Concurrent Trials Research Articles

Visualizing and diagnosing spillover within randomized concurrent controlled trials through the application of diagnostic test assessment methods

BackgroundSpillover of effect, whether positive or negative, from intervention to control group patients invalidates the Stable Unit Treatment Variable Assumption (SUTVA). SUTVA is critical to valid causal inference from randomized concurrent controlled trials (RCCT). Spillover of infection prevention is an important population level effect mediating herd immunity. This herd effect, being additional to any individual level effect, is subsumed within the overall effect size (ES) estimate derived by contrast-based techniques from RCCT’s. This herd effect would manifest only as increased dispersion among the control group infection incidence rates above background.Methods and resultsThe objective here is to explore aspects of spillover and how this might be visualized and diagnosed. I use, for illustration, data from 190 RCCT’s abstracted in 13 Cochrane reviews of various antimicrobial versus non-antimicrobial based interventions to prevent pneumonia in ICU patients. Spillover has long been postulated in this context. Arm-based techniques enable three approaches to identify increased dispersion, not available from contrast-based techniques, which enable the diagnosis of spillover within antimicrobial versus non-antimicrobial based infection prevention RCCT’s. These three approaches are benchmarking the pneumonia incidence rates versus a clinically relevant range, comparing the dispersion in pneumonia incidence among the control versus the intervention groups and thirdly, visualizing the incidence dispersion within summary receiver operator characteristic (SROC) plots. By these criteria there is harmful spillover effects to concurrent control group patients.ConclusionsArm-based versus contrast-based techniques lead to contrary inferences from the aggregated RCCT’s of antimicrobial based interventions despite similar summary ES estimates. Moreover, the inferred relationship between underlying control group risk and ES is ‘flipped’.

Teletherapy to address language disparities in deaf and hard-of-hearing children: study protocol for an inclusive multicentre clinical trial

IntroductionChildren who are deaf or hard-of-hearing (DHH) are at risk for speech and language delay. Language outcomes are worse in DHH children from lower socioeconomic backgrounds, due in part to...

Dried porcine soluble augments dietary fishmeal replacement by poultry by-product meal for large yellow croaker Larimichthys crocea

Two concurrent feeding trials was conducted to assess the effects of replacing fishmeal with poultry by-product meal (PBM) and supplementing dried porcine soluble (DPS) in large yellow croaker Larimichthys crocea diets at the optimal dietary protein level. In trial I, the reference diet (F40) contained fishmeal at 400 g/kg, and 40%, 60% and 80% of the fishmeal was substituted with PBM (the diets were termed as F24, F16 and F8). In trial II, the control diet (F16D0) contained fishmeal at 160 g/kg, and DPS was added at 4, 8, 12 and 16 g/kg in F16D0 (the diets were termed as F16D4, F16D8, F16D12 and F16D16). Fish initially weighing 20.0 ± 0.2 g were fed the test diets for 10 weeks. Fishmeal replacement level significantly influenced final body weight (FBW), weight gain, feed conversion ratio, nitrogen and energy retention efficiencies, ratio of fish-in to fish-out (FIFO), feed cost, activity of superoxide dismutase and catalase in plasma and liver, activity of glutathione peroxidase in plasma, and malondialdehyde content in liver. However, neither fishmeal replacement level nor DPS supplementation level resulted in significant change in condition factor, hepatosomatic index and body composition. There were no significant differences in weight gain and FBW either between F40, F24 and F16 or between F40 and F16D0, F16D4, F16D8, F16D12 and F16D16. The FBW of F16 declined by 3.2% relative to F40, while the FBW of F16D12 increased by 10.1% relative to F16D0. This study reveals that dietary fishmeal level for large yellow croaker could be reduced to 160 g/kg by using PBM as a sole substitute, and DPS supplementation could augment dietary fishmeal replacement by PBM.

The implementation study of nurses’ work related low back pain prevention and care guideline: A quasi-experimental study

AimTo understand the implementation process and outcomes of nurses' work related low back pain (WLBP) prevention and care guideline. BackgroundWLBP is a common occupational injury for clinical nurses. We developed the first evidence-based guideline of nurses' WLBP prevention and care of its kind both at home and abroad, and it is necessary for us to explore its feasibility, appropriateness and effectiveness in practice. MethodsBased on the model of the integrated Promoting Action on Research Implementation in Health Services, we performed a four-phase implementation study in a tertiary hospital. The study was a non-randomized concurrent controlled trial design，and multilevel measures were examined including implementation outcomes and clinical outcomes. ResultsFor the implementation outcomes, the tailored recommendations of the guideline were found to be acceptable, appropriate, feasible, and well adopted both at the unit level and the hospital level. The clinical outcomes indicated that, compared with the control unit, nurses of the treatment unit performed better in awareness, knowledge, practice of WLBP prevention and care. ConclusionsThe implementation study supports the successful application of the guideline, which can serve as a valuable evidence-based document to improve back health of nursing personnel.

