBeAg SC was significantly affected by TVs at the end of follow up (log OR = 0.49, P = .01), with significant HBsAg mean difference (MD = -0.62, P = .00). At the end of treatment, the TVs had no significant effect on HBV DNA negativity over the SOC (log OR = 0.62, P = .09) or placebo (log OR = -0.07, P = .91). TVs do not significantly affect the risk of serious adverse events (RD 0.02, 95% CI 0.00-0.04). In patients with CHB, TVs had significant effects on HBeAg SC compared to the SOC or placebo. There was no significant difference between serious adverse events. TVs are promising treatment strategy to overcome CHB.

The Safety of Methoxyflurane for Emergency Pain Relief in Children and Adolescents: A Retrospective Cohort Study

Objectives The use of methoxyflurane is becoming increasingly popular in the treatment of pain in an emergency setting, in part due to its ease of administration. However, little is known about the risk of serious adverse events in children and adolescents. The aim of this study was to examine the safety of methoxyflurane in a pediatric population. Methods The study was a retrospective cohort study of pediatric prehospital events using probabilistic linked health data. All ambulance transfers in Western Australia between 1990 and 2016 involving children and adolescent patients were identified. Patients were categorized based on administered analgesia: methoxyflurane, an opioid analgesic, both methoxyflurane and an opioid analgesic, or no analgesic. Hospital and mortality data were linked to transferred patients to identify deaths, adverse drug reactions, liver and kidney toxicity, and re-admissions to hospital following ambulance transfer. Generalized linear models, adjusting for sociodemographic and ambulance transfer characteristics, were used to compare outcomes between children exposed to methoxyflurane and the other three groups. Results The study cohort consisted of 37,211 children, including 9,472 patients (25.5%) treated with methoxyflurane alone, 2,764 (7.4%) treated with an opioid analgesic, 1,235 (3.3%) treated with both methoxyflurane and an opioid analgesic, and 23,740 (63.8%) treated with no analgesic. Death in children and adolescents was uncommon, with less than five deaths (<0.1%) observed in the 12 months following treatment with methoxyflurane and no deaths in those treated with both methoxyflurane and an opioid analgesic. Adverse drug reaction was rare (<0.1%) in patients treated with methoxyflurane, as was liver and kidney toxicity with no case observed. At 90-days follow-up, there was no significant difference in hospitalization in patients treated with methoxyflurane and those treated with methoxyflurane and an opioid analgesic (adjusted OR:1.01, 95%CI:0.85-1.21). Compared with methoxyflurane treated patients, patients treated with an opioid analgesic were more likely to be hospitalized (aOR:1.23, 95%CI:1.09-1.39), while patients treated with no analgesic were less likely to be hospitalized (aOR:0.85, 95%CI:0.79-0.92). Conclusions In children and adolescents transported by ambulance, the use of methoxyflurane was not associated with an increased risk of hospitalization, death, serious adverse drug reactions or liver and kidney toxicity.

Immunogenicity and Safety of Chikungunya Vaccines: A Systematic Review and Meta-Analysis

Several vaccines against chikungunya fever have been developed and tested, and one has been recently licensed. We performed a meta-analysis to estimate the immunogenicity and safety of all chikungunya vaccines that have been progressed to clinical trial evaluation (VLA1553; mRNA-1388/VAL-181388; PXVX0317/VRC-CHKVLP059-00-VP; ChAdOx1 Chik; MV-CHIK). We included trials retrieved from MedLine, Scopus, and ClinicalTrials.gov. The outcomes were the rates of seroconversion/seroresponse and serious adverse events (SAEs) after the primary immunization course. We retrieved a total of 14 datasets, including &gt;4000 participants. All candidate chikungunya vaccines were able to elicit an immunogenic response in ≥96% of vaccinated subjects, regardless of the vaccination schedule and platform used, and the seroconversion/seroresponse rates remained high 6 to 12 months after vaccination for most vaccines. Four of the five candidate vaccines showed a good overall safety profile (no data were available for ChAdOx1 Chik), with no significant increase in the risk of SAEs among the vaccinated, and a low absolute risk of product-related SAEs. Overall, the present findings support the potential use of the candidate vaccines for the prevention of chikungunya and the current indication for use in adult travelers to endemic regions of the licensed VLA 1553 vaccine. In order to extend chikungunya vaccination to a wider audience, further studies are needed on individuals from endemic countries and frail populations.

