Adverse Safety Outcomes Research Articles

Risk-stratified treatment for drug-susceptible pulmonary tuberculosis

The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54–0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07–1.91; extensive disease: HR 2.02, 95%CI 1.07–3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment.

Adverse Impacts of PEGylated Protein Therapeutics: A Targeted Literature Review.

The beneficial effects of polyethylene glycol (PEG)-conjugated therapeutics, such as increased half-life, solubility, stability, and decreased immunogenicity, have been well described. There have been concerns, however, about adverse outcomes with their use, but understanding of those adverse outcomes is still relatively limited. The present study aimed to characterize adverse outcomes associated with PEGylation of protein-based therapeutics on immunogenicity, pharmacologic properties, and safety. A targeted review of English language articles published from 1990 to September 29, 2023, was conducted. Of the 29 studies included in this review, 18 reported adverse safety outcomes such as hematologic complications, hepatic toxicity, injection site reactions, arthralgia, nausea, infections, grade 3 or 4 adverse events (AEs), and AE-related discontinuations and dose modifications. Fifteen studies reported immunogenicity-related outcomes, such as the prevalence of pre-existing antibodies to PEG, treatment-emergent antibody response, and hypersensitivity reactions to PEGylated drugs. Seven studies reported pharmacological outcomes such as increased clearance and reduced activity in response to PEGylated drugs. This review aims to contribute to a balanced view of PEGylated therapies by summarizing the adverse outcomes or lack of benefit associated with PEGylated therapeutics reported in the literature. We identified several studies characterizing adverse outcomes, pharmacological effects, and immunogenicity associated with the use of PEGylated therapeutics. Our findings suggest that using PEGylated therapeutics may require careful monitoring for adverse safety outcomes, including screening and monitoring for pre-existing antibodies and those induced in response to PEGylated therapy, as well as monitoring and adjusting the dosing of PEGylated therapeutics.

Activation of Heme Metabolism Promotes Tissue Health After Intraarticular Injury or Surgical Exposure.

Posttraumatic osteoarthritis (PTOA) is a well-recognized public health burden without any disease modifying treatment. This occurs despite noted advances in surgical care in the past 50 years. Mitochondrial oxidative damage pathways initiate PTOA after severe injuries like intraarticular fracture that often require surgery and contribute to PTOA after less severe injuries that may or may not require surgery like meniscal injuries. When considering the mitochondrial and redox environment of the injured joint, we hypothesized that activation of heme metabolism, previously associated with healing in many settings, would cause prototypic mitochondrial reprogramming effects in cartilage ideally suited for use at the time of injury repair. Activation of heme metabolism can be accomplished through the gasotransmitter carbon monoxide (CO), which activates hemeoxygenase-1 (HO1) and subsequent heme metabolism. In this study, we employed unique carbon monoxide (CO)-containing foam (COF) to stimulate heme metabolism and restore chondrocyte oxygen metabolism in vitro and in vivo . Doxycycline-inducible, chondrocyte-specific HO1 overexpressing transgenic mice show similar mitochondrial reprogramming after induction compared to COF. CO is retained at least 24 h after COF injection into stifle joints and induces sustained increases in heme metabolism. Lastly, intraarticular injection of COF causes key redox outcomes without any adverse safety outcomes in rabbit stifle joints ex vivo and in vivo . We propose that activation of heme metabolism is an ideal adjuvant to trauma care that replenishes chondrocyte mitochondrial metabolism and restores redox homeostasis.

Prognostic clinical decision support for pneumonia in the emergency department: A randomized trial.

