Adverse Clinical Events Research Articles

Veno-arterial ECMO ventricular assistance as a direct bridge to heart transplant: A single center experience in a low-middle income country.

The use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) as a direct bridge to heart transplantation (BTT) is not common in adults worldwide. BTT with ECMO is associated with increased early/mid-term mortality compared with other interventions. In low- and middle-income countries (LMIC), where no other type of short-term mechanical circulatory support is available, its use is widespread and increasingly used as rescue therapy in patients with cardiogenic shock (CS) as a direct bridge to heart transplantation (HT). To assess the outcomes of adult patients using VA-ECMO as a direct BTT in an LMIC and compare them with international registries. We conducted a single-center study analyzing consecutive adult patients requiring VA-ECMO as BTT due to refractory CS or cardiac arrest (CA) in a cardiovascular center in Argentina between January 2014 and December 2022. Survival and adverse clinical events after VA-ECMO implantation were evaluated. Of 86 VA-ECMO, 22 (25.5%) were implanted as initial BTT strategy, and 52.1% of them underwent HT. Mean age was 46 years (SD 12); 59% were male. ECMO was indicated in 81% for CS, and the most common underlying condition was coronary artery disease (31.8%). Overall, in-hospital mortality for VA-ECMO as BTT was 50%. Survival to discharge was 83% in those who underwent HT and 10% in those who did not, p<.001. In those who did not undergo HT, the main cause of death was hemorrhagic complications (44%), followed by thrombotic complications (33%). The median duration of VA-ECMO was 6 days (IQR 3-16). There were no differences in the number of days on ECMO between those who received a transplant and those who did not. In the Spanish registry, in-hospital survival after HT was 66.7%; the United Network of Organ Sharing registry estimated post-transplant survival at 73.1%±4.4%, and in the French national registry 1-year posttransplant survival was 70% in the VA-ECMO group. In adult patients with cardiogenic shock, VA-ECMO as a direct BTT allowed successful HT in half of the patients. HT provided a survival benefit in listed patients on VA-ECMO. We present a single center experience with results comparable to those of international registries.

Statistical analysis plan for the SQUEEZE trial: A trial to determine whether septic shock reversal is quicker in pediatric patients randomized to an early goal-directed fluid-sparing strategy vs. usual care (SQUEEZE)

BackgroundThe SQUEEZE trial is a multicentred randomized controlled trial which seeks to determine the optimal approach to fluid resuscitation in paediatric septic shock. SQUEEZE also includes a nested translational study, SQUEEZE-D, investigating the value of plasma cell-free DNA for prediction of clinical outcomes. ObjectiveTo present a pre-specified statistical analysis plan (SAP) for the SQUEEZE trial prior to finalizing the trial data set and prior to commencing data analysis. DesignSQUEEZE is a pragmatic, two-arm, open-label, prospective multicentre randomized controlled trial. SettingCanadian paediatric tertiary care centres. ParticipantsPaediatric patients with suspected sepsis and persistent signs of shock in need of ongoing resuscitation. Sample size target: 400 participants. InterventionsThe trial is designed to compare a fluid-sparing resuscitation strategy to usual care. Main outcome measuresThe primary outcome for the SQUEEZE trial is the time to shock reversal (in hours). The primary outcome analysis will assess the difference in time to shock reversal between the intervention and control groups, reported as point estimate with 95% confidence intervals. The statistical test for the primary analysis will be a two-sided t-test. Secondary outcome measures include clinical outcomes and adverse events including measures of organ dysfunction and mortality outcomes. ResultsThe SAP presented here is reflective of and where necessary clarifies in detail the analysis plan as presented in the trial protocol. The SAP includes a mock CONSORT diagram, figures and tables. Data collection methods are summarized, primary and secondary outcomes are defined, and outcome analyses are described. ConclusionsWe have developed a statistical analysis plan for the SQUEEZE Trial for transparency and to align with best practices. Analysis of SQUEEZE Trial data will adhere to the SAP to reduce the risk of bias. RegistrationClinicalTrials.gov identifiers: Definitive trial NCT03080038; Registered Feb 28, 2017. Pilot Trial NCT 01973907; Registered Oct 27, 2013.

Efficacy and safety of arterial FOLFOX chemotherapy plus anti-PD-(L)1 immunotherapy as first-line treatment for unresectable intrahepatic cholangiocarcinoma: A propensity score matched analysis.

