Meaningful Benefit Research Articles

Is There a Role for Daratumumab Retreatment in Patients with Relapsed/Refractory Multiple Myeloma?

Multiple myeloma (MM) is a hematologic disease characterized by the clonal expansion of malignant plasma cells that accumulate in the bone marrow, leading to osteolytic bone disease, hypercalcemia, anemia, and renal dysfunction. Daratumumab was the first monoclonal anti-CD38 antibody approved for the treatment of MM, initially in relapse/refractory settings and, more recently, for newly diagnosed patients. Increased first-line usage of daratumumab will also substantially change treatment approaches for patients with relapsed/refractory disease. Due to the cost and availability of bispecific T cell redirecting antibodies (BsAbs) and chimeric antigen receptor T cell therapy (CAR-T) in real-life settings in many countries, retreatment with daratumumab in subsequent lines of therapy might be a reasonable choice. Data regarding efficacy and optimal combinations of daratumumab retreatment are lacking, and here we provide a short literature review of available data. We identified only a small number of articles based on retrospective analysis of medical records in real-life settings. A strong consistency in results regarding response rates and treatment duration was noticed among mainly heavily pre-treated MM patients, with approximately half of patients achieving at least partial remission (PR) after retreatment with daratumumab-based protocol. The duration of treatment and time to the next treatment for retreatment episodes were considerable and consistent with clinical expectations for later lines of therapy. The analysis of data in this literature review indicates that daratumumab retreatment may provide meaningful clinical benefit to some patients with relapsed/refractory MM despite having prior exposure. However, further research is needed to identify clinical and biological parameters that may predict favorable responses to daratumumab retreatment.

Pneumology : what's new in 2024

In 2024, several important innovations have enriched the management of respiratory diseases, including pulmonary hypertension, tuberculosis, COPD, and obstructive sleep apnea syndrome (OSAS). Notable advancements include the introduction of sotatercept in Switzerland for pulmonary arterial hypertension and mediastinal cryobiopsies, reflecting a shift toward more personalized medicine. Meanwhile, biologic therapies for COPD offer promising perspectives, and a potential path is emerging for shortening the treatment of certain forms of tuberculosis. These developments open the door to new therapeutic options, with the hope of enhancing care and delivering meaningful clinical benefits to patients.

Universities’ policies on feedback speed do not meaningfully predict students’ satisfaction with assessment and feedback

It is widely believed that an essential property of feedback’s effectiveness is its timeliness, and students frequently report untimely feedback as a significant source of dissatisfaction in their studies. Most UK universities have responded by implementing institutional policies that stipulate a time-period within which students should receive feedback on the assessments they submit. These policies serve to enhance the student experience, but concerns are well-documented about their side effects on feedback quality and staff well-being. The present study involved a secondary analysis of UK universities’ policies on feedback turnaround times, examining to what extent these are associated with variation in students’ satisfaction with assessment and feedback, as measured by the National Student Survey. Overall, the number of turnaround days permitted in feedback policies was negatively – but weakly and nonsignificantly – associated with overall student satisfaction in this domain. Feedback ­policy was associated more strongly with student satisfaction in the domain of organisation and management, which raises pertinent questions about causal pathways. University leaders are advised to be wary of expecting that mandating ever-quicker feedback will deliver meaningful benefits to student satisfaction. They are advised to look elsewhere if they seek to have a worthwhile positive impact on student satisfaction and feedback quality.