Hospitalization rates for childhood pneumonia vary widely. Risk-based clinical decision support (CDS) interventions may reduce unwarranted variation. We conducted a pragmatic randomized trial in two US pediatric emergency departments(EDs) comparing electronic health record (EHR)-integrated prognostic CDS versus usual care for promoting appropriate ED disposition in children (<18 years) with pneumonia. Encounters were randomized 1:1 to usual care versus custom CDS featuring a validated pneumonia severity score predicting risk for severe in-hospital outcomes. Clinicians retained full decision-making authority. The primary outcome was inappropriate ED disposition, defined as early transition to lower- or higher-level care. Safety and implementation outcomes were also evaluated. The study enrolled 536 encounters (269 usual care and 267 CDS). Baseline characteristics were similar across arms. Inappropriate disposition occurred in 3% of usual care encounters and 2% of CDS encounters (adjusted odds ratio: 0.99, 95% confidence interval: [0.32, 2.95]). Length of stay was also similar and adverse safety outcomes were uncommon in both arms. The tool's custom user interface and content were viewed as strengths by surveyed clinicians (>70% satisfied). Implementation barriers include intrinsic (e.g., reaching the right person at the right time) and extrinsic factors (i.e., global pandemic). EHR-based prognostic CDS did not improve ED disposition decisions for children with pneumonia. Although the intervention's content was favorably received, low subject accrual and workflow integration problems likely limited effectiveness.Clinical Trials Registration: NCT06033079.

Standard Versus Intensive Blood Pressure Control in Acute Ischemic Stroke Patients Successfully Treated With Endovascular Thrombectomy: A Systemic Review and Meta-Analysis of Randomized Controlled Trials.

The optimal blood pressure (BP) control after successful endovascular thrombectomy (EVT) in acute ischemic stroke (AIS) with large vessel occlusion (LVO) remains debatable. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that evaluate the efficacy and safety of standard BP control (with systolic BP ≤180 mm Hg) versus intensive BP control (systolic BP <140 mm Hg) during the 24 hours after successful EVT in AIS with LVO. PubMed, Scopus, the Cochrane Central Register of Controlled Trials, and Embase were searched to identify relevant trials. The crude odds ratio (OR) and 95% confidence interval (CI) were calculated and estimates using random-effects models were pooled. This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO ID: CRD42023450673). Four RCTs involving 1,559 participants were included. Regarding efficacy outcomes, intensive BP control was associated with a lower likelihood of functional independence (OR: 0.68; 95% CI: 0.51-0.91 for modified Rankin Scale [mRS] ≤2) and walking without assistance (OR: 0.65; 95% CI: 0.53-0.81 for mRS ≤3). For safety outcomes, consistent with the efficacy findings, intensive BP control was significantly associated with severe disability or death (mRS 5 or 6) (OR: 1.34; 95% CI: 1.07-1.69). However, there were no significant differences including all-cause mortality, any intracerebral hemorrhage (ICH), symptomatic ICH, parenchymal hematoma type 2, and stroke recurrence. While all four RCTs were conducted to demonstrate the superiority of intensive BP control over standard BP control, standard BP control may be beneficial for the outcome after EVT for AIS with LVO without increasing adverse safety outcomes. Caution should be needed with the application of intensive BP control during the 24 hours following successful recanalization after EVT.

Scrutinizing the Bathroom Binary: Equal Protection Theories for Nonbinary Students

Over the past decade, transgender students have challenged discriminatory school bathroom policies under the Equal Protection Clause with varying success. But another group of students, facing similar discrimination, has yet to see its day in court. Like their transgender peers, nonbinary students often lack access to gender-appropriate restrooms at school. Many K–12 schools offer only “boys” and “girls” restrooms, ignoring the needs of students who identify as neither boys nor girls, as both of those genders, or as something else entirely. Forced to use sex-segregated bathrooms (or no bathroom at all), nonbinary students suffer adverse health, safety, and educational outcomes. To illustrate pathways to relief, this Note provides an inventory of equal protection claims nonbinary students can make to challenge discriminatory bathroom policies. Each theory—alleging unconstitutional discrimination on the basis of sex, transgender status, or nonbinary status—is promising and limited in its own respect. Independently or together, these theories can support a viable equal protection challenge that triggers heightened scrutiny.

