Exploratory Subgroup Analysis Research Articles

Prevalence of physical violence against people in insecure migration status: A systematic review and meta-analysis.

This study summarised evidence on the prevalence of interpersonal, community and state physical violence against people in insecure migration status. We conducted a systematic review and meta-analysis of primary studies that estimated prevalence of physical violence against a population in insecure migration status. We searched Embase, Social Policy and Practice, Political Science Complete, SocINDEX and Web of Science Social Sciences Citation Index for reports published from January 2000 until 31 May 2023. Study quality was assessed using an adapted version of the Joanna Briggs assessment tool for cross-sectional studies. Two reviewers carried out screening, data extraction, quality assessment and analysis. Meta-analysis was conducted in Stata 17, using a random effects model and several exploratory subgroup analyses. We retrieved 999 reports and included 31 retrospective cross-sectional studies with 25,997 migrants in insecure status. The prevalence estimate of physical violence was 31.16% (95% CI 25.62-36.70, p < .00). There was no statistically significant difference in the estimates for prevalence of violence for men (35.30%, 95% CI 18.45-52.15, p < .00) and for women (27.78%, 95% CI 21.42-34.15, p < .00). The highest point estimate of prevalence of violence was where insecure status was related to employment (44.40%, 95% CI 18.24-70.57, p < .00), although there were no statistically significant difference in the subgroup analysis. The prevalence of violence for people in undocumented status was not significantly different (29.13%, 95% CI 19.86-38.41, p < .00) than that for refugees and asylum seekers (33.29%, 95% CI 20.99-45.59, p < .00). The prevalence of violence in Asia was 56.01% (95% CI 22.47-89.55, p < .00). Europe had the lowest point prevalence estimate (17.98%, 95% CI 7.36-28.61, p < .00), although the difference was not statistically significant. The prevalence estimate during the migration journey was 32.93% (95% CI 24.98-40.88, p < .00). Intimate partner violence attached to insecure status was estimated at 29.10%, (95% CI 8.37-49.84, p = .01), and state violence at 9.19% (95% CI 6.71-11.68, p < .00). The prevalence of physical violence is a concern among people in a range of insecure migration statuses. Prevalence of violence is not meaningfully higher for people in undocumented status than for people in other types of insecure status. PROSPERO (CRD42021268772).

Commercial Versus Medicaid Insurance and Use of High-Priced Anticancer Treatments.

Because the markups on cancer drugs vary by payor, providers' financial incentive to use high-price drugs is differential according to each patient's insurance type. We evaluated the association between patient insurer (commercial vs Medicaid) and the use of high-priced cancer treatments. We linked cancer registry, administrative claims, and demographic data for individuals diagnosed with cancer in North Carolina from 2004 to 2011, with either commercial or Medicaid insurance. We selected cancers with multiple FDA-approved, guideline-recommended chemotherapy options and large price differences between treatment options: advanced colorectal, lung, and head and neck cancer. The outcome was a receipt of a higher-priced option, and the exposure was insurer: commercial versus Medicaid. We estimated risk ratios (RRs) for the association between insurer and higher-priced treatment using log-binomial models with inverse probability of exposure weights. Of 812 patients, 209 (26%) had Medicaid. The unadjusted risk of receiving higher-priced treatment was 36% (215/603) for commercially insured and 27% (57/209) for Medicaid insured (RR: 1.31, 95% CI: 1.02-1.67). After adjustment for confounders the association was attenuated (RR: 1.15, 95% CI: 0.81-1.65). Exploratory subgroup analysis suggested that commercial insurance was associated with increased receipt of higher-priced treatment among patients treated by non-NCI-designated providers (RR: 1.53, 95% CI: 1.14-2.04). Individuals with Medicaid and commercial insurance received high-priced treatments in similar proportion, after accounting for differences in case mix. However, modification by provider characteristics suggests that insurance type may influence treatment selection for some patient groups. Further work is needed to determine the relationship between insurance status and newer, high-price drugs such as immune-oncology agents.

Cannabinoid Use and Obstructive Sleep Apnea: A Retrospective Cohort Study.

Obstructive sleep apnea (OSA) is a sleep disorder with no widely accepted pharmacological therapy. Cannabinoids have been suggested to reduce OSA severity in small human studies. The purpose of this retrospective cohort study was to explore the association of self-reported cannabis use on OSA severity and sleep parameters in a large cohort of adults undergoing in-laboratory polysomnography. Sleep and medication data were collected for all consecutive adults who completed diagnostic polysomnography at Sunnybrook Health Sciences Centre from 2010 to 2022. Multivariable linear regression models were employed that adjusted for age, sex, and BMI (minimally adjusted model), as well as medication and comorbidity data (maximally adjusted model). An exploratory subgroup analysis was additionally run in patients with moderate to severe OSA. Of 6,958 individuals (mean age 54.7 ± 16.3, BMI 29.1 ± 6.8, 51.0% female), 71 reported cannabis use. In our minimally adjusted models, cannabis use predicted a reduced respiratory disturbance index (RDI) (β: -4.8 [95% CI: -9.4, -0.2]; p = 0.042); this association became nonsignificant in the fully adjusted models. In an exploratory analysis of patients with moderate to severe OSA (n = 613), cannabis use (n = 7) predicted increased stage N3 sleep (β: 33.5 [95% CI: 15.6, 51.4]; p < 0.001) and decreased REM sleep (β: 16.0 [95% CI: 0.3, 31.7]; p = 0.046). Self-reported cannabis use was not associated with OSA severity after adjusting for confounders. In an exploratory subgroup analysis of patients with moderate to severe OSA, cannabis use impacted sleep architecture. Future studies should further explore these findings.