Development and evaluation of a narrative therapy program combined with a solution-focused approach for nursing home residents: A quasi-experimental study

The transition from the family home to a nursing home can be an emotionally stressful experience for older adults. This study aimed to examine the feasibility and effects of a narrative therapy combined with a solution focus (NTCSF) program on the psychological adjustment, depression, and self-efficacy of nursing home residents. A non-random concurrent controlled trial was conducted in Fujian, China that involved 81 participants (intervention = 41, comparison = 40) from four separate nursing homes. The control group received routine institutional care, while the intervention group underwent a three-week NTCSF program in addition to receiving routine care. In the variance analyses, significant differences were found in “psychological adjustment” (T = 4.007, P < 0.001) and “self-efficacy” (T = 3.204, P = 0.002), compared to the control group. There was no significant difference in “depression” (t = -1.550, P = 0.125) between the groups at the baseline, but the experimental group showed a significant decrease in depression (t = -2.204, P = 0.033) after the intervention. The NTCSF program was found to be effective in improving the psychological adjustment of nursing home residents.Trial registration This study was registered on the Chinese Clinical Trial Registry (Registration No: ChiCTR-2100042767).

Redesigning Medication Management in the Emergency Department: The Impact of Partnered Pharmacist Medication Charting on the Time to Administer Pre-Admission Time-Critical Medicines, Medication Order Completeness, and Venous Thromboembolism Risk Assessment.

In order to enhance interdisciplinary collaboration and promote better medication management, a partnered pharmacist medication charting (PPMC) model was piloted in the emergency department (ED) of an Australian referral hospital. The primary objective of this study was to evaluate the impact of PPMC on the timeliness of time-critical medicines (TCMs), completeness of medication orders, and assessment of venous thromboembolism (VTE) risk. This concurrent controlled retrospective pragmatic trial involved individuals aged 18 years and older presenting to the ED from 1 June 2020 to 17 May 2021. The study compared the PPMC approach (PPMC group) with traditional medical officer-led medication charting approaches in the ED, either an early best-possible medication history (BPMH) group or the usual care group. In the PPMC group, a BPMH was documented promptly soon after arrival in the ED, subsequent to which a collaborative discussion, co-planning, and co-charting of medications were undertaken by both a PPMC-credentialled pharmacist and a medical officer. In the early BPMH group, the BPMH was initially obtained in the ED before proceeding with the traditional approach of medication charting. Conversely, in the usual care group, the BPMH was obtained in the inpatient ward subsequent to the traditional approach of medication charting. Three outcome measures were assessed -the duration from ED presentation to the TCM's first dose administration (e.g., anti-Parkinson's drugs, hypoglycaemics and anti-coagulants), the completeness of medication orders, and the conduct of VTE risk assessments. The analysis included 321 TCMs, with 107 per group, and 1048 patients, with 230, 230, and 588 in the PPMC, early BPMH, and usual care groups, respectively. In the PPMC group, the median time from ED presentation to the TCM's first dose administration was 8.8 h (interquartile range: 6.3 to 16.3), compared to 17.5 h (interquartile range: 7.8 to 22.9) in the early BPMH group and 15.1 h (interquartile range: 8.2 to 21.1) in the usual care group (p < 0.001). Additionally, PPMC was associated with a higher proportion of patients having complete medication orders and receiving VTE risk assessments in the ED (both p < 0.001). The implementation of the PPMC model not only expedited the administration of TCMs but also improved the completeness of medication orders and the conduct of VTE risk assessments in the ED.

Abstract CT146: AZD0466 in patients with advanced non-Hodgkin lymphoma: Efficacy and safety in an open-label phase 1 trial