A quasi-experimental study of a bundled diagnostic stewardship intervention for ventilator-associated pneumonia

ObjectivesDiagnostic error in the use of respiratory cultures for ventilator-associated pneumonia (VAP) fuels misdiagnosis and antibiotic overuse within intensive care units. In this prospective quasi-experimental study (NCT05176353), we aimed to evaluate the safety, feasibility, and efficacy of a novel VAP-specific bundled diagnostic stewardship intervention (VAP-DSI) to mitigate VAP over-diagnosis/overtreatment. MethodsWe developed and implemented a VAP-DSI using an interruptive clinical decision support tool and modifications to clinical laboratory workflows. Interventions included gatekeeping access to respiratory culture ordering, preferential use of non-bronchoscopic bronchoalveolar lavage for culture collection, and suppression of culture results for samples with minimal alveolar neutrophilia. Rates of adverse safety outcomes, positive respiratory cultures, and antimicrobial utilization were compared between mechanically ventilated patients (MVPs) in the 1-year post-intervention study cohort (2022–2023) and 5-year pre-intervention MVP controls (2017–2022). ResultsVAP-DSI implementation did not associate with increases in adverse safety outcomes but did associate with a 20% rate reduction in positive respiratory cultures per 1000 MVP days (pre-intervention rate 127 [95% CI: 122–131], post-intervention rate 102 [95% CI: 92–112], p < 0.01). Significant reductions in broad-spectrum antibiotic days of therapy per 1000 MVP days were noted after VAP-DSI implementation (pre-intervention rate 1199 [95% CI: 1177–1205], post-intervention rate 1149 [95% CI: 1116–1184], p 0.03). DiscussionImplementation of a VAP-DSI was safe and associated with significant reductions in rates of positive respiratory cultures and broad-spectrum antimicrobial use. This innovative trial of a VAP-DSI represents a novel avenue for intensive care unit antimicrobial stewardship. Multicentre trials of VAP-DSIs are warranted.

90. The Diagnosis of Ventilator-associated pneumonia (DIVA) trial: Results of a Clinical Trial of a Bundled VAP Diagnostic Stewardship Intervention

Abstract Background Ventilator-associated pneumonia (VAP) is commonly overdiagnosed &amp; a primary driver of antibiotic overuse within intensive care units (ICUs). Antimicrobial stewardship programs have successfully leveraged diagnostic stewardship interventions (DSIs) to prevent overdiagnosis/overtreatment of diverse clinical syndromes, yet this approach has not been extended to VAP. In this trial, we aimed to evaluate the safety, feasibility &amp; efficacy of a novel DSI care bundle (DSI-CB) targeting VAP. Methods The DIVA trial (NCT05176353) was a pilot/feasibility trial conducted in 2 ICUs at Michigan Medicine from February 2022-February 2023. A DSI-CB targeting the respiratory culture testing pathway was implemented sequentially in study ICUs, using an interruptive electronic health record clinical decision support tool &amp; modifications to microbiology laboratory workflows (Table 1). Providers were counseled on DSI-CB use during bimonthly educational sessions during trial rollout &amp; via monthly email reminders thereafter. Rates of prespecified co-primary safety and secondary efficacy outcomes were compared between the postintervention study cohort &amp; 5-year preintervention historical controls using negative binomial regression. Interrupted time series analysis was used to evaluate ICU antibiotic utilization rates (ICU-AURs) to account for temporal trends. Results 1810 patients were admitted to study ICUs following DSI-CB implementation, 29% of whom were eligible for DSI-CB use. DSI-CB was utilized in 77% of eligible patients. Patient demographics, comorbidities &amp; measures of acute severity of illness were similar pre- &amp; post-intervention. DSI-CB implementation was not associated with increases in primary adverse safety outcomes (Table 2). DSI-CB implementation was associated with significant reductions in rates of total respiratory cultures ordered, rates of positive respiratory cultures &amp; reductions in both total &amp; broad-spectrum ICU-AURs (Table 2, Figure 1). Conclusion Implementation of a novel VAP DSI-CB was safe, feasible &amp; associated with significant reductions in rates of respiratory culture positivity and ICU-AURs. This represents the first trial of a DSI targeting VAP &amp; a novel avenue for ICU antimicrobial stewardship. Large-scale trials are warranted. Disclosures Owen Albin, MD, Biomeriux: Grant/Research Support|Charles River Laboratories: Advisor/Consultant|Shionogi: Advisor/Consultant Weirauch J. Andrew, RRT, Drager Medical: Equipment loaned for research purposes, but no monetary funds were provided.|Jones and Bartlett Learning: Honoraria Krishna Rao, MD, MS, Merck &amp; Co.: Grant/Research Support|Rebiotix: Advisor/Consultant|Seres Therapeutics: Advisor/Consultant|Summit Therapeutics: Advisor/Consultant Keith S. Kaye, MD, MPH, Entasis: Advisor/Consultant|Entasis: Honoraria|GSK: Advisor/Consultant|GSK: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria|VenatoRx: Advisor/Consultant|VenatoRx: Honoraria

