Run-in Period Research Articles

Short-course radiotherapy (SCRT) followed by fruquintinib plus adebrelimab and CAPOX in the total neoadjuvant therapy of locally advanced rectal cancer (LARC): A multicenter, single-arm, open-label, phase II study (UNION TNT).

192 Background: We have demonstrated that neoadjuvant SCRT followed by PD-1 inhibitor plus CAPOX for LARC patients (pts) showed a higher pCR rate and a well-tolerated safety profile in phase III UNION study. Fruquintinib is a potent and highly selective VEGFR inhibitor, which had been approved for previously treated mCRC pts. This study aimed to investigate the efficacy and safety of SCRT followed by fruquintinib plus adebrelimab and CAPOX as a total neoadjuvant therapy for high-risk LARC pts. Methods: In this prospective, open-label, multi-centers, single-arm phase 2 study (NCT06234007), pts diagnosed with newly diagnosed and high risk LARC were recruited. Pts received SCRT (25Gy/5f) followed by six cycles of fruquintinib (4mg, qd, po, q3w,for the initial 6 pts in the safety run-in period, dosage would be adjusted based on dose-limited toxicities in the 1st cycle) combined with adebrelimab (1200mg, iv, d1, q3w) and CAPOX (q3w). Primary endpoint was CR rate (including clinical CR & pathologic CR). Secondary endpoints included 3-year EFS rate, OS, R0 resection rate and safety. Results: As of 30 Aug 2024, 45 pts were enrolled (median age 59 years [range: 24-75], 26 males, 23 clinical T4 stage and 20 clinical N2 stage, 36 with EMVI positive, 31 with MRF positive, 22 tumor located ≤5cm from the anal verge). Up to 20 Sep 2024, all pts completed SCRT, 73.33% (33/45), 57.78% (26/45) and 31.11% (14/45) pts completed two, four and six cycles of combination therapy, respectively. At data cut-off, of 33 pts included in the efficacy analysis, 28 pts underwent MRI examination and mrTRG results were available, the remaining 5 pts had early surgery due to AEs/serious AEs. 35.7% (10/28) and 46.43% (13/28) pts were classified as mrTRG1 and mrTRG2, respectively. Of 19 pts who underwent surgery, R0 rate was achieved in all 19 pts (100%) and pCR was achieved in 12 pts (63.16%). Moreover, 1 pt achieved cCR during neoadjuvant therapy, thus the treatment strategy provided a CR rate of 65% (1 cCR plus 12 pCR divided by 20). Grade 3/4 adverse effects (AEs) occurred in 16 pts (47.06%), and most commonly were lymphocyte count decreased (n=6, 18.18%), diarrhea (n=5, 15.15%) and AST increased (n=2, 6.06%). 4 serious AEs reported with intestinal perforation and all achieved pCR after surgery therapy. No treatment related death was reported. Conclusions: SCRT followed by fruquintinib combined with adebrelimab and CAPOX as a total neoadjuvant therapy showed promising CR rate and favorable pCR for high-risk LARC pts, and the safety profile was generally manageable. This treatment strategy might be a potential option as neoadjuvant therapy for high-risk LARC pts. Updated data will be presented in the future. Clinical trial information: NCT06234007 .

Effects of the Transcutaneous Electrical Stimulation System on Heartburn, Regurgitation and Esophageal Acid Exposure in GERD Patients-An Uncontrolled Feasibility Study.

Proton pump inhibitors (PPI) for gastroesophageal reflux disease (GERD) are associated with a high failure rate. Our uncontrolled feasibility study aimed determining the effect of a transcutaneous electrical stimulation system (TESS) on GERD symptoms and acid exposure time (AET). Recruited patients with heartburn and regurgitation. During the first phase (one-week, run-in period, off-PPI's), patients completed symptom diaries and demographic questionnaires. Thereafter, all patients underwent gastroscopy with subsequent placement of a wireless esophageal pH capsule, off-PPI. Based on pH analysis in the first 24 h, only those with increased AET (percent total time pH < 4 above 6%) continued to the next phase. During that phase, patients were treated for up to 3 weeks with TESS and documented their symptoms. The Primary endpoint was the magnitude of reduction in GERD-related symptoms. The secondary endpoints were the magnitude of reduction of AET and DeMeester score, as compared with their baseline values. Included 31 patients and of those, 26 patients (42% females, aged 49 ± 15 years, mean BMI 25 ± 3 kg/m2) completed the first two phases of the study. At baseline, mean number of daily heartburn and regurgitation episodes was 2.55 ± 1.79 and 1.40 ± 1.73, respectively. Following TESS, mean number of daily heartburn and regurgitation episodes dropped to 0.77 ± 0.75 and 0.36 ± 0.8, respectively (p < 0.001). At base line, mean AET and DeMeester score were 12.4 ± 5.6 and 32.1 ± 12.7, respectively. Following TESS mean AET dropped to 6.0 ± 3.5 and DeMeester score dropped to 16.2 ± 8.2 (p < 0.001). TESS is effective in reducing both symptoms and esophageal AET in GERD patients.