Deep brain stimulation for Parkinson’s disease: systematic review with meta-analysis and trial sequential analysis

ObjectiveTo assess the benefits and harms of deep brain stimulation for Parkinson’s disease.DesignSystematic review with meta-analysis and trial sequential analysis.Data sourcesCochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, Latin...

Rates and Impact of Serious Adverse Events after Endovascular Thrombectomy among Large Vessel Occlusion Stroke Patients.

Complications or serious adverse events (SAEs) are common in the treatment of patients with large vessel occlusion stroke. There has been limited study of the impact of SAEs for patients after endovascular thrombectomy (EVT). The goal of this study was to characterize the rates and clinical impact of SAEs following EVT. A post hoc analysis was performed using pooled databases of the "DEVT" and "RESCUE BT" trials. SAEs were designated as symptomatic intracranial hemorrhage, brain herniation or craniectomy, respiratory failure, circulatory failure, pneumonia, deep venous thrombosis, and systemic bleeding. The primary endpoint was functional independence (modified Rankin scale score 0-2 within 90 days). Logistic regression analysis was used to determine the predictors and associations between SAEs and outcomes. Of 1,182 enrolled patients, 402 (34%) had a procedural complication and 745 (63%) had 1,404 SAE occurrences with 4.65% in-hospital mortality. The three most frequent SAEs were pneumonia (620, 52.5%), systemic bleeding (174, 14.7%), and respiratory failure (173, 14.6%). Pneumonia, systemic bleeding, or deep venous thrombosis was less life-threatening. Patients with advanced age (adjusted odds ratio, 1.28 [95% confidence interval, 1.14-1.43]), higher NIHSS (1.09 [1.06-1.11]), occlusion site (middle cerebral artery-M1 vs. internal carotid artery [ICA]: 0.75 [0.53-1.04]; M2 vs. ICA: 1.30 [0.80-2.12]), longer procedure time (1.01 [1.00-1.01]), and unsuccessful vessel recanalization (1.79 [1.06-2.94]) were more likely to experience SAEs. Compared with no SAE, patients with SAEs had lower odds of functional independence (0.46 [0.40-0.54]). Overall, SAEs diagnosed following thrombectomy in patients with stroke were common (more than 60%) and associated with functional dependence. Patients with advanced age, higher NIHSS, longer procedure time, and failed recanalization were more likely to experience SAEs. There was no statistical difference in the risk of SAEs among patients with M1 and M2 occluded compared with those ICA occluded. An understanding of the prevalence and predictors of SAEs could alert clinicians to the estimated risk of an SAE for a patient after EVT.

Safety and Effectiveness of Thiopurines and Small Molecules in Elderly Patients with Inflammatory Bowel Diseases.

The management of inflammatory bowel diseases (IBD) requires weighing an individual patient's therapeutic benefits and therapy-related complication risks. The immunomodulators that have been commonly used so far in IBD therapy are thiopurines, including 6-mercaptopurine and azathioprine. As our understanding of the IBD pathomechanisms is widening, new therapeutic approaches are being introduced, including the Janus kinase (JAK) inhibitors and Sphingosine 1-phosphate receptor (S1PR) modulators' development. Non-selective JAK inhibitors are represented by tofacitinib, while selective JAK inhibitors comprise filgotinib and upadacitinib. As for the S1PR modulators, ozanimod and etrasimod are approved for UC therapy. The number of elderly patients with IBD is growing; therefore, this review aimed to evaluate the effectiveness and safety of the oral immunomodulators among the subjects aged ≥60. Possible complications limit the use of thiopurines in senior patients. Likewise, the promising effectiveness of new drugs in IBD therapy in those with additional risk factors might be confined by the risk of serious adverse events. However, the data regarding this issue are limited.

