Comparison Of Treatment Research Articles

Randomization-based covariance adjustment of win ratios and win odds for randomized multi-visit studies with ordinal outcomes

In many randomized multi-visit studies, some response variables have an ordinal scale for outcomes. The win odds (accounts for ties) and the win ratio (ignores ties) are useful for treatment comparisons for ordinal outcomes. This paper discusses the application of randomization-based covariance and stratification adjustment of the win odds (and win ratio) to enable their more convenient use. Adjustment for strata is through the weighted average of within stratum two-sample U statistics for numerators and denominators for the stratified win odds (or win ratio). As randomization-based, invocation of covariance adjustment is through constraints to zeros for baseline covariate differences in the joint vector with logarithms of stratified win odds (or win ratios) for the respective visits. Such adjustment has no formal assumptions about the distributions of response variables or co-variates or the relationships of covariates to response variables; but the resulting adjusted stratified win odds (or win ratios) have narrower confidence intervals than their unadjusted counterparts when covariates have at least moderately strong associations with response variables. There is illustration of such results for the stratified win odds (and win ratio) for a randomized multi-visit clinical trial with an ordinal outcome for a chronic respiratory disorder. Journal of Statistical Research 2024, Vol. 58, No. 1, pp. 33-48

First-Line Nivolumab Plus Relatlimab Versus Nivolumab Plus Ipilimumab in Advanced Melanoma: An Indirect Treatment Comparison Using RELATIVITY-047 and CheckMate 067 Trial Data.

Nivolumab plus relatlimab and nivolumab plus ipilimumab have been approved for advanced melanoma on the basis of the phase II/III RELATIVITY-047 and phase III CheckMate 067 trials, respectively. As no head-to-head trial comparing these regimens exists, an indirect treatment comparison was conducted using patient-level data from each trial. Inverse probability of treatment weighting (IPTW) adjusted for baseline characteristic differences. Minimum follow-ups (RELATIVITY-047, 33 months; CheckMate 067, 36 months) were selected to best align assessments. Outcomes included progression-free survival (PFS), confirmed objective response rate (cORR), and melanoma-specific survival (MSS) per investigator; overall survival (OS); and treatment-related adverse events (TRAEs). A Cox regression model compared PFS, OS, and MSS. A logistic regression model compared cORRs. Subgroup analyses were exploratory. After IPTW, key baseline characteristics were balanced for nivolumab plus relatlimab (n = 339) and nivolumab plus ipilimumab (n = 297). Nivolumab plus relatlimab demonstrated similar PFS (hazard ratio [HR], 1.08 [95% CI, 0.88 to 1.33]), cORR (odds ratio, 0.91 [95% CI, 0.73 to 1.14]), OS (HR, 0.94 [95% CI, 0.75 to 1.19]), and MSS (HR, 0.86 [95% CI, 0.67 to 1.12]) to nivolumab plus ipilimumab. Subgroup comparisons showed larger numerical differences favoring nivolumab plus ipilimumab with acral melanoma, BRAF-mutant melanoma, and lactate dehydrogenase >2 × upper limit of normal, but were limited by small samples. Nivolumab plus relatlimab was associated with fewer grade 3-4 TRAEs (23% v 61%) and any-grade TRAEs leading to discontinuation (17% v 41%). Nivolumab plus relatlimab demonstrated similar efficacy to nivolumab plus ipilimumab in the overall population, including most-but not all-subgroups, and improved safety in patients with untreated advanced melanoma. Results should be interpreted with caution.

Anatomical classification of canine congenital extrahepatic portosystemic shunts based on CT angiography: A SVSTS and VIRIES multi-institutional study in 1082 dogs.

Canine congenital extrahepatic portosystemic shunt (EHPSS) morphologies have not been fully elucidated. The goal of this retrospective, multi-institutional study was to use CT angiography to create an anatomical-based nomenclature system for canine congenital EHPSS. These shunt morphologies were then evaluated to identify any significant association with patient age, sex, breed, weight, or subjective portal perfusion score. Data collected respectively from the SVSTS and VIRIES list-serves included patient DOB, sex, breed, weight, CT date, and reported diagnosis. A single author (C.W.) viewed all CT scans and classified shunts based on the shunt portal vessel(s) of origin, the shunt systemic vessel(s) of insertion, and any substantial portal vessels contributing to the shunt. Additionally, hepatic portal perfusion was subjectively scored between one (poor/none) and five (good/normal) based on the caliber of the intrahepatic portal veins. A total of 1182 CT scans were submitted from 13 different institutions. Due to exclusion criteria, 100 (8.5%) were removed, leaving 1082 CT scans to be included. Forty-five different EHPSS anatomies were identified with five classifications accounting for 85% of all shunts (left gastric-phrenic [27%], left gastric-azygos [19%], left gastric-caval [15%], aberrant left gastric-caval with right gastric vein [12%], and aberrant left gastric-caval with right gastric vein and short gastric vein [11%]). Shunt origin involved the left gastric vein in 95% of the described classifications. Significant differences were identified among the five most common shunt types with respect to age at the time of the CT scan (P<.001), sex (P=.009), breed (P<.001), weight (P<.001), and subjective portal perfusion score (P<.001). An anatomical classification system for canine EHPSS may enable improved understanding, treatment comparisons, and outcome prediction for these patients.

Analysis of Nonconcurrent Controls in Adaptive Platform Trials: Separating Randomized and Nonrandomized Information.

Adaptive platform trials allow treatments to be added or dropped during the study, meaning that the control arm may be active for longer than the experimental arms. This leads to nonconcurrent controls, which provide nonrandomized information that may increase efficiency but may introduce bias from temporal confounding and other factors. Various methods have been proposed to control confounding from nonconcurrent controls, based on adjusting for time period. We demonstrate that time adjustment is insufficient to prevent bias in some circumstances where nonconcurrent controls are present in adaptive platform trials, and we propose a more general analytical framework that accounts for nonconcurrent controls in such circumstances. We begin by defining nonconcurrent controls using the concept of a concurrently randomized cohort, which is a subgroup of participants all subject to the same randomized design. We then use cohort adjustment rather than time adjustment. Due to flexibilities in platform trials, more than one randomized design may be in force at any time, meaning that cohort-adjusted and time-adjusted analyses may be quite different. Using simulation studies, we demonstrate that time-adjusted analyses may be biased while cohort-adjusted analyses remove this bias. We also demonstrate that the cohort-adjusted analysis may be interpreted as a synthesis of randomized and indirect comparisons analogous to mixed treatment comparisons in network meta-analysis. This allows the use of network meta-analysis methodology to separate the randomized and nonrandomized components and to assess their consistency. Whenever nonconcurrent controls are used in platform trials, the separate randomized and indirect contributions to the treatment effect should bepresented.

Effect of butyrate sources in a high-concentrate diet on rumen structure and function in growing rams

Dietary butyrate is considered to have mostly positive impacts on the ruminal epithelium. However, its supplementation in a high-concentrate diet may not be justified as excessive ruminal butyrate may negatively affect the rumen. Furthermore, butyrate impact on the rumen may depend on its source. Thirty-two Świniarka growing rams (30.6 ± 2.5 kg; 11–14 months of age) were used to investigate the effect of a high-concentrate diet and sodium butyrate (SB) or tributyrin (TB) supplementation in a high-concentrate diet on the rumen structure and selected functions. The rams were allocated to four treatments and fed diets with: (1) low concentrate inclusion (22.5% of diet DM; L); (2) high concentrate inclusion (60% of diet DM; H); (3) H with SB (3.2% of diet DM; H+SB); and (4) H with TB (2.93% of diet DM; H+TB). The preplanned contrasts were used for treatment comparisons (L vs H treatments (H, H+SB, and H+TB), H vs H+SB, and H vs H+TB). The BW, BW gain and DM intake did not differ between treatments. In the atrium ruminis, epithelium thickness did not differ between the L and H treatments (P = 0.46), tended to be higher for H+SB than for H (P = 0.09) but did not differ between H+TB and H (P = 0.61). The expression of downregulated in adenoma was higher for L than for H treatments (P = 0.03) but was not affected by SB or TB supplementation (P ≥ 0.26). In the ventral rumen, the mucosa surface and epithelium thickness were lower for L than for H treatments (P < 0.01), were or tended to be higher for H+SB than for H (P ≤ 0.06) but did not differ between H+TB and H (P ≥ 0.26). The expression of monocarboxylate transporter 1 was lower for L than for H treatments (P = 0.02) but was not affected by SB or TB supplementation (P ≥ 0.28). The expression of putative anion transporter-1 and downregulated in adenoma did not differ between the L and H treatments (P ≥ 0.76); however, expression of the former tended to be higher and the latter tended to be lower for H+SB than for H (P ≤ 0.09), whereas no differences were observed between H+TB and H (P ≥ 0.14). In summary, SB supplementation, but not TB supplementation, in a high-concentrate diet stimulated ruminal epithelium growth and affected short-chain fatty acid transporters expression in the ruminal epithelium.

Characterization and optimization of continuous ohmic thermal sterilization based on the development of a predictive computational toolbox

Continuous thermal processing (CTP) is a common method for sterilizing food. However, it can result in an uneven temperature distribution, which can lead to a varying degree of processing intensity. Ohmic heating (OH) can be advantageous in this regard, as it enables volumetric heating for more homogenous treatments. However, evaluating the processing intensity distribution inside the equipment for OH is challenging due to the complex interaction between electrical, mechanical and thermal phenomena. Furthermore, the comparison of OH and conventional heating treatments often lack a profound basis of comparable treatment intensity considerations. To gain a deeper mechanistic understanding of the technology, a numerical computational fluid dynamics model for the OH sterilization of a clear carrot juice from the heating region to the cooling process was developed. The model was validated with thermal and electrical measurements and showed an error rate below 2.5% in its prediction capacities. Moreover, the model was implanted for the validation of the products sterilization and compared to a conventional validation approach, reviling a 33.3% underestimation of the thermal load by conventional manners, which can lead to faulty sterilization of the food product. Additionally, the model was expanded to also be able to predict the microbial inactivation ratio of the system with an average error of 1.10±0.74%. In addition, results indicate that the numerical calculation of the F0 values and their validation with the microbial inactivation ratio have a notable potential for localization and evaluation of hotspots in OH simulations. Therefore, it can be seen as a promising step for establishing a foundation for computer-assisted optimization of CTP and targeted processing.

Treatment comparison of hydroxyurea versus ruxolitinib in essential thrombocythaemia: A matched-cohort analysis.

Hydroxyurea is the preferred first-line cytoreductive treatment for high-risk essential thrombocythaemia (ET), but many patients are intolerant or refractory to hydroxyurea. Ruxolitinib has been shown to improve symptoms in patients with ET. This post hoc analysis compared the clinical outcomes of patients with ET who received hydroxyurea only with those who switched from hydroxyurea to ruxolitinib due to intolerance/resistance to hydroxyurea. Patients with ET refractory/intolerant to hydroxyurea treated with ruxolitinib in a completed phase 2 study (HU-RUX) were propensity score matched with patients who received hydroxyurea only in an observational study (HU). Changes in leukocyte and platelet counts were reported at 6-month intervals during the 48-month follow-up. Following propensity score matching, 37 patients were included for analysis in each cohort. Mean (standard deviation [SD]) leukocyte and platelet counts at index were higher for HU-RUX versus HU (leukocyte: 9.3 [5.1] vs. 6.8 [3.1]×109/L; platelet: 1027.4 [497.8] vs. 513.9 [154.7]×109/L), both of which decreased significantly from index to 6 months through to 48 months in HU-RUX (mean [SD] change from index at 6 months-leukocyte: -1.8 [4.6]×109/L; platelet: -391.7 [472.9]×109/L; at 48 months-leukocyte: -3.8 [5.3]×109/L; platelet: -539.0 [521.8]×109/L), but remained relatively stable in HU (mean [SD] change from index at 6 months-leukocyte: 0 [1.8]×109/L; platelet: -5.7 [175.3]×109/L; at 48 months-leukocyte: -0.1 [2.7]×109/L; platelet: -6.9 [105.1]×109/L). In conclusion, these results demonstrate that switching from hydroxyurea to ruxolitinib in patients with ET who are intolerant or refractory to hydroxyurea could improve abnormal haematologic values similar to those who receive first-line hydroxyurea.

Lenvatinib plus pembrolizumab for untreated advanced renal cell carcinoma: a systematic review and cost-effectiveness analysis.

Renal cell carcinoma is the most common type of kidney cancer, comprising approximately 85% of all renal malignancies. Patients with advanced renal cell carcinoma are the focus of this National Institute for Health and Care Excellence multiple technology appraisal. A patient's risk of disease progression depends on a number of prognostic risk factors; patients are categorised as having intermediate/poor risk or favourable risk of disease progression. The objectives of this multiple technology appraisal were to appraise the clinical effectiveness and cost-effectiveness of lenvatinib plus pembrolizumab versus relevant comparators listed in the final scope issued by the National Institute for Health and Care Excellence: sunitinib, pazopanib, tivozanib, cabozantinib and nivolumab plus ipilimumab. The assessment group carried out clinical and economic systematic reviews and assessed the clinical and cost-effectiveness evidence submitted by Eisai, Hatfield, Hertfordshire, UK (the manufacturer of lenvatinib) and Merck Sharp & Dohme, Whitehouse Station, NJ, USA (the manufacturer of pembrolizumab). The assessment group carried out fixed-effects network meta-analyses using a Bayesian framework to generate evidence for clinical effectiveness. As convergence issues occurred due to sparse data, random-effects network meta-analysis results were unusable. The assessment group did not develop a de novo economic model, but instead modified the partitioned survival model provided by Merck Sharp & Dohme. The assessment group clinical systematic review identified one relevant randomised controlled trial (CLEAR trial). The CLEAR trial is a good-quality, phase III, multicentre, open-label trial that provided evidence for the efficacy and safety of lenvatinib plus pembrolizumab compared with sunitinib. The assessment group progression-free survival network meta-analysis results for all three risk groups should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons owing to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. The assessment group overall survival network meta-analysis results for the intermediate-/poor-risk subgroup suggested that there was a numerical, but not statistically significant, improvement in the overall survival for patients treated with lenvatinib plus pembrolizumab compared with patients treated with cabozantinib or nivolumab plus ipilimumab. Because of within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption, the assessment group overall survival network meta-analysis results for the favourable-risk subgroup and the all-risk population should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons. Only one cost-effectiveness study was included in the assessment group review of cost-effectiveness evidence. The study was limited to the all-risk population, undertaken from the perspective of the US healthcare system and included comparators that are not recommended by the National Institute for Health and Care Excellence for patients with untreated advanced renal cell carcinoma. Therefore, the extent to which resource use and results are generalisable to the NHS is unclear. The assessment group cost-effectiveness results from the modified partitioned survival model focused on the intermediate-/poor-risk and favourable-risk subgroups. The assessment group cost-effectiveness results, generated using list prices for all drugs, showed that, for all comparisons in the favourable-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated fewer benefits than all other treatments available to NHS patients. For the intermediate-/poor-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated more benefits than treatment with cabozantinib and nivolumab plus ipilimumab. Good-quality clinical effectiveness evidence for the comparison of lenvatinib plus pembrolizumab with sunitinib is available from the CLEAR trial. For most of the assessment group Bayesian hazard ratio network meta-analysis comparisons, it is difficult to reach conclusions due to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. However, the data (clinical effectiveness and cost-effectiveness) used to populate the economic model are relevant to NHS clinical practice and can be used to inform National Institute for Health and Care Excellence decision-making. The assessment group cost-effectiveness results, generated using list prices for all drugs, show that lenvatinib plus pembrolizumab is less cost-effective than all other treatment options. This study is registered as PROSPERO CRD4202128587. This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR134985) and is published in full in Health Technology Assessment; Vol. 28, No. 49. See the NIHR Funding and Awards website for further award information.

Talquetamab Versus Real-World Physician's Choice Treatment: Comparative Effectiveness in Patients With Triple-Class Exposed Relapsed/Refractory Multiple Myeloma

BackgroundTalquetamab, a first-in-class GPRC5D×CD3 bispecific antibody, is approved for treatment of triple-class exposed (TCE) patients with relapsed/refractory multiple myeloma (RRMM) based on MonumenTAL-1 results. We evaluated the comparative effectiveness of talquetamab in MonumenTAL-1 versus real-world physician's choice (RW) treatment. Materials and MethodsAn external control arm for MonumenTAL-1 was created from eligible patients in the Flatiron Health database who satisfied key MonumenTAL-1 eligibility criteria (n = 629 with 1169 eligible lines of therapy). Patient-level data from MonumenTAL-1 were included for patients who received subcutaneous talquetamab 0.4 mg/kg QW (n = 143) and 0.8 mg/kg Q2W (n = 145). After adjusting for baseline covariate imbalances, comparative effectiveness was assessed for progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). ResultsBaseline covariates were comparable across cohorts after adjustment. Talquetamab 0.4 mg/kg QW and 0.8 mg/kg Q2W cohorts, respectively, showed significant improvement in PFS (HR, 0.55 [95% CI, 0.44-0.69; P<0.0001; median, 7.5 vs. 4.0 months] and 0.40 [95% CI, 0.31-0.53; P<0.0001; median, 14.2 vs. 4.0 months]), TTNT (HR, 0.59 [95% CI, 0.47-0.74; P<0.0001; median, 9.1 vs. 5.1 months] and 0.45 [95% CI, 0.35-0.59; P<0.0001; median, 13.3 vs. 5.1 months]), and OS (HR, 0.56 [95% CI, 0.40-0.78; P=0.0007; median, NR vs. 16.5 months] and 0.48 [95% CI, 0.33-0.70; P=0.0002; median NR vs. 15.9 months]) versus RW treatment. ConclusionBoth talquetamab schedules demonstrated superior effectiveness over RW treatment for all outcomes assessed. These data suggest talquetamab as an effective novel immunotherapy option in patients with TCE RRMM. MicroabstractTalquetamab has been evaluated in the single-arm MonumenTAL-1 trial in patients with relapsed/refractory multiple myeloma. Effectiveness of talquetamab was assessed against outcomes of real-world treatments using indirect treatment comparison methodology. Talquetamab led to better outcomes compared to standard treatments, suggesting that novel immunotherapies such as talquetamab may be a superior treatment option versus previous standard regimens.

Ability of Nicotinamide Riboside to Prevent Muscle Fatigue of Barrows Subjected to a Performance Test.

The objective of this study was to determine the daily dietary nicotinamide riboside (NR) dose required to maximize the delay of subjective muscle fatigue onset. Barrows (N = 100) were assigned to one of five treatments: a conventional swine finishing diet containing 0 (CON), 15 (15NR), 30 (30NR), 45 (45NR) mg·kg body weight-1·d-1 NR, or CON supplemented with 45 mg·kg body weight-1·d-1 NR by drench or cookie dough (DRE). All treatments were administered for the final 11 days of feeding. On supplementation d 10, barrows individually experienced a performance test at 1.09 m/s until they were subjectively exhausted. Wireless electromyography (EMG) sensors were affixed to the biceps femoris (BF), tensor fascia latae (TFL), and semitendinosus (ST) to measure real-time muscle activity. There were no treatment effects for barrow speed (p = 0.57), a tendency for a treatment effect (p = 0.07) for distance, and a treatment effect (p = 0.04) on time to exhaustion. Barrows of the 15NR and DRE treatments had greater (p = 0.05) distances to exhaustion than CON barrows but did not differ from other NR barrows (p > 0.11). Barrows in the 45NR treatment did not differ (p = 0.11) in distance from 30NR barrows but tended to have a greater (p = 0.07) distance compared to CON barrows. All other treatment comparisons did not differ (p > 0.27). Barrows in the DRE treatment moved for longer (p < 0.01) than CON barrows, but all other treatments did not differ from each other (p > 0.15). There was no treatment × period interaction for all muscles' root mean square (RMS) values (p > 0.16), but there were Period effects for all muscles (p < 0.01) and a Treatment effect (p = 0.04) in the TFL. For all muscles, period 4 had greater RMS values than all other periods (p < 0.01), who did not differ from each other (p > 0.29). In the TFL, CON barrows had greater RMS values during the performance test compared to all NR treatments (p < 0.02), who did not differ from each other (p > 0.18). Overall, NR demonstrates potential in being a useful tool in fatigue prevention, but efficient administration of the compound needs further investigation.

Racial-Ethnic Comparison of Treatment for Papillary Thyroid Cancer in the Military Health System.

We aimed to compare Asian or Pacific Islander, Black, Hispanic, and non-Hispanic White patients in treatment for papillary thyroid cancer (PTC) in the equal access Military Health System to better understand racial-ethnic cancer health disparities observed in the United States. We used the MilCanEpi database to identify a cohort of men and women aged 18 or older who were diagnosed with PTC between 1998 and 2014. Low- or high-risk status was assigned using tumor size and lymph node involvement. Treatment with surgery (e.g., thyroidectomy) overall and treatment by risk status [active surveillance (low-risk) or adjuvant radioactive iodine (RAI) (high-risk)] was compared between racial-ethnic groups using multivariable logistic regression and expressed as adjusted odds ratios (AOR) with 95% confidence intervals (CIs). The study included 598 Asian, 553 Black, 340 Hispanic, and 2958 non-Hispanic White patients with PTC. Asian (AOR = 1.21, 95% CI 0.98, 1.49), Black (AOR = 1.07, 95% CI 0.87, 1.32), and Hispanic (AOR = 0.92, 95% CI 0.71, 1.19) patients were as likely as White patients to receive surgery. By risk status, there were no significant racial-ethnic differences in receipt of active surveillance or thyroidectomy for low-risk PTC or in thyroidectomy or total thyroidectomy with adjuvant RAI for high-risk PTC. In the Military Health System, where patients have equal access to care, there were no overall racial-ethnic differences in surgical treatment for PTC. As American Thyroid Association guidelines evolve to include more conservative treatment, further research is warranted to understand potential disparities in active surveillance and surgical management in U.S. healthcare settings.

The impact of heterogeneity on the analysis of platform trials with normally distributed outcomes

BackgroundA platform trial approach allows adding arms to on-going trials to speed up intervention discovery programs. A control arm remains open for recruitment in a platform trial while intervention arms may be added after the onset of the study and could be terminated early for efficacy and/or futility when early stopping is allowed. The topic of utilising non-concurrent control data in the analysis of platform trials has been explored and discussed extensively. A less familiar issue is the presence of heterogeneity, which may exist for example due to modification of enrolment criteria and recruitment strategy.MethodWe conduct a simulation study to explore the impact of heterogeneity on the analysis of a two-stage platform trial design. We consider heterogeneity in treatment effects and heteroscedasticity in outcome data across stages for a normally distributed endpoint. We examine the performance of some hypothesis testing procedures and modelling strategies. The use of non-concurrent control data is also considered accordingly. Alongside standard regression analysis, we examine the performance of a novel method that was known as the pairwise trials analysis. It is similar to a network meta-analysis approach but adjusts for treatment comparisons instead of individual studies using fixed effects.ResultsSeveral testing strategies with concurrent control data seem to control the type I error rate at the required level when there is heteroscedasticity in outcome data across stages and/or a random cohort effect. The main parameter of treatment effects in some analysis models correspond to overall treatment effects weighted by stage wise sample sizes; while others correspond to the effect observed within a single stage. The characteristics of the estimates are not affected significantly by the presence of a random cohort effect and/ or heteroscedasticity.ConclusionIn view of heterogeneity in treatment effect across stages, the specification of null hypotheses in platform trials may need to be more subtle. We suggest employing testing procedure of adaptive design as opposed to testing the statistics from regression models; comparing the estimates from the pairwise trials analysis method and the regression model with interaction terms may indicate if heterogeneity is negligible.

Towards multicenter β-amyloid PET imaging in mouse models: A triple scanner head-to-head comparison

Aimβ-amyloid (Aβ) small animal PET facilitates quantification of fibrillar amyloidosis in Alzheimer's disease (AD) mouse models. Thus, the methodology is receiving growing interest as a monitoring tool in preclinical drug trials. In this regard, harmonization of data from different scanners at multiple sites would allow the establishment large collaborative cohorts and may facilitate efficacy comparison of different treatments. Therefore, we objected to determine the level of agreement of Aβ-PET quantification by a head-to-head comparison of three different state-of-the-art small animal PET scanners, which could help pave the way for future multicenter studies. MethodsWithin a timeframe of 5 ± 2 weeks, transgenic APPPS1 (n = 9) and wild-type (WT) (n = 8) mice (age range: 13–16 months) were examined three times by Aβ-PET ([18F]florbetaben) using a Siemens Inveon DPET, a MedisonanoScan PET/MR, and a MedisonanoScan PET/CT with harmonized reconstruction protocols. Cortex-to-white-matter 30–60 min p.i. standardized uptake value ratios (SUVRCTX/WM) were calculated to compare binding differences, effect sizes (Cohen's d) and z-score values of APPPS1 relative to WT mice. Correlation coefficients (Pearson's r) were calculated for the agreement of individual SUVR between different scanners. Voxel-wise analysis was used to determine the agreement of spatial pathology patterns. For validation of PET imaging against the histological gold standard, individual SUVR values were subject to a correlation analysis with area occupancy of methoxy‑X04 staining. ResultsAll three small animal PET scanners yielded comparable group differences between APPPS1 and WT mice (∆PET=20.4 % ± 2.9 %, ∆PET/MR=18.4 % ± 4.5 %, ∆PET/CT=18.1 % ± 3.3 %). Voxel-wise analysis confirmed a high degree of congruency of the spatial pattern (Dice coefficient (DC)PETvs.PET/MR=83.0 %, DCPETvs.PET/CT=69.3 %, DCPET/MRvs.PET/CT=81.9 %). Differences in the group level variance of the three scanners resulted in divergent z-scores (zPET=11.5 ± 1.6; zPET/MR=5.3 ± 1.3; zPET/CT=3.4 ± 0.6) and effect sizes (dPET=8.5, dPET/MR=4.5, dPET/CT=4.1). However, correlations at the individual mouse level were still strong between scanners (rPETvs.PET/MR=0.96, rPETvs.PET/CT=0.91, rPET/MRvs.PET/CT=0.87; all p ≤ 0.0001). Methoxy-X04 staining exhibited a significant correlation across all three PET machines combined (r = 0.76, p < 0.0001) but also at individual level (PET: r = 0.81, p = 0.026; PET/MR: r = 0.89, p = 0.0074; PET/CT: r = 0.93, p = 0.0028). ConclusionsOur comparison of standardized small animal Aβ-PET acquired by three different scanners substantiates the possibility of moving towards a multicentric approach in preclinical AD research. The alignment of image acquisition and analysis methods achieved good overall comparability between data sets. Nevertheless, differences in variance of sensitivity and specificity of different scanners may limit data interpretation at the individual mouse level and deserves methodological optimization.

Outcomes and safety of atezolizumab plus bevacizumab in the treatment of hepatocellular carcinoma: treatment prognosis and comparison with tyrosine kinase inhibitors in a French multicenter matched real-life study.

The combination of atezolizumab plus bevacizumab (Atz/Bev) has radically changed the treatment strategy for advanced hepatocellular carcinoma (HCC) but raises questions. Our objectives were to determine survival outcomes and safety in a real-life multicenter French cohort, to investigate the on-treatment prognostic value of the bioinflammatory RECA score, and to perform a matched comparison with patients who previously received tyrosine kinase inhibitors (TKIs). A retrospective analysis of 109 consecutive patients enrolled from September 2020 to January 2023 and a post matched comparison with a TKI cohort ( n = 79) by the propensity score matching method. The Atz/Bev population was mainly nonviral disease patients (69%) with Child-Pugh grade A (90%), performance status 0/1 (90%), and Barcelona Clinic Liver Cancer stage B (38%) or stage C (62%) classification. After a median follow-up of 6.5 months (3.6-11.7), overall survival (OS) was 13.0 (5.1-28.7) months. OS was independently associated with metastasis, increased alkaline phosphatase, and serum bilirubin levels. Treatment-related adverse events were reported in 78% of patients, mostly grade 1 or 2. The RECA score clearly revealed two different prognosis groups after three cycles. No difference in OS was observed after matching between sequential treatment with TKIs and Atz/Bev. This real-life study highlights the importance of liver function when using Atz/Bev combination and the necessity of identifying predictive markers of response to HCC therapies. Our findings suggest a change in practices, with a marked proportion of intermediate stages, and support the on-treatment prognostic value of an inflammatory score.

A Comparison of Oral and Intravenous Treatments in Managing Spontaneous Bacterial Peritonitis

Abstract Background: In cirrhotics, spontaneous bacterial peritonitis (SBP) is a potentially fatal illness that requires immediate antibiotic administration. This meta-analysis aimed to examine the effectiveness of IV and oral antibiotics in patients with SBP. Objectives: We compared the efficacy, safety, and cost-effectiveness of oral vs intravenous antibiotic therapy for the treatment of SBP using data from a retrospective cohort analysis. Study design: Retrospective cohort study Place and duration of study: A tertiary care Hospital in Peshawar from Jan 2022 to Jan 20243 Methods:At Tertiary Care Hospital Peshawar, a Retrospective Cohort Study was conducted including all patients diagnosed with SBP between January 2022 and January 2023. The patients were split into two groups based on the kind of antibiotics administered: Group B: patients in need of ampicillin, cephalosporines, or IV IV therapy; Group A: patients on oral antibiotics and ciprofloxacin/cotrimoxazole with norfloxacin (patient 44). Patients who were eighteen years of age or older were eligible for inclusion. Based on an ascitic PMN cell count of ≥250 cells/mm³ and positive bacterial cultures, they were diagnosed with hospital-acquired SBP. Secondary peritonitis and serious co-morbidities requiring non-study antibiotic therapy were excluded criteria. Results:Group B, which received metronidazole orally, had an 85% resolution rate and an in-hospital mortality rate.The highest mortality rate and length of hospital stay were determined to be 10% and 7 ±3 days, respectively. With a 90% resolution rate and a roughly 8% overall mortality rate, Group B only needed to stay in the hospital for 10 (±4) days. 15% recurrences in Group A Group B: 12 percent recurrences Conclusion:Oral antibiotics are statistically no different from IV in terms of mortality, length of stay, or other outcomes when used to treat SBP. The proven outcomes back up the introduction of oral therapy for individuals who qualify in order to improve adherence and save costs. Keywords: Oral antibiotics, Systematic &amp; individual, IV therapy

Long term study on the fate and environmental risks of favipiravir in wastewater treatment plants and comparison with COVID-19 cases

In recent years especially during COVID-19, the increased usage of antiviral drugs has led to increased interest in monitoring their presence in wastewater worldwide. In this study, it was examined the occurrence, fate and environmental risks of favipiravir which is used for COVID-19 treatment in two wastewater treatment plants (WWTPs) with different treatment processes in Istanbul, Turkey. Favipiravir was measured in WWTPs influent samples, effluent samples and sludge samples with maximum concentrations of 97 μg/L, 64.11 μg/L and 182.47 μg/g, respectively. Favipiravir had removal efficiency below 55 % for both WWTPs. Mass balance analysis showed that favipiravir removal in WWTPs mainly attributed to biodegradation/biotransformation. Statistical analysis revealed a significant correlation between favipiravir concentration and COVID-19 incidence in Istanbul. The microbial distribution analysis indicated that comparison of collected COVID-19 pandemic sludge and post-pandemic period sludge samples, a noteworthy reduction in the Chloroflexi and Actinobacteriota phyla at the phylum level was observed. Environmental risk assessment using risk quotients ranged from 168 to 704, indicating that the presence of this antiviral drug posed significant ecological risks to aquatic organisms. The study concluded that WWTPs were releasing antiviral drugs into the environment, thereby posing risks to both the aquatic ecosystem and public health. The results of this study demonstrate the persistence of favipiravir in WWTPs and offer crucial supporting data for further research into the advancement of wastewater treatment technology. Also, this study shows wastewater based monitoring is supplementary and early warning system for determining the occurrence of antiviral drugs.

Comparison of Negative-Pressure Wound Therapy and Gradual Wound Approximation Treatments for Infected Fasciotomy Wounds.

Negative-pressure wound therapy (NPWT) and gradual wound approximation (GWA) are effective and reliable methods of treating fasciotomy wounds. However, the effectiveness of these 2 methods in treating infected wounds remains unclear. The aim of our study was to compare these 2 delayed primary closure methods of treating infected fasciotomy wounds on the limbs. Patients who underwent fasciotomy surgery on the extremities after sustaining crushing injuries in the 2023 Kahramanmaraş-centered earthquakes and who were referred owing to infected open wounds during follow-up were included in the study. Patients who completed the wound closure process at our clinic were divided into 2 groups: the NPWT and GWA groups. Using retrospectively collected data, the groups were compared in terms of demographic characteristics, time until wound closure, number of surgeries, skin graft requirements, and complications. Laboratory parameters were also examined. Thirteen patients, (with 21 wounds) who underwent NPWT and 14 (with 22 wounds) who underwent GWA, were examined. The average age of the NPWT group was 32.85 ± 18.37 years, whereas that of the GWA group was 25.21 ± 16.31 years. The number of surgeries in the NPWT and GWA groups were 5.38 ± 2.11 and 4.23 ± 1.27, respectively, and the difference was statistically significant (P = .040). The average wound closure times of the NPWT and GWA groups (P = .0210) (11.00 ± 4.86 days and 8.27 ± 2.41 days, respectively) also differed significantly. Skin grafting was performed in 5 patients in the NPWT group and 2 in the GWA group. There were no significant differences between the 2 groups in terms of skin graft requirements or complication rates. NPWT and GWA are effective and reliable methods of closing infected fasciotomy wounds. Closure of these wounds can be achieved in a shorter time and with fewer surgeries using GWA than using NPWT.

Comparison of different acupuncture therapies for dry eye disease: A systematic review and network meta-analysis

IntroductionDry eye disease (DED) has become increasingly prevalent in ophthalmology, significantly impacting patients' quality of life. Despite the widespread use of acupuncture therapies in treating DED, the most effective acupuncture treatment strategy remains uncertain. This study aimed to provide guidance in clinical practice for selecting the most effective acupuncture treatment strategy using the network meta-analysis (NMA) method. MethodsSeven English and Chinese databases were searched from