Pre-specified Outcomes Research Articles

Neonatal Hypoglycemia and Neurodevelopmental Outcomes—An Updated Systematic Review and Meta-Analysis

Background and Objective: The effects of neonatal hypoglycemia on the developing brain are well known, resulting in poor neurological outcomes. We aimed to perform an updated meta-analysis on neonatal hypoglycemia, the severity of hypoglycemia, and the associated neurodevelopmental outcomes from infancy to adulthood. Methods: A systematic literature search was conducted from inception until March 2024, using the PubMed, CINAHL, Embase, and the CENTRAL databases. Randomized/quasi-randomized trials and observational studies that evaluated at least one of the pre-specified outcomes were included. A random-effects model meta-analysis was performed to yield the pooled OR and its 95% CI for each outcome due to the expected heterogeneity in the studies. The study findings were reported as per the PRISMA guidelines. Neurodevelopmental impairment (NDI), cognitive impairment, and visual-motor or visual impairment were the primary outcomes. Results: A total of 17 studies (19 publications) were included in the final analysis. NDI, as defined by authors, was significantly higher in early- (OR = 1.16; 95% CI = 1.11–1.43) and mid-childhood (OR = 3.67; 95%CI = 1.07–12.2) in infants with neonatal hypoglycemia. ‘Any cognitive impairment’ was significantly more common in infants with neonatal hypoglycemia (OR = 2.12; 95%CI = 1.79–2.52). Visual-motor impairment (OR = 3.33; 95%CI = 1.14–9.72) and executive dysfunction (OR = 1.99; 95%CI = 1.36–2.91) were also more common in the hypoglycemic group. No difference in the incidence of epilepsy, motor impairment, emotional-behavioral problems, or hearing impairment were noted. Certainty of evidence was adjudged as ‘low’ to ‘very low’ for most outcomes. The severity of hypoglycemia was studied at different intervals, with NDI more common with a blood glucose interval between 20 and 34 mg/dL (1.1–1.9 mmol/L). Conclusions: Low-quality evidence from large observational studies finds a significant association with hypoglycemia in the early neonatal period and long-term neurodevelopmental problems. Additional studies with long enough follow-up are paramount to determine the cut-off concentration and to quantify the impact beyond the infancy period.

Abstract 4134668: Title: Mandibular advancement device versus CPAP on cardiovascular health and quality of life in OSA a pre-specified 12 months follow up of outcomes

Background: Obstructive sleep apnoea (OSA) is a significant cause of hypertension. ACC/AHA Guidelines recommended screening and treatment of OSA in patients with hypertension; however, evidence comparing mandibular advancement devices (MAD) to continuous positive airway pressure (CPAP) on cardiovascular health is lacking. We present the complete 12 months follow-up data on the comparative effectiveness of MAD versus CPAP in ambulatory BP reduction, QoL, cardiac arrhythmia, and myocardial remodelling. Method: In a randomized, non-inferiority trial (margin 1.5 mmHg), 321 participants, aged over 40, with hypertension and high cardiovascular risk were recruited. Of these, 220 participants with OSA (apnoea–hypopnea index ≥15 events/h) were randomized to either MAD or CPAP (1:1). Pre-specified secondary outcomes include: ambulatory BP, quality of life (QoL) (sleep-specific: ESS, SAQLI, FOSQ; non-sleep-specific: SF-36, EQ-5D), ambulatory ECG monitoring, and cardiac MRI. Results: A total of 89 (80.9% of 110) participants from MAD, and 91 (82.7% of 110) participants from CPAP completed 12 months follow-up. The median daily usage was 5.5 hours for MAD and 4.9 hours for CPAP. The between-group difference in 24h mean BP from baseline to 12 months was - 0.57 mmHg (95% confidence interval: (-2.53 to 1.39, non-inferiority P < 0.001). Compared with the CPAP group, MAD group demonstrated a larger reduction in all the 24h with the most pronounced differences observed in the asleep BP parameters (Table 1). Both the MAD and CPAP improved QoL (Table 2). CPAP had greater improvement in FOSQ from sleep-specific questionnaires (P=0.038), and social QoL in SF-36 from non-sleep-specificl questionnaires (P=0.013). The ambulatory ECG monitoring (MAD: 2.8 ± 1.0 days, CPAP: 2.3 ± 1.1 days) showed no between-group differences in % atrial fibrillation(P=0.209), % ventricular ectopic isolated count (P=0.790) and % supraventricular ectopic isolated count (P= 0.333). The cardiac MRI sub-study (101 participants : MAD= 45, CPAP= 56) showed CPAP had greater improvement in right ventricular stroke volume (P=0.023) and MAD had greater improvement in circumferential strain favours the MAD group (P=0.015) (Table 3). Conclusion: At 12 months , MAD was non-inferior to CPAP for reducing 24h mean arterial BP. MAD showed greater reduction in 24h BPs, especially during asleep. While both the MAD and CPAP are effective in improving QoL, CPAP is more effective in improving FOSQ and social QoL (SF-36).