Impact of extended-course oral nirmatrelvir/ritonavir in established Long COVID: a case series

BackgroundPrior case series suggest that a 5-day course of oral Paxlovid (nirmatrelvir/ritonavir) benefits some people with Long COVID, within and/or outside of the context of an acute reinfection. To the best of our knowledge, there have been no prior case series of people with Long COVID who have attempted longer courses of nirmatrelvir/ritonavir.MethodsWe documented a case series of 13 individuals with Long COVID who initiated extended courses (>5 days; range: 7.5–30 days) of oral nirmatrelvir/ritonavir outside (n = 11) of and within (n = 2) the context of an acute SARS-CoV-2 infection. Participants reported on symptoms and health experiences before, during, and after their use of nirmatrelvir/ritonavir.ResultsAmong those who take an extended course of nirmatrelvir/ritonavir outside of the context of an acute infection, some experience a meaningful reduction in symptoms, although not all benefits persist. Others experience no effect on symptoms. One participant stopped early due to intense stomach pain. For the two participants who took an extended course of nirmatrelvir/ritonavir within the context of an acute reinfection, both report eventually returning to their pre-re-infection baseline.ConclusionsExtended courses of nirmatrelvir/ritonavir may have meaningful benefits for some people with Long COVID but not others. We encourage researchers to study how and why nirmatrelvir/ritonavir benefits some and what course length is most effective, with the goal of informing clinical recommendations for using nirmatrelvir/ritonavir and/or other antivirals as a potential treatment for Long COVID.

Healthy Lifestyle Care vs Guideline-Based Care for Low Back Pain

An unhealthy lifestyle is believed to increase the development and persistence of low back pain, but there is uncertainty about whether integrating support for lifestyle risks in low back pain management improves patients' outcomes. To assess the effectiveness of the Healthy Lifestyle Program (HeLP) compared with guideline-based care for low back pain disability. This superiority, assessor-blinded randomized clinical trial was conducted in Australia from September 8, 2017, to December 30, 2020, among 346 participants who had activity-limiting chronic low back pain and at least 1 lifestyle risk (overweight, poor diet, physical inactivity, and/or smoking), referred from hospital, general practice, and community settings. Statistical analysis was performed from January to December 2021. Participants were block randomized to the HeLP intervention (n = 174; 2 postrandomization exclusions) or guideline-based physiotherapy care (n = 172), stratified by body mass index, using a concealed function in REDCap. HeLP integrated healthy lifestyle support with guideline-based care using physiotherapy and dietetic consultations, educational resources, and telephone-based health coaching over 6 months. The primary outcome was low back pain disability (Roland Morris Disability Questionnaire [RMDQ] score; 0-24 scale, where higher scores indicate greater disability) at 26 weeks. Secondary outcomes were weight, pain intensity, quality of life, and smoking. Analyses were performed by intention to treat. We estimated the complier average causal effect (CACE) as sensitivity analyses. The sample of 346 individuals (mean [SD] age, 50.2 [14.4] years; 190 female participants [55%]) had a baseline mean (SD) RMDQ score of 14.7 (5.4) in the intervention group and 14.0 (5.5) in the control group. At 26 weeks, the between-group difference in disability was -1.3 points (95% CI, -2.5 to -0.2 points; P = .03) favoring HeLP. CACE analysis revealed clinically meaningful benefits in disability among compliers, favoring HeLP (-5.4 points; 95% CI, -9.7 to -1.2 points; P = .01). HeLP participants lost more weight (-1.6 kg; 95% CI, -3.2 to -0.0 kg; P = .049) and had greater improvement in quality of life (physical functioning score; 1.8, 95% CI, 0.1-3.4; P = .04) than control participants. Combining healthy lifestyle management with guideline-based care for chronic low back pain led to small improvements in disability, weight, and quality of life compared with guideline-based care alone, without additional harm. Targeting lifestyle risks in the management of chronic low back pain may be considered safe and may offer small additional health benefits beyond current guideline-based care. http://anzctr.org.au Identifier: ACTRN12617001288314.

Finerenone and new-onset diabetes in heart failure: a prespecified analysis of the FINEARTS-HF trial.