Abstract Background Overexpression of pro-survival proteins Bcl-2 and Bcl-xL have been associated with poor prognosis in patients with non-Hodgkin lymphoma (NHL). AZD0466 is a drug-dendrimer conjugate consisting of the dual Bcl-2/Bcl-xL inhibitor AZD4320 covalently conjugated to a pegylated poly-L-lysine dendrimer, which allows for gradual release by hydrolysis. Preclinically, AZD0466 monotherapy has demonstrated efficacy in xenograft models of diffuse large B-cell lymphoma (DLBCL). Here, we report results from a Phase 1 trial (NCT05205161) of AZD0466 in relapsed/refractory (R/R) advanced B-cell NHL (B-NHL). Methods Eligible patients were ≥18 years old and had received 2-5 prior lines of therapy. AZD0466 was administered intravenously, with a dose ramp-up on days 1 and 4 of a 28-day cycle, and weekly administration of the target dose from day 8. The primary objective of the dose escalation phase was to assess the safety and tolerability of AZD0466 in patients with R/R B-NHL and to identify the maximum tolerated dose and recommended phase 2 dose. Preliminary efficacy was evaluated using Lugano 2014 criteria. Secondary objective was evaluation of pharmacokinetic (PK) parameters for the study drug. Results As of November 02, 2023, 7 patients (DLBCL n=5, follicular lymphoma n=1, marginal zone lymphoma (MZL) n=1; median age, 57 [26−79] years) had received AZD0466 at 600 mg (n=3), 1200 mg (n=3), or 2400 mg (n=1). All patients experienced adverse events (AEs). AEs possibly related to AZD0466 were reported in 6 patients, most common: platelet count decrease (57.1%), neutropenia/neutrophil count decrease (42.9%), and hypophosphatemia (28.6%). Grade ≥3 AEs possibly related to AZD0466 were reported in 4 patients: 2 Grade 3 and 1 Grade 4 neutropenia/neutrophil count decrease, and 2 AEs that led to treatment discontinuation (Grade 3 platelet count decrease and dose-limiting Grade 3 troponin increase). Among 6 evaluable patients across all dose levels, 1 patient with MZL treated at 1200 mg had an objective response (partial response). Another 3 patients had a best overall response of stable disease and 2 patients had progressive disease. One patient discontinued the study prior to disease assessment. AZD4320 exposure was dose-proportional, with PK profiles similar to studies with other hematologic malignancies. As a surrogate of Bcl-xL on-target activity, transient thrombocytopenia with moderate platelet count recovery prior to the next dose was observed in most patients, in line with preclinical modeling. Pharmacodynamic modulation based on cleaved caspase-3 induction by AZD0466 was observed at 1200 and 2400 mg. Conclusion AZD0466 ≤1200 mg was clinically well tolerated but evidence of asymptomatic myocardial injury was observed at 2400 mg. The study was terminated due to similar findings in a concurrent trial (D8241C00001; NIMBLE). With an objective response observed at the 1200 mg dose level, further development of agents targeting Bcl-2/xL in NHL is warranted with efforts to reduce the cardiotoxicity profile. Citation Format: Geoffrey Chong, Franck Morschhauser, Alex Herrera, Ki-Seong Eom, Tae Min Kim, Michael Wang, Connor Hall, Fathima Zumla Cader, Kaitlyn Beyfuss, Patricia Cheung, Wei Quan, Shringi Sharma, Yotvat Marmor, Jamal Saeh, Jose Mariz. AZD0466 in patients with advanced non-Hodgkin lymphoma: Efficacy and safety in an open-label phase 1 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT146.

Deep brain stimulation of the subthalamic nucleus increases the risk of sialorrhea in patients with advanced Parkinson's disease

IntroductionSialorrhea is a common neurological manifestation of Parkinson's disease (PD). No specifically designed prospective study has tested the effects of deep brain stimulation of the subthalamic nucleus (STN-DBS) on sialorrhea in patients with advanced PD. We focused on the effect of STN-DBS on the incidence of sialorrhea in patients with PD. MethodsThis multicenter, prospective, non-randomized concurrent clinical trial analyzed the incidence of sialorrhea during long-term follow-up in 170 patients with advanced PD (84 patients with STN-DBS and 86 patients with medication therapy). ResultsAfter STN-DBS, 58.1% of patients presented with sialorrhea (Drooling Rating Scale (DRS) > 5) compared with 39.3% of patients with medication therapy (P < 0.001). STN-DBS stimulation demonstrated a significant increase in DRS and Drooling Severity and Frequency Scale (DSFS) compared with the patients with medication therapy (P < 0.001). At follow-up, the onabotulinumtoxin-A (BTX-A) injection ratio was significantly higher in the STN-DBS group (29.8% vs. 11.9%, P = 0.0057) compared with the patients with medication therapy. ConclusionsSTN-DBS increased the risk of sialorrhea in patients with advanced PD. Trial registrationclinicaltrials. gov (NCT06090929)

Technical note: utilization of various allotment strategies to evaluate variation and replications required to detect statistical significance in nursery pig research.