Benralizumab does not elicit therapeutic effect in patientswith chronic spontaneous urticaria: results from the phase IIb multinational randomized double-blind placebo-controlled ARROYO trial.

Chronic spontaneous urticaria (CSU) is a relatively common skin disease associated with hives and angio-oedema. Eosinophils play a role in CSU pathogenesis. Benralizumab, an anti-interleukin-5 receptor-α monoclonal antibody, has been shown to induce nearly complete depletion of eosinophils. To determine the clinical efficacy and safety of benralizumab in patients with CSU who were symptomatic despite H1 antihistamine treatment. The 24-week, randomized, double-blind, placebo-controlled, phase IIb portion of the ARROYO trial enrolled adult patients with CSU who were currently on H1 antihistamine treatment. Patients were randomized to one of five treatment groups according to benralizumab dose and regimen for a 24-week treatment period. The primary endpoint was change from baseline in Itch Severity Score (ISS)7 at week 12. The key secondary endpoint was change from baseline in Urticaria Activity Score (UAS)7 at week 12. Additional secondary endpoints included other metrics to assess CSU at week 24, blood eosinophil levels, and pharmacokinetics and immunogenicity assessments. Exploratory subgroup analyses were conducted to explore responses according to demographics, clinical features and biomarkers. Safety was assessed in all treatment groups. Of 155 patients, 59 were randomized to benralizumab 30 mg, 56 to benralizumab 60 mg and 40 to placebo. Baseline and disease characteristics were consistent with what was expected for patients with CSU. There were no significant differences in change from baseline in ISS7 score at week 12 between benralizumab and placebo [benralizumab 30 mg vs. placebo, least-squares mean difference -1.01, 95% confidence interval (CI) -3.28 to 1.26; benralizumab 60 mg vs. placebo, least-squares mean difference -1.79, 95% CI -4.09 to 0.50] nor in change from baseline in UAS7 score at week 12 between benralizumab and placebo (benralizumab 30 mg vs. placebo, P = 0.407; benralizumab 60 mg vs. placebo, P = 0.082). Depletion of blood eosinophil levels was observed at week 24 in patients treated with benralizumab. All other secondary endpoints and exploratory/subgroup analyses indicated no significant differences between benralizumab and placebo. Safety results were consistent with the known profile of benralizumab. Although benralizumab resulted in near-complete depletion of blood eosinophils, there was no clinical benefit over placebo.

Improved Activities of Daily Living With Adjunctive Intravenous Steroids in Bacterial Meningitis: A Nationwide, Population-Based Medical Database Study.

The benefit of using adjunctive intravenous steroids (IVS) to reduce the neurological sequelae in bacterial meningitis remains inconclusive. This study evaluated the effect of IVS on improving the subsequent Activities of Daily Living (ADL) in bacterial meningitis by analyzing data from a large nationwide administrative medical database in Japan. Data from 1,132 hospitals, covered by the administrative Diagnosis Procedure Combination (DPC) payment system from 2016 to 2022, were evaluated. The ADL levels at admission and discharge were measured using the Barthel Index (BI). Out of the cumulative 47,366,222 patients hospitalized, 8,736 were diagnosed with acute bacterial meningitis and had BI data available. The BI at discharge, adjusted for sex, age, and BI at admission, was significantly better among those treated with IVS (p<0.0001). Exploratory subgroup analyses suggested that this benefit is expected across a broad spectrum of bacterial species. In summary, the use of IVS for improving the subsequent ADL level in bacterial meningitis was suggested.

The effect of laser-assisted hatching on vitrified/warmed blastocysts: the ALADDIN randomized controlled trial

ObjectiveTo evaluate whether laser-mediated assisted hatching (AH) performed on vitrified/warmed blastocysts before embryo transfer can improve live birth rate. DesignThe “pArtiaL zonA pelluciDa removal by assisteD hatchINg of blastocysts (ALADDIN)” is a 2-center comparative study with a parallel randomized controlled design. SubjectsParticipants were recruited between September 2018 and November 2021. They were aged 18 to 39 years, underwent non-donor IVF cycles, and were scheduled for elective single embryo transfer with vitrified/warmed blastocysts. Those with uterine abnormalities, BMI >35 kg/m2, severe male factor infertility, or performing preimplantation genetic testing were excluded. InterventionAssisted hatching was performed using a 1480 nm diode laser, removing approximately one-third of the zona pellucida with continuous 0.2 ms pulses applied from the 1 to 5 o’clock positions. Main Outcome MeasuresThe primary outcome was the live birth rate. Secondary endpoints included clinical pregnancy, miscarriage, multiple pregnancies, preterm births, obstetrical and neonatal complications, and congenital anomalies. ResultsOverall, 698 participants met the inclusion criteria and were randomized: 352 patients were assigned to the AH arm and 346 to the control arm. One-hundred and five (29.8%) and 101 (29.2%) participants achieved a live birth following treatment, respectively (p=0.87). The relative risk of live birth in patients with vitrified/warmed blastocysts treated with AH was 1.02 (95%CI: 0.86-1.19). Exploratory subgroup analyses for women’s age, recruiting centers, indications for IVF, method of insemination, blastocyst quality, and days of blastocyst development failed to highlight any clinical situation that could benefit from AH in thawed blastocysts. ConclusionIn patients undergoing frozen embryo transfer with vitrified/warmed blastocysts, laser AH does not improve the live birth rate. Further studies are required to rule out milder but potentially interesting benefits in specific subgroups of patients.

Efficacy and safety of tirzepatide in people with type 2 diabetes by baseline body mass index: An exploratory subgroup analysis of SURPASS-AP-Combo.