Data on the effect of mineralocorticoid receptor antagonist therapy on HbA1c levels and new-onset diabetes are conflicting. We aimed to examine the effect of oral finerenone, compared with placebo, on incident diabetes in the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure (FINEARTS-HF) trial. In this randomised, double-blind, placebo-controlled trial, 6001 participants with heart failure with New York Heart Association functional class II-IV, left ventricular ejection fraction 40% or higher, evidence of structural heart disease, and elevated N-terminal pro-B-type natriuretic peptide levels were randomly assigned to finerenone or placebo, administered orally. Randomisation was performed with concealed allocation. The primary outcome of the trial was the composite of cardiovascular death and total (first and recurrent) heart failure events (ie, heart failure hospitalisation or urgent heart failure visit). In the present analysis, participants with diabetes at baseline (investigator-reported history of diabetes or baseline HbA1c ≥6·5%) were excluded. New-onset diabetes was defined as a HbA1c measurement of 6·5% or higher on two consecutive follow-up visits or new initiation of glucose-lowering therapy. The full-analysis set comprised all participants randomly assigned to study treatment, analysed according to their treatment assignment irrespective of the treatment received (ie, intention to treat). The safety analysis set comprised participants randomly assigned to study treatment who took at least one dose of the investigational product, analysed according to the treatment actually received. This trial is registered with ClinicalTrials.gov, NCT04435626, and is closed to new participants. Between Sept 14, 2020, and Jan 10, 2023, 6001 participants were recruited and randomly assigned to finerenone or placebo. 3222 (53·7%) participants did not have diabetes at baseline and comprised the study population. During a median duration of follow-up of 31·3 months (IQR 21·5-36·3), 115 (7·2%) participants in the finerenone group and 147 (9·1%) in the placebo group developed new-onset diabetes, corresponding to a rate of 3·0 events per 100 person-years (95% CI 2·5-3·6) in the finerenone group and 3·9 events per 100 person-years (3·3-4·6) in the placebo group. Compared with placebo, finerenone significantly reduced the hazard of new-onset diabetes by 24% (hazard ratio [HR] 0·76 [95% CI 0·59-0·97], p=0·026). Fine-Gray competing risk analysis, accounting for the competing risk of death, yielded a similar finding (subdistribution HR 0·75 [0·59-0·96], p=0·024). Results were similar in sensitivity analyses, in which the definition of new-onset diabetes was expanded to include initiation of SGLT2 inhibitor treatment with diabetes as indication, restricted to HbA1c measurements only, and restricted to new initiation of glucose-lowering drugs only (excluding SGLT2 inhibitor treatment). Findings were similar when participants treated with glucose-lowering drugs at baseline were excluded (n=15). The effect of finerenone, compared with placebo, on new-onset diabetes was consistent across key participant subgroups. Seven participants had an adverse event of new diabetes not captured by any of the definitions above. In participants with heart failure with mildly reduced or preserved ejection fraction without diabetes, oral finerenone reduced the hazard of new-onset diabetes, representing a meaningful additional clinical benefit of this treatment in these individuals. Bayer.

Selected Aspects of the Neuroimmunology of Cell Therapies for Neurologic Disease: Perspective.

Neurologic disease remains a cause of incalculable suffering, a formidable public health burden, and a wilderness of complex biology and medicine. At the same time, advances in basic science, technology, and the clinical development toolkit bring meaningful benefit for patients along with realistic hope for those whose conditions remain inadequately treated. This perspective focuses on cell-based therapies for neurologic disease, with particular emphasis on neuroimmunologic disorders and on the immunologic considerations of cell therapy for nonimmune conditions. I will consider the use of chimeric antigen receptor (CAR)-T effector cells and regulatory T-cell therapies for autoimmune conditions. I will briefly discuss the immune aspects of pluripotent stem cell (PSC)-derived neuronal therapies. With apologies for the omission, we do not discuss mesenchymal stem cells, glial progenitor cells, or CAR-NK cells, primarily for space limitations.

Does metacognitive training for psychosis (MCT) improve neurocognitive performance? A systematic review and meta-analysis.