A total of 720 barrows (line 200 × 400, DNA genetics) were used in two 42-d nursery trials (initially 6.20 ± 0.12kg and 5.63 ± 0.16kg, respectively) to evaluate strategies for allotting pigs to pens in randomized controlled trials. At placement, the population was split into three cohorts with similar average weight and standard deviation and randomly assigned to one of the three allotment strategies. Strategy 1 (random) utilized a simple randomization strategy with each pig randomized to pens independent of all other pigs. Strategy 2 (body weight [BW] distribution) sorted each pig within the cohort into one of the five BW groups. One pig from each weight group was then randomly assigned to a pen such that distribution of BW within pen was uniform across pens. Strategy 3 (BW grouping) sorted pigs within the cohort into 3 BW categories: light, medium, and heavy. Within each BW category, pigs were randomized to pen to create pens of pigs from each BW category. Within each experiment, there were 72 pens with five pigs per pen and 24 pens per allotment strategy. For all strategies, once pigs were allotted to pens, pens were allotted to one of the two treatments for a concurrent trial. In experiment 1, environmental enrichment using ropes tied near the pan of the feeder was compared to a control with no enrichment. In experiment 2, treatment diets consisted of basal levels of Zn and Cu from the trace mineral premix for the duration of the study (110 and 17mg/kg, respectively; control), or diets (supplemented control) with carbadox (50g/ton; Mecadox, Phibro Animal Health, Teaneck, NJ) fed in phase 1 (days 0 to 22) and 2 (days 22 to 43), pharmacological levels of Zn and Cu (2,414mg/kg Zn from ZnO; 168mg/kg Cu from CuSO4) fed in phase 1, and only pharmacological levels of Cu (168mg/kg Cu from CuSO4) fed in phase 2. These treatment designs were used to determine the impact on coefficient of variation (CV) and to estimate the number of replications required to find significant treatment differences based on allotment strategy. There were no meaningful allotment strategy × treatment interactions for either study. For between-pen CV, pigs allotted using BW distribution and BW grouping strategies had the lowest CV at allotment and final weight in both trials. For overall average daily gain in experiments 1 and 2 in experiment 2, the BW distribution strategy required the fewest replications to detect differences in performance. However, there is no meaningful difference between allotment strategies in replications required to detect significant differences for gain:feed ratio.

Design Research to Embed mHealth into a Community-Led Blood Pressure Management System in Uganda: Protocol for a Mixed Methods Study.

Uncontrolled hypertension is a leading risk factor for cardiovascular diseases. In Uganda, such diseases account for approximately 10% of all deaths, with 1 in 5 adults having hypertension (>90% of the hypertensive cases are uncontrolled). Although basic health care in the country is available free of cost at government facilities, regularly accessing medication to control hypertension is difficult because supply chain challenges impede availability. Clients therefore frequently suspend treatment or buy medication individually at private facilities or pharmacies (incurring significant costs). In recent years, mobile health (mHealth) interventions have shown increasing potential in addressing health system challenges in sub-Saharan Africa, but the acceptability, feasibility, and uptake conditions of mobile money approaches to chronic disease management remain understudied. This study aims to design and pilot-test a mobile money-based intervention to increase the availability of antihypertensive medication and lower clients' out-of-pocket payments. We will build on existing local approaches and assess the acceptability, feasibility, and uptake of the designed intervention. Furthermore, rather than entering the study setting with a ready-made intervention, this research will place emphasis on gathering applied ethnographic insights early, which can then inform the parameters of the intervention prototype and concurrent trial. We will conduct a mixed methods study following a human-centered design approach. We will begin by conducting extensive qualitative research with a range of stakeholders (clients; health care providers; religious, cultural, and community leaders; academics; and policy makers at district and national levels) on their perceptions of hypertension management, money-saving systems, and mobile money in the context of health care. Our results will inform the design, iterative adaptation, and implementation of an mHealth-facilitated pooled financing intervention prototype. At study conclusion, the finalized prototype will be evaluated quantitatively via a randomized controlled trial. As of August 2023, qualitative data collection, which started in November 2022, is ongoing, with data analysis of the first qualitative interviews underway to inform platform and implementation design. Recruitment for the quantitative part of this study began in August 2023. Our results aim to inform the ongoing discourse on novel and sustainable pathways to facilitate access to medication for the management of hypertension in resource-constrained settings. German registry of clinical trials DRKS00030922; https://drks.de/search/en/trial/DRKS00030922. DERR1-10.2196/46614.

Alterations in the gut microbiota of toddlers with cow milk protein allergy treated with a partially hydrolyzed formula containing synbiotics: A nonrandomized controlled interventional study.

Formulas containing intact cow milk protein are appropriate alternatives when human milk (HM) is not feasible. However, for babies with a physician-diagnosed cow milk protein allergy (CMPA), hydrolyzed formulas are needed. We conducted a 3-month, open-label, nonrandomized concurrent controlled trial (ChiCTR2100046909) between June 2021 and October 2022 in Qingdao City, China. In this study, CMPA toddlers were fed with a partially hydrolyzed formula containing synbiotics (pHF, n = 43) and compared with healthy toddlers fed a regular intact protein formula (IF, n = 45) or HM (n = 21). The primary endpoint was weight gain; the secondary endpoints were changes in body length and head circumference of both CMPA and healthy toddlers after 3-month feeding; and the exploratory outcomes were changes in gut microbiota composition. After 3 months, there were no significant group differences for length-for-age, weight-for-age, or head circumference-for-age Z scores. In the gut microbiota, pHF feeding increased its richness and diversity, similar to those of IF-fed and HM-fed healthy toddlers. Compared with healthy toddlers, the toddlers with CMPA showed an increased abundance of phylum Bacteroidota, Firmicutes, class Clostridia, and Bacteroidia, and a decreased abundance of class Negativicutes, while pHF feeding partly eliminated these original differences. Moreover, pHF feeding increased the abundance of short-chain fatty acid producers. Our data suggested that this pHF partly simulated the beneficial effects of HM and shifted the gut microbiota of toddlers with CMPA toward that of healthy individuals. In conclusion, this synbiotic-containing pHF might be an appropriate alternative for toddlers with CMPA.