Clinical Assessment of Puressentiel® Muscles and Joints Gel Aromatherapy in the Management of Osteoarthritis-Related Knee Pain.

Knee osteoarthritis (OA) is a degenerative joint disease that affects millions globally, causing chronic pain and limited mobility. Pharmacological treatments for OA-related knee pain come with risks, making alternative or complementary therapies attractive. This post-market trial evaluates the efficacy of Puressentiel® Muscles and Joints gel, an aromatherapy gel with 14 essential oils, in managing OA-related knee pain. In this 12-week open-label trial (NCT04736563), participants aged 45-90 with OA-related knee pain applied Puressentiel® Muscles and Joints gel twice daily for 4 weeks, following a 4-week run-in period without treatment. Pain, joint stiffness, and function were assessed using the Western Ontario McMaster Universities Arthritis Index (WOMAC) and Visual Analog Scale (VAS) at baseline, 4 weeks, 8 weeks, and 12 weeks, and oral analgesic intake was recorded daily. Significant improvements in WOMAC and VAS scores were observed during treatment (p = 0.0262; p < 0.0001, respectively) and sustained 4 weeks post-treatment (p = 0.0190; p < 0.0001, respectively). Paracetamol intake significantly decreased from baseline to the end of treatment (p = 0.0230), though anti-inflammatory intake did not change significantly. No adverse events were reported. Puressentiel® Muscles and Joints gel was well-tolerated, improved WOMAC and VAS scores, and reduced paracetamol use, presenting a viable natural option for pain management in knee OA.

Optimization of cropping patterns in the Bhimsagar canal irrigation scheme using linear programming approach

ABSTRACT Optimization techniques can be employed to determine the best cropping patterns to ensure optimum net benefits, food production, and labor employment. Therefore, the current investigation employed the linear programming module in LINGO 14.0 software to develop optimal crop area allocation plans in the Right Main Canal (RMC) of the Bhimsagar irrigation project. The optimal cropping patterns (OCPs) were generated for 2013–2014 under different canal run (CR) periods in a month, i.e., 30, 24, and 21 days using three objective functions, viz., net benefit, food production, and labor-days maximization. In addition, the OCP scenarios were generated for long-term agriculture sustainability scenarios, viz., 2015, 2020, and 2025. Results revealed that the net benefit was increased by 122.2, 93.4, and 95.5% for Ratanpura (RT), Chaplada (CP), and Maraita II (MT) minor, respectively, under OCP estimated for 30-day CR in 2013–2014, whereas food production was increased by 22.4, 33.8, and 25.9% for RT, CP, and MT, respectively, under OCP over existing cropping patterns. Similarly, under OCP, labor employment had increased by 40.9, 33.8, and 33.1% for RT, CP, and MT, respectively, for 30-day CR. These findings infer that higher net benefits, food production, and labor employment may be achieved by shifting to OCPs.

Substituting animal protein with black soymilk reduces advanced glycation end product level and improves gut microbiota composition in obese prediabetic individuals: a randomized crossover intervention trial.

Prediabetes (PreDM) and obesity increase the risk of type 2 diabetes. Individuals with these conditions often consume diets higher in animal protein than in plant protein, which are associated with elevated levels of dietary advanced glycation end products (dAGEs). Increased dAGE intake has been linked to blood glucose abnormalities, oxidative stress, and dysbiosis of the microbiota, all of which exacerbate metabolic disorders. Black soybeans, as a plant-based protein source, contain substantially lower levels of dAGEs compared with pork. This study aimed to investigate the effects of substituting animal protein with black soybeans on advanced glycation end product (AGE) levels, oxidative stress, and the gut microbiota in individuals with both PreDM and obesity. This study was a randomized crossover intervention trial conducted over 16 weeks. We recruited men and women aged 20-64 years with both prediabetes and obesity. This study had four periods: 0-4 weeks for the run-in period, 4-8 weeks and 12-16 weeks for the pork or black soymilk intervention period, and 8-12 weeks for the wash-out period. During the intervention period, the participants consumed pork or black soymilk with similar protein content as their dietary protein source. The participants maintained 3 day dietary records, and we measured anthropometric items and collected blood and fecal samples for analysis. The results showed that partially substituting pork with black soymilk as a dietary protein source for 4 weeks significantly reduced dAGE intake. The black soymilk group also exhibited significantly lower blood AGE fluorescence intensity, oxidative stress, and levels of glycative stress markers. Furthermore, black soymilk consumption significantly increased the relative abundance of short-chain fatty acid-producing genera compared with pork consumption. In conclusion, partially substituting dietary pork with black soymilk may reduce serum AGE levels, reduce oxidative and glycation stress, and increase the abundance of short-chain fatty acid-producing microbiota in individuals with both PreDM and obesity. Registration number of Clinical Trial: NCT05290519 (ClinicalTrials.gov).