e16189 Background: This study aimed to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) plus anti-programmed death (ligand)-1 [PD-(L)1] immunotherapy compared to systemic chemotherapy (SCT) plus anti-PD-(L)1 immunotherapy as first-line treatment for patients with unresectable intrahepatic cholangiocarcinoma (uICC). Methods: In this retrospective study, unresectable treatment-naive ICC patients who were treated with HAIC plus anti-PD-(L)1 immunotherapy [HAIC+αPD-(L)1] or SCT plus anti-PD-(L)1 immunotherapy [SCT+αPD-(L)1] were included. The clinical characteristics, therapeutic outcomes and adverse events (AEs) of patients between the two groups were compared. The propensity score matching (PSM) was performed to minimize biases between groups. Results: From January 2019 to January 2023, a total of 182 patients were enrolled, including 147 patients in HAIC+αPD-(L)1 group and 35 patients in SCT+αPD-(L)1 group. After PSM, 61 and 26 patients were included in the HAIC+αPD-(L)1 and SCT+αPD-(L)1 groups, respectively. The HAIC+αPD-(L)1 group showed longer median overall survival (OS) and progression free survival (PFS) than the SCT+αPD-(L)1 group (OS: 14.5 vs 10.5 months, P = 0.019; PFS: 6.4 vs 10.1 months, P = 0.020). The disease control rate of HAIC+αPD-(L)1 group were higher than those of SCT+αPD-(L)1 group (91.8% vs 69.2%, P = 0.007). The overall incidence of adverse events (AEs) was comparable between the two groups, but the HAIC+αPD-(L)1 group showed a lower incidence of grade 3~4 AEs related to anemia, weight loss and fatigue. Conclusions: HAIC plus anti-PD-(L)1 immunotherapy had acceptable toxic effects and might improve outcomes compared to SCT plus anti-PD-(L)1 immunotherapy as first-line treatment for patients with uICC.

Real-world Bruton tyrosine kinase inhibitor (BTKi) treatment patterns and outcomes among patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) in US community oncology practices.

e19020 Background: BTKi therapies are standard of care for CLL/SLL, with acalabrutinib (acala) and zanubrutinib (zanu) having improved safety profiles vs ibrutinib (ibru). This study assessed real-world clinical characteristics, treatment patterns, and adverse events (AEs) among BTKi-treated patients with CLL/SLL. Methods: This is a retrospective observational study, updated with 5 months of additional data from a previous analysis. Adults in the US community oncology setting initiated BTKi treatment between Jan 1, 2020, and Jul 31, 2023, and were followed to Oct 31, 2023. De-identified structured electronic health records were analyzed from the Integra Connect-PrecisionQ real-world database. Cardiovascular (CV) AEs (based on ICD codes), time to treatment discontinuation (TTD), and time to next treatment (TTNT) were reported. Results: A total of 3064 patients initiated BTKi therapies during the index period (1L n=2815; 2L+ n=249). Median age (range) was 72 years (33-90) in 1L and 72 years (42-89) in 2L+. There were 63.1% and 65.5% males in 1L and 2L+, respectively. In 1L, 49.3% of patients were treated with ibru, 43.4% with acala, and 7.2% with zanu. Similar trends were observed for 2L+. More patients experienced CV AEs among those who received 1L ibru vs acala or zanu; 12.1%, 7.6%, and 7.3% at month 6 ( P&lt;0.05) and 14.6%, 9.4%, and 8.5% at month 9 ( P&lt;0.05). With longer follow-up, there was a trend for a more favorable CV safety profile for zanu. Of patients treated with 1L ibru, 12.7% discontinued ibru and switched to acala or zanu. Median TTD in 1L was shorter for ibru than acala or zanu (Table). The associated probability of remaining on treatment was higher with zanu vs ibru or acala at months 6 and 12 (Table). Median TTNT was not reached for zanu, while it was 30.2 months for ibru and 35.8 months for acala. Conclusions: While zanu had relatively smaller sample size and shorter follow-up, this study demonstrated better real-world safety and efficacy outcomes for acala and zanu vs ibru. Additional research is needed to explain and validate observed differences favoring zanu over acala. [Table: see text]

Clinical Results of Primary Repair Versus Reconstruction of the Anterior Cruciate Ligament: A Systematic Review and Meta-analysis of Contemporary Trials.

Primary anterior cruciate ligament (ACL) repair has gained renewed interest in select centers for patients with proximal or midsubstance ACL tears. Therefore, it is important to reassess contemporary clinical outcomes of ACL repair to determine whether a clinical benefit exists over the gold standard of ACL reconstruction (ACLR). To (1) perform a meta-analysis of comparative trials to determine whether differences in clinical outcomes and adverse events exist between ACL repair versus ACLR and (2) synthesize the midterm outcomes of available trials. Systematic review; Level of evidence, 3. The PubMed, OVID/Medline, and Cochrane databases were queried in August 2023 for prospective and retrospective clinical trials comparing ACL repair and ACLR. Data pertaining to tear location, surgical technique, adverse events, and clinical outcome measures were recorded. DerSimonian-Laird random-effects models were constructed to quantitatively evaluate the association between ACL repair/ACLR, adverse events, and clinical outcomes. A subanalysis of minimum 5-year outcomes was performed. Twelve studies (893 patients; 464 ACLR and 429 ACL repair) were included. Random-effects models demonstrated a higher relative risk (RR) of recurrent instability/clinical failure (RR = 1.64; 95% confidence interval [CI], 1.04-2.57; P = .032), revision ACLR (RR = 1.63; 95% CI, 1.03-2.59; P = .039), and hardware removal (RR = 4.94; 95% CI, 2.10-11.61; P = .0003) in patients who underwent primary ACL repair versus ACLR. The RR of reoperations and complications (knee-related) were not significantly different between groups. No significant differences were observed when comparing patient-reported outcome scores. In studies with minimum 5-year outcomes, no significant differences in adverse events or Lysholm scores were observed. In contemporary comparative trials of ACL repair versus ACLR, the RR of clinical failure, revision surgery due to ACL rerupture, and hardware removal was greater for primary ACL repair compared with ACLR. There were no observed differences in patient-reported outcome scores, reoperations, or knee-related complications between approaches. In the limited literature reporting on minimum 5-year outcomes, significant differences in adverse events or the International Knee Documentation Committee score were not observed.