Abstract 13912: Insights From a Multi-Center Consortium for HCV-Viremic Donor Heart Transplant: Outcomes Are Excellent Across Regimens Often Without Major Changes to Statin or PPI

Introduction: With the availability of pangenotypic direct-acting antivirals (DAA) for facile, curative treatment of hepatitis C virus (HCV) infections, HCV-viremic donors are utilized regularly to partially address the shortage of suitable organs for heart transplant (HT). This multi-center, retrospective registry characterized HT outcomes from HCV-positive donors. Methods: Of 138 isolated HT recipients from 8 sites across the US, the most common DAAs were the pangenotypic antiviral combinations sofosbuvir-velpatasvir (SOF/VEL, n=39) and glecaprevir-pibrentasvir (GLE/PIB, n=76); these 115 cases were analyzed in terms of primary graft dysfunction (PGD), episodes of rejection ≥ pAMR1 and/or Grade 2R, post-transplant infection, sustained virologic response at 12 weeks post-treatment (SVR12), and survival up to 1 year. Results: Comparing these two most common pangenotypic regimens, HT recipients differed in their listing status (p&lt;0.001), hospital stay length (p=0.04), time until HCV+ (p=0.01), DAA payor (p=0.01), induction therapy (p=0.03) and statin therapy (p=0.01). A concurrent open-label trial accounted for up to 13/39 SOF/VEL patients, partially accounting for differences in DAA payor. Despite potential interactions, statin and proton pump inhibitor (PPI) therapy typically continued uninterrupted with minimal dose adjustment. Both treatment groups showed 100% cure (SVR12) of donor-derived HCV. Although not powered for comparative effectiveness of DAA agents, there were no significant differences in study outcomes. SOF/VEL and GLE/PIB-treated patients demonstrated 97% and 96% survival at 1 year, respectively. Conclusions: As utilized to achieve cure of HT donor-derived HCV, two pangenotypic DAA regimens are safe and feasible, with coverage accessed across a variety of DAA payors. SVR12 can be achieved often without major modifications to PPIs or statins with either pangenotypic DAA regimen (with pravastatin most commonly utilized).

Indirect (herd) effects of topical antibiotic prophylaxis and oral care versus non-antimicrobial methods increase mortality among ICU patients: realigning Cochrane review data to emulate a three-tier cluster randomised trial

ObjectiveThis study aimed to estimate the direct effects to recipients and indirect (herd) effects to non-recipients of each of topical antibiotic prophylaxis (TAP) and oral care methods on patient mortality...

294 Evaluation of Variation in Nursery Pig Growth Performance Utilizing Different Allotment Strategies

Abstract A total of 720 pigs (200×400, DNA) were used in two 42-day nursery trials (initial BW = 6.20 ± 0.12 kg and 5.63 ± 0.16 kg, respectively) to evaluate multiple strategies for allotting pigs to pens in research. At placement, the population was split into 3 cohorts with similar average BW and standard deviation. Each cohort was randomly assigned 1 of 3 allotment strategies. Strategy 1 (random) utilized a simple randomization strategy with each pig randomized to pen independent of all other pigs. Strategy 2 [bodyweight (BW) distribution] sorted each pig within the cohort into 1 of 5 BW groups. One pig from each weight group was then randomly assigned to pen, such that distribution of BW within pen was uniform across pens. Strategy 3 (BW grouping) sorted pigs within the cohort into 3 BW categories: light, medium, and heavy. Within each BW category, pigs were randomized to pen to create pens of pigs from each BW category. Within each experiment, there were 72 pens with 5 pigs per pen and 24 pens per allotment strategy. For all strategies, once pigs were allotted to pens, pens were allotted to 1 of 2 treatments for a concurrent trial. In Exp. 1, environmental enrichment using ropes tied near the pan of the feeder was compared with a control with no enrichment. In Exp. 2, treatment diets consisted of basal levels of Zn and Cu from the trace mineral premix for the duration of the study (110 and 17 mg/kg, respectively; NC), or diets (PC) with carbadox (50 g/ton; Mecadox, Phibro Animal Health, Teaneck, NJ) fed in phase 1 and 2, pharmacological levels of Zn and Cu (2,414 mg/kg Zn from ZnO; 168 mg/kg Cu from CuSO4) in phase 1 and only Cu (168 mg/kg Cu from CuSO4) in phase 2. There were no meaningful allotment × treatment interactions (P &amp;gt; 0.10) for either study (Table). In Exp. 1, there were no effects of environmental enrichment on growth performance (P &amp;gt; 0.10). In Exp. 2, pigs fed the PC diet had greater (P &amp;lt; 0.001) ADG, ADFI, G:F, and final BW compared with pigs fed the NC diet. The coefficient of variation (CV) within pen between all pens on that allotment strategy and for the entire population of that allotment strategy were calculated for both trials. For between-pen CV, pigs allotted using BW distribution and BW grouping strategies had the least CV at allotment and final weigh day in both trials. Results were used to estimate the replication required with each allotment strategy to obtain significant differences with different percentage responses. Fewer replications are required to discern significant differences in ADG when allotting pigs utilizing BW grouping. However, there is no meaningful difference between allotment strategies in replications required to detect significant differences for G:F.