Brexpiprazole and Sertraline Combination Treatment in Posttraumatic Stress Disorder

New pharmacotherapy options are needed for posttraumatic stress disorder (PTSD). To investigate the efficacy, safety, and tolerability of brexpiprazole and sertraline combination treatment (brexpiprazole + sertraline) compared with sertraline + placebo for PTSD. This was a parallel-design, double-blind, randomized clinical trial conducted from October 2019 to August 2023. The study had a 1-week, placebo run-in period followed by an 11-week, double-blind, randomized, active-controlled, parallel-arm period (with 21-day follow-up) and took place at 86 clinical trial sites in the US. Adult outpatients with PTSD were enrolled (volunteer sample). Oral brexpiprazole 2 to 3 mg per day (flexible dose) + sertraline 150 mg per day or sertraline 150 mg per day + placebo (1:1 ratio) for 11 weeks. The primary end point was change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total score (which measures the severity of 20 PTSD symptoms) from randomization (week 1) to week 10 for brexpiprazole + sertraline vs sertraline + placebo. Safety assessments included adverse events. A total of 1327 individuals were assessed for eligibility. After 878 screen failures, 416 participants (mean [SD] age, 37.4 [11.9] years; 310 female [74.5%]) were randomized. Completion rates were 137 of 214 participants (64.0%) for brexpiprazole + sertraline and 113 of 202 participants (55.9%) for sertraline + placebo. At week 10, brexpiprazole + sertraline demonstrated statistically significant greater improvement in CAPS-5 total score (mean [SD] at randomization, 38.4 [7.2]; LS mean [SE] change, -19.2 [1.2]; n = 148) than sertraline + placebo (randomization, 38.7 [7.8]; change, -13.6 [1.2]; n = 134), with LS mean difference, -5.59 (95% CI, -8.79 to -2.38; P < .001). All key secondary and other efficacy end points were also met. Treatment-emergent adverse events with incidence of 5% or greater for brexpiprazole + sertraline (and corresponding incidences for sertraline + placebo) were nausea (25 of 205 [12.2%] and 23 of 196 [11.7%]), fatigue (14 of 205 [6.8%] and 8 of 196 [4.1%]), weight increase (12 of 205 [5.9%] and 3 of 196 [1.5%]), and somnolence (11 of 205 [5.4%] and 5 of 196 [2.6%]). Discontinuation rates due to adverse events were 8 of 205 participants (3.9%) for brexpiprazole + sertraline and 20 of 196 participants (10.2%) for sertraline + placebo. Results of this randomized clinical trial show that brexpiprazole + sertraline combination treatment statistically significantly improved PTSD symptoms vs sertraline + placebo, indicating its potential as a new efficacious treatment for PTSD. Brexpiprazole + sertraline was tolerated by most participants, with a safety profile consistent with that of brexpiprazole in approved indications. ClinicalTrials.gov Identifier: NCT04124614.

Methodological Considerations When Studying Resistance-Trained Populations: Ideas for Using Control Groups.

Hammert, WB, Dankel, SJ, Kataoka, R, Yamada, Y, Kassiano, W, Song, JS, and Loenneke, JP. Methodological considerations when studying resistance-trained populations: Ideas for using control groups. J Strength Cond Res 38(12): 2164-2171, 2024-The applicability of training effects from experimental research depends on the ability to quantify the degree of measurement error accurately over time, which can be accounted for by including a time-matched nonexercise control group. Yet, control groups are rarely included in studies on resistance-trained individuals. Many authors instead report short-term relative or absolute measures of reliability for the interpretation of statistical tests and the size or meaning of effects observed and assume that good short-term reliability justifies the lack of a control group. In this article, we offer some potential alternatives for employing control groups in research studies on resistance-trained individuals. We wish to suggest researchers consider using a "time-matched training group" (i.e., resistance-trained individuals who keep an exercise log, continue their normal training, and perform the pre- and posttest measures spanning the same duration as that of the exercise group or groups) and/or a time-matched nonexercise control group (i.e., non-resistance-trained individuals who perform only the pre- and posttest measures spanning the same duration as that of the exercise training group or groups). If it is not feasible (e.g., researchers do not wish to randomly assign individuals to a time-matched training group or include a time-matched nonexercise control group) to employ such designs, or relevant, then an alternative approach might be to include a run-in (i.e., control) period that spans the same duration as the exercise training intervention. Our hope is that this article can help strengthen future research designs conducted on resistance-trained individuals.