Efficacy and safety of topical NSAIDs combined with physiotherapy for frozen shoulder: a randomized controlled trial.

Frozen shoulder is a prevalent condition among individuals in their middle and later years. Invasive therapy has shown promising results in the treatment of frozen shoulders, but its widespread adoption has been hampered by high costs and the need for advanced medical technology. As a result, patients with frozen shoulders often turn to non-steroidal anti-inflammatory drugs (NSAIDs) for symptomatic relief. However, the oral administration of NSAIDs can lead to troublesome adverse effects on the gastrointestinal, cardiovascular, and urinary systems. In contrast, topical NSAIDs have gained attention for their excellent efficacy and lower adverse effects in various chronic pain conditions. Therefore, our study aimed to investigate the efficacy and safety of topical NSAIDs in improving pain and mobility among patients with frozen shoulders. A total of 108 patients experiencing moderate to severe pain and mobility impairment due to frozen shoulder were enrolled in this study. The participants were randomly assigned to either the experimental group (n=72) or the control group (n=36). The experimental group received daily treatment with the loxoprofen hydrogel patch (LOX-P) in addition to basic rehabilitation physiotherapy. The control group was treated with flurbiprofen cataplasm (FLU-C) twice a day, along with rehabilitation physiotherapy. The primary endpoint for evaluating the efficacy of the two patches was the Constant-Murley score (CMS). Clinical symptom data, adverse events, and patient satisfaction were also recorded. After 14 days of treatment, the effective rate was 66.67% (n=48) in the experimental group and 41.67% (n=15) in the control group. The overall difference in the effective rates was 25.00% (95% CI=5.20-42.52; p=0.013). The safety profiles of the two topical agents were similar, with only a few adverse events reported. The loxoprofen hydrogel patch demonstrates a significant ability to alleviate shoulder pain and restore shoulder function in the treatment of frozen shoulder, with minimal adverse reactions. Chictr.org.cn ID: ChiCTR2100052375.

Timing of P2Y12 Inhibitor Administration in Patients With STEMI Undergoing Primary PCI

BackgroundThe optimal timing of P2Y12 inhibitor administration in patients with ST-segment elevation myocardial infarction (STEMI) has not been completely elucidating. ObjectivesThis analysis from a prospective multicenter registry sought to assess the safety and effectiveness of P2Y12 inhibitor pretreatment in patients transferred for primary percutaneous coronary intervention (PCI) within a regional STEMI network. MethodsPretreatment was defined as P2Y12 inhibitor administration before coronary angiography. Endpoints were major adverse cardiac events (MACE), major bleeding, and net adverse clinical events, a composite of MACE or major bleeding, within 30 days of index admission. Association of P2Y12 inhibitor pretreatment with outcomes was modeled using doubly robust weighted estimators based on propensity score analysis. ResultsOf 1,624 patients included, 1,033 received P2Y12 inhibitors before angiography and 591 in the catheterization laboratory (cath lab). The non-pretreated cohort more often had history of coronary artery disease and were more likely to receive antiplatelet therapy before the index admission. After adjustment for confounding and dependent censoring, pretreatment with P2Y12 inhibitors predicted lower risk of MACE (adjusted HR: 0.53; 95% CI: 0.37-0.76), without increasing bleeding risk (adjusted HR: 0.62; 95% CI: 0.36-1.05), resulting in superior net clinical benefit (adjusted HR: 0.47; 95% CI: 0.26-0.86) compared with in-cath lab administration of P2Y12 inhibitors. There was a significant treatment-by-time interaction for MACE risk, whereby the observed benefits of pretreatment only became apparent when time between P2Y12 inhibitor administration and PCI was longer than 80 minutes. ConclusionsIn contemporary patients with STEMI transferred for primary PCI, pretreatment with P2Y12 inhibitors was associated with a significant time-dependent reduction of 30-day MACE without increasing bleeding risk.

Sex-Based Outcomes of Dual-Antiplatelet Therapy After Percutaneous Coronary Intervention: A Pairwise and Network Meta-Analysis.