Comprehension of international safety signs: A prospective technical workers context

An effective method for educating workers about occupational hazards is the use of safety signs in the workplace. However, workers' understanding may vary due to factors such as cultural background, familiarity, and training. This study aimed to assess the comprehension of international safety signs among participants representing the prospective technical workforce in Indonesian industries. Two groups of participants (n = 71), comprising vocational high school students and college-level engineering students, were involved to assess their comprehension of symbol elements, comprehension of complete signs, compliance intention, and familiarity towards a selected set of international safety signs. The study revealed that the complete signs significantly increased the comprehension and compliance intention of the prospective technical workers regarding the selected signs (p < .001). However, most safety signs under the fire equipment and safe condition categories investigated in the study had low comprehension and compliance intention scores (<67%). Conversely, signs under the mandatory and warning categories generally exhibited better comprehension and compliance intention scores. Additionally, participants in the study were generally not familiar with the investigated signs (<50%). The familiarity with the signs was strongly correlated with the comprehension and compliance intention of the participants (p < .001). Relevance to industryUnderstanding the findings, which revealed that the comprehension, compliance intention, and familiarity of the prospective technical worker participants with some international safety signs generally did not meet the standards, interventions such as training and redesigning the safety signs are highly recommended to minimize future adverse safety outcomes when they enter the workforce.

Exploring the relationships among safety leadership, safety climate, psychological contract of safety, risk perception, safety compliance, and safety outcomes

BackgroundRecently, two types of safety compliance behaviors including deep compliance and surface compliance were differentiated. The current study aimed to investigate the relationships among safety leadership, safety climate, psychological contract of safety (PCS), risk perception, and deep compliance and surface compliance behavior of workers. In addition, the effects of both deep and surface compliance on safety outcomes were considered.MethodsWorkers’ perceptions in terms of safety leadership, safety climate, PCS, risk perception, deep compliance, and surface compliance were measured by appropriate questionnaires. Three questions were asked to measure undesired safety outcomes. Structural equation modeling and correlation analysis were applied to examine the research model and relationships among variables.Results and discussionThe results of the current study showed that deep compliance was positively predicted by safety leadership, safety climate, and PCS and negatively predicted by risk perception. Surface compliance was positively predicted by safety leadership and safety climate and negatively predicted by risk perception. Surface compliance is not significantly predicted by PCS. With regard to the adverse safety outcomes, the results showed that both deep and surface compliance were negatively associated with adverse safety outcomes, however, deep compliance had a stronger negative correlation with adverse safety outcomes than surface compliance.

Prevalence and Impact of Cerebral Microbleeds on Clinical and Safety Outcomes in Acute Ischaemic Stroke Patients Receiving Reperfusion Therapy: A Systematic Review and Meta-Analysis.