Metacognitive training for psychosis (MCT) offers benefits for addressing hallmark deficits/symptoms in schizophrenia spectrum disorders including reductions in cognitive biases and positive/negative symptoms as well as improvements in social cognition and functioning. However, differing results exist regarding the relationship between MCT and neurocognition. A comprehensive understanding of the nature of this relationship would significantly contribute to the existing literature and our understanding of the potential added value of MCT as a cognitive intervention for psychosis. Across eleven electronic databases, 1312 sources were identified, and 14 studies examining MCT and neurocognition in psychosis were included in this review. Measures of estimated effect sizes were calculated with Hedge's g, moderator analyses used Cochrane's Q statistic and significance tests to measure group differences according to control conditions. Twelve studies, 11 randomized controlled trials (RCTs) and 1 non-RCT, were included in the main meta-analyses, consisting of 673 participants (nMCT=345, ncontrol=328). When comparing MCT against control interventions, non-significant differences in estimated effect sizes were observed across all neurocognitive domains when evaluating pre-post changes (g≤0.1, p>.05). Two additional studies corroborated these results in a narrative review. These findings suggest that when compared against control conditions, MCT does not pose a statistically meaningful benefit to neurocognitive performance. General practice/learning effects are likely the main contributor that explains improvement in neurocognitive performance, and not a difference of intervention allocation when considering MCT against the included control comparators. These findings help establish the specificity of the effects of MCT.

Defining benefit: Clinically and biologically meaningful outcomes in the next-generation Alzheimer's disease clinical care pathway.

To understand the potential benefits of emerging Alzheimer's disease (AD) therapies within and beyond clinical trial settings, there is a need to advance current outcome measurements into meaningful information relevant to all stakeholders. The relationship between the impact on disease biology and clinically measurable outcomes in cognition, function, and behavior must be considered when defining the meaningful benefit of early AD therapies. In this review, we discuss: (1) the lack of consideration for biomarkers in the current concept of meaningfulness in AD; (2) the lack of gold standards for determining minimal biologically and clinically important differences (MBCIDs) in AD trials; (3) how the treatment benefits of disease-modifying treatments are cumulative and increase over time; and (4) the different concepts of meaningfulness among key stakeholders. This review utilizes the future clinical biological framework of AD and aims to further integrate and expand the parameters of meaningful benefits toward a precision medicine framework. HIGHLIGHTS: Definition of meaningful benefit from Alzheimer's disease (AD) treatment varies across disease stage and stakeholder perspectives. Observable and meaningful outcomes must consider the clinical-biological nature of AD. Statistically significant effects or outcomes do not always equate to clinically meaningfulness. Assessment tools must reflect stage-specific subtle changes following treatment. Real-world evidence will support consensus, definition, and interpretation of clinical meaningfulness.

Stressbusters: a pilot study investigating the effects of OMT on stress management in medical students.