Comparative efficacy of interpersonal psychotherapy and antidepressant medication for adult depression: a systematic review and individual participant data meta-analysis.

Interpersonal psychotherapy (IPT) and antidepressant medications are both first-line interventions for adult depression, but their relative efficacy in the long term and on outcome measures other than depressive symptomatology is unknown. Individual participant data (IPD) meta-analyses can provide more precise effect estimates than conventional meta-analyses. This IPD meta-analysis compared the efficacy of IPT and antidepressants on various outcomes at post-treatment and follow-up (PROSPERO: CRD42020219891). A systematic literature search conducted May 1st, 2023 identified randomized trials comparing IPT and antidepressants in acute-phase treatment of adults with depression. Anonymized IPD were requested and analyzed using mixed-effects models. The prespecified primary outcome was post-treatment depression symptom severity. Secondary outcomes were all post-treatment and follow-up measures assessed in at least two studies. IPD were obtained from 9 of 15 studies identified (N = 1536/1948, 78.9%). No significant comparative treatment effects were found on post-treatment measures of depression (d = 0.088, p = 0.103, N = 1530) and social functioning (d = 0.026, p = 0.624, N = 1213). In smaller samples, antidepressants performed slightly better than IPT on post-treatment measures of general psychopathology (d = 0.276, p = 0.023, N = 307) and dysfunctional attitudes (d = 0.249, p = 0.029, N = 231), but not on any other secondary outcomes, nor at follow-up. This IPD meta-analysis is the first to examine the acute and longer-term efficacy of IPT v. antidepressants on a broad range of outcomes. Depression treatment trials should routinely include multiple outcome measures and follow-up assessments.

Daily Remote Ischaemic Preconditioning for Intermittent Claudication: A Sham Controlled Randomised Trial

Remote ischaemic preconditioning (RIPC) is a promising non-invasive strategy in which brief episodes of ischaemia and reperfusion can increase skeletal muscle resistance to ischaemia and improve mobility. This study aimed to determine whether 28 consecutive days of RIPC improves intermittent claudication (IC) symptoms compared with sham intervention. This single centre, parallel, randomised, sham controlled, double blind trial was conducted from January 2022 to April 2023 in outpatient settings. Forty two patients with stable IC Fontaine stage IIa or IIb were randomised to RIPC or sham for 28 days. The prespecified primary outcome was a change in the maximal walking distance (MWD) after 28 days measured with a treadmill test. A > 10% change in MWD was considered clinically significant. Change in intermittent claudication distance (ICD), time to relief from claudication (TRC), and health related quality of life (HRQoL) measured with the VascuQoL-6 questionnaire were the secondary outcomes (ClinicalTrials.gov ID: NCT05084066). Forty one men (RIPC = 23, sham = 18) aged 64.9 ± 7.4 years were analysed. A change of > 10% in MWD occurred in 14 patients in the RIPC group vs. eight patients in the sham group (relative risk 1.37, 95% confidence interval 0.74 - 2.25; p = .35). Changes in ICD, TRC, and HRQoL between the groups were not statistically significant. In this trial, RIPC did not significantly improve MWD, ICD, or TRC compared with treatment with a sham device.

Associations of Maternal Nutritional Status and Supplementation with Fetal, Newborn, and Infant Outcomes in Low-Income and Middle-Income Settings: An Overview of Reviews.

Despite advances in maternal nutritional knowledge, the effect of maternal diet, micronutrient status and undernutrition, and the effect of maternal supplementation on fetal, neonatal and infant outcomes still have gaps in the literature. This overview of reviews is intended to assess the available information on these issues and identify the main maternal nutritional factors associated with offspring outcomes in low- and middle-income countries as possible targets for public health interventions. The literature search was performed in Medline (PubMed) and Cochrane Library datasets in June 2024. Pre-specified outcomes in offspring were pooled using standard meta-analytical methods. We found consistent evidence on the impact of maternal undernutrition indicated by low body mass index (BMI), mid-upper arm circumference (MUAC), and stature, but not of individual micronutrient status, on intrauterine-growth retardation, preterm birth, low birth weight, and small for gestational age, with research showing a possible effect of maternal undernutrition in later child nutritional status. Studies on micronutrient supplementation showed possible beneficial effects of iron, vitamin D, and multiple micronutrients on birthweight and/or decreasing small for gestational age, as well as a possible effect of calcium on preterm birth reduction. Interventions showing more consistent beneficial outcomes were balanced protein-energy and lipid base supplements, which demonstrated improved weight in newborns from supplemented mothers and a decreased risk of adverse neonatal outcomes. Further research is needed to identify the benefits and risks of maternal individual micronutrient supplementation on neonatal and further child outcomes.