Correlation of Urinary Soluble CD163 Levels With Disease Activity and Treatment Response in IgA Nephropathy

BackgroundThe TESTING trial demonstrated that corticosteroids reduce the risk of kidney failure in IgA nephropathy (IgAN) patients but increase the risk of serious adverse events. Reliable noninvasive biomarkers are needed to identify patients who would benefit most from corticosteroid therapy. Previous studies suggest glomerular macrophage infiltration is associated with the response to immunosuppressive therapy in IgAN and urinary soluble CD163(u-sCD163, a marker of M2c macrophage) is correlated with clinical remission in vasculitis. This study aims to investigate the association between u-sCD163 and response of steroids therapy in IgAN. MethodsWe measured u-sCD163 in patients from a large IgAN cohort including China participants of the TESTING trial. The correlation of baseline or serial u-sCD163 and their response of corticosteroids therapy or kidney outcomes were investigated. ResultsIn cross-sectional analysis, u-sCD163 levels correlated with kidney macrophage infiltration, especially in crescentic areas, and with active lesions. Subgroup analysis of the TESTING cohort showed higher levels u-sCD163 were associated with greater benefits from corticosteroids therapy in proteinuria remission [OR, 35.56 (95% CI, 7.62-292.34) vs 3.94 (95% CI, 1.39-12.93), p for interaction 0.036]. Corticosteroids therapy significantly reduced u-sCD163 levels at 6th month compared to placebo group [79% (IQR 58%,91%) vs 37% (-11%,58%), P<0.001]. There was no difference in the suppressive effects on u-sCD163 by either dosage of corticosteroids (full and reduced-dose). The suppression of u-sCD163 was significantly associated with a reduced risk of kidney progression events (adjusted HR 0.52,95% CI 0.30 to 0.93, P=0.027). ConclusionsU-sCD163 is a reliable noninvasive biomarker associated with active pathological lesions in IgAN and can guide glucocorticoid therapy.

The Safety of Intraoperative Photodynamic Diagnosis Using 5-Aminolevulinic Acid Combined with Talaporfin Sodium Photodynamic Therapy in Recurrent High-Grade Glioma

Intraoperative photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA) is a widely adopted technique to enhance the extent of resection during high-grade glioma (HGG) surgery. Recent updates to the package insert for 5-ALA in Japan now allow its use in combination with drugs that may induce photosensitivity, such as talaporfin sodium (TS). TS is employed in intraoperative photodynamic therapy (PDT) and has been shown to improve overall survival. The combination of 5-ALA with TS is expected to offer further benefits. However, the safety of this combination had not been established. This study reports on the safety of 5-ALA-PDD with TS-PDT in the treatment of recurrent HGG. 7 patients with recurrent HGG underwent tumor resection using a combination of 5-ALA-PDD and TS-PDT. The incidence of photosensitivity as an adverse effect associated with 5-ALA and TS was evaluated as described in the package insert. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Tumor-specific fluorescence intensity was strong in 4 cases and weak in 3. Photosensitivity occurred in only 1 patient (14.3%). Three patients exhibited CTCAE grade 1 or 2 abnormal liver function, and 1 patient experienced CTCAE grade 1 γ-GTP elevation. All abnormalities improved during follow-up. The combined use of 5-ALA-PDD and TS-PDT for HGG surgery did not increase the risk of serious adverse events in our study. Further investigations with a larger number of cases are needed for a more accurate assessment of its safety and efficacy.

Risk of serious adverse events after primary shoulder replacement: development and external validation of a prediction model using linked national data from England and Denmark