Medical students report high levels of perceived stress and burnout, especially during the preclinical years. The combination of physical stressors from poor posture, poor sleep quality, and mental stressors from the rigorous curriculum stimulates the sympathetic nervous system (SNS) to secrete cortisol. Previous studies have shown that persistent elevated cortisol levels are associated with negative health outcomes. We conducted an Institutional Review Board (IRB)-approved study to determine if regular osteopathic manipulative treatments (OMTs) could impact the stress levels of first-year osteopathic medical students (OMSs) at Touro College of Osteopathic Medicine (TouroCOM) Harlem campus by measuring physiologic stress through changes in weekly salivary cortisol levels, perceived emotional and psychological stress levels, and cognitive function. We recruited 10 first-year OMSs who were not currently receiving external OMT outside of weekly coursework; other forms of external stress management, such as yoga or meditation, were not controlled for in this study. Utilizing a random number generator, the 10 student respondents were split into a control group that received no treatment and a treatment group that received 15 min of weekly OMT for 6weeks. The treatment consisted of condylar decompression, paraspinal inhibition, and supine rib raising, which are techniques that are known to balance the SNS and parasympathetic nervous system (PNS). Cortisol levels were quantified by enzyme-linked immunosorbent assay (ELISA) cortisol immunoassay via salivary samples collected at the beginning of each weekly session, prior to treatment for the treatment group, at the same time of day each week. We also measured participants' weekly subjective perception of stress utilizing the College Student Stress Scale (CSSS) and cognitive function utilizing the Lumosity Performance Index (LPI). We conducted a two-tailed, unpaired t-test as well as a U test for the cortisol levels, given the smaller sample size and potential for a nonnormal distribution. A lower cortisol level was correlated to a higher optical density (OD), the logarithmic measure of percent transmission of light through a sample; analysis of our data from the ELISA cortisol immunoassay showed an average weekly change in OD (∆OD) for the treatment group of 0.0215 and an average weekly ∆OD of-0.0044 in the control group. The t-test showed p=0.0497, and our U test showed a p=0.0317. Both tests indicated a statistically significant decrease across the weekly salivary cortisol levels in the treatment group utilizing a p<0.05. An additional effect-size analysis supported our finding of a significant decrease in weekly cortisol levels in the treatment group, Cohen's d=1.460. Based on the CSSS responses, there was no significant difference in perceived stress between the control and treatment groups (p=0.8655, two-tailed). Analysis of the LPI revealed no statistically significant difference in cognitive performance (p=0.9265, two-tailed). Our study supports the claim that OMT that targets the SNS and PNS has a significant impact on cortisol levels. While the reduction in cortisol levels was statistically significant, the broader physiological impact remains unclear. Further research is necessary to determine whether this reduction translates to meaningful clinical benefits.

Efficacy and safety of evenamide, a glutamate modulator, added to a second-generation antipsychotic in inadequately/poorly responding patients with chronic schizophrenia: results from a randomized, double-blind, placebo-controlled, phase 3, international clinical trial.

Evenamide, a glutamate modulator, is currently in phase 3 of development as add-on treatment to antipsychotics in patients with inadequate response or treatment-resistant schizophrenia. This study was designed to determine if patients with chronic schizophrenia inadequately responding to a second-generation antipsychotic would benefit from add-on treatment with evenamide at a dose of 30 mg bid. Study 008A was a prospective, 4-week, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and efficacy of oral doses of evenamide of 30 mg bid in patients with chronic schizophrenia treated at stable therapeutic doses of a second-generation antipsychotic. Outpatients aged ≥18 years, both males and females, with a diagnosis of schizophrenia (DSM-V), who had been receiving antipsychotics for at least 2 years at stable doses, but still symptomatic (PANSS 70-85, CGI-S 4-6, predominant positive symptoms), were eligible for the study. Patients were randomised equally to evenamide 30 mg or placebo, given bid, after completing a 21-day screening period. The primary outcome (change from baseline in PANSS total score) was assessed weekly, with the primary endpoint at 4 weeks RESULTS: A total of 291 patients were enrolled, of which 11 (3·8%) discontinued prematurely, overall. Add-on treatment with evenamide was associated to a statistically significant (the absolute difference of the two treatment groups for the PANSS Total at Day 29, primary efficacy endpoint, was = 2·5 [p-value<0.05] that is associated with a Cohen's d effect size = 0·33) and clinically meaningful benefit compared to placebo across all efficacy measures, and was well tolerated. The demonstration of statistically significant and clinically meaningful benefit of evenamide, a glutamate modulator, as add-on treatment in patients with chronic schizophrenia inadequately responding to their second-generation antipsychotic may represent a new treatment paradigm for this population.

Effects of vagus nerve stimulation on daily function and quality of life in markedly treatment-resistant major depression: Findings from a one-year, randomized, sham-controlled trial.