Although dual antiplatelet therapy (DAPT) improves the outcomes of patients undergoing percutaneous coronary intervention (PCI), sex-specific differences in efficacy and safety of DAPT remain unresolved. We compared sex differences for DAPT outcomes and DAPT durations (1-3 months [short-term], 6months [mid-term], and >12months [extended] vs. 12months). We searched databases through 31 December 2023 for trials reporting DAPT after PCI. The endpoints were major adverse cardiovascular and cerebrovascular events (MACCE), net adverse clinical and cerebrovascular events (NACCE), and any bleeding. Extracted data were pooled in a frequentist network and pairwise, random-effects meta-analysis. Twenty-two trials (99,591 participants, 25.2% female) were included. Female sex was significantly associated with a higher 1-year MACCE risk (hazard ratio 1.14 [95% confidence interval 1.02-1.28]) and bleeding (1.13 [1.00-1.28]), but not NACCE (1.12 [0.96-1.31]). In sub-analyses, the association between female sex and MACCE was related to use of clopidogrel as the second antiplatelet agent(1.11 [1.03-1.20]), whereas higher bleeding events were related to newer P2Y12 inhibitors (P2Y12i) (1.58 [1.01-2.46]). For DAPT duration, short-term DAPT followed by P2Y12i monotherapy was non-inferior for MACCE in females and males (0.95 [95% CI 0.83-1.10; and 0.96 [0.80-1.16]) but tended to be superior in males for NACCE versus 12-month DAPT (0.96 [0.91-1.01]); mid-term DAPT tended to be associated with a lower bleeding risk in males (0.43 [0.17-1.09]). Female sex is associated with higher MACCE and bleeding when newer P2Y12i agents are used. Short-term DAPT followed by P2Y12i monotherapy is safe and effective in both sexes undergoing PCI. PROSPERO ID: CRD42021278663.

Association of the pattern of new-onset post-operative atrial fibrillation with adverse clinical events over 1 year follow-up: insights from the VISION Cardiac Surgery Cohort

Abstract Background New-onset post-operative atrial fibrillation (AF) affects approximately 1 in 3 patients after cardiac surgery and is associated with adverse outcomes. Whether the amount of time spent in AF is associated with outcomes is unknown. Methods VISION Cardiac Surgery was an international, prospective cohort of patients who underwent cardiac surgery in 12 countries. We divided participants according to their pattern of AF: no new-onset AF, duration &amp;lt;24 h, duration 24-48 h, duration 48-72 h, duration &amp;gt;72 h and discharged in AF. We created a separate category for those who received electrical cardioversion. We excluded participants with a history of AF before surgery and participants with unknown duration of AF. We assessed the association of different patterns of AF, as compared to no AF, with clinical events occurring between 30 days post-operatively and 1 year of follow up. For each outcome, we created a Cox proportional hazards model adjusted for CHA2DS2-VASc score, smoking, hemodialysis, prior cardiac surgery, surgery type and antithrombotic use at hospital discharge (oral anticoagulation alone, oral anticoagulation plus antiplatelet, antiplatelet alone, or none). Results Among 12,234 eligible participants, 3,887 (30.3%) had new-onset post-operative AF and 3,711 had a known duration of AF. The proportion of patients with new-onset AF who were discharged from hospital on oral anticoagulation was 39%. Table 1 displays event rates by AF pattern. Compared to participants without AF, we observed a higher risk of a composite of stroke or vascular death at one year in participants with estimated AF duration &amp;gt;72 h (3.9%, adjusted hazard ratio (aHR) 1.72; 95% CI 1.03-2.87) and in those who underwent electrical cardioversion (3.7%, aHR 2.18; 95%CI 1.16-4.11). Only AF duration &amp;gt;72 h was associated with an increased risk of stroke (2.1%; aHR 2.42; 95%CI 1.15-5.09). We observed a higher risk of all-cause mortality in participants who were in AF at hospital discharge (4.1%, aHR 1.83; 95%CI 1.10-3.05) and in participants who received electrical cardioversion (5.8%, aHR 2.81; 95%CI 1.67-4.73). Only being in AF at discharge was associated with an increased risk of heart failure (3.8%; aHR 2.63; 95% CI 1.49-4.63). All patterns of AF were associated with AF detection in follow-up, with the strongest associations observed in participants who were in AF at hospital discharge (31.8%, aHR 73.4; 95%CI 51.4- 105.0) and in those who received electrical cardioversion (12.5%, aHR 17.9; 95%CI 11.1-28.8). Conclusions Among patients with new-onset post-operative AF following cardiac surgery, duration of AF &amp;gt;72 h, electrical cardioversion and being in AF at discharge are all markers of adverse events in the year following surgery. All patterns of AF confer a higher risk of AF detection in follow-up. Duration and treatment of early post-operative AF may have implications regarding the longer-term risk of adverse outcomes and recurrent AF.

The efficacy and safety of apatinib combined with S-1 for advanced gastric cancer: A systematic review and meta-analysis.

Advanced gastric cancer (AGC) that does not respond to first-line therapy poses a challenge to clinical management. The objective of this study was to compare the efficacy and safety of apatinib combined with S-1 in second-line and above treatment of AGC. Cochrane Library, Science Direct, EMBASE, PubMed, and CNKI were searched for randomized controlled trial until August 2023. Only patients who met "Standardized Diagnosis and Treatment Guide for Gastric Cancer" were included in the study. The accurate data and distinguishing between follow-up time and drug dose were extracted to reduce heterogeneity and the risk of bias of the included trials was evaluated according to the Cochrane Handbook. Finally, the survival benefit of the treatment was evaluated based on clinical response rate, survival period, biochemical index, and adverse event occurrence in the trial. The meta-analysis included 29 randomized controlled trials involving 2149 participants. Statistically significant increases in clinical effective rate (odds ratios = 2.61, 95% confidence interval [2.13-3.20], P < .00001) and disease control rate (odds ratios = 3.16, 95% confidence interval [2.54-3.94], P < .00001) were found when apatinib combined with S-1, and also had obvious advantages in reducing tumor markers and regulating immune factors. In addition, apatinib combined with S-1 significantly increased the risk of hypertension but reduced damage to liver function, while the improvement of other adverse events was not pronounced. Apatinib combined with S-1 is more effective and safe for second-line and above treatment of AGC. This study minimized the conclusion bias caused by the basic data sources, but more high-quality studies are still needed to validate these conclusions.