Efficacy evaluation of 0.05% cyclosporine A and 0.1% tacrolimus eye drops in the treatment of severe dry eye associated with chronic graft-versus-host disease

Objective: To evaluate the effectiveness and safety of 0.05% cyclosporine A and 0.1% tacrolimus eye drops in treating severe dry eye associated with chronic graft-versus-host disease (cGVHD). Methods: This non-randomized concurrent control trial enrolled 83 eyes from 83 patients with cGVHD-associated severe dry eye. The treatment had two phases. During the initial shock treatment period (0-3 months), 44 patients received 0.05% cyclosporine A eye drops (4 times/day; group A) and 39 patients received 0.1% tacrolimus eye drops (twice/day; group B) alongside basic treatment. In the maintenance treatment period (3-6 months), both groups used 0.05% cyclosporine A eye drops (twice/day) and sodium hyaluronate. Examinations were conducted at 1, 3, and 6 months after treatment initiation, assessing the Ocular Surface Disease Index (OSDI), corneal fluorescein staining (CFS) score, and fluorescein tear break-up time (BUT) for efficacy. visual acuity and intraocular pressure (IOP) were evaluated for safety, and patients' post-medication irritation symptoms were recorded. Results: The study included 52 males and 31 females, aged (28.57±15.67) years. After 1 month of treatment, the CFS score in group A significantly decreased from 10.0 (6.0, 14.0) to 5.0 (3.0, 8.5) (P<0.001). in group B, the CFS score also significantly decreased from 10.0 (6.0, 15.0) to 6.0 (2.0, 10.0), and the BUT increased from 2.0 (1.0, 2.0) s to 2.0 (1.8, 3.3) s (P<0.001). No significant OSDI decrease was observed in either group. No significant differences were found in OSDI, CFS score, and BUT between the two groups. After 3 months, group A showed significant improvement in OSDI, CFS score, and BUT (P<0.05), while group B only demonstrated significant CFS score decrease (P<0.05). OSDI was significantly lower in group A than group B (P<0.05). No significant differences were noted in CFS score and BUT between groups. After 6 months, OSDI, CFS score, and BUT were 18.9 (9.3, 34.2), 7.0 (3.0, 8.5), and 2.0 (1.0, 3.0) s in group A, and 10.9 (3.6, 35.4), 5.5 (2.8, 10.0), and 2.0 (1.0, 10.0) s in group B. In both groups, CFS scores significantly decreased and BUT increased (P<0.05). Visual acuity improved significantly in group A at 1, 3, and 6 months (P<0.05), while no significant changes were seen in group B. Irritation symptoms were transient and self-resolving in both groups. Conclusions: Both 0.05% cyclosporine A and 0.1% tacrolimus eye drops, when combined with local glucocorticoids, exhibited significant anti-inflammatory effects, effectively and safely treating severe dry eye in cGVHD patients. Although the onset of 0.05% cyclosporine A was slower than 0.1% tacrolimus, it offered more stable long-term effects and better symptom improvement.