Depression treatments aim to minimize symptom burden and optimize quality of life (QoL) and psychosocial function. Compare the effects of adjunctive versus sham vagus nerve stimulation (VNS) on QoL and function in markedly treatment-resistant depression (TRD). In this multicenter, double-blind, sham-controlled trial, 493 adults with TRD and ≥4 adequate but unsuccessful antidepressant treatment trials (current episode) were randomized to active (n=249) or sham (n=244) VNS (plus treatment as usual) over a 12-month observation period. Quarterly outcomes included QoL with the Q-LES-Q, Mini-Q-LES-Q, and EQ-5D-5L, and function with the WHODAS 2.0 and Work Productivity and Activity Impairment Questionnaire (WPAI) item 6. Differences between treatment groups in change in scores from baseline and percentage of time with a meaningful response in Q-LES-Q, Mini-Q-LES-Q, and WPAI item 6 scores were analyzed. Active VNS was superior to sham in mean change in scores from baseline in the Mini-Q-LES-Q (P=0.050) and WPAI item 6 (health condition's effect on regular activities [P=0.050]) used as continuous variables, with a similar trend for Q-LES-Q (P=0.061). Active VNS was superior to sham in time spent in clinically meaningful benefit (categorical analyses) using the Q-LES-Q (P=0.029), Mini-Q-LES-Q (P=0.011), and WPAI item 6 (P=0.039). The WHODAS 2.0 (P=0.304) and EQ-5D visual analog scale (P=0.125) failed to reveal between-group differences. Active VNS was superior to sham VNS in improving QoL and psychosocial function in patients with TRD. VNS has a broader therapeutic impact than symptom improvement alone in patients with marked psychosocial impairment.

Comparison of the analgesic efficacy of intra-articular steroid injections and its combination with suprascapular nerve block for adhesive capsulitis of the shoulder joint: a randomized clinical trial

BackgroundAdhesive capsulitis is a distressing ailment that progressively limits the active and passive mobility of the shoulder joint. Physical therapy (PT) combined with intra-articular steroid (IAS) injection and suprascapular nerve...

Therapeutic Potential of Intranasal Corticosteroids for Chronic Cough.

Background: Chronic cough, a condition defined as a cough persisting for more than 8 weeks, remains a significant clinical challenge with a considerable impact on quality of life. Intranasal corticosteroids (INCS) are widely recommended in clinical guidelines for managing chronic cough, particularly in patients with associated upper airway conditions. However, the evidence base directly supporting this practice is surprisingly sparse, leaving clinicians to navigate a disconnect between guidelines and real-world applicability. Objective: This article offers a critical perspective on the role of INCS in chronic cough management, drawing attention to the paucity of direct evidence and proposing a roadmap for future research. Discussion: A recent systematic review aiming to evaluate the efficacy and safety of INCS for chronic cough yielded no eligible studies, despite extensive database searches. This unexpected outcome highlights a major gap in the literature and raises important questions about the foundation of current guideline recommendations. While INCS are biologically plausible and have demonstrated efficacy in related conditions, such as allergic rhinitis and chronic rhinosinusitis, their specific role in chronic cough remains unverified. The lack of robust clinical trials underscores the need for targeted research to determine whether INCS provide meaningful benefit in this population. Conclusion: The disconnect between recommendations and evidence in chronic cough management underscores a critical need for well-designed randomized controlled trials. Until such data are available, clinicians must balance existing guidelines with clinical judgment, individualizing treatment to address the unique needs of their patients. Bridging this evidence gap will not only enhance patient care but also refine guideline development, ensuring recommendations are firmly grounded in high-quality research.

Retrospective cohort study of the economic value of providing microprocessor knees to the population of Medicare fee-for-service K2 beneficiaries with a knee disarticulation/above knee amputation.