Cerebral microbleeds (CMBs), a notable neuroimaging finding often associated with cerebral microangiopathy, demonstrate a heightened prevalence in patients diagnosed with acute ischemic stroke (AIS), which is in turn linked to less favourable clinical prognoses. Nevertheless, the exact prevalence of CMBs and their influence on post-reperfusion therapy outcomes remain inadequately elucidated. Through systematic searches of PubMed, Embase and Cochrane databases, studies were identified adhering to specific inclusion criteria: (a) AIS patients, (b) age ≥ 18 years, (c) CMBs at baseline, (d) availability of comparative data between CMB-positive and CMB-negative groups, along with relevant post-reperfusion therapy outcomes. The data extracted were analysed using forest plots of odds ratios, and random-effects modelling was applied to investigate the association between CMBs and symptomatic intracerebral haemorrhage (sICH), haemorrhagic transformation (HT), 90-day functional outcomes, and 90-day mortality post-reperfusion therapy. In a total cohort of 9776 AIS patients who underwent reperfusion therapy, 1709 had CMBs, with a pooled prevalence of 19% (ES 0.19; 95% CI: 0.16, 0.23, p < 0.001). CMBs significantly increased the odds of sICH (OR 2.57; 95% CI: 1.72; 3.83; p < 0.0001), HT (OR 1.53; 95% CI: 1.25; 1.88; p < 0.0001), as well as poor functional outcomes at 90 days (OR 1.59; 95% CI: 1.34; 1.89; p < 0.0001) and 90-day mortality (OR 1.65; 95% CI: 1.27; 2.16; p < 0.0001), relative to those without CMBs, in AIS patients undergoing reperfusion therapy (encompassing intravenous thrombolysis [IVT], endovascular thrombectomy [EVT], either IVT or EVT, and bridging therapy). Variations in the level of association can be observed among different subgroups of reperfusion therapy. This meta-analysis underscores a significant association between CMBs and adverse postprocedural safety outcomes encompassing sICH, HT, poor functional outcome, and increased mortality in AIS patients undergoing reperfusion therapy. The notable prevalence of CMBs in both the overall AIS population and those undergoing reperfusion therapy emphasizes their importance in post-stroke prognostication.

Safety and efficacy of biological agents in the treatment of Systemic Lupus Erythematosus (SLE)

BackgroundTo determine the safety and efficacy of biological agents used in the treatment of systemic lupus erythematosus (SLE) in adults.MethodsSystematic review and meta-analysis following PRISMA guidelines.Data sourcesMEDLINE (through Pubmed), EMBASE, Cochrane library, Clinicaltrials.gov, Australianclinicaltrials.gov.au, ANZCTR.org.au and WHO International Clinical Trials Registry Platform for studies published from 20 May 2021 and 15 years prior. A grey literature search was performed and completed on 31 May 2021.Study criteriaPhase II, III or quasi randomised controlled trials, studies with only cerebral or cutaneous lupus were excluded. Data extraction: Two authors independently screened studies for eligibility, extracted, reviewed data for accuracy, and used the Cochrane tool to assess risk of bias.ResultsForty-four studies were identified, consisting of 15 groups of drugs and 25 different biological agents, totalling 16,889 patients. The main outcomes assessed included Systemic Lupus Erythematosus Responder Index (SRI), BILAG-Based Composite Lupus Assessment (BICLA) and combined combined/partial renal remission (CRR/PRR).Four groups of biologics were found to improve outcomes. Anti-interferons: Anifrolumab increased BICLA response and SRI 5 to 8, decreased prednisone dosages, with increased herpes zoster infections, but fewer serious adverse events. Sifalimumab improved SRI but also increased herpes zoster infections. Anti BAFF/BLyS and/or APRIL: Belimumab consistently improved SRI 4, decreased prednisone dosages, increased combined CRR/PRR, and had no adverse safety outcomes. Tabalumab increased SRI 5 at 52 weeks with no steroid sparing effect but was associated with increased infusion related adverse events. Telitacicept improved SRI 4 at 52 weeks, with no increased adverse events, though data was rather sparse. Anti CD-20 monoclonal antibody, Obinutuzumab increased combined CRR/PRR at 1 and 2 years. Anti IL12/23 monoclonal antibody, Ustekinumab, increased SRI 4 to 6, but not BICLA at 24 weeks, with no concerning safety outcomes.ConclusionMultiple biologic agents are shown in high quality studies to have a significant therapeutic impact on outcomes in SLE.

Effect of Delayed Endoscopy Protocol on Timing and Safety of Endoscopy for Foreign Body Ingestion and Esophageal Food Impaction.