Relative effectiveness of high-dose versus standard-dose quadrivalent influenza vaccine against hospitalizations and mortality according to frailty score: a post-hoc analysis of the DANFLU-1 trial

Abstract Background Frailty is a major risk factor for adverse cardiovascular events. Influenza vaccination has been shown to protect against cardiovascular fatal and nonfatal events. However, limited data exist on the added benefit of high-dose versus standard-dose influenza vaccination according to frailty status. Purpose We sought to assess the relative effectiveness of high-dose (QIV-HD) versus standard-dose (QIV-SD) quadrivalent influenza vaccination according to frailty status in elderly individuals. Methods This is a post-hoc analysis of the randomized controlled feasibility trial of QIV-HD versus QIV-SD conducted during the 2021–2022 influenza season in adults aged 65–79 years. We assessed the following prespecified outcomes: hospitalizations for pneumonia or influenza, cardio-respiratory hospitalizations, cardiovascular hospitalizations, all-cause hospitalizations and all-cause mortality. Level of frailty was defined according to the Hospital Frailty Risk Score based on ICD-10 codes for relevant comorbidities any time prior to vaccination. We divided the participants into two categories according to Frailty Score (FS): low frailty (0-4 points) and intermediate or high frailty (≥5 points). We analyzed outcomes as time to first event using Cox proportional hazards regression. Results Among 12,473 randomly assigned participants to QIV-HD versus QIV-SD (mean age 71.7 years, 47.1% female), 10,711 (85.9%) were categorized as having low frailty and 1,762 (14.1%) had intermediate or high frailty. In total, 38 individuals were hospitalized for pneumonia or influenza during follow-up, 219 were hospitalized for cardiorespiratory illness, 1055 were hospitalized due to any cause and 62 died during follow-up. FS significantly modified the effect of QIV-HD versus QIV-SD for all-cause mortality (P for interaction 0.02). In participants with low frailty, QIV-HD was associated with a lower risk of all-cause mortality (Figure 1: HR 0.26, 95% CI 0.13 to 0.55), whereas there was no evidence of effect among those with intermediate or high frailty (HR 1.68, 95% CI 0.66 to 4.26). QIV-HD versus QIV-SD was associated with a lower incidence of hospitalizations for pneumonia and influenza, this effect was consistent regardless of frailty status (P for interaction 0.88). QIV-HD was not associated with a significantly lower incidence of hospitalizations due to cardiovascular, cardiorespiratory or respiratory disease or any cause regardless of frailty status. Conclusions In this post-hoc analysis of a large-scale pragmatic trial, QIV-HD was similarly associated with a lower incidence of hospitalizations for pneumonia and influenza among older adults irrespective of frailty status. The potential benefit of QIV-HD versus QIV-SD may therefore be applicable regardless of frailty status. However, our results suggest that QIV-HD is associated with a lower risk of all-cause mortality among adults with low frailty only.Figure 1.

Results of a randomized controlled superiority trial of the effect of modified collaborative assessment vs. standard assessment on patients’ readiness for psychotherapy (CO-ASSM-RCT)

BackgroundAvoidant personality disorder (AvPD) and social phobia (SP) are associated with high personal and societal costs. While psychotherapy can be efficient, many patients drop out during treatment. Little is known about what can be done to increase a patient’s readiness for psychotherapy. However, research highlights the fields of collaborative and therapeutic assessment as a possible means to enhance readiness for psychotherapy.MethodsWe conducted a randomized controlled feasibility and superiority trial on patients with SP or AvPD who were to initiate psychotherapeutic treatment in outpatient mental health services. Patients were randomized 1:1 to either assessment as usual or modified collaborative assessment (MCA), provided as a pre-treatment intervention before psychotherapy initiation. MCA included the collaborative administration of a battery of psychological tests designed to assess the patient’s psychopathology more systematically. The tests were administered in collaboration with the patient, and detailed oral and written feedback was provided. We investigated the feasibility of the MCA intervention regarding acceptability, patient satisfaction, and adherence. We also investigated MCA’s effect on readiness for psychotherapy, as assessed with the University of Rhode Island Change Assessment Scale (URICA), and outcomes relating to symptomatology and dropout rates.ResultsAll three prespecified feasibility outcomes were met. At the end of treatment, no significant difference was observed in any other outcome, except client satisfaction, which favored MCA (− 7.42 (95% CI − 11.75; − 3.09; p = 0.002)).DiscussionWe found that MCA was feasible, and patients were highly satisfied with the intervention. It is relevant to investigate another implementation of MCA.Trial registrationClinicalTrials.gov NCT05018312. Registered on August 24, 2021.