Lower urinary tract dysfunction in the central nervous system neurogenic bladder and the real-life treatment outcome of botulinum toxin A.

Neurogenic lower urinary tract dysfunction (NLUTD) is common in patients with central nervous system (CNS) lesions. Cases of cerebrovascular accidents (CVA), Parkinson's disease, dementia, and other intracranial lesions develop poor bladder control with or without urinary difficulty due to loss of cortical perception of bladder filling sensation and poor coordination of urethral sphincter relaxation during reflex micturition. Patients with CNS lesions usually have overactive bladder (OAB) symptoms, including urgency, frequency, incontinence, voiding symptoms of dysuria, large postvoid residual volume, and retention. In elderly patients with severe CNS disease the OAB symptoms are usually difficult to adequately relieve by medical treatment, and thus, their quality of life is greatly. Botulinum toxin A (BoNT-A) is currently licensed and has been applied in patients with idiopathic and neurogenic OAB due to spinal cord injury or multiple sclerosis. However, the application of BoNT-A in the treatment of urinary incontinence due to NLUTD in chronic CNS lesions has not been well-documented. Although cohort studies and case series support BoNT-A treatment for neurogenic OAB, chronic urine retention after intravesical BoNT-A injection for OAB and exacerbated urinary incontinence after urethral BoNT-A injection for voiding dysfunction have greatly limited its application among patients with NLUTD due to CNS lesions. This article reviews the pathophysiology and clinical characteristics of NLUTD in patients with CNS lesions and the clinical effects and adverse events of BoNT-A injection for patients with NLUTD. A flowchart was created to outline the patient selection and treatment strategy for neurogenic OAB.

#684 Safety and Tolerability of adipose-derived mesenchymal stem cell “ADR-001” in the treatment of immunoglobulin A nephropathy

Abstract Background and Aims Immunoglobulin A (IgA) nephropathy is one of the most frequent glomerular diseases and is sometimes refractory, requiring kidney replacement therapy. Although corticosteroids are mainly used for treatment, infection is a serious adverse event, and evidence for therapeutic efficacy is insufficient; therefore, new therapeutic options are highly desired. Mesenchymal stem cells (MSCs) contribute to the amelioration of inflammation and recovery of organ function. Due to these properties of MSCs, they have been clinically applied to various inflammatory diseases. Therefore, we decided to conduct the world's first investigator-initiated clinical trial to administer MSCs for refractory IgA nephropathy. Method This trial was a phase 1, open-label, multiple-center, dose-escalation study of adult patients with refractory IgA nephropathy resistant to or difficult to treat with existing therapies. This trial was registered and assigned the number, jRCT2043200002 and NCT04342325. ADR-001 was administered intravenously from three to six patients at a dose of 1 × 108 cells once in the first cohort and to six patients twice at two-week intervals in the second cohort (Fig. 1A). When MSCs were administered, heparin was also administered. The observational period continued until 52 weeks. The primary endpoint was the safety up to 6 weeks after ADR-001 administration. Secondary endpoints will be the respective percentages of patients with adverse events and efficacy, such as clinical remission, partial remission, remission of urine protein, remission of hematuria, time to remission, changes in urine protein, hematuria, and estimated glomerular filtration rate. Results First, regarding the primary endpoint, three patients in the first cohort received single dose of ADR-001, and the data safety monitoring board determined that the safety of the ADR-001 was well controlled because no adverse clinical events occurred. Therefore, the trial shifted the second cohort, and six patients received two doses of ADR-001. In the second cohort, the data safety monitoring board determined that safety was well controlled and that ADR-001 was safe and well tolerated for clinical use. Next, regarding the secondary endpoint, especially regarding to efficacy, kidney damage marker (Fig. 1B) and urinary protein were drastically reduced immediately after administration of ADR-001. Conclusion The safety and tolerability of ADR-001, an adipose-derived MSC, were confirmed. Furthermore, the efficacy of ADR-001 is strongly expected.

Outcome of Transjugular Intrahepatic Portosystemic Shunt in Patients with Cirrhosis and Refractory Hepatic Hydrothorax: A Systematic Review and Meta-analysis.