Endoscopic procedures for foreign body ingestion (FBI) and esophageal food impactions (EFI) performed during on-call hours are associated with increased stress, risk, and cost. We implemented a Foreign Body Algorithm (FBA) designed to delay all but the most urgent endoscopy for EFI and FBI until regular working hours. Using endoscopy records from multiple academic and community hospitals within a large integrated health system in the United states, we identified esophagogastroduodenoscopy (EGD) performed for food impactions and foreign body ingestions occurring between May 2011 and February 2021. We identified 479 EGDs performed for FBI and EFI. The introduction of the FBA was associated with a shorter length of stay (LOS) for overall cases (0.35 vs. 0.8d P<0.001), day cases (0.16 vs. 1.0d P<0.001), and night cases (0.40 vs. 0.6d P=0.03). The introduction of the FBA did not change the rate of overall adverse events (AE) or night AE. AE from the entire cohort was rare (3%; 16 total). Of the AE, most were sedation related. The introduction of the FBA did not affect the overall rate of night cases or AE, but the rate of after-hours endoscopy for intentional ingestions decreased from 17.2% to 3.1% (P=0.01). This is one of the largest studies of esophageal impactions and foreign bodies in adults in the United States, and the first to examine the effects of a protocol designed to avoid after-hours endoscopy. These results suggest that postponing after-hours EGD until the daytime is not associated with adverse safety outcomes or increased LOS.

Pilot feasibility testing of biomathematical model recommendations for personalising sleep timing in shift workers.

Sleep disturbances and circadian disruption play a central role in adverse health, safety, and performance outcomes in shift workers. While biomathematicalmodels of sleep and alertness can be used to personalise interventions for shift workers, their practical implementation of is undertested. This study tested the feasibility of implementing two biomathematical models-the Phillips-Robinson Model and the Model for Arousal Dynamics-in 28 shift-working nurses, 14 in each group. The study examined the overlap and adherence between model recommendations and sleep behaviours, and changes in sleep following the implementation of recommendations. For both groups combined, the mean (SD) percentage overlap between when a model recommended an individual to sleep and when sleep was obtained was 73.62% (10.24%). Adherence between model recommendations and sleep onset and offset times was significantly higher with the Model of Arousal Dynamics compared to the Phillips-Robinson Model. For the Phillips-Robinson model, 27% of sleep onset and 35% of sleep offset times were within ± 30 min of model recommendations. For the Model of Arousal Dynamics, 49% of sleep onset, and 35% of sleep offset times were within ± 30 min of model recommendations. Compared to pre-study, significant improvements were observed post-study for sleep disturbance (Phillips-Robinson Model), and insomnia severity and sleep-related impairments (Model of Arousal Dynamics). Participants reported that using a digital, automated format for the delivery of sleep recommendations would enable greater uptake. These findings provide a positive proof-of-concept for using biomathematical models to recommend sleep in operational contexts.

Long-term outcomes of peripheral atherectomy for femoropopliteal endovascular interventions.

The use of atherectomy during peripheral endovascular interventions (PVI) has increased dramatically, but data regarding its safety and effectiveness are lacking. Aims: This study sought to determine the long-term safety of atherectomy in contemporary practice. Methods: Medicare fee-for-service beneficiaries who underwent femoropopliteal artery PVI from 2015-2018 were identified in a 100% sample of inpatient, outpatient, and carrier file data using procedural claims codes. The primary exposure was the use of atherectomy. Inverse probability of treatment weighting was used to adjust for measured differences in patient populations. Kaplan-Meier methods and multivariable Cox proportional hazards regression were used to compare outcomes. Results: Among 168,553 patients who underwent PVI, 59,142 (35.1%) underwent atherectomy. The mean patient age was 77.0±7.6 years, 44.9% were female, 81.9% were white, and 46.7% had chronic limb-threatening ischaemia. Over a median follow-up time of 993 days (interquartile range 319-1,377 days), atherectomy use was associated with no difference in the risk of either the composite endpoint of death and amputation (adjusted hazard ratio [aHR] 0.99, 95% confidence interval [CI]: 0.97-1.01; p=0.19) or of major adverse limb events (aHR 1.02, 95% CI: 0.99-1.05; p=0.26). Patients who underwent atherectomy had a modest reduction in the risk of subsequently undergoing amputation or surgical revascularisation (aHR 0.92, 95% CI: 0.90-0.94; p<0.01) but an increase in the risk of undergoing a subsequent PVI (aHR 1.19, 95% CI: 1.16-1.21; p<0.01). The use of atherectomy during femoropopliteal artery PVI was not associated with an increase in the risk of long-term adverse safety outcomes among patients with peripheral artery disease.