Length of intensive care unit stay and the apparent efficacy of antimicrobial-based versus non-antimicrobial-based ventilator pneumonia prevention interventions within the Cochrane review database

The risk of acquiring ventilator associated pneumonia (VAP) increases with intensive care unit (ICU) length of stay (LOS). The objectives here are to estimate, using data derived from RCCT's of non-antimicrobial versus antimicrobial interventions, the relation of LOS with firstly, apparent VAP prevention effect, and secondly, with VAP incidence in control and intervention groups. Control and intervention group data derived from 13 Cochrane reviews of 78 randomized concurrent control trials (RCCT's) of antimicrobial based interventions versus 111 RCCT's of various non-antimicrobial based VAP prevention interventions. In meta-regression models of VAP prevention effect versus group mean LOS, the effect size of non-antimicrobial based interventions regress towards the null (+0.028; +0.002 to +0.054) whereas antimicrobial based interventions regress away from the null (-0.043; -0.08 to -0.004). The day 9 to 10 VAP incidence increase is 1.28 (0.97 - 1.6) percentage points among the control groups of antimicrobial interventions with group mean LOS. By contrast, this increase among antimicrobial (0.45; 0.19 - 0.71) and non-antimicrobial (0.58; 0.29 - 0.87) intervention groups and in control groups of non-antimicrobial (0.76; 0.46 - 1.05) interventions are all similar to each other. Antimicrobial based, versus non-antimicrobial based, interventions show overall greater apparent VAP prevention which is most apparent with longer group mean LOS. The basis for this surprising relationship with LOS resides, paradoxically, within the control rather than the intervention groups. This discrepancy implicates indirect (spill-over) effects, inapparent within individual antimicrobial based RCCT's, which could spuriously conflate the appearance of VAP prevention.

Precision and Accuracy of Field Versus Laboratory Bioassay Insecticide Efficacy for the Control of Immature Bemisia tabaci.

Ecotoxicological studies often result in reports on the limitation and sometime failures of biological assay data to predict field response to similar treatments. Nevertheless, it is widely accepted that controlled bioassays can better quantify the specific mortality response of a target pest species to a specific toxin. To quantify the relationship between whitefly bioassay and field response data, we evaluated a controlled laboratory bioassay and a concurrent cucurbit field trial method to assess insecticide efficacy for controlling the sweetpotato whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae). This was based on oviposition and nymphal development. We specifically tested the assumptions that a maximum dose bioassay would more precisely measure insecticide efficacy as compared with a comparable field spray test evaluation, and the response would be equal between the bioassay and the field as a measure of control accuracy for both adult oviposition and development of nymphal stages. To make a direct comparison, we tested the same whitefly population subsamples from 352 plots in eight cucurbit field experiments in Georgia, USA, in 2021 and 2022. The bioassays provide significantly precision for estimating proportional whitefly response. As expected, treatment-specific nonequivalence in immature whitefly counts between the bioassay and field, i.e., a lack of accuracy, only occurred with insecticides that were not highly toxic to all growth stages of whiteflies.

The prospect of Xihuang pill in the treatment of cancers

BackgroundXihuang pill, a Traditional Chinese Medicine (TCM) prescription and a representative of Huoxuehuayu therapy (one of the TCM therapies to promote blood circulation and remove blood stasis), has been widely used in breast cancer treatments. Although some evidence suggests the efficacy and safety of the Xihuang pill in treating certain cancer, the overall efficacy of the Xihuang pill in other cancer treatment is uncertain. ObjectiveThis study aimed to summarize the current clinical literature and provided evidence support for addressing the research question of whether the Xihuang pill is safe and effective in the treatment of various cancers as Huoxuehuayu therapy, and possibly identify the clinical dosage range and therapeutic effect of Xihuang pills. MethodSeven Chinese and English databases such as PubMed, CNKI, and Google Scholar were searched to collect the publications on Xihuang pill and cancer. Then the researchers extracted data from the articles that met the inclusion criteria and used SAS statistical program version 9.4 (by SAS Institute, Cary, North Carolina, USA) for statistical statistics. ResultsOur search identified 78 studies, including 69 RCTs (randomized control trials), 6 NRCCs (non-randomized concurrent control trials), and 3 BAS (before-after study), evaluating 3151 patients in total. The daily doses of Xihuang pills/capsule were between 2 g and 60 g, and duration between 2 weeks and 5 years, mostly used in the middle or late stage of cancer. The therapeutic effect of the Xihuang pill was mainly reflected in improving Complete Response (CR, a term from The Response Evaluation Criteria In Solid Tumors) or Partial Response (PR, a term from The Response Evaluation Criteria In Solid Tumors), reducing adverse reactions, promoting quality of life (QoL), regulating immunity, alleviating pain, prolonging survival, reducing metastasis and recurrence, reducing inflammation, regulating estrogen levels, decreasing hypercoagulative status, and reducing tumor markers. ConclusionXihuang pill representing Huoxuehuayu therapy has a good prospect in the treatment of cancer.

Leveraging published randomized controlled trials to inform clinical trial design: a simulation-based study of laminectomy versus laminectomy and fusion.