Background Around 5% of patients with cirrhosis of the liver develop hepatic hydrothorax (HH). For patients with refractory HH (RHH), transjugular intrahepatic portosystemic shunt (TIPS) has been investigated in small studies. Hence, the present meta-analysis aimed to summarize the current data on the outcome of TIPS in patients with RHH. Methods From inception through June 2023, MEDLINE, Embase, and Scopus were searched for studies analyzing the outcome of TIPS in RHH. Clinical response, adverse events (AEs), mortality, and shunt dysfunction were the primary outcomes assessed. The event rates with their 95% confidence interval were calculated using a random-effects model. Results A total of 12 studies ( n = 466) were included in the final analysis. The pooled complete and partial response rates were 47.2% (35.8-58.5%) and 25.5% (16.7-34.3%), respectively. The pooled incidences of serious AEs and post-TIPS liver failure after TIPS in RHH were 5.6% (2.1-9.0%) and 7.6% (3.1-12.1%), respectively. The pooled incidences of overall hepatic encephalopathy (HE) and severe HE nonresponsive to standard treatment after TIPS in RHH were 33.2% (20.0-46.4%) and 3.6% (0.4-6.8%), respectively. The pooled 1-month and 1-year mortality rates were 14.0% (8.3-19.6%) and 42.0% (33.5-50.4%), respectively. The pooled incidence of shunt dysfunction after TIPS in RHH was 24.2% (16.3-32.2%). Conclusion RHH has a modest response to TIPS in patients with cirrhosis, with only half having a complete response. Further studies are required to ascertain whether early TIPS can improve the outcome of patients with cirrhosis and HH.

Two-Year Outcomes for Patients with Non-ST-Elevation Acute Coronary Syndrome Treated with Magmaris and Absorb Bioresorbable Scaffolds in Large-Vessel Lesions.

The acute coronary syndrome (ACS) continues to be a fundamental indication for revascularization by percutaneous coronary intervention (PCI). Drug-eluting stent (DES) implantation remains a part of contemporary practice but permanent caging of the vascular structure with the metallic stent structure may increase the rate of device-related adverse clinical events. As an alternative to classic metallic DESs, the bioresorbable scaffolds (BRSs) have emerged as a temporary vascular support technology. We evaluated the mid-term outcomes of two generations of bioresorbable scaffolds-Absorb (Abbott-Vascular, Chicago, IL, USA) and Magmaris (Biotronik, Germany)-in patients with non-ST-elevation ACS. The study cohort consisted of 193 subjects after Magmaris implantation and 160 patients following Absorb implantation in large-vessel lesions. At 2 years, a significantly lower rate of a primary outcome (cardiac death, myocardial infarction, stent thrombosis) was observed with Magmaris (5.2% vs. 15%; p = 0.002). In addition, we observed a significantly lower rate of MI in the target vessel (2.6% vs. 9.4%; p = 0.009) and a lower rate of scaffold thrombosis (0% vs. 3.7%; p = 0.008). The TLF rate between the two groups was not significantly different. Magmaris demonstrated a good safety profile and more favorable clinical outcomes when compared to Absorb in patients with non-ST-elevation ACS.

Immune checkpoint inhibition as a therapeutic strategy for HIV eradication: current insights and future directions.

HIV-1 infection contributes substantially to global morbidity and mortality, with no immediate promise of an effective prophylactic vaccine. Combination antiretroviral therapy (ART) suppresses HIV replication, but latent viral reservoirs allow the virus to persist and reignite active replication if ART is discontinued. Moreover, inflammation and immune disfunction persist despite ART-mediated suppression of HIV. Immune checkpoint molecules facilitate immune dysregulation and viral persistence. However, their therapeutic modulation may offer an avenue to enhance viral immune control for patients living with HIV-1 (PLWH). The success of immune checkpoint inhibitor (ICI) therapy in oncology suggests that targeting these same immune pathways might be an effective therapeutic approach for treating PLWH. Several ICIs have been evaluated for their ability to reinvigorate exhausted T cells, and possibly reverse HIV latency, in both preclinical and clinical HIV-1 studies. Although there are very encouraging findings showing enhanced CD8 + T-cell function with ICI therapy in HIV infection, it remains uncertain whether ICIs alone could demonstrably impact the HIV reservoir. Moreover, safety concerns and significant clinical adverse events present a hurdle to the development of ICI approaches. This review provides an update on the current knowledge regarding the development of ICIs for the remission of HIV-1 in PWH. We detail recent findings from simian immunodeficiency virus (SIV)-infected rhesus macaque models, clinical trials in PLWH, and the role of soluble immune checkpoint molecules in HIV pathogenesis.