Effectiveness of N-3 fatty acids supplementation on spondyloarthritis: A systematic review and meta-analysis

Background & AimsThe study aims to systematically review and meta-analyze randomized controlled trials (RCTs) assessing the effects of n-3 fatty acids (FA) supplementation on spondyloarthritis (SpA) disease activity, inflammatory markers, and imaging. MethodsThe study protocol was developed and registered online in advance. The PubMed, SCOPUS, and Cochrane Central Register of Controlled Trials (CENTRAL) electronic databases were systematically searched for RCTs up to April 2024. Two independent reviewers screened, assessed for eligibility, and extracted data from the eligible RCTs. The revised Cochrane Risk of Bias tool was used to assess the quality of trials. The random-effects model was used to calculate the pooled estimates. ResultsWe included four RCTs, involving 245 patients with SpA. Supplementation with n-3 FA did not improve physician-reported outcomes [number of tender joints (four trials, standardized mean difference (SMD): -0.22; 95% confidence interval (CI): -0.74 to 0.29; I2=61%), number of swollen joints (two trials, SMD: -0.13; 95% CI: -0.42 to 0.15; I2=0%)], and patient-reported outcomes [pain (three trials, SMD: -0.16; 95% CI: -1.03 to 0.70; I2=74%), Health Assessment Questionnaire (three trials, SMD: -0.04; 95% CI: -0.78 to 0.70; I2=71%). The other nine pre-specified outcomes were not analyzed due to lack of information from the original RCTs which were evaluated as «some concerns» or «high risk» of bias. ConclusionsIn the present systematic review and meta-analysis including placebo-controlled RCTs, n-3 FA supplementation did not show improvement in the reported outcomes. Future RCTs should be conducted with homogenous intervention, placebo, and outcomes to re-examine possible beneficial effects.

Effect of perioperative erythropoietin on postoperative morbidity and mortality after cardiac surgery: a meta-analysis of randomized controlled trials

ObjectiveCardiac surgery is known to have high rates of perioperative red blood cell (RBC) transfusions which are associated with increased postoperative mortality and morbidity. Perioperative erythropoietin (EPO) has been suggested to lower perioperative RBC transfusions, and the effect on postoperative morbidity or mortality is unknown. MethodsThe registered study protocol is available on PROSPERO (CRD42022314538). We searched the Pubmed, EMbase, and Cochrane CENTRAL databases for randomized controlled trials (RCT) of EPO in cardiac surgery. Outcomes were short-term mortality, acute kidney injury (AKI), re-operation, cerebrovascular accident (CVA), perioperative myocardial infarction (MI), infectious complications, and RBC transfusions. RCT studies of perioperative EPO that reported at least one prespecified outcome of interest were included. ResultsA total of 21 RCT’s (n = 2,763 patients) were included. Mortality analysis included 17 studies (EPO 1,272 patients, control 1,235) and showed no significant difference (risk difference (RD) 0.0004, 95%CI: −0.016, 0.009). EPO did not reduce the incidence of AKI (RD −0.006, 95% CI: −0.038, 0.026) and reoperation (RD 0.001, 95% CI: −0.013, 0.015). The incidence of CVA (RD −0.004, 95% CI: −0.015, 0.007) and perioperative MI (RD −0.008, 95% CI: −0.021, 0.005) was similar between the groups. ConclusionsAlthough EPO had been proven to reduce perioperative RBC transfusions, we did not find that it reduces the incidence of postoperative short-term mortality, AKI, and reoperation. The study results support that perioperative EPO is also safe, with no rise in thrombotic events, including CVA and perioperative MI.

Younger-onset compared with later-onset type 2 diabetes: an analysis of the UK Prospective Diabetes Study (UKPDS) with up to 30 years of follow-up (UKPDS 92).