Despite a rising rate of serious medical complications after shoulder replacement surgery, there are no prediction models in widespread use to guide surgeons in identifying patients at high risk and to provide patients with personalised risk estimates to support shared decision making. Our aim was to develop and externally validate a prediction model for serious adverse events within 90 days of primary shoulder replacement surgery. Linked data from the National Joint Registry, National Health Service Hospital Episode Statistics Admitted Patient Care of England, and Civil Registration Mortality databases and Danish Shoulder Arthroplasty Registry and National Patient Register were used for our modelling study. Patients aged 18-100 years who had a primary shoulder replacement between April 1, 2012, and Oct 2, 2020, in England, and April 1, 2012, and Oct 2, 2018, in Denmark, were included. We developed a multivariable logistic regression model using the English dataset to predict the risk of 90-day serious adverse events, which were defined as medical complications requiring admission to hospital and all-cause death. We undertook internal validation using bootstrapping, and internal-external cross-validation across different geographical regions of England. The English model was externally validated on the Danish dataset. Data for 40 631 patients undergoing primary shoulder replacement (mean age 72·5 years [SD 9·9]; 28 709 [70·7%] women and 11 922 [29·3%] men) were used for model development, of whom 2270 (5·6%) had a 90-day serious adverse event. On internal validation, the model had a C-statistic of 0·717 (95% CI 0·707-0·728) and was well calibrated. Internal-external cross-validation showed consistent model performance across all regions in England. Upon external validation on the Danish dataset (n=6653; mean age 70·5 years [SD 10·3]; 4503 [67·7%] women and 2150 [32·3%] men), the model had a C-statistic of 0·750 (95% CI 0·723-0·776). Decision curve analysis showed clinical utility, with net benefit across all risk thresholds. This externally validated prediction model uses commonly available clinical variables to accurately predict the risk of serious medical complications after primary shoulder replacement surgery. The model is generalisable and applicable to most patients in need of a shoulder replacement. Its use offers support to clinicians and could inform and empower patients in the shared decision-making process. National Institute for Health and Care Research and the Department of Orthopaedic Surgery, Herlev and Gentofte Hospital, Denmark.

Efficacy and outcomes of BCG re-vaccination in COVID-19: a systematic review, meta-analysis, and meta-regression of randomized controlled trials.

The Bacillus Calmette-Guerin (BCG) vaccine has a beneficial "off-target" effect that offers heterologous protection against respiratory tract infections by inducing trained immunity. The need for producing antigen-specific COVID-19 vaccines leads to delays in vaccine administration. Current randomized controlled trials (RCTs) report conflicting data on BCG's efficacy in COVID-19 infection. A comprehensive literature search was conducted using major bibliographic databases to identify RCTs evaluating the outcomes of BCG re-vaccination in COVID-19. For dichotomous outcomes, odds ratios (ORs) with 95% CIs were pooled using the DerSimonian-Laird random-effects model. Statistical significance was set at P less than 0.05. Thirteen RCTs with 13939 participants (7004 in the BCG re-vaccination group and 6935 in the placebo group) were included. BCG re-vaccination did not lead to a statistically significant difference in the incidence of COVID-19 infection [OR: 1.04; 95% CI: 0.91, 1.19; P=0.56], COVID-19-related hospitalizations [OR: 0.81; 95% CI: 0.38, 1.72; P=0.58), ICU admissions [OR: 0.43; 95% CI: 0.13, 1.46; P=0.18], or mortality [OR: 0.67; 95% CI 0.15, 3.04; P=0.60]. For safety outcomes, BCG re-vaccination led to a significant increase in the local injection site complications [OR: 99.79; 95% CI: 31.04, 320.80; P<0.00001], however, the risk of serious adverse events was similar [OR: 1.19; 95% CI: 0.84, 1.67; P=0.33]. BCG re-vaccination does not decrease the incidence of COVID-19 infection, COVID-19-related hospitalizations, ICU admissions, COVID-19-related mortality, and serious adverse events; however, it leads to a rise in local injection site complications. Caution should be exercised when overstating BCG's efficacy in COVID-19 prevention.

Implementation of a Patient Decision Aid for Atrial Fibrillation Ablation Improves Patient Procedural Knowledge but Does Not Impact Perceived Involvement With the Shared Decision-Making Process.