To assess the efficacy and safety of tirzepatide versus insulin glargine in people with type 2 diabetes (T2D) by baseline body mass index (BMI). Participants with T2D from the Phase 3 SURPASS-AP-Combo trial (NCT04093752) were categorized into three BMI subgroups (normal weight [<25 kg/m2 ], overweight [≥25 and <30 kg/m2 ], and obese [≥30 kg/m2 ]) according to World Health Organization criteria. Exploratory outcomes including glycaemic control, body weight, cardiometabolic risk, and safety were compared among three tirzepatide doses (5, 10 or 15 mg) and insulin glargine. Of 907 participants, 235 (25.9%) had a BMI <25 kg/m2 , 458 (50.5%) a BMI ≥25 to <30 kg/m2 , and 214 (23.6%) a BMI ≥30 kg/m2 at baseline. At Week 40, all tirzepatide doses led to a greater reduction in mean glycated haemoglobin (HbA1c; -2.0% to -2.8% vs. -0.8% to -1.0%, respectively) and percent change in body weight (-5.5% to -10.8% vs. 1.0% to 2.5%, respectively) versus insulin glargine, across the BMI subgroups. Compared with insulin glargine, a higher proportion of tirzepatide-treated participants achieved treatment goals for HbA1c and body weight reduction. Improvements in other cardiometabolic indicators were also observed with tirzepatide across all the BMI subgroups. The safety profile of tirzepatide was similar across all subgroups by BMI. The most frequent adverse events with tirzepatide were gastrointestinal-related events and decreased appetite, with relatively few events leading to treatment discontinuation. In participants with T2D, regardless of baseline BMI, treatment with tirzepatide resulted in statistically significant and clinically meaningful glycaemic reductions and body weight reductions compared with insulin glargine, with a safety profile consistent with previous reports.

Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial

Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock. APROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 μg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The trial was registered at ClinicalTrials.gov (NCT00625209). Of 1241 patients included in the APROCCHSS trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio [OR] 0·60, 95% CI 0·43-0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70-1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53-0·98) in patients with ARDS and 0·85 (0·61-1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46-0·89) in the CAP subgroup and 1·02 (0·75-1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction). In a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup. Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004.

Efficacies of anlotinib monotherapy versus gemcitabine-based chemotherapy for patients with advanced soft tissue sarcoma after the failure of anthracycline-based chemotherapy

ObjectiveThe purpose of this study was to compare the antitumor efficacy of anlotinib with gemcitabine-based chemotherapy as subsequent treatment regimens in patients with advanced non-specific soft tissue sarcoma (STS) after the failure of anthracycline-based chemotherapy.MethodsPatients diagnosed with advanced STS who were treated with either anlotinib or gemcitabine-based chemotherapy between May 2009 and May 2023 in our center were eligible. All patients experienced disease progression or recurrence after the anthracycline-based chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were disease control rate (DCR), overall survival (OS) and safety.ResultsWe included 49 patients receiving anlotinib and 45 patients receiving gemcitabine-based chemotherapy. The median follow-up time was 76.9 weeks (range 2.9–678.9 weeks). The DCR (65.3% vs. 57.8%; p = 0.610), PFS (24.0 weeks vs. 18.6 weeks; p = 0.669) and OS (79.4 weeks vs. 87.0 weeks; p = 0.471) of anlotinib and gemcitabine-based chemotherapy indicated similar clinical efficacy. Moreover, exploratory subgroup analyses showed that patients with STS originating from limbs and trunk were inclined to benefit from anlotinib treatment (median PFS: 31.3 weeks vs. 12.4 weeks; p = 0.045). ECOG PS was an independent predictor of the PFS [Hazard Ratio (HR) 0.31; 95% confidence interval (CI) 0.11–0.85; p = 0.023] and OS (HR 0.26, 95%CI 0.10–0.70; p = 0.008) in the anlotinib group. While neutrophil-to-lymphocyte ratio (NLR) was an independent prognostic factor of the PFS (HR 0.33, 95%CI 0.11–0.98; p = 0.045) in the gemcitabine-based chemotherapy group. The incidence of grade 3 or higher related AEs in anlotinib and gemcitabine-based chemotherapy was 20.4% (n = 10) and 20.0% (n = 9), respectively.ConclusionOur research suggested that anlotinib and gemcitabine-based chemotherapy showed similar clinical efficacy and safety in the subsequent treatment of advanced STS after the failure of anthracycline-based chemotherapy.

Differences in the Incidence of Hypotension and Hypertension between Sexes during Non-Cardiac Surgery: A Systematic Review and Meta-Analysis.

Background: Major determinants of blood pressure (BP) include sex and age. In youth, females have lower BP than males, yet in advanced age, more pronounced BP increases result in higher average BPs in females over 65. This hypothesis-generating study explored whether age-related BP divergence impacts the incidence of sex-specific intraoperative hypotension (IOH) or hypertension. Methods: We systematically searched PubMed and Embase databases for studies reporting intraoperative BP in males and females in non-cardiac surgery. We analyzed between-sex differences in the incidence of IOH and intraoperative hypertension (primary endpoint). Results: Among 793 identified studies, 14 were included in this meta-analysis, comprising 1,110,636 patients (56% female). While sex was not associated with IOH overall (females: OR 1.10, 95%CI [0.98-1.23], I2 = 99%), a subset of studies with an average age ≥65 years showed increased exposure to IOH in females (OR 1.17, 95%CI [1.01-1.35], I2 = 94%). One study reported sex-specific differences in intraoperative hypertension, with a higher incidence in females (31% vs. 28%). Conclusions: While sex-specific reporting on intraoperative BP was limited, IOH did not differ between sexes. However, an exploratory subgroup analysis offers the hypothesis that females of advanced age may face an increased risk of IOH, warranting further investigation.