Microprocessor knees (MPKs) improve the functional mobility, quality of life, and safety of individuals with a knee disarticulation or above knee amputation and are cost-effective when adjusting for quality-of-life years gained. However, few studies have been conducted on the K2 population, and to this point, the Centers for Medicare and Medicaid Services has not covered MPKs for the K2 population. The aim of this study was to determine the extent to which MPK provision to the K2 population is cost effective at the person and population levels. A secondary objective was to determine the effectiveness of MPKs at reducing injurious falls within the K2 population. A retrospective cohort study using Medicare fee-for-service claims data from the Centers for Medicare and Medicaid Services. Propensity score weighting using inverse probability treatment weights was used to balance beneficiary characteristics and a generalized linear regression with log-link function and Gamma distribution was run to determine per-member-per-month cost and prosthetic device cost. A 10-year Congressional Budget Office-style score was conducted. A logistic regression was run for the fallers analysis. Microprocessor knee provision to K2 beneficiaries reduced injured fallers by 18.5% and resulted in medical savings of $1,351 per-member-per-month, amortizing the $25,075 difference between the MPK and nonmicroprocessor knee in 19 months. Providing MPKs to K2 users resulted in cumulative Medicare savings of $410.3 million over 10 years. The MPK prosthetic device could provide meaningful safety benefits to the K2 population and result in fiscal savings to Medicare at both the person and population levels.

Dry needling as an adjunct treatment to multimodal rehabilitation protocol following rotator cuff repair surgery: a preliminary, randomized sham-controlled trial

BackgroundRotator cuff repair (RCR) is one of the most prevalent procedures to manage rotator cuff tears (RCT). Postoperative shoulder pain is a common complication following RCR and may be aggravated by activation of myofascial trigger points (MTrP) associated with the injury to the soft tissues surrounding the surgical incision. This study aimed to describe a preliminary, randomized, sham-controlled trial to evaluate the effectiveness of implementing 4 sessions of myofascial trigger point dry needling (MTrP-DN) as a muscle treatment approach along with 10 sessions of multimodal rehabilitation protocol (MRh) consisting of therapeutic exercise, manual therapy, and electrotherapy on postoperative shoulder pain, range of motion (ROM), strength, and functional outcome scores for patients following RCR surgery.MethodsForty-six patients aged 40–75 following RCR surgery were recruited and randomly allocated into 2 groups: (1) MTrP-DN plus MRh (experimental group), and (2) sham dry needling (S-DN) plus MRh (control group). This trial had a 4-week intervention period. The primary outcome was the Numeric Pain Rating Scale (NPRS) for postoperative shoulder pain. Secondary outcomes were the Shoulder Pain and Disability Index (SPADI), ROM, and strength. The mentioned outcomes were measured at baseline and week 4. In the current study, adverse events were recorded as well.ResultsNo statistically significant differences were observed between groups when adding MTrP-DN to MRh for postoperative shoulder pain after 4 weeks of intervention (mean difference 0.32, [95% CI -0.41,1.05], p = 0.37). However, this trial found a small effect size for postoperative shoulder pain. No significant between-group differences were detected in any of the secondary outcomes (p > 0.05) either. We found significant within-group changes in all studied outcome measures. (p < 0.001). This study also reported minor adverse events. following the needling approach.ConclusionThe lack of statistically significant differences in the outcomes and small clinical significance in shoulder pain highlights the complexity of pain management, suggesting that alternative methodologies may be needed for meaningful clinical benefits. Future studies should consider different control groups, long-term follow ups, larger sample sizes, and more MTrP-DN sessions to better understand their potential impact.Trial registrationThis trial was registered at (https://www.irct.ir), (IRCT20211005052677N1) on 19/02/2022.

Extended-release hydrocortisone formulations - Is there a clinically meaningful benefit?