Evaluation of patient profiles, treatment paradigms and clinical efficacy, and safety outcomes in adult patients with vitamin D deficiency or insufficiency in India: A multicenter, prospective, non-interventional study

Background: Nationwide studies assessing sociodemographic factors associated with poor vitamin D status and efficacy-safety of vitamin D supplementation in Indian clinical practice are limited. Methods: In this multicenter, prospective, non-interventional study, patients with vitamin D deficiency (25[OH]D &lt;20 ng/mL)/insufficiency (25[OH]D 21-29 ng/mL) were enrolled at 9 sites across India and prescribed vitamin D supplements per routine practice. Primary endpoints were patient profiles associated with vitamin D deficiency/insufficiency and change in visual analog scale (VAS) scores for clinical signs/symptoms from baseline to weeks 4 and 8. Key secondary endpoints were prescription pattern of vitamin D supplements and incidence of adverse drug reactions (ADRs)/serious ADRs. Change in systolic/diastolic blood pressure (SBP/DBP [hypertensive patients]) and glycated hemoglobin (HbA1c [diabetic patients]) were assessed from baseline to weeks 8 and 12, respectively. Paired t test was used to assess statistical significance, except for patient profile association, where analysis of variance model was used. Results: Of 201 enrolled patients (mean [standard deviation] age: 43.4 [14.52] years), 61.7% were women. Most demographic and anthropometric factors, except for current sunscreen use (p=0.0297) and socioeconomic status (p=0.0222), were not significantly associated with vitamin D deficiency/insufficiency. Upper-lower class had significantly higher odds (p=0.033) for vitamin D deficiency versus insufficiency versus lower class. Most of the patients were prescribed 60000 IU/week orally. VAS scores for bone and lower back pain, bone loss, low bone mineral density, and muscle pain were significantly reduced at weeks 4 and 8 (p&lt;0.001). SBP/DBP of hypertensive patients and HbA1c of diabetic patients were also significantly decreased (p&lt;0.05). No ADRs/serious ADRs were observed. Conclusion: Sunscreen use and socioeconomic status were significantly associated with vitamin D deficiency/insufficiency. Vitamin D supplementation improved clinical symptoms, HbA1c levels (diabetic patients), and SBP/DBP (hypertensive patients), without any adverse safety outcomes. Nevertheless, studies with long-term follow-up and larger sample sizes are warranted.

Intensive versus standard blood pressure control in older persons with or without diabetes: a systematic review and meta-analysis of randomised controlled trials.

To assess and compare the benefits and harms of intensive versus standard blood pressure (BP) control in older people with or without diabetes mellitus (DM). Systematic review and meta-analysis. Randomised controlled trials comparing intensive versus standard BP control, identified from MEDLINE, Embase, The Cochrane library, Web of Science and a search of bibliographies from inception till August 2022. Older people (≥65 years) with or without DM. Study-specific risk ratios (RRs) with 95% confidence intervals (CIs) were pooled for adverse vascular and safety outcomes. We included six randomised controlled trials (RCTs) comprising 20,985 patients (intensive BP = 10,474 and standard BP = 10,511) with a weighted mean follow-up of 3.1 years. In the general population, the RRs (95% CIs) of intensive versus standard BP control for composite cardiovascular events or major adverse cardiovascular events (CVD/MACE), CVD mortality, coronary heart disease, stroke and heart failure were 0.71 (0.62-0.82), 0.65 (0.49-0.86), 0.75 (0.60-0.95), 0.75 (0.61-0.92) and 0.58 (0.41-0.82), respectively. Intensive BP control did not increase the risk of renal failure or serious adverse events in the general population. Two RCTs reported results for composite CVD/MACE in patients with DM with a pooled estimate of 0.85 (0.67-1.07). Aggregate trial evidence shows that intensive BP control (<120 to <140 mmHg) reduces the risk of adverse cardiovascular outcomes in older hypertensive patients in the general population with no increase in adverse events. Intensive BP control may confer similar benefits for older patients with DM with no evidence for harm, but this is based on limited data.PROSPERO Registration: CRD42022349791.

Laser-Assisted Drug Delivery: A Systematic Review of Safety and Adverse Events.