Phase II trial of cabozantinib (cabo) plus durvalumab (durva) in chemotherapy refractory microsatellite stable (MSS) patients with advanced gastric and esophageal (G/E) adenocarcinoma: CAMILLA G/E cohort results.

373 Background: Cabo is a multi-tyrosine kinase inhibitor harboring anti-VEGFR2, MET, AXL, MER and TYRO3 activity. Immunomodulatory and synergistic anti-tumor activity of cabo in combination with PD-1/L1 inhibitors have been demonstrated preclinically and in prior studies in various solid tumors. The phase Ib gastrointestinal (GI) basket CAMILLA trial evaluating cabo + durva confirmed manageable toxicity and anti-tumor activity, leading to the expansion into a multi-cohort phase 2 study. Herein, we report the results of the phase II G/E adenocarcinoma cohort. Methods: Patients (Pts) enrolled in the phase II G/E adenocarcinoma cohort were administered cabo + durva at the RP2D of 40mg QD and 1500mg IV Q4W respectively. Enrolled pts must have progressed on &gt;1 line(s) of systemic therapy. Prior exposure to PD-1/L1 inhibitors was allowed. Those with HER2 positive disease must have progressed on anti-HER2 therapies. The primary outcome was objective response rate (ORR). Secondary outcomes were treatment-related adverse events (TRAEs), disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Exploratory subgroup analyses were conducted in PD-L1 CPS &gt;5. Results: 31 patients were enrolled, with 29 patients evaluable for efficacy. The median age was 61 years (range 32-79). 86% had an ECOG performance status of one. 48% had ≥ 2 prior lines of systemic therapies (range 1-4). Of the 29 pts evaluable for efficacy, 6 pts had confirmed objective responses (5 PR + 1 CR = ORR 20.69%). The most common TRAEs were fatigue (65%), anorexia (58%), elevated liver enzymes (39%), and diarrhea (35%). Grade &gt;3 TRAEs occurred in 19% of pts. Grade &gt;3 immune-related adverse events (irAE) rate was 6%. DCR was 86.2% (25/29). Median PFS and OS were 4.4 (95% confidence interval (CI) 2.2-5.4) and 5.6 months (95% CI 3.6-8.3) respectively. In patients with PD-L1 CPS &gt;5 (12/29), ORR was 25%, and median PFS and OS were 5.5 months (95% CI 1.8-12.4) and 19.3 months (95% CI 2.3-28.2) respectively. Conclusions: Cabo + durva showed anti-tumor activity and manageable toxicity in advanced chemotherapy refractory G/E adenocarcinoma. Further evaluation in patients with high PD-L1 CPS ≥ 5 is warranted in a future randomized trial. Clinical trial information: NCT03539822 .

Atezolizumab plus bevacizumab (A+B) in patients with unresectable hepatocellular carcinoma (uHCC): Real-world experience from a US community oncology network.

447 Background: A+B is the standard first-line (1L) treatment for uHCC based on the IMbrave150 trial, which demonstrated superior efficacy over sorafenib with longer median overall survival (19.2 vs 13.4 months) and progression-free survival (6.8 vs 4.3 months) among patients with Child Pugh (CP) A cirrhosis. Evidence about A+B use and outcomes in routine clinical practice, including in patients with impaired liver function, remains limited. Methods: This retrospective observational study included adult patients who initiated 1L A+B for uHCC within The US Oncology Network between 1/1/2019 and 8/31/2022 (followed through 11/30/2022) using structured and unstructured electronic health records (EHR) based data. CP classes were reported by physicians or derived from risk factors. Kaplan-Meier methods were used to assess real-world overall survival (rwOS) and progression-free survival (rwPFS) from initiation of A+B. Exploratory subgroup analyses were conducted by CP class, albumin-bilirubin (ALBI) grade, liver disease etiology, and race/ethnicity. Results: We identified 374 patients with uHCC who initiated 1L A+B during the study period. Compared with patients enrolled in IMbrave150 (n=336), those treated with A+B in clinical practice were older (median age: 69 vs 64 years), had worse liver function (CP A: 61% vs 100%; ALBI Grade &gt;1: 66% vs 43%), and had poorer performance status (ECOG PS&gt;1: 18% vs 0%). At a median follow-up of 5.6 months, 78% (n=293) had discontinued treatment. Among them, 57% discontinued was progression and 4% discontinued due to toxicity alone. Median rwOS was 13.2 months (95%CI: 9.5–15.9) and median rwPFS was 6.4 months (95%CI: 5.1–7.7). Subgroup results are shown (Table). Conclusions: In community oncology settings, 1L A+B demonstrates effectiveness in diverse patient cohorts, including those with impaired liver function, non-viral liver disease, and racial/ethnic minorities. Predictive biomarkers can help identify subgroups who may most benefit from 1L A+B. [Table: see text]

Short-term outcomes of secondary tricuspid regurgitation after left-sided heart valve surgery