Shared decision-making (SDM) is a method for a patient and physician to cooperatively consider a diagnostic or therapeutic option, ultimately empowering the patient to make an informed decision. Atrial fibrillation (AF) ablation is a procedure that would benefit from SDM given the risk of serious adverse events, the high rate of arrhythmia recurrence, and alternative treatment options. Implementing a patient decision aid (PDA) may help facilitate AF ablation SDM by succinctly conveying important information to patients. Patients scheduled for initial AF catheter ablation were randomized to a virtual SDM visit utilizing a PDA, which covered procedural risks and benefits, or a virtual control visit with a tool outlining periprocedural processes. Preoperatively, patients completed a questionnaire assessing procedural risk and benefit knowledge, as well as perceived involvement with the decision-making process. Unpaired t-tests were used to compare groups. The SDM group scored significantly better overall on knowledge-based questions compared to the control group (69% correct [n=34] vs 53% [n=32]; P=0.00013). In particular, the SDM group was significantly more likely to answer questions correctly about stroke risk (P=0.01), anticoagulation (P=0.01), and potential need for additional procedures (P=0.03 and P=0.03). Perceived involvement in the decision-making process was overall not improved with PDA use (4.7 vs 4.6 out of 5; P=0.72). The addition of a PDA for AF ablation significantly improved procedural knowledge but did not impact patients' perceived involvement in the decision-making process compared to traditional preprocedural discussion alone.

O-086 Risk of serious adverse event after fertility preservation procedures: a comparison of cancer and non-cancer patients

Abstract Study question Do cancer patients have a higher risk of serious adverse event associated to fertility preservation procedures compared to non-cancer patients ? Summary answer No increased risk of adverse event after fertility preservation procedures was identified in cancer patients compared to non-cancer patients undergoing fertility preservation for other indications. What is known already Current recommendations encourage a prompt and exhaustive discussion on the different techniques of fertility preservation that can be performed in cancer patients of reproductive age prior to cancer treatments. Although cryopreservation of mature oocytes and/or embryos is the technique of reference in the absence of contraindication, ovarian stimulation and subsequent oocyte retrieval are associated to complications. Cancer patients might present an additional risk given tumoral hypervascularity and proinflammatory environment, as well as possible immune or coagulation disorders. However, whether cancer patients have an increased risk of serious adverse event associated to fertility preservation procedures compared to non-cancer patients remains unknown. Study design, size, duration A bicentric, retrospective study between January 1st, 2014 and December 31st, 2021. Participants/materials, setting, methods All women undergoing fertility preservation procedures by oocyte and/or embryo cryopreservation after controlled ovarian stimulation or in vitro maturation.The main endpoint was the occurrence of a serious adverse event (hospitalization for ovarian hyperstimulation syndrome, hemorrhage, infection, thromboembolic event, ovarian torsion, acute urine retention or death) in cancer patients compared to non-cancer patients undergoing fertility procedures. Main results and the role of chance A total of 4476 cycles (n = 3180 patients) were included, of which 3761 after controlled ovarian stimulation and 715 in vitro maturation cycles. Among the 4476 cycles, 1678 were performed in an oncological context (n = 1546 cancer patients) and 2798 were fertility preservation cycles for an indication other than cancer (n = 1634 patients). A total of 29 serious adverse events associated to fertility preservation procedures were registered, of which 17 intraperitoneal hemorrhages, 8 cases of ovarian hyperstimulation syndrome, 3 cases of infection and 1 case of acute urine retention. The risk of serious adverse event associated to fertility preservation procedures was not significantly different between cancer patients and non-cancer patients (0.36% vs. 0.82%, respectively, P = 0.06). Young age (P = 0.002), a higher number of oocytes retrieved (P = 0.006) and a higher number of oocytes vitrified (P = 0.002) were significantly associated to the risk of presenting a serious adverse event after fertility preservation. Limitations, reasons for caution Although rates of serious adverse events in our study are similar to that reported in previous literature and that the declaration and registration of any serious adverse event is mandatory according to French legislation, it is possible that not all serious adverse events were declared and registered. Wider implications of the findings Given the trend of delaying parenthood and the improved survival rates after cancer treatments, these findings are of particular importance, emphasizing the safety of performing fertility preservation procedures for cancer patients of reproductive age who might have a pregnancy desire after cancer treatment. Trial registration number not applicable

Effects of the discontinuation of antihypertensive treatment on neuropsychiatric symptoms and quality of life in nursing home residents with dementia (DANTON): a multicentre, open-label, blinded-outcome, randomised controlled trial.