Safety and efficacy of monthly high-dose vitamin D3 supplementation in children and adolescents with sickle cell disease

Little is known about the impact of vitamin D supplementation on hand grip strength (HGS) and health-related quality of life (HRQoL) in children and adolescents with sickle cell disease (SCD). We aimed to evaluate the safety and efficacy of monthly high-dose vitamin D3 supplementation and its implications on bone mineral density (BMD), HGS, and HRQoL in patients with SCD and healthy controls. The study included 42 children with SCD and 42 healthy matched controls. The study participants were supplemented with high-dose monthly oral vitamin D3. Changes in the serum level of 25(OH) vitamin D3, maximum HGS, and BMD from baseline to 6 months were assessed, and the HRQoL questionnaire and Childhood Health Assessment Questionnaire (CHAQ) were used to evaluate the functional capacity. At baseline, SCD subjects had poorer growth status indicated by negative Z scores. Suboptimal BMD was detected by significantly lower Z score, and lower HGS and worse HRQL parameters were found compared to the controls (P < 0.001). Median 25(OH) vitamin D3 was significantly lower in SCD patients compared to controls (16.5 vs. 28 ng/mL, respectively (P < 0.001)). After 6 months of vitamin D supplementation, there was significant improvement in the DEXA Z-score (P < 0.001), limitation of physical health (P = 0.02), pain scores (P < 0.001), and CHAQ grades (P = 0.01) in SCD patients. A significant improvement in HGS (P < 0.001 and P = 0.005) as well as the CHAQ score (P < 0.001 and P = 0.003) was detected in the SCD group and controls, respectively. There were no reported clinical adverse events (AEs) or new concomitant medications (CMs) during the study duration, and safe levels of Ca and 25 (OH) D3 were observed at 3 and 6 months for both groups. There was a significant positive correlation between HGS and total physical score (r = 0.831, P < 0.001) and a negative correlation with CHAQ score (r = − 0.685, P < 0.001). We also detected a significant positive correlation between vitamin D levels at 6 months and HGS (r = 0.584, P < 0.001), pain score (r = 0.446, P < 0.001), and a negative correlation with CHAQ score (r = − 0.399, P < 0.001). Conclusion: Monthly oral high-dose vitamin D supplementation was safe and effective in improving vitamin D levels, HGS, and HRQoL in SCD children and healthy subjects, and BMD scores in SCD patients. Further randomized controlled trials are warranted to assess an optimal dosing strategy and to investigate the impact on clinically significant outcomes in children and adolescents with SCD and their healthy counterparts. Trial registration: ClinicalTrials.gov, identifier NCT06274203, date of registration: 23/02/2024, retrospectively registered.What is known:• Several studies have reported a high prevalence of vitamin D deficiency and suboptimal bone mineral density (BMD) in sickle cell disease (SCD) patients.• Musculoskeletal dysfunction is reported in SCD patients with a negative impact on physical activity and health-related quality of life (HRQL).• Little is known regarding the impact of vitamin D3 supplementation in children and adolescents with SCD.What is new:• We found that monthly oral high-dose vitamin D3 supplementation was safe, tolerated, and effective in improving serum vitamin D levels, HGS, BMD scores, and HRQL in SCD patients.

Bleeding Risk of Cold Versus Hot Snare Polypectomy for Pedunculated Colorectal Polyps Measuring 10 mm or Less: Subgroup Analysis of a Large Randomized Controlled Trial.

Concerns regarding bleeding remain in cold snare polypectomy (CSP) for small pedunculated (0-Ip) polyps. The aim of this study was to compare the risk of CSP and hot snare polypectomy (HSP) for such lesions. Data on 0-Ip colorectal polyps ≤10 mm were extracted from a large, pragmatic, randomized trial. Immediate postpolypectomy bleeding (IPPB), defined as the perioperative use of a clip for bleeding, was evaluated through polyp-level analysis. Delayed postpolypectomy bleeding (DPPB), defined as bleeding occurring within 2 weeks postoperatively, was assessed at the patient-level among patients whose polyps were all ≤10 mm, including at least one 0-Ip polyp. A total of 647 0-Ip polyps (CSP: 306; HSP: 341) were included for IPPB analysis and 386 patients (CSP: 192; HSP: 194) for DPPB analysis. CSP was associated with a higher incidence of IPPB (10.8% vs 3.2%, P < 0.001) but no adverse clinical events. The procedure time of all polypectomies was shorter for CSP than for HSP (123.0 ± 117.8 vs 166.0 ± 237.7 seconds, P = 0.003), while the procedure time of polypectomies with IPPB were similar (249.8 ± 140.2 vs 227.4 ± 125.9 seconds, P = 0.64). DPPB was observed in 3 patients (1.5%) in the HSP group, including one patient (0.5%) with severe bleeding, but not in the CSP group. Despite CSP being associated with more IPPB events, it could be timely treated without adverse outcomes. Notably, no delayed bleeding occurred in the CSP group. Our findings support the use of CSP for 0-Ip polyps ≤ 10 mm.

Combined biomarker testing for the assessment of cardio-renal interactions among myocardial infarction patients