Background: Secondary tricuspid regurgitation (TR) is a common finding in patients undergoing surgery for leftsided heart valve disease. The indications for concomitant tricuspid valve (TV) repair have been progressively expanded based on data suggesting adverse sequelae for patients in whom secondary TR is not treated. Method: This was a prospective observational study of patients undergoing left-sided valve surgery with at least mild TR. Eighty-three patients were enrolled between July 2019 - April 2021. Patients received either conservative management (no TV repair) or concomitant TV repair (TV repair) based upon a guidelinedirected, multidisciplinary team approach. Primary outcomes were freedom from recurrent TR, poor functional status, and mortality at 6 months. The secondary outcomes were to identify predictors of recurrent TR and compare no TV repair vs. TV repair outcomes in patients with moderate or severe pre-operative TR. Results: The mean age was 49 ± 15.5 years and 51.8% (43 of 83) were female. Thirty-seven (44.6%) had rheumatic heart disease. The most common procedures involved the mitral (50.6%) and aortic (28.9%) valves in isolation. Additional procedures were performed in 33 (39.8%) patients, including resection of the left atrial appendage in 21 (63.6%). Pre-operative moderate or severe TR was present in 34 (40.9%) patients, and TV repair was performed in 9 (10.8%) patients who all received rigid ring annuloplasty. At 6 months the 56 patients (67.5%) were free of significant TR, 14 (16.9%) were in a poor functional state and 72 (86.7%) were alive. Suggested predictors of recurrent TR at 6 months were female gender (OR 9.9, p=0.04), rheumatic leftsided valvopathy (OR 14.4, p=0.02), and elevated right ventricular systolic pressure (OR 1.1, p&lt;0.01). An exploratory sub-group analysis did not reveal any primary outcomes differences between no TV repair vs. TV repair at 6 months, despite the latter group demonstrating more high-risk features. Conclusion: Guideline-directed, multidisciplinary team approach for the management of secondary TR associated with left-sided valve disease produced good overall short-term outcomes that appeared similar whether or not the TV was repaired. Prospective studies with long-term outcomes are required to determine the optimal treatment strategy for secondary TR in patients undergoing left-sided valve surgery.

Reduction in Breast Cancer Death With Adjuvant Chemotherapy Among US Women According to Race, Ethnicity, and the 21-Gene Recurrence Score.

We previously showed the 21-gene breast recurrence score (RS) has lower prognostic accuracy for non-Hispanic Black (NHB) compared with non-Hispanic White (NHW) women with estrogen receptor (ER)-positive/HER2-negative breast cancer. The purpose of this study was to determine the clinical validity of the RS for predicting chemotherapy benefit as recommended in the current NCCN Guidelines for Breast Cancer among women from diverse racial/ethnic groups. Using the SEER Oncotype database, we estimated propensity score-weighted hazard ratios (HRs) and 95% confidence intervals for breast cancer death with chemotherapy for women with ER-positive/HER2-negative, AJCC stages I-II, axillary node-negative, invasive breast cancer according to race/ethnicity. We included 6,033 (8.2%) Asian/Pacific Islander (API), 5,697 (7.8%) NHB, 6,688 (9.1%) Hispanic, and 54,945 (74.9%) NHW women. Breast cancer death was reduced with chemotherapy for NHB (HR, 0.48, 95% CI, 0.28-0.81), Hispanic (HR, 0.48; 95% CI, 0.25-0.94), and NHW (HR, 0.80; 95% CI, 0.65-0.99) women with an RS of 26 to 100. There was a nonsignificant reduction for API women (HR, 0.59; 95% CI, 0.28-1.24). For women with an RS of 11 to 25, there was no reduction in death for any racial/ethnic group. Among women aged ≤50 years, the reduction in breast cancer death with chemotherapy differed according to race (NHB: HR, 0.37 [95% CI, 0.20-0.67]; NHW: HR, 0.56 [95% CI, 0.44-0.74]; Pinteraction for chemotherapy * race <.0499). An exploratory subgroup analysis found that young NHB women may benefit from chemotherapy at a lower RS cutoff than other women. The RS was clinically validated as a predictive biomarker for NHB, Hispanic, and NHW women with ER-positive, axillary node-negative breast cancer, but it may underestimate the benefit of chemotherapy for young NHB women. If this finding is confirmed, the RS cutoff for recommending adjuvant chemotherapy for young NHB women with ER-positive, axillary node-negative breast cancer may need to be lower than for other women.

Electronically Delivered Nudges to Increase Influenza Vaccination Uptake in Older Adults With Diabetes

Influenza vaccination is associated with a reduced risk of mortality in patients with diabetes, but vaccination rates remain suboptimal. To assess the effect of electronic nudges on influenza vaccination uptake according to diabetes status. The NUDGE-FLU (Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake) trial was a nationwide clinical trial of Danish citizens 65 years or older that randomized participants at the household level to usual care or 9 different electronic nudge letters during the 2022 to 2023 influenza season. End of follow-up was January 1, 2023. This secondary analysis of the NUDGE-FLU trial was performed from May to July 2023. Nine different electronic nudge letters designed to boost influenza vaccination were sent in September to October 2022. Effect modification by diabetes status was assessed in a pooled analysis of all intervention arms vs usual care and for individual letters. The primary end point was receipt of a seasonal influenza vaccine. The trial included 964 870 participants (51.5% female; mean [SD] age, 73.8 [6.3] years); 123 974 had diabetes. During follow-up, 83.5% with diabetes vs 80.2% without diabetes received a vaccine (P < .001). In the pooled analysis, nudges improved vaccination uptake in participants without diabetes (80.4% vs 80.0%; difference, 0.37 percentage points; 99.55% CI, 0.08 to 0.66), whereas there was no evidence of effect in those with diabetes (83.4% vs 83.6%; difference, -0.19 percentage points; 99.55% CI, -0.89 to 0.51) (P = .02 for interaction). In the main results of NUDGE-FLU, 2 of the 9 behaviorally designed letters (cardiovascular benefits letter and a repeated letter) significantly increased uptake of influenza vaccination vs usual care; these benefits similarly appeared attenuated in participants with diabetes (cardiovascular gain letter: 83.7% vs 83.6%; difference, 0.04 percentage points; 99.55% CI, -1.52 to 1.60; repeated letter: 83.5% vs 83.6%; difference, -0.15 percentage points; 99.55% CI, -1.71 to 1.41) vs those without diabetes (cardiovascular gain letter: 81.1% vs 80.0%; difference, 1.06 percentage points; 99.55% CI, 0.42 to 1.70; repeated letter: 80.9% vs 80.0%; difference, 0.87 percentage points; 99.55% CI, 0.22 to 1.52) (P = .07 for interaction). In this exploratory subgroup analysis, electronic nudges improved influenza vaccination uptake in persons without diabetes, whereas there was no evidence of an effect in persons with diabetes. Trials are needed to investigate the effect of digital nudges specifically tailored to individuals with diabetes. ClinicalTrials.gov Identifier: NCT05542004.