The US-based Spinal Laminectomy versus Instrumented Pedicle Screw (SLIP) trial reported improvement in disability following laminectomy with fusion versus laminectomy alone for patients with lumbar spondylolisthesis. Despite using similar methods, a concurrent Swedish trial investigating the same question did not reach the same conclusion. The authors performed a simulation-based analysis to elucidate potential causes of these divergent results. The mean and standard deviation of the preoperative and 2-year postoperative Oswestry Disability Index (ODI) scores for each study group (laminectomy with fusion and laminectomy alone) were collected from the spondylolisthesis stratum of the Swedish trial and used to create a MATLAB simulator using linear transformations to predict postoperative ODI distributions. Applying this simulator to both varied and published preoperative ODI distributions from the SLIP trial, the authors simulated the results of the US-based trial using treatment effects from the Swedish study and compared simulated US results to those published in the SLIP trial. Simulated US results showed that as preoperative disability increased, the difference in postoperative ODI scores grew between treatment groups and increasingly favored laminectomy alone (p < 0.0001). In 100 simulations of a similarly sized US trial, the average mean change in ODI scores postoperatively was significantly higher than was published for laminectomy alone in the SLIP trial (-21.3 vs -17.9), whereas it was significantly lower than published for fusion (-16.9 vs -26.3). The expected benefit of surgical treatments for spondylolisthesis varied according to preoperative disability. Adapting Swedish-estimated treatment effects to the US context mildly overapproximated the improvement in postoperative disability scores for laminectomy, but more severely underapproximated the improvement reported for laminectomy and fusion in the SLIP trial. The observed heterogeneity between these studies is influenced more by patient response to fusion than response to laminectomy. This analysis paves the way for future studies on the impact of preoperative treatment group heterogeneity, differences in surgical methods, and empirical design on reported clinical benefits. Although bayesian reanalysis of published randomized controlled trial data is susceptible to biases that typically limit post hoc analyses, the authors' method offers a simple and cost-effective approach to improve the understanding of published clinical trial results and their implications for future studies.

Study on the Effect of Bushen Zhuanggu Tablet Combined with Conventional Regimen on Bone Mineral Density Improvement, Functional Recovery and Fracture Risk Prevention in Patients with Postmenopausal Osteoporosis.

This case-control study was to explore the effect of Bushen Zhuanggu tablet combined with routine regimen on bone mineral density (BMD) improvement, functional recovery, and fracture prevention in postmenopausal osteoporosis (PMOP) patients. 180 postmenopausal osteoporosis patients were randomly selected from communities A, B, and C cohorts as research subjects from January to May 2021. The study subjects were divided into three groups. The groups were in a 1 : 1 ratio according to the principles of nonrandomised, concurrent controlled trials, and methods. There were 60 participants in each group (group A, group B, and group C). Group A was treated with Bushen Zhuanggu tablet for antiosteoporosis + basic treatment (calcium supplement and vitamin D). Group C was given Bushen Zhuanggu tablet for antiosteoporosis intervention. Group B was given basic treatment (calcium supplement and vitamin D supplementation) as a control group. The follow-up time was 6 months after treatment. Finally, we compare the differences in calcium and phosphorus metabolism indexes, BMD, bone metabolism indexes, upper and lower limb muscle strength, and quality of life scores. Group A, B, and C's effective rate was 98.33%, 80.00%, and 93.33%, respectively. The group A's effective rate was significantly higher than that in group B and C, and the difference was statistically significant (P < 0.05). After 6 months intervention, the levels of serum Ca2+, serum phosphorus (P), serum creatinine (Cr), and parathyroid hormone (PTH) in 3 groups decreased. Ca, P, Scr, and PTH levels in group A were the lowest among study groups, and the difference was statistically significant (P < 0.05). The increase in the BMD of lumbar spine, the left femoral neck, and Ward's triangle area of the three groups were observed with the highest data in group A. After 6 months of treatment, the levels of serum N-terminal propeptide of type I procollagen, PINP, and serum osteocalcin (OC) increased, while the levels of β-cross-linked C-terminal telopeptide of type I collagen (β-CTX) and alkaline phosphatase (ALP) decreased in the three groups. The improvement of all bone metabolic indexes in group A was significantly better than that in B and C groups, and the difference was statistically significant (P < 0.05). The enhanced upper limb muscle strength and the shorter standing-walking timing test (TUGT) time were observed after 6 months of treatment. The improvement effect of upper and lower limb muscle strength in group A was significantly better than that in B and C groups, and the difference was statistically significant (P < 0.05). There were significant differences in physiological function, life function, general health status, physical pain, mental state, emotional function, vitality, and social function among the three groups after 6 months treatment, and the difference was statistically significant (P < 0.05). The score of quality of life in group A was higher than that in B and C groups, and the difference was statistically significant (P < 0.05). Bushen Zhuanggu tablet combined with conventional therapy is effective in the postmenopausal osteoporosis treatment, which effectively increase the BMD, regulate calcium and phosphorus metabolism, promote the recovery of limb function, prevent the recurrence of fracture, and improve the patients' quality of life. This treatment scheme is worth popularizing.