Abstract Funding Acknowledgements None. Background The utility of different biomarkers for the prediction of either renal or cardiovascular outcomes following ST-elevation myocardial infarction (STEMI) has been evaluated in several studies however, very few data exist on the prognostic value of combining biomarkers. Among numerous biomarkers examined, C-reactive protein (CRP) and Neutrophil gelatinase associated Lipocalin (NGAL) stand high in their utility to assess the cardiorenal crosstalk. The aim of this study was to assess the prognostic value of combined CRP and NGAL measurement for the assessment of renal and cardiovascular outcomes in reperfused STEMI patients. Methods Blood samples for plasma NGAL and CRP were drawn 24 hours after admission. High NGAL and CRP were defined as values within the 4th quartile (&amp;gt;75percentile). Patients were stratified into 4 study groups: Low NGAL/Low CRP, LOW NGAL/high CRO, High NGAL /low CRP and high NGAL/high CRP. Patients were assessed for the occurrence of in-hospital adverse clinical events (MACE). These included occurrence of acute kidney injury , 30-day mortality and their combination. Results A total of 311 patients were included (mean age 66 ± 14 years, 81% males). According to the 4 study groups, there was a stepwise increase in the proportion of in hospital MACE ( 9% vs. 21% vs. 40% vs. 68% ;p,0.001,figure 1). In a multivariate regression model , compared to patients having low NGAL/low CRP we observed a graded, independent increase in the risk for MACE for low NGAL/high CRP , high NGAL/low CRP and high NGAL/high CRP levels( OR 2.89, p=0.02 vs. OR 3.29,p&amp;lt;0.001 vs. OR 17.6,p&amp;lt;0.001 respectively). Peak concentrations showed significant areas under the curves (AUCs) for the prediction of MACE for both CRP AUC (0.692,95% CI 0.62-0.76) and NGAL ( AUC 0.778,95% CI 0.72-0.84). The combination of NGAL and CRP yielded a significant increase in AUC to 0.822 (95% CI 0.77 to 0.88) (combined biomarkers vs CRP: p&amp;lt;0.001 and combined vs. NGAL :p=0.02,figure 2). Conclusions In patients with reperfused STEMI, the combined assessment of NGAL and CRP provided incremental prognostic information for the prediction of in hospital MACE when compared with single-biomarker measurement.Proportion of in-hospital MACEAUC CR NGAL

Cenobamate Plasma Levels in Patients with Epilepsy: Correlation with Efficacy and Tolerability?

Objective: Cenobamate is approved by the European Medicine Agency for the treatment of adult patients with epilepsy (PWEs) with ongoing focal-onset seizures despite appropriate treatment with at least two established antiseizure medications. Pivotal trials and post-marketing real-world observational studies suggest high efficacy with unusually high seizure-free rates. The authors sought to investigate the plasma levels of cenobamate under steady-state conditions in seizure-free versus non-responding PWEs, and in PWEs who experienced adverse events versus those who did not. Methods: Blood samples were collected from adult PWEs who were treated with adjunct cenobamate under steady-state conditions. Daily doses, concomitant medications, efficacy, and tolerability were assessed. The plasma cenobamate levels of seizure-free versus non-responding PWEs and between PWEs with and those without clinical adverse events were compared. Results: Samples from 101 PWEs were included. Thirty-six PWEs were seizure-free and 65 were non-responders. In 31 PWEs, adverse events were apparent, whereas in the remaining 70, no tolerability issues were reported. A linear correlation was found between the daily doses (range: 100 mg-400 mg) and the plasma levels (3.8 mg/L-54.6 mg/L). Neither the daily doses nor the plasma levels differed significantly between the investigated subgroups. The main reason for this result was that the individual therapeutic ranges varied widely: seizure freedom and adverse effects were observed alongside low doses and plasma levels in some PWEs. Conversely, there were examples of PWEs who did not respond or who reported no tolerability issues at high doses or plasma levels. Conclusions: To evaluate the individual therapeutic range and to better understand the influence of other drugs in cases where concomitant medications are used, the therapeutic drug monitoring of cenobamate may be useful. A general therapeutic range cannot be defined.

Driving quality in delirium care through a patient-centered monitoring system in palliative care: Protocol for the two-staged exploratory sequential mixed methods MODEL-PC study

Introduction Delirium is a serious acute neurocognitive condition that is common in palliative care units and yet under-addressed. To improve delirium care in this setting, we will develop and pilot a monitoring system that integrates the Delirium Clinical Care Standard, Palliative Care Outcomes Collaboration (PCOC) methods, and perspectives of patients, carers and staff. Methods This paper reports the protocol for a two-stage, exploratory, sequential mixed-methods implementation study. Stage 1 data collection includes Delirium Standard-aligned process mapping and clinical audits, and Critical Incident Technique interviews with patients, carers and staff with a recent experience of delirium. We will present integrated stage 1 findings to stakeholders then collaboratively develop a delirium monitoring system that aligns with the Delirium Standard and PCOC methods. In stage 2, we will pilot the new system and repeat stage 1 data collection and analyses, adding PCOC and adverse event measures. Implementation principles and strategies such as audit and feedback and education will be applied. We developed simplified participants information sheets and consent forms for interview and process mapping participants, who will provide written informed consent; and waiver of consent to collect clinical audit, PCOC and adverse event data from patients’ medical records is approved. At study end, we will report implementation, effectiveness and safety outcomes, including systemic utility of the delirium monitoring system for wider testing and use to meet the Delirium Standard in palliative care units. Quantitative data analyses will include descriptive and inferential statistics and qualitative analyses will incorporate thematic content analysis aligned to the Critical Incident Technique. Mixed methods data integration will be at the end of each stage. Discussion This protocol paper describes the mixed methods, systems integration, and innovative measures and study processes of the MODEL-PC study. We also share data collection tools and a simplified information sheet and consent form for patients.