Rationale and Design of a Randomized, Open-Label, Parallel-Group Study of Esaxerenone Versus Angiotensin Receptor Blockers in Older Patients With Uncontrolled Hypertension on Calcium Channel Blocker Monotherapy (ESCORT-HT).

Angiotensin II receptor blockers (ARBs) and calcium channel blockers (CCBs) are commonly prescribed as first- and second-line treatments for older Japanese patients with hypertension. However, due to age-related decline in renin activity, the effectiveness of ARBs may decrease. This highlights the need for other antihypertensive agents to be used in combination with CCBs to replace ARBs for more effective blood pressure (BP) control. The ESCORT-HT study is a multicenter, randomized, controlled, open-label, parallel-group study with a 4-week run-in period and 12-week treatment period. This study aims to evaluate the efficacy of esaxerenone as a second-line treatment for hypertension and to determine whether its BP-lowering effect is noninferior to that of ARBs in older patients with uncontrolled hypertension on CCB monotherapy. The safety profiles of esaxerenone and ARBs will also be evaluated. Patients will be randomly assigned in a 1:1 ratio to receive either esaxerenone or an ARB. The primary efficacy endpoint will be the change from baseline in morning home systolic BP at the end of the treatment period. The BP-lowering effect of esaxerenone will be considered noninferior to that of ARBs if the upper limit of the two-sided 95% confidence interval (CI) for the difference in systolic BP change between esaxerenone and ARB is <3.8mmHg, and will be considered superior if the upper limit of the two-sided 95% CI is <0. The findings may elucidate the possible benefits of earlier use of mineralocorticoid receptor blockers in combination with CCBs in older patients with essential hypertension.

Macroscale Superlubrication Achieved with Shear-Thinning Semisolid Lubricants.

Macrosuperlubric materials are pivotal for reducing friction and wear in engineering applications. However, current solid superlubricants require intricate fabrication and specific conditions (e.g., vacuum or inert atmospheres), while liquid superlubricants are prone to creep, leakage, and corrosion. Here, a novel semisolid subnanometer nanowire (SNW) superlubrication material based on the shear-thinning effect is introduced to overcome these challenges. The SNWs achieve an exceptionally low friction coefficient (0.008-0.009) with silicon nitride (Si3N4) and polytetrafluoroethylene (PTFE) tribo-pairs, demonstrating a brief running-in period (≈39 s) and stable superlubrication over extended friction (12 h, >120000 cycles). The combination of the shear-thinning network structure mechanism, the adsorption membrane mechanism, and hydrodynamic effects provides a synergistic effect, playing a crucial role in achieving superlubricity. Additionally, SNWs can be combined with various base oils to create semisolid gel lubricants with superlubricating properties. This innovative approach addresses the limitations of current superlubrication systems and introduces a new category of semisolid gel lubricants, significantly expanding the applications of superlubrication materials.

Efficacy and safety of electroacupuncture for metabolic dysfunction-associated fatty liver disease: a study protocol for a multicentre, randomised, sham acupuncture-controlled, patient-blinded clinical trial

BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease in the world and carries an increased risk of liver-related events, but no approved medicine. Electroacupuncture has...

Abstract 4134333: Blood pressure reduction in diabetic patients with resistant hypertension: results from the aprocitentan PRECISION study

Background: In patients with resistant hypertension (RHT), diabetes is a frequent comorbidity that increases the risk of cardiovascular events. The phase-3 PRECISION study demonstrated the efficacy of aprocitentan (APRO), a dual endothelin ET A /ET B receptor antagonist, to lower blood pressure (BP) in patients with RHT. In this pre-planned PRECISION post hoc analysis, we evaluated the BP lowering effect of APRO in diabetic patients. Methods: Eligible patients were hypertensive despite treatment with ≥3 antihypertensive medications from different classes. After ≥4 weeks of combination therapy (amlodipine/valsartan/hydrochlorothiazide), patients still hypertensive received single-blind placebo for a run-in period, followed by a 4-week double-blind part (APRO 12.5 mg, 25 mg, or placebo), a 32-week single-blind part (APRO 25 mg) and a 12-week double-blind withdrawal part (APRO 25 mg or placebo). The primary endpoint was change from baseline to Week 4 in mean trough office SBP. Results: Out of 730 patients, 395 (54%) had diabetes (APRO 12.5 mg, n=112; 25 mg, n=107; placebo, n=116). At Week 4, APRO reduced office SBP (12.5 mg: −14.6; 25 mg: −14.1 mmHg) vs placebo (−9.4 mmHg) in diabetic patients, with no treatment/diabetes status interaction (p=0.77). The reduction was maintained at Week 36 (−16.2 mmHg). APRO also reduced mean 24-hour ambulatory SBP at Week 4 (12.5 mg: −7.4 mmHg; 25 mg: −9.5 mmHg) vs placebo (−2.2 mmHg), most pronounced on night-time values (12.5 mg: −8.9 mmHg; 25 mg: −13.1 mmHg; placebo: −1.6 mmHg). At Week 40, after 4 weeks of withdrawal, office SBP increased in placebo patients (+3.6 mmHg) and remained stable with APRO 25 mg (+0.2 mmHg). A substantial reduction in urine albumin–creatinine ratio of 33% and 37% was observed at Week 4 for APRO 12.5 mg and 25 mg, respectively, compared with an increase of 11% for placebo. Edema/fluid retention were the most common adverse events; they were mild-to-moderate in most cases and dose dependent (9%, 23%, and 2% of patients receiving APRO 12.5 mg, 25 mg, and placebo, respectively, up to Week 4). During the study, 11 patients were hospitalized for heart failure (10 treated with APRO 25 mg and one with placebo). Among these, 6 had chronic kidney disease stage 3–4, and 5 had medical history of heart failure; no cases were fatal. Conclusion: APRO produced clinically relevant and sustained BP reduction in diabetic patients with RHT, consistent with the effect observed in the overall population.