3 L split-dose polyethylene glycol is superior to 2 L polyethylene glycol in colonoscopic bowel preparation in relatively high-BMI (≥ 24 kg/m2) individuals: a multicenter randomized controlled trial

BackgroundWhether body mass index (BMI) is a risk factor for poor bowel preparation is controversial, and the optimal bowel preparation regimen for people with a high BMI is unclear.MethodsWe prospectively included 710 individuals with high BMIs (≥ 24 kg/m2) who were scheduled to undergo colonoscopy from January to November 2021 at 7 hospitals. Participants were randomly allocated into 3 L split-dose polyethylene glycol (PEG) group (n=353) and 2 L PEG group (n=357). The primary outcome was the rate of adequate bowel preparation, and the secondary outcomes included Boston Bowel Preparation Scale (BBPS) score, polyp detection rate, cecal intubation rate, and adverse reactions during bowel preparation. Furthermore, we did exploratory subgroup analyses for adequate bowel preparation.ResultsAfter enrollment, 15 individuals didn’t undergo colonoscopy, finally 345 participants took 3 L split-dose PEG regimen, and 350 participants took 2 L PEG regimen for colonoscopic bowel preparation. 3 L split-dose PEG regimen was superior to 2 L PEG regimen in the rate of adequate bowel preparation (81.2% vs. 74.9%, P = 0.045), BBPS score (6.71±1.15 vs. 6.37±1.31, P < 0.001), and the rate of polyp detection (62.0% vs. 52.9%, P = 0.015). The cecal intubation rate was similar in both groups (99.7%). Regarding adverse reactions, individuals were more likely to feel nausea in the 3 L PEG group (30.9% vs. 19.3%; P = 0.001); however, the degree was mild. In the subgroup analysis for adequate bowel preparation, 3 L split-dose PEG regimen performed better than 2 L PEG regimen in the overweight (BMI 25-29.9 kg/m2 ) (P = 0.006) and individuals with constipation (P = 0.044), while no significant differences were observed in relatively normal (BMI 24-24.9 kg/m2) (P = 0.593) and obese individuals (BMI ≥ 30 kg/m2) (P = 0.715).Conclusions3 L split-dose PEG regimen is superior to 2 L PEG regimen for colonoscopic Bowel Preparation in relatively high-BMI individuals, especially overweight individuals (BMI 25-29.9 kg/m2 ).Trial RegistrationThis trial was registered in the Chinese Clinical Trials Registry (ChiCTR2000039068). The date of first registration, 15/10/2020, http://www.chictr.org.cn

Skeletal Muscle Index, As a Measure of Muscle Mass, Is a Significant Prognostic Factor for Newly Diagnosed Diffuse Large B-Cell Primary CNS Lymphoma Patients

Background: Primary cerebral lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL) with a particularly poor outcome compared to systemic DLBCL. Several prognostic scores have been developed for PCNSL. These include the International Extranodal Lymphoma Study Group (IELSG) score with five prognostic factors (patient age, serum lactate dehydrogenase [LDH] level, Eastern Cooperative Oncology Group performance status [PS], deep brain involvement and cerebrospinal fluid [CSF] protein level), and the Memorial Sloan-Kettering Cancer Center (MSKCC) score, which is based on age and the Karnofsky Performance Score (KPS). However, the reproducibility of these two scoring systems is low, and the IESLG score requires CSF protein and LDH levels evaluation, which are not often available. None of these scores incorporate data on nutritional status, in particular albumin, which has been shown to be an important prognostic factor in systemic DLBCL. In addition, a recent study demonstrated that the muscle density and mass determined by imaging segmentation, were strong prognostic factors for newly diagnosed systemic DLBCL patients (Jullien et al. Cancers 2021). Our aim was to determine whether these imaging data were also predictive factors for outcome in newly diagnosed diffuse large B-cell PCNSL patients. Methods: For each patient included in the study, muscle mass and density were estimated using skeletal muscle index (SMI) and mean skeletal muscle radiation attenuation (SMRA), respectively. SMI and SMRA were computed at L3 level using the whole-body scan (WBS) performed at the diagnosis of PCNSL, by the mean of an automated segmenting algorithm. Muscle characteristics were then classified as normal or low using already validated cut-off according to patients' age and body mass index (Westenberg et al. Sci Rep 2023). Patients' outcomes were then compared based on their muscle quality, albumin level at diagnosis and other clinical variables commonly included in PCNSL prognostic scores. Results: Between 2015 and 2022, 98 consecutive diffuse large B-cell PCNSL patients were newly diagnosed at Hematology Department of Hospital Lyon Sud, France. Among them, 77 had WBS at diagnosis with available data for this study. The median age was 69 years (range 24-87) and 22 patients (29%) presented an altered ECOG PS (PS 3-4 score). All patients were treated with first-line high-dose methotrexate-based chemotherapy in combination with rituximab. SMI was normal in 64 patients (83%) and 17 patients (17%) had low SMI. Patients with low SMI had more frequently an altered PS (p=0.07) and had lower albumin level (mean 36.7 g/L vs 32.0 g/L, p=0.007). SMRA was normal in 30 patients (39%) and 47 patients (61%) had low SMRA. Patients with low SMRA were older (60 vs 70 years old, p=0.001). In univariate analysis, patients with low SMI had worse outcome with significantly shorter overall survival (p=0.002, median OS, 21.4 months vs not reached) and a trend towards shorter event-free survival (p=0.055, median EFS, 11.9 months vs 42.3 months, Figure 1). No significant prognostic difference was seen for SMRA for EFS or OS. The multivariate analysis showed that SMI (Hazard ratio [HR]=3.33, 95% confidence interval [95%CI]= 1.21-9.20, p=0.02) and age (HR =1.86, 95%CI =1.15-3.0, p=0.012) were strongly associated with OS but not tumor localization (HR =1.46, 95%CI =0.60-3.55, p=0.4), PS (HR = 1.54, 95%CI =0.65-3.65, p=0.32) and albumin level (HR =1.05, 95%CI =0.47-2.32, p=0.91). Age was significantly associated with EFS (HR=1.4, p = 0.04) with a more limited association of SMI with EFS (HR=2.03, p=0.095). In exploratory subgroup analyses, we showed that SMI still influenced OS in patients with PS 4 (10 months vs not reached, p= 0.002), suggesting that SMI may be a more appropriate prognostic factor than PS, especially for patients with motor deficit for whom PS is difficult to estimate. Conclusions: This retrospective analysis of newly diagnosed PCNSL patients showed a significant association between decreased muscle mass, measured by SMI and overall survival, after controlling for other prognostic variables. These findings warrant confirmative analyses to explore the relationship between muscle mass/density and diffuse large B-cell PCNSL patient's outcome and integrate SMI in PCNSL prognostic scores.