Younger-onset type 2 diabetes is associated with accelerated complications. We assessed whether complications and mortality rates differed for younger age compared with older age at diagnosis over 30 years of follow-up. In this study, we used data from the UKPDS, collected between 1977 and 2007, of participants aged 25-65 years with newly diagnosed type 2 diabetes with younger-onset (younger than 40 years) or later-onset (40 years or older), and without diabetes autoantibodies. We analysed standardised mortality ratios (SMR) using UK general population data, and incidence rates of prespecified outcomes by 10-year age intervals at diagnosis. Of 4550 participants testing negative to all measured autoantibodies, 429 (9·4%) had younger-onset type 2 diabetes. 2704 (59·4%) were male, and mean HbA1c was 76 mmol/mol (SD 24·6). The median follow-up was 17·5 years (IQR 12·7-20·8). SMR for younger-onset type 2 diabetes was higher (3·72 [95% CI 2·98-4·64]) compared with later-onset type 2 diabetes (1·54 [1·47-1·61]). The incidence rate was higher for all outcomes in later-onset type 2 diabetes, except for microvascular disease (younger-onset 14·5 (11·9-17·7) vs later-onset 12·1 (11·3-13·0) per 1000 person-years). However, at any given age, the 5-year incidence of any diabetes-related endpoint, all-cause mortality, microvascular disease, and myocardial infarction was higher with younger age at diagnosis. Annual mean HbA1c was higher in the first 20 years in younger-onset compared with later-onset type 2 diabetes. Among participants randomised to intensive versus conventional glycaemic control, we observed no interactions by subgroup of younger-onset versus later-onset type 2 diabetes for any outcome. The risk of dying relative to the general population is even greater for people diagnosed with type 2 diabetes at younger ages. The increased risk of complications and poorer glycaemic control in younger-onset type 2 diabetes calls for the development of services to identify and manage these individuals. National Institute of Health and Care Research's Biomedical Research Centre.

Impacts of the Mindset Teams Programme on Teacher Outcomes and Pupil Educational Attainment: Secondary Data Analysis

We evaluated the impact of a growth mindset intervention on pre-specified teacher outcomes and pupil academic attainment and attendance. Delivered over 12 months, the Mindset Teams intervention provides teachers with formal and self-directed online learning, and an opportunity to implement evidence-based growth mindset practice in the classroom setting. The intervention aims to influence teacher practices to improve pupil resilience for learning and bring about positive impacts on pupil attainment and health outcomes. Impacts on teachers were explored through pre- and post-intervention survey data (570 and 301 respectively). Pupil attainment and attendance data from 1220 schools, 72 of which received the intervention, across years 2017–2021 (minus 2020), were analyzed using weighted mixed effects models, using a Difference-in-differences framework. Bayes factors were calculated as a measure of strength of evidence. Results suggest positive impacts of the intervention on teacher outcomes and indicate a moderate effect (+3% (95%CI +1%, +6%)) of programme delivery on writing attainment, but no evidence of effect for other outcomes. Findings highlight important issues for further research, specifically the need to explore programme impacts using pupil or classroom level data.

Randomised controlled trials on radiation dose fractionation in breast cancer: systematic review and meta-analysis with emphasis on side effects and cosmesis

ObjectiveTo provide a comprehensive assessment of various fractionation schemes in radiation therapy for breast cancer, with a focus on side effects, cosmesis, quality of life, risks of recurrence, and survival...

The effects of acupressure, laughter yoga, and a mindfulness-based stress reduction program applied to postmenopausal women for menopause symptoms and quality of life.

This research was conducted to determine the effects of acupressure, laughter yoga, and a mindfulness-based stress reduction program applied to postmenopausal women for menopause symptoms and quality of life. A randomized controlled design was used. The study was conducted with a total of 146 women, including 41 acupressure, 31 laughter yoga, 37 mindfulness-based stress reduction, and 37 control group women. The women in the acupressure group were administered acupressure twice a week, which accounted for 16 sessions in total. Women in the laughter yoga and mindfulness-based stress reduction groups received a total of eight sessions of the related intervention, which was performed once a week. Study data were collected using a participant information form, the Menopause Rating Scale (MRS), and the Menopause-Specific Quality of Life Scale (MENQOL). Descriptive statistics, paired-samples t test, χ 2 test, analysis of variance test, and intention to treat analysis were used to analyze the data. Before the intention to treat analysis was performed, the multiple imputation method was employed to deal with missing data. In the study, it was found that there was a decrease in the MRS total score after the intervention in women in all three intervention groups compared to the control group ( P < 0.05). In the laughter yoga group, total MRS scores decreased by 3.16 points ( P < 0.05). In the acupressure group, total MRS scores decreased by 5.46 points ( P < 0.05). In the mindfulness-based stress reduction (MBSR) program group, total MRS scores decreased by 4.65 points ( P < 0.05). It was determined that the mean scores of women in the laughter yoga and acupressure groups on all subscales of the MENQOL decreased after the intervention compared to the control group ( P < 0.05). The comparison of the MBSR group and the control group showed that there was a decrease only in the psychosocial domain subdimension of the MENQOL ( P < 0.05). In conclusion, it was determined that laughter yoga, acupressure, and MBSR could be effective in reducing menopause symptoms and improving quality of life, although findings require further testing in a rigorously controlled study and in a study with only a single prespecified outcome.