Based on observational studies and randomised controlled trials (RCTs), the benefit-harm balance of antihypertensive treatment in older adults with dementia is unclear. To assess whether discontinuing antihypertensive treatment reduces neuropsychiatric symptoms (NPSs) and maintains quality of life (QoL) in nursing home residents with dementia. Open-label, blinded-outcome RCT. Randomisation 1:1, stratified by nursing home organisation and baseline NPS. Trial registration: NL7365. Dutch long-term care residents with moderate-to-severe dementia and systolic blood pressure (SBP) ≤160mmHg during antihypertensive treatment. Exclusion criteria included heart failure NYHA-class-III/IV, recent cardiovascular events/procedures or life expectancy <4months (planned sample size n = 492). Co-primary outcomes NPS (Neuropsychiatric Inventory-Nursing Home [NPI-NH]) and QoL (Qualidem) at 16weeks. From 9 November 2018 to 4 May 2021, 205 participants (median age 85.8 [IQR 79.6-89.5] years; 79.5% female; median SBP 134 [IQR 123-146] mmHg) were randomised to either antihypertensive treatment discontinuation (n = 101) or usual care (n = 104). Safety concerns, combined with lacking benefits, prompted the data safety and monitoring board to advice a premature cessation of randomisation. At 16-week follow-up, no significant differences were found between groups for NPI-NH (adjusted mean difference 1.6 [95% CI -2.3 to 5.6]; P = 0.42) or Qualidem (adjusted mean difference - 2.5 [95% CI -6.0 to 1.0]; P = 0.15). Serious adverse events (SAEs) occurred in 36% (discontinuation) and 24% (usual care) of the participants (adjusted hazard ratio 1.65 [95% CI 0.98-2.79]). All 32-week outcomes favoured usual care. Halfway through this study, a non-significant increased SAE risk associated with discontinuing antihypertensive treatment was observed, and an associated interim analysis showed that significant worthwhile health gain for discontinuation of antihypertensive treatment was unlikely. This unbeneficial benefit-harm balance shows that discontinuation of antihypertensive treatment in this context does not appear to be either safe or beneficial enough to be recommended in older adults with dementia.

Intrapleural Thrombolytics for Parapneumonic Effusion: A Network Metaanalysis.

Intrapleural thrombolytics have been trialed for facilitating pleural fluid drainage in patients with complicated parapneumonic effusion. The present study is a network metaanalysis of randomized clinical trials (RCTs) that have evaluated these thrombolytics. Electronic databases (Medline, Cochrane CENTRAL, and Google Scholar) were searched for appropriate RCTs evaluating the therapeutic effect of thrombolytics in patients with complicated parapneumonic effusion. Mortality, the proportion of patients referred for surgical intervention, and serious adverse events were the outcome measures. Random-effects model was used for generating direct and mixed treatment comparison pooled estimates. Grading of the evidence for key comparisons was carried out. Odds ratio with 95% confidence intervals was used to represent the pooled estimates. Seventy-six studies were retrieved with the search strategy, of which 16 were included. No significant differences were observed in mortality. Compared to normal saline, significantly less proportion of patients was referred for surgical intervention with streptokinase (0.4, 0.2 to 0.8), urokinase (0.4, 0.2 to 0.8), alteplase (0.3, 0.1 to 0.7), and alteplase + DNase (0.2, 0.1 to 0.7). DNase alone increased the risk of referral to surgical intervention (3.4, 1.5 to 7.6). Only streptokinase was observed with an increased risk of serious adverse events compared to normal saline (2.8, 1.1 to 7.1) and alteplase (6.7, 1.1 to 39.9). Moderate quality of evidence was observed for streptokinase with normal saline for the proportion of patients referred for surgical intervention, while either low or very low quality strength was observed for all other comparisons. Streptokinase, urokinase, alteplase, and alteplase + DNase were observed in patients referred for surgical interventions when used intrapleural in patients with parapneumonic effusion. Alteplase + DNase is likely to outperform others as it was observed with the least risk of patients referred for surgical interventions. Until additional data emerges that changes the pooled estimates, thrombolytics other than streptokinase are preferred due to the increased risk of serious adverse events.