Despite best practice replacement therapy with corticosteroids, patients with adrenal insufficiency report diminished quality of life and face increased mortality and morbidity. Conventional formulations of hydrocortisone have short half-lives (about 90 minutes) requiring multiple dosing during the day. Extended-release hydrocortisone (ER-HC) formulations have since 2011 been available enabling once, sometimes twice daily dosing. Most studies comparing ER-HC formulations with conventional hydrocortisone therapy report reduction in body weight, blood pressure and glucose levels, and improved quality of life. However, it is still unclear if the reported beneficiary effects are due to differences in cortisol exposure or alterations in pharmacokinetics. Here we review studies comparing conventional and ER-HC treatment in adrenal insufficiency and discuss whether these novel formulations are safe and offer clinically significant benefits.

Effect of empiric antibiotics against Pseudomonas aeruginosa on mortality in hospitalized patients: a systematic review and meta-analysis.

Empiric antibiotics active against Pseudomonas aeruginosa are recommended by professional societies for certain infections and are commonly prescribed for hospitalized patients. The effect of this practice on mortality is uncertain. A systematic literature search was conducted using Embase, Medline, PubMed, Web of Science, Cochrane, Scopus and Google Scholar from earliest entry through 9 October 2023. We included studies of patients hospitalized with P. aeruginosa infections that compared mortality rates depending on whether patients received active empiric antibiotics. We found 27 studies of 12 522 patients that reported adjusted OR of active empiric antibiotics on mortality. The pooled adjusted OR was 0.40 (95% CI, 0.32-0.50), favouring active empiric antibiotics. In practice, the mortality effect of empiric antibiotics against P. aeruginosa depends on the prevalence of P. aeruginosa and baseline mortality. The estimated absolute mortality benefit was 0.02% (95% CI, 0.02-0.02) for soft tissue infections, 0.12% (95% CI, 0.10-0.13) for urinary tract infections and community-acquired pneumonia, 0.3% (0.25-0.34) for sepsis without shock, 1.1% (95% CI, 0.9-1.4) for septic shock and 2.4% (95% CI, 1.9-2.8) for nosocomial pneumonia. The mortality effect for empiric antibiotics against P. aeruginosa depends crucially on the prevalence of P. aeruginosa and baseline mortality by type of infection. For soft tissue infections, urinary tract infections and community-acquired pneumonia, the mortality benefit is low. Meaningful benefit of empiric antibiotics against P. aeruginosa is limited to patients with approximately 30% mortality and 5% prevalence of P. aeruginosa, which is largely limited to patients in intensive care settings.

In vivo adenine base editing ameliorates Rho-associated autosomal dominant retinitis pigmentosa.

Mutations in the Rhodopsin (RHO) gene are the main cause of autosomal dominant retinitis pigmentosa (adRP), 84% of which are pathogenic gain-of-function point mutations. Treatment strategies for adRP typically involve silencing or ablating the pathogenic allele, while normal RHO protein replacement has no meaningful therapeutic benefit. Here, we present an adenine base editor (ABE)-mediated therapeutic approach for adRP caused by RHO point mutations in vivo. The correctable pathogenic mutations are screened and verified, including T17M, Q344ter, and P347L. Two adRP animal models are created carrying the class 1 (Q344ter) and class 2 (T17M) mutations, and dual AAV-delivered ABE can effectively repair both mutations in vivo. The early intervention of ABE8e efficiently corrects the Q344ter mutation that causes a severe form of adRP, delays photoreceptor death, and restores retinal function and visual behavior. These results suggest that ABE is a promising alternative to treat RHO mutation-associated adRP. Our work provides an effective spacer-mediated point mutation correction therapy approach for dominantly inherited ocular disorders.

EE637 Assessment of Clinically Meaningful Benefits and Incremental Costs of Adding Bevacizumab to Trifluridine/Tipiracil for Metastatic Colorectal Cancer: A Comparison With Other Combination Regimens

EE637 Assessment of Clinically Meaningful Benefits and Incremental Costs of Adding Bevacizumab to Trifluridine/Tipiracil for Metastatic Colorectal Cancer: A Comparison With Other Combination Regimens