Laser-assisted drug delivery (LADD) is an increasingly studied and applied methodology for drug delivery. It has been used in a wide variety of clinical applications. Given the relatively low barrier to entry for clinicians as well as ongoing research in this area, the authors aimed to review outcomes relating to safety in laser-assisted drug delivery. A systematic review was conducted, with the databases PubMed, Medline and Embase searched in September 2022. Included articles were those that mentioned laser-assisted drug delivery in human subjects that also reported adverse effects or safety outcomes. There were no language-based exclusions. Conference abstracts and literature reviews were excluded. The results were then tabulated and categorized according to the application of LADD. In total, 501 articles were obtained. Following deduplication, screening, and full text review 70 articles of various study designs were included. Common findings were erythema, oedema, pain, and crusting following LADD. Several notably more severe adverse effects such as generalized urticaria, infection, scarring and dyspigmentation were noted. However, these events were varied depending on the clinical use of LADD. Relevant negatives were also noted whereby no studies reported life-threatening adverse effects. Limitations included limited details regarding the adverse effects within the full texts, lack of follow-up, and risk of bias. In conclusion, there were multiple adverse effects that clinicians should consider prior to carrying out LADD, where treatment goals and patient tolerability should be considered. Further evidence is needed to quantitatively determine these risks.

Safety and efficacy of direct oral anticoagulants in geriatric patients with non-valvular atrial fibrillation: A single-center retrospective study

IntroductionDirect oral anticoagulants (DOACs) are widely employed for antithrombotic prophylaxis in patients with atrial fibrillation (AF). However, there is still uncertainty about their risk-benefit profile in older patients. Here, we evaluated the efficacy, safety, and dose appropriateness of DOACs in a real-world population of outpatients with non-valvular AF, with a specific focus on subjects aged over 80 years and/or with reduced renal function. Materials and methodsSingle-center retrospective study including patients who had been prescribed a DOAC between May 2014 and May 2021 for long-term anticoagulation in non-valvular AF. Patients anticoagulated for <4 weeks were excluded. The primary efficacy outcome was a composite of cardiovascular (CV) death, stroke, or systemic embolism. The primary safety outcome was major bleeding. ResultsA total of 1154 patients (median age 84 yrs., range 57–100 yrs.), among which 862 were 80 years and older, were included. In the subgroup of subjects ≥80 yrs., a subtherapeutic dose of DOAC was associated with an increased incidence of CV mortality, stroke, or systemic embolism (multivariable Cox regression, HR = 2.09, 95 % CI: 1.09–4.02), with no benefit in terms of prevalence of bleeding events (21.5 % vs. 18.6 %, p = 0.428), and the incidence of adverse safety and efficacy outcomes was not increased in patients with a reduced renal function (eGFR ≤30 mL/min). Plasma concentration of DOACs, assessed in a subset of 367 patients, did not increase with advanced age (≥ 80 yrs., two-way ANOVA, p = 0.656) nor with declining eGFR (≤30 mL/min, two-way ANOVA, p = 0.643) and was not associated with adverse safety and efficacy outcomes. ConclusionsData from our study support the use of DOACs in populations of older adults and remark on the risks associated with inappropriate prescriptions in terms of CV mortality and adverse events.

Effects of the Federal Aviation Administration's Compliance Program on aircraft incidents and accidents

• Restorative justice-based policies in aviation may be unsafe. • The FAA’s Compliance Program may reduce aviation safety. • Population-level data was evaluated using GLARMA modeling. • An increase in aircraft incidents and accidents resulted from the FAA’s Compliance Program. • A decrease in punishment may affect human behavioral responses. A novel enforcement policy based on restorative justice principles was implemented by the United States Federal Aviation Administration (FAA) in 2015. In this study, interrupted time series regression analyses using generalized linear autoregressive moving average (GLARMA) models were used to analyze FAA investigated incident and accident counts, runway incursion caused by pilot deviation, and National Transport Safety Board (NTSB) accident count data from June 2010 to September 2020. An association was observed between the change in FAA’s enforcement policy and the increase in aircraft incidents, accidents, and runway incursions post-intervention (2015–2020). These adverse safety outcomes appear to be directly related to this policy change. Results highlight the risk of moving away from punishment as a means of reinforcing safe behavior and the need for careful theory-based implementation of alternative approaches.