Patients with High-Risk Myelodysplastic Neoplasms Do Not Benefit from Remission Induction with Azacitidine Prior to Hematopoietic Cell Transplantation: A Retrospective, Single-Center Analysis with Extended Follow-up

Background: The value of remission induction in high-risk myelodysplastic neoplasms (MDS) with increased blasts prior to allogeneic hematopoietic cell transplantation (HCT) remains controversial. The new ELN recommendations include the re-designation of patients with 10-20% blasts as AML/MDS, raising the question of whether these patients should receive induction chemotherapy before HCT. An alternative is treatment with hypomethylating agents (HMA) such as azacitidine, for which allo-sensitizing effects have been proposed. In contrast, bridging to HCT with HMA may increase drop-out rate for allogeneic HCT, while at the same time not further benefiting patients who subsequently receive HCT. Methods: We report on 135 patients diagnosed with MDS, chronic myelomonocytic leukemia or myelodysplastic/myeloproliferative neoplasm who received HCT at our center between 2010 and 2022. Median age was 60 years (range 26 to 77 years) and 44.4% of patients were female. IPSS-R score was high in 25.8% of patients and very high in 44.8% of patients. 33.3% of patients received remission induction prior to HCT, 28.8% of all patients with HMA. Conditioning regimens were myeloablative in 8.1%, FLAMSA-based reduced intensity conditioning (RIC) in 26.7%, and RIC in 60.7% of cases. Donors were matched (8/8) related in 23.7%, matched (8/8) unrelated in 53.3%, and mismatched (7/8 or haploidentical) in 23%. Relationships between outcomes and patient, treatment and disease parameters were analyzed using multivariate Cox proportional hazards regression and, in the case of relapse, non-relapse mortality (NRM) and graft-versus-host disease (GVHD), competing risk analysis. P-values were adjusted for multiple comparisons using false discovery rate adjustment. Results: Median follow-up after HCT was 46 months. Kaplan-Meier estimates for OS and RFS at 5 years were 56.6% and 43%, respectively. The cumulative incidences of relapse, NRM, acute GVHD grade II to IV, and chronic GVHD at 5 years were 39%, 17.8%, 36.4%, and 40%, respectively. OS was significantly correlated with the IPSS-R cytogenetic risk category but not with the percentage of blasts in bone marrow before treatment initiation. In multivariate regression analysis, OS was significantly worse in patients with poor or very poor IPSS-R cytogenetic category (HR 1.56; p&amp;lt;0.001) but not in patients with a pre-treatment bone marrow blast count exceeding 10% (HR 1.25; p=0.19). Similarly, cytogenetic risk, but not bone marrow blast count, was significantly associated with worse RFS (HR 1.5 vs. 1.2; p&amp;lt;0.001 vs. 0.199) and higher cumulative hazard of relapse (HR 1.74 vs. 1.36; &amp;lt;0.0001 vs. p=0.31). Bridging or induction treatment with azacitidine before HCT by trend showed a higher cumulative hazard of relapse (HR 2.3; p=0.057) and worse RFS (HR 1.7; p=0.088). In exploratory subgroup analyses of patients with a bone marrow blast count above 10% (n=69), OS was not significantly different between patients who received remission induction prior to HCT and those who did not (HR 1.3; p=0.5), while the cumulative hazard of relapse by trend even increased in the first group (HR 1.85; p=0.13). Furthermore, there was no significant difference in OS between patients with a bone marrow blast count above 10% who received intensified sequential conditioning with FLAMSA-RIC versus fludarabine/treosulfan (n=44; HR 1.45; p=0.52). Donor mismatch was the only parameter significantly associated with higher NRM (HR 2.4 and p=0.044), and GVHD prophylaxis with anti-thymocyte globulin and/or tacrolimus the only parameters associated with a significant reduction of chronic GVHD severity (f²=0.05 and 0.06; p=0.03 and 0.02), while no single parameter was associated with a significant difference in acute GVHD severity. Conclusions: This study reports promising long-term outcomes for MDS patients undergoing HCT in the real-world setting. In our analysis, cytogenetic risk, but not bone marrow blast count, was the main determinant of transplantation outcomes. Furthermore, remission induction prior to HCT with azacitidine, which is commonly used in patients with increased bone marrow blasts, was not associated with a survival benefit but by trend even with higher relapse risk and worse RFS in multivariate analysis. This suggests that the perceived role of azacitidine as a bridge-to-transplant should be questioned. Rather, eligible patients should receive HCT as soon as possible.