Beclometasone Dipropionate/Formoterol Fumarate is Similarly Effective to Budesonide/Formoterol Fumarate in Chinese Patients with COPD: The FORSYYN Double-Blind, Randomised Study

The fixed-dose combination of beclometasone dipropionate/formoterol fumarate (BDP/FF) delivered via pressurised metered-dose inhaler (pMDI) has demonstrated efficacy in chronic obstructive pulmonary disease (COPD), in studies predominantly conducted in Caucasian adults. The current study evaluated the efficacy and safety of BDP/FF pMDI in Chinese patients with COPD, as part of registration for COPD in China. This double-blind, double-dummy, randomised, parallel-group study was conducted in patients with COPD of Chinese ethnicity aged ≥40 years. After a 4-week open-label budesonide/formoterol fumarate (BUD/FF) run-in period, patients were randomised to BUD/FF or BDP/FF for 24 weeks. The primary objective was to demonstrate non-inferiority of BDP/FF to BUD/FF in terms of change from baseline in pre-dose morning forced expiratory volume in 1 sec (FEV1) at Week 24 (i.e. the lower 95% CI limit of the difference was above the pre-defined non-inferiority margin of −0.07 L). Of 750 patients randomised (377 BDP/FF; 373 BUD/FF), 87.6% completed the study. The primary endpoint was met in both the per-protocol (adjusted mean difference −0.001 L [95% CI: −0.025, 0.022], non-inferiority p < 0.001) and intention-to-treat populations (–0.001 L [–0.024, 0.022]; non-inferiority p < 0.001). There were no statistically significant BDP/FF–BUD/FF differences for the secondary endpoints, and a similar proportion of patients had adverse events (BDP/FF, 51.7%; BUD/FF, 51.2%), with most mild/moderate in severity. In conclusion, BDP/FF pMDI was non-inferior to BUD/FF in terms of pre-dose morning FEV1, supported by a range of secondary endpoints. Both treatments were similarly tolerated. The study supports the use of BDP/FF pMDI in Chinese patients with COPD. STUDY REGISTRATION China Centre for Drug Evaluation (CTR20180475).

Development of wear and pitting curves with vibration analysis for lubricating grease under contamination conditions

The application of grease under contaminated environmental conditions typically leads to its degradation and subsequent damage to lubricated surfaces. This study examines the effects of various concentrations of environmental particles and water content, both separately and in combination, on the variation of tribological characteristics of lithium-based grease during wear. Wear and pitting curves are established for grease contaminated with varying weight percentages of water and particles. The introduction of water into grease reduces wear by absorbing friction heat but increases pitting, while particles extend the running-in period and destabilize surface roughness. In mixed conditions, particles exert a greater influence on the tribological behavior than water. To improve pitting monitoring, vibration indicators FM4 and NA4 are modified by incorporating the cumulative effect of the friction coefficient over time, accounting for the progressive accumulation of wear and vibration energy. The modified FM4 indicator proves more effective in detecting pitting variations under contaminated conditions.