Clinical and service delivery outcomes following medication abortion provided with or without pretreatment ultrasound or pelvic examination: An updated comparative analysis

ObjectivesThis study aimed to compare medication abortion outcomes among people screened without or with ultrasound or pelvic examination. Study designWe used data collected from March 24, 2020, to September 27, 2021, at five TelAbortion Project sites that provided medication abortion with mifepristone and misoprostol by mail. Using logistic regression weighted on propensity scores, we compared outcomes in participants who had neither ultrasound nor examination before treatment (No-Test group) or had such tests (Test group). We analyzed outcomes separately for participants screened early in the analysis period (before September 15, 2020) or later. Outcomes included procedural abortion completion or ongoing pregnancy, serious adverse events, and unplanned posttreatment abortion-related clinical visits. ResultsAmong 416 participants in the early period, the No-Test group had a significantly higher risk than the Test group of procedural abortion completion or ongoing pregnancy (5.6% vs 0.9%, risk difference 4.6%, 95% CI 1.5%, 7.7%) and abortion-related clinical visits (13.3% vs 6.3%; risk difference 7.0%; 95% CI 1.1%, 12.8%). Among 364 participants screened later, the risk of procedural abortion completion or ongoing pregnancy did not differ by group, while unplanned abortion-related clinical visits were less common in the No-Test group (9.9% vs 20.5%; risk difference −10.6%; 95% CI −20.1%, −1.1%). The risk of serious adverse events did not differ by group in either period. ConclusionsWhen providers first began omitting ultrasound or pelvic examination before medication abortion, the practice was associated with increased risks of failure of complete abortion and posttreatment clinical visits; however, these increased risks resolved over time. ImplicationsMedication abortion without pretreatment ultrasound or examination is effective and safe. This model should be routinely offered to eligible patients.

Once-weekly semaglutide in people with HIV-associated lipohypertrophy: a randomised, double-blind, placebo-controlled phase 2b single-centre clinical trial

HIV-associated lipohypertrophy, which is characterised by an abnormal accumulation of abdominal visceral adipose tissue, remains problematic in people with HIV. Effective interventions are lacking, despite HIV-associated lipohypertrophy carrying a substantial risk of cardiometabolic comorbidity. The primary aim of this trial was to investigate effects of the GLP-1 receptor agonist, semaglutide, on adipose tissue in HIV-associated lipohypertrophy. This randomised, double-blind, placebo-controlled phase 2b clinical trial was conducted at a single US site. Key inclusion criteria included people with HIV aged 18 years or older with controlled HIV-1, a BMI of 25 kg/m2 or more, and lipohypertrophy but without type 1 or type 2 diabetes. Participants were randomly assigned 1:1 to receive 32 weeks of once-weekly subcutaneous semaglutide (8-week dose titration and 24 weeks at 1·0 mg) or placebo; all research personnel and participants remained masked to treatment assignment. Primary outcomes were changes at 32 weeks in adipose tissue quantity by body compartment. Analyses, including safety, were performed using intention-to-treat principles. This trial was registered ClinicalTrials.gov (NCT04019197) and is complete. Between June 10, 2019, and July 28, 2022, 108 participants were randomly assigned to receive semaglutide (n=54) or placebo (n=54). Eight (15%) in each group withdrew prematurely. Significant effects of semaglutide were seen over the 32-week study period in sex-adjusted multiplicative regression analyses for the primary outcome, abdominal visceral adipose tissue (β -30·82 cm2, 95% CI -50·13 to -11·51; % change -30·6%). Decreases were also seen in other key measures, including abdominal subcutaneous adipose tissue (β -42·01 cm2, 95% CI -75·49 to -8·52; % change -11·2%) and total body fat (natural logarithmic -0·21 kg, 95% CI -0·33 to -0·08; % change -18·9%). There were no statistically significant differences in possibly related or related adverse events (absolute risk difference 0·1111, 95% CI -0·0727 to 0·2869); however, one semaglutide-related grade 4 elevated lipase and two possibly related cases of cholelithiasis (grades 1 and 2) were observed. Semaglutide holds promise as an effective treatment for HIV-associated lipohypertrophy. The potential risk of serious adverse events deserves further scrutiny in large trials in people with HIV. National Institutes of Health.