Comparing clinico-demographics and neuropsychiatric symptoms for immigrant and non-immigrant aged care residents living with dementia: a retrospective cross-sectional study from an Australian dementia-specific support service

BackgroundNeuropsychiatric symptoms of dementia such as agitation and aggression are common in people living with dementia. The presentation of neuropsychiatric symptoms is influenced by the cultural background of people living with dementia. Further, identifying factors contributing to neuropsychiatric symptoms may be complicated if people living with dementia are immigrants or from non-English-speaking backgrounds. Most of what is known about differences in neuropsychiatric symptoms between racial and ethnic groups living with dementia come from community-based samples. This study investigated differences in clinico-demographics and neuropsychiatric symptoms between immigrants and non-immigrants living with dementia in residential aged care homes who were referred to two Dementia Support Australia programs.MethodsThis was a retrospective observational cross-sectional study from 2018 to 2022 using data extracted from the Dementia Support Australia database. Immigrant status was identified by documented country of birth. We conducted exploratory subgroup analyses for English-speaking or non-English-speaking immigrants in comparison to non-immigrants. Neuropsychiatric Inventory and PainChek® were used to assess neuropsychiatric symptoms of dementia and pain, respectively.ResultsOf the 23,889 referrals, 36% were immigrants living with dementia. Immigrants were 0.8 years older than non-immigrants on average. Immigrants had a slightly higher prevalence of mixed dementia (9.5%) than non-immigrants (8.2%). Overall, the groups had no difference in the severity of neuropsychiatric symptoms and associated caregiver distress. However, there was a significant difference in the total number of neuropsychiatric inventory domains (Cohen’s d = -0.06 [-0.09, - 0.02], p <.001) between non-English-speaking immigrants and non-immigrants. Immigrants were more likely to present with agitation/aggression, while non-immigrants were more likely to present with hallucinations. Factors contributing to neuropsychiatric symptoms were common between the groups, with language barriers and cultural considerations frequently endorsed for immigrants.ConclusionThis study reveals a mixed picture of neuropsychiatric symptoms between immigrants and non-immigrants. However, due to the exploratory nature of the hypotheses, our findings need to be replicated in future studies to confirm any conclusions. There is a need for increased awareness on the impact of culture and language on neuropsychiatric symptoms for people receiving residential care. Future studies investigating neuropsychiatric symptoms in different immigrant groups will help increase our understanding of neuropsychiatric symptoms for all people.

Association between sex and efficacy of intravenous ferric carboxymaltose in patients with acute heart failure and iron deficiency: an AFFIRM-AHF subgroup analysis

Abstract Background/Introduction Heart failure (HF) pathophysiology, clinical presentation and treatment response is known to differ between males and females (1). In the AFFIRM-AHF trial, intravenous (IV) ferric carboxymaltose (FCM) reduced the risk of HF hospitalisations and improved quality of life vs placebo in patients with iron deficiency who had stabilised following an acute HF (AHF) episode (2,3); the effect of sex on outcomes with iron-repletion therapy in these high-risk patients has not been fully explored. Purpose To investigate the interaction between sex and the effects of FCM vs placebo on clinical outcomes in the AFFIRM-AHF population. Methods In AFFIRM-AHF, patients with left ventricular ejection fraction &amp;lt;50% and iron deficiency (defined as serum ferritin &amp;lt;100 ng/mL, or 100–299 ng/mL if transferrin saturation is &amp;lt;20%) who had stabilised following recent hospitalisation for AHF were randomised 1:1 to receive IV FCM or placebo for up to 24 weeks.2 The primary endpoint was a composite of total HF hospitalisations and cardiovascular (CV) death up to Week 52; secondary endpoints are listed in the Figure.2 In this prespecified analysis, AFFIRM-AHF patients were stratified into male and female subgroups and the interaction between sex and clinical outcomes with FCM vs placebo was explored. Results Of the 1108 patients included in the AFFIRM-AHF full analysis set, 614 (FCM: 314; placebo: 300) were male and 494 (FCM: 244; placebo: 250) were female. At baseline, a New York Heart Association functional class of III and above was more common in females (59.0%) than in males (48.4%). For the primary endpoint, the adjusted annualised event rate per 100 patient-years with FCM vs placebo was 53.3 vs 83.3 in males (rate ratio [RR] 0.64; 95% confidence interval [CI] 0.46–0.89) and 63.1 vs 60.3 in females (RR 1.05; 95% CI 0.72–1.53) (Figure). For all secondary endpoints except time to CV death, effect sizes in male and female subgroups were similar to those for the primary endpoint. The interaction between sex and treatment effect was non-significant for the primary endpoint (P-interaction=0.054) but reached significance for the secondary endpoints of total CV hospitalisations and CV death (P-interaction=0.024) and time to first HF hospitalisation or CV death (P-interaction=0.043). Conclusion(s) The results of this exploratory subgroup analysis suggest that iron deficiency treatment with IV FCM following an AHF episode may be more effective in males than in females; this may be related to baseline differences between sex subgroups, beyond the factors adjusted for in this analysis.Figure