Recaticimab as Add-On Therapy to Statins for Nonfamilial Hypercholesterolemia: The Randomized, Phase 3 REMAIN-2 Trial

BackgroundCurrently available antiproprotein convertase subtilisin/kexin type 9 monoclonal antibodies can effectively decrease low-density lipoprotein cholesterol (LDL-C) levels, but require frequent dosing. Recaticimab is a novel humanized monoclonal antibody against proprotein convertase subtilisin/kexin type 9. In a phase 1b/2 trial, recaticimab as add-on to stable statins showed robust LDL-C reduction with a dosing interval up to every 12 weeks (Q12W) in patients with hypercholesterolemia. ObjectivesREMAIN-2 (REcaticiMab Add-on therapy In patients with Nonfamilial hypercholesterolemia) aimed to assess the efficacy and safety of 48-week treatment with recaticimab as add-on therapy to statins in nonfamilial hypercholesterolemia. MethodsREMAIN-2 was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. During the run-in period, patients received stable moderate or high-intensity statin, with or without cholesterol absorption inhibitors (ezetimibe) or fenofibrate, for ≥4 weeks. Patients with an LDL-C of ≥1.8 mmol/L (if with atherosclerotic cardiovascular disease [ASCVD]) or ≥2.6 mmol/L (if without ASCVD) were then randomized (2:2:2:1:1:1) to receive recaticimab 150 mg every 4 weeks (Q4W), 300 mg every 8 weeks (Q8W), or 450 mg Q12W, or matching placebo injections (Q4W, Q8W, or Q12W) for 48 weeks. The primary efficacy endpoint was percentage change from baseline to week 24 in LDL-C level. ResultsA total of 689 randomly assigned patients received treatment (mean age, 55.8 years; male, 64.4%; ASCVD history, 69.5%; concomitant ezetimibe, 11.2%; mean baseline LDL-C, 2.8 mmol/L). Percentage change in LDL-C from baseline to week 24 was significantly more pronounced with recaticimab vs placebo (P < 0.0001), with least-squares mean differences of −62.2% (95% CI: −67.0% to −57.4%), −59.7% (95% CI: −65.0% to −54.4%), and −53.4% (95% CI: −58.7% to −48.2%) for the 150 mg Q4W, 300 mg Q8W, and 450 mg Q12W regimens, respectively. The decreases in LDL-C with recaticimab were maintained through week 48. Secondary lipid variables, including non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) also favored the recaticimab groups. During the treatment period, the incidence of treatment-related adverse events (28.5% vs 26.6%) and serious treatment-related adverse events (0.4% vs 0.4%) was similarly low in both the recaticimab and placebo groups. ConclusionsRecaticimab as add-on to stable statin therapy significantly decreased LDL-C levels at week 24 and sustained the decreases through week 48, providing a novel therapeutic alternative with a dosing interval of up to every 12 weeks in patients with nonfamilial hypercholesterolemia.

A Theoretical Review on Budget Deficit in Nigeria

The study empirically examined budget deficit in Nigeria. Based on the theoretical review conducted, the following findings were made: As the current account deficit worsens, it results to the depreciation of the domestic currency which may impact the economy negatively due to the inflationary pressures and thus increase interest rates. As a consequence, the cost of borrowing goes up for the government and this exerts pressure on the government budget due to high debt service and thus high deficit levels. These vicious cycles will continue again and again, and the potential spiral effects are creating anxieties in the Nigerian economy. Empirically, there is a tendency for a country’s budget deficits to crowd out its domestic investment in the short run and its stock of capital in the long run. The main problem of this study is to investigate the impact of budget deficit on economic performance in Nigeria in terms of its implications on the real gross domestic product in the short run as well as the long run periods. Budget deficit has a negative and significant effect on economic growth in Nigeria. It was recommended that government should strive to mop the leakages in accrued foreign loans, eliminate room for misappropriation of borrowed funds and hence foster the influence of this resource on the economy so as to achieve better growth especially in the short-run.

The economic implications of Nigeria’s foreign debt servicing and sustainability

Despite extensive literature examining the role foreign debt plays in the growth of the Nigerian economy, seldom do they simultaneously consider the effect of external debt servicing and sustainability. Accordingly, this study examined the impact of external debt servicing and sustainability on the economic growth of Nigeria for the period between 1980 and 2022. The auto-regressive distributed lag (ARDL) model was adopted to measure the effect of the explanatory variables on the dependent variable. Empirically, the study demonstrated that the impact of debt sustainability was insufficient on the economy; notwithstanding being positive in the long run. Thus, suggesting the presence of a sovereign Ponzi finance in Nigeria’s debt management. However, the effects of external debt servicing and foreign debt interest payment were significant and negative on the economy in the short and long run periods. Thus, showing that resources being used to service the debt of the nation, crowd-out funds that could have been used to spur growth of the economy. Generally, the study affirmed the applicability of the debt-overhang hypothesis for the country. Conversely, exchange rate significantly and positively impacted the economy, indicating that an improvement in the value of the Naira, will be indicative of an improvement in the economy. Hence, the study recommends amongst others that effective external debt management strategies such as the debt for equity swap programme should be adopted by fiscal authorities in the country.