Heterogeneous Outcome Selection and Incomplete Prespecification of Outcomes in Systematic Reviews: A Case Study on Pressure Injury.

To understand how reviewers select and prespecify outcomes for systematic reviews (SRs), the authors report on the outcomes used in SRs of pressure injury (PI) intervention and treatment and evaluate their completeness of prespecification. The authors searched four electronic databases for SRs involving PI prevention and/or treatments. Inclusion criteria were SRs and meta-analyses evaluating interventions for preventing or treating PI. Studies without systematic search or risk-of-bias assessment, conference proceedings, and articles not in Chinese or English were excluded. Two reviewers extracted and categorized the outcomes in domains, assessing outcome prespecification using a five-element framework. Data items included study characteristics, target population, type of interventions, and outcome variables. This review included 95 SRs that reported a total of 432 instances of 24 different outcome domains. An average of four outcome domains were reported per SR. The most frequently reported domains were PI healing, PI occurrence, and PI status. Of the 62 SRs that prespecified primary outcomes, 40 (64.52%) reported more than one primary outcome. Only 24 of the 432 instances (5.56%) were completely specified. Among the 24 outcome domains, 12 (50.00%) were listed as primary outcomes at least once. Primary outcomes were more completely specified than nonprimary outcomes. Systematic reviews of PI prevention and/or treatment report diverse, incompletely prespecified outcomes, highlighting the need for a core outcome set to standardize key clinical outcomes.

Validation of Breast Idea Volume Estimator Application in Transfeminine People.

Accurate estimation of breast volume is important as researchers aim to achieve optimal feminization for transfeminine people. The Breast Idea Volume Estimator (BIVE) application allows estimation of breast volume using two-dimensional (2D) photographs but has not been validated in the chests of people who have undergone testosterone-mediated puberty. To estimate breast volume, clinical photographs and 3D scans were collected at baseline and 6 months, as a prespecified secondary outcome of a randomized clinical trial of antiandrogen therapy in transfeminine people commencing hormone therapy. BIVE was used to estimate breast volume by two independent researchers and compared with the gold standard of 3D scan calculated volume at different timepoints. Statistical analysis was performed, including the mean absolute difference, standard error of measurement, and intraclass correlation, to determine accuracy, precision, and interrater agreement. Clinical photography and 3D scans were collected from 82 breasts of 41 participants. The median (interquartile range) age of participants was 25 (22-28) years, and the median (interquartile range) body mass index was 24.6 (21.2-28.9) kg/m2. The BIVE sagittal and transverse algorithms demonstrated robust performance, with mean absolute difference less than 20 mL and intraclass correlation greater than 0.87 indicating clinical reliability with high interrater agreement. BIVE provided an accurate, precise, and reliable measure of breast volume in the chests of people who have undergone testosterone-mediated puberty, compared with the gold standard of 3D scan.

Effects of Semaglutide on Heart Failure Outcomes in Diabetes and Chronic Kidney Disease in the FLOW Trial

BackgroundPeople with type 2 diabetes (T2D) and chronic kidney disease (CKD) are at high risk for heart failure (HF) and premature death from cardiovascular (CV) causes. The FLOW (Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease), which enrolled participants with T2D and CKD, demonstrated that semaglutide, a glucagon-like peptide-1 receptor agonist, reduced the incidence of the primary composite outcome (persistent ≥50% decline in estimated glomerular filtration rate, persistent estimated glomerular filtration rate <15 mL/min/1.73 m2, kidney replacement therapy, and kidney or CV death) by 24%. ObjectivesThis prespecified analysis examined the effects of semaglutide on HF outcomes in this high-risk population. MethodsParticipants were randomized (1:1) to once-weekly subcutaneous semaglutide 1 mg or placebo. The prespecified main outcome was a composite of HF events (new onset or worsening of HF leading to an unscheduled hospital admission or an urgent visit, with initiation of or intensified diuretic/vasoactive therapy) or CV death. HF data were collected by the investigator. CV death was adjudicated by an independent committee. ResultsA total of 3,533 randomized participants were followed for a median of 3.4 years. HF was present at baseline in 342 participants (19.4%) in the semaglutide group and 336 (19.0%) in the placebo group. In the overall trial population, semaglutide increased time to first HF events or CV death (HR: 0.73; 95% CI: 0.62-0.87; P = 0.0005), HF events alone (HR: 0.73; 95% CI: 0.58-0.92; P = 0.0068), and CV death alone (HR: 0.71; 95% CI: 0.56-0.89; P = 0.0036). The risk reduction for the composite HF outcome was similar in those with (HR: 0.73; 95% CI: 0.54-0.98; P = 0.0338) and without (HR: 0.72; 95% CI: 0.58-0.89; P = 0.0028) HF at baseline. The risk of HF outcomes (HF events or CV death) was generally higher in participants categorized as NYHA functional class III and those with the HF reduced ejection fraction subtype, regardless of treatment. ConclusionsSemaglutide substantially reduced the risk of time to first composite outcome of HF events or CV death, as well as HF events and CV death alone, in a high-risk population with T2D and CKD. These effects were consistent regardless of history of HF. (A Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease [FLOW]; NCT03819153)