Acceptability of Microbiota-Directed Complementary Foods in Treating Indian Children with Moderate Acute Malnutrition: eACT-MAM Pre-Proof-of-Concept Study

BackgroundIn India, currently, there are no standard guidelines for the management of moderate acute malnutrition (MAM). Previous research in Bangladesh has shown that children with MAM have impaired gut microbiota development, and microbiota-directed complementary foods (MDCF) can potentially repair their gut microbiota. ObjectivesThe objectives of this study were to evaluate the acceptability and safety of supplementing shelf-stable formulation of MDCF in Indian children with MAM as compared with a locally prepared ready-to-use supplementary food (RUSF) in 3 geographically distinct Indian populations and to establish and pilot systems of intervention delivery, collection, transport, and storage of stool samples using stringent protocols. MethodsThis pre-proof-of-concept (prePOC), multicentric, open-labeled, age-stratified, randomized controlled trial was done in children aged 6–18 mo with MAM. After a run-in period of 2 wk, the participants were supplemented with MDCF or RUSF for 4 wk through direct observation and followed up for another 2 wk post intervention. Maternal responses to the acceptability of the organoleptic properties of supplements were recorded weekly during the intervention phase of 4 wk. Compliance was reported based on the amount of supplement consumed by the children. Feasibility of weekly stool sample collection (except 7th week) within 30 min of passage was recorded. Anthropometric measurements were done at baseline and endline. Monitoring for adverse events was done throughout the course of the study. ResultsA total of 240 children with MAM were randomly selected to receive either MDCF or RUSF, of which 221 (92.1%) completed follow-up. The overall acceptability for >80% of the maternal responses was reported as good or very good for all organoleptic properties in both MDCF and RUSF arms. MDCF and RUSF interventions had good-to-high compliance in 83.0% and 79.8% of participants, respectively. At the end of the intervention phase, 53.2% (58/109) of children in MDCF arm against 42.0% (47/112) in RUSF arm had weight-for-length Z score >–2. The overall incidence of acute gastroenteritis reported was low; higher in MDCF compared with RUSF but not statistically significant. ConclusionThe prePOC study demonstrates good acceptability and safety of MDCF among Indian children with MAM including the age group of 6–12 mo of age. The study demonstrates the feasibility of conducting a long-term supplementation study in this population.The study was registered at the clinical trial registry of India as CTRI/2023/01/048716.

Does radiofrequency radiation impact sleep? A double-blind, randomised, placebo-controlled, crossover pilot study.

The most common source of Radiofrequency Electromagnetic Field (RF-EMF) exposures during sleep includes digital devices, yet there are no studies investigating the impact of multi-night exposure to electromagnetic fields emitted from a baby monitor on sleep under real-world conditions in healthy adults. Given the rise in the number of people reporting to be sensitive to manmade electromagnetic fields, the ubiquitous use of Wi-Fi enabled digital devices and the lack of real-world data, we investigated the effect of 2.45 GHz radiofrequency exposure during sleep on subjective sleep quality, and objective sleep measures, heart rate variability and actigraphy in healthy adults. This pilot study was a 4-week randomised, double-blind, crossover trial of 12 healthy adults. After a one-week run-in period, participants were randomised to exposure from either an active or inactive (sham) baby monitor for 7 nights and then crossed over to the alternate intervention after a one-week washout period. Subjective and objective assessments of sleep included the Pittsburgh Insomnia Rating Scale (PIRS-20), electroencephalography (EEG), actigraphy and heart rate variability (HRV) derived from electrocardiogram. Sleep quality was reduced significantly (p < 0.05) and clinically meaningful during RF-EMF exposure compared to sham-exposure as indicated by the PIRS-20 scores. Furthermore, at higher frequencies (gamma, beta and theta bands), EEG power density significantly increased during the Non-Rapid Eye Movement sleep (p < 0.05). No statistically significant differences in HRV or actigraphy were detected. Our findings suggest that exposure to a 2.45 GHz radiofrequency device (baby monitor) may impact sleep in some people under real-world conditions however further large-scale real-world investigations with specified dosimetry are required to confirm these findings.

Diuretic therapy strategies in decompensated acute heart failure: a systematic review and network metanalysis

Abstract Background Congestion in acute heart failure (AHF) is treated with furosemide, mainly in continuous infusion (furosemide continuous, FC) or iv boluses, and combination of different diuretics. Randomized controlled trials (RCTs) only compared the efficacy and safety of some diuretic strategies with discordant results. Purpose To provide a comprehensive synthesis of the effects of diuretic regimens in AHF. Methods The PubMed, EMBASE, SCOPUS and Cochrane databases were searched for phase III RCTs until July 31st, 2023, evaluating diuretics without any other intervention in patients admitted for AHF, with randomization within 48 hours, no run-in period and/or need of clinical stabilization. The arms assigned to iv boluses or undefined schemas of furosemide/loop diuretic (LD) were grouped together as "furosemide bolus" (FB). The endpoints were weight loss over 24 hours (WL), worsening renal function (WRF), total urine output (tUO) and net urine output (nUO) over 24 hours, hypokalemia (hypoK), and hyponatremia (hypoNa). Heterogeneity was estimated by Thompsons’ I2 statistics, and odds ratios (OR) with 95% confidence intervals were calculated by means of a random-effects model with inverse variance weighting. A leave-one-out analysis, an analysis limited to studies with specified mode of furosemide/LD administration, and an analysis of measures of congestion/decongestion were also carried out. Results Twenty-five RCTs were selected, for a total of 7,095 patients with mean age 69.2±11.1 years and mean LVEF 38.1±12.7%. In subjects treated with furosemide/LD, the mean furosemide equivalent dose was 154.7±53.0 mg/24 hours. Heterogeneity was moderate-to-high (37.3%-66.0% across the study endpoints). FC, FB plus tolvaptan, FB plus sodium-glucose cotransporter inhibitor (SGLT2i), and FB plus thiazide were associated with greater WL than FB (Figure 1A). The combination of FB and thiazide or SGLT2i also portended higher odds of WRF than FB alone, as did the combination of FB and acetazolamide (Figure 1B). tUO was greater with FC (OR 2.77 [1.98-3.88]), FB plus tolvaptan (OR 1.69 [1.22-2.35]), and FB plus SGLT2i (OR 1.95 [1.16-3.28]) than with FB, and nUO was greater with FC (OR 1.50 [1.06-2.13]) and FB plus tolvaptan (OR 1.76 [1.06-2.92]) than with FB. Compared with FB, hypoK was more frequent with FB and thiazide (OR 1.68 [1.29-2.19]), while there was a trend for less hypoK events with FB plus tolvaptan (OR 0.86 [0.69-1.08]). No differences in hypoNa rates were found. Sensitivity analyses were consistent with the main one. Thirteen (52%) and 14 (56%) studies had published information about symptoms and signs of congestion, respectively, and 6 (24%) adopted pre-specified scoring systems. Conclusions FC and most combination diuretic regimens have greater efficacy than FB in promoting WL and diuresis, but at the cost of WRF and hyoK, especially when thiazide is used. Congestion has inconsistently been evaluated in RCTs of diuretic therapy in AHF.

Inclisiran-containing low-density lipoprotein cholesterol reduction effectively stabilizes atherosclerotic plaques

Abstract Background/Introduction Near-infrared spectroscopy (NIRS) allows to quantify lipid composition of coronary artery lesions. High plaque lipid content has been associated with increased adverse cardiovascular event risk. Purpose Aim of this study was to evaluate atherosclerotic plaque lipid content reduction in association with low-density lipoprotein (LDL-C) lowering on the background of intensive hypolipidaemic therapy. Methods NIRS investigation was performed in stable coronary artery disease patients having 20-50% stenosis in the proximal or middle third of a coronary artery. Segment of interest was repeatedly evaluated after 15 months. Lipid-rich plaques (LRPs) were defined as lesions with maximum lipid-core burden index within 4 mm (maxLCBI4 mm) &amp;gt;250. Study participants were taking high-intensity statin (atorvastatin 40 or 80 mg and rosuvastatin 20 or 40 mg) with or without ezetimibe for a run-in period of 4-6 weeks. Afterwards, in patients not achieving LDL-C level &amp;lt;1.8 mmol/l, add-on inclisiran was started. Baseline LDL-C was defined as the level at the time of initiation of optimal lipid-lowering therapy. Statistical significance level of 0.05 was set. Results Data of 36 patients was analyzed. Mean baseline maxLCBI4 mm was 203.9, reduced by 39.8% (-81.1, 95%CI -129.2 to -33.0) at 15-month follow-up (P=0.003). In 15 patients LRPs were detected with mean baseline maxLCBI4 mm 363.5, which was decreased by 35.8% (-130.3, 95%CI -235.0 to -25.7) (P=0.020). Mean LDL-C level at baseline was 2.5 mmol/l among all participants, lowered by 32.0% (-0.8, 95%CI -1.1 to -0.5) after 15 months of treatment (P&amp;lt;0.001). 19 patients received inclisiran in addition to high-dose statin and optional ezetimibe therapy. In 24 patients achieving LDL-C target &amp;lt;1.8 mmol/l at 15-month follow-up, a significant maxLCBI4 mm reduction from 208.5 by 48.4% (-101.0, 95%CI -169.3 to -32.7) was established (P=0.010). Among those having LDL-C &amp;gt;1.8 mmol/l, maxLCBI4 mm reduction from 194.7 by 21.2% (-41.25, 95%CI -94.7 to 12.2) was observed, however the change was not statistically significant (P=0.114). Conclusion LDL-C lowering with high-intensity hypolipidaemic therapy, including escalation to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, demonstrated atherosclerotic plaque stabilization by NIRS-detected lipid content decrease.