Effect of Semaglutide on Cardiac Structure and Function in Patients With Obesity-Related Heart Failure

BackgroundObesity is associated with adverse cardiac remodeling and is a key driver for the development and progression of heart failure (HF). Once-weekly semaglutide (2.4 mg) has been shown to improve HF-related symptoms and physical limitations, body weight, and exercise function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), but the effects of semaglutide on cardiac structure and function in this population remain unknown. ObjectivesIn this echocardiography substudy of the STEP-HFpEF Program, we evaluated treatment effects of once-weekly semaglutide (2.4 mg) vs placebo on cardiac structure and function. MethodsEchocardiography at randomization and 52 weeks was performed in 491 of 1,145 participants (43%) in the STEP-HFpEF Program (pooled STEP-HFpEF [Semaglutide Treatment Effect in People with Obesity and HFpEF] and STEP-HFpEF DM [Semaglutide Treatment Effect in People with Obesity, HFpEF, and Type 2 Diabetes] trials). The prespecified primary outcome was change in left atrial (LA) volume, with changes in other echocardiography parameters evaluated as secondary outcomes. Treatment effects of semaglutide vs placebo were assessed using analysis of covariance stratified by trial and body mass index, with adjustment for baseline parameter values. ResultsOverall, baseline clinical and echocardiographic characteristics were balanced among those receiving semaglutide (n = 253) and placebo (n = 238). Between baseline and 52 weeks, semaglutide attenuated progression of LA remodeling (estimated mean difference [EMD] in LA volume, −6.13 mL; 95% CI: −9.85 to −2.41 mL; P = 0.0013) and right ventricular (RV) enlargement (EMD in RV end-diastolic area: −1.99 cm2; 95% CI: −3.60 to −0.38 cm2; P = 0.016; EMD in RV end-systolic area: −1.41 cm2; 95% CI: −2.42 to −0.40] cm2; P = 0.0064) compared with placebo. Semaglutide additionally improved E-wave velocity (EMD: −5.63 cm/s; 95% CI: −9.42 to −1.84 cm/s; P = 0.0037), E/A (early/late mitral inflow velocity) ratio (EMD: −0.14; 95% CI: −0.24 to −0.04; P = 0.0075), and E/e′ (early mitral inflow velocity/early diastolic mitral annular velocity) average (EMD: −0.79; 95% CI: −1.60 to 0.01; P = 0.05). These associations were not modified by diabetes or atrial fibrillation status. Semaglutide did not significantly affect left ventricular dimensions, mass, or systolic function. Greater weight loss with semaglutide was associated with greater reduction in LA volume (Pinteraction = 0.033) but not with changes in E-wave velocity, E/e′ average, or RV end-diastolic area. ConclusionsIn the STEP-HFpEF Program echocardiography substudy, semaglutide appeared to improve adverse cardiac remodeling compared with placebo, further suggesting that treatment with semaglutide may be disease modifying among patients with obesity-related HFpEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM]; NCT04916470)

Systematic literature review of asthma biologic self-administration enhanced by a patient perspective

BackgroundSeveral biologics for the treatment of severe asthma are available as self-administration devices. ObjectivePerform a systematic literature review (SLR) to understand the use, benefits and challenges of these self-administration devices. MethodsElectronic databases and conference proceedings were searched using terms for asthma, biologic treatment, and at-home/self-administration (GSK study 213094). Publications were scanned for relevance using pre-specified Population, Intervention, Comparison, Outcomes and Study design (PICOS) criteria. Data on efficacy, safety, patient experience and economic outcomes were extracted; study quality was assessed. A first-hand patient perspective was obtained. ResultsThirty-five of 504 records met the inclusion criteria. Across four Phase III studies, ≥95% of biologic self-administrations were successful based on pre-defined criteria. At-home self-administration was preferred over in-clinic administration by 43–96% of patients across five studies. Most patients (≥89%) in two Phase III studies reported completing self-administration easily without repeated reference to instructions; high proportions of patients (≥98%) were confident in their ability to self-administer their biologic and ≥96% rated it as ‘extremely’, ‘very’ or ‘moderately’ easy to self-administer. Across 16 studies reporting efficacy data, there was evidence of reduced blood eosinophil counts and improved asthma control with biologic self-administration, with improved health-related quality of life shown across six studies. Economic outcomes data were limited. From a patient perspective, autonomy is the major benefit of self-administration. ConclusionWhile more evidence is needed, this SLR provides consistent evidence of high injection success rates, and supported by a patient perspective, preference for self-administration of biologics among patients with severe asthma.

Effect of Opaganib on Supplemental Oxygen and Mortality in Patients with Severe SARS-CoV-2 Based upon FIO2 Requirements.

Once a patient has been diagnosed with severe COVID-19 pneumonia, treatment options have limited effectiveness. Opaganib is an oral treatment under investigation being evaluated for treatment of hospitalized patients with severe COVID-19 pneumonia. A randomized, placebo-controlled, double-blind phase 2/3 trial was conducted in 57 sites worldwide from August 2020 to July 2021. Patients received either opaganib (n = 230; 500 mg twice daily) or matching placebo (n = 233) for 14 days. The primary outcome was the proportion of patients no longer requiring supplemental oxygen by day 14. Secondary outcomes included changes in the World Health Organization Ordinal Scale for Clinical Improvement, viral clearance, intubation, and mortality at 28 and 42 days. Pre-specified primary and secondary outcome analyses did not demonstrate statistically significant benefit (except nominally for time to viral clearance). Post-hoc analysis revealed the fraction of inspired oxygen (FIO2) at baseline was prognostic for opaganib treatment responsiveness and corresponded to disease severity markers. Patients with FIO2 levels at or below the median value (≤60%) had better outcomes after opaganib treatment (n = 117) compared to placebo (n = 134). The proportion of patients with ≤60% FIO2 at baseline that no longer required supplemental oxygen (≥24 h) by day 14 of opaganib treatment increased (76.9% vs. 63.4%; nominal p-value = 0.033). There was a 62.6% reduction in intubation/mechanical ventilation (6.84% vs. 17.91%; nominal p-value = 0.012) and a clinically meaningful 62% reduction in mortality (5.98% vs. 16.7%; nominal p-value = 0.019) by day 42. No new safety concerns were observed. While the primary analyses were not statistically significant, post-hoc analysis suggests opaganib benefit for patients with severe COVID-19 requiring supplemental oxygen with an FIO2 of ≤60%. Further studies are warranted to prospectively confirm opaganib benefit in this subpopulation.

Randomized Crossover Clinical Trial of Nicotinamide Riboside and Coenzyme Q10 on Metabolic Health and Mitochondrial Bioenergetics in CKD.

Mitochondria-driven oxidative/redox stress and inflammation play a major role in chronic kidney disease (CKD) pathophysiology. Compounds targeting mitochondrial metabolism may improve mitochondrial function, inflammation, and redox stress; however, there is limited evidence of their efficacy in CKD. We conducted a randomized, double-blind, placebo-controlled crossover trial comparing the effects of 1200 mg/day of coenzyme Q10 (CoQ10) or 1000 mg/day of nicotinamide riboside (NR) supplementation to placebo in 25 people with moderate-to-severe CKD (eGFR <60mL/min/1.73 m2). We assessed changes in the blood transcriptome using 3'-Tag-Seq gene expression profiling and changes in pre-specified secondary outcomes of inflammatory and oxidative stress biomarkers. For a subsample of participants (n=14), we assessed lymphocyte and monocyte bioenergetics using an extracellular flux analyzer. The (mean±SD) age, eGFR, and BMI of the participants were 61±11 years, 37±9 mL/min/1.73m2, and 28±5 kg/m2 respectively. Of the participants, 16% had diabetes and 40% were female. Compared to placebo, NR-mediated transcriptomic changes were enriched in gene ontology (GO) terms associated with carbohydrate/lipid metabolism and immune signaling while, CoQ10 changes were enriched in immune/stress response and lipid metabolism GO terms. NR increased plasma IL-2 (estimated difference, 0.32, 95% CI of 0.14 to 0.49 pg/mL), and CoQ10 decreased both IL-13 (estimated difference, -0.12, 95% CI of -0.24 to -0.01 pg/mL) and CRP (estimated difference, -0.11, 95% CI of -0.22 to 0.00 mg/dL) compared to placebo. Both NR and CoQ10 reduced 5 series F2-Isoprostanes (estimated difference, -0.16 and -0.11 pg/mL, respectively; P<0.05 for both). NR, but not CoQ10, increased the bioenergetic health index (BHI) (estimated difference, 0.29, 95% CI of 0.06 to 0.53) and spare respiratory capacity (estimated difference, 3.52, 95% CI of 0.04 to 7 pmol/min/10,000 cells) in monocytes. Six weeks of NR and CoQ10 improved in oxidative stress, inflammation, and cell bioenergetics in persons with moderate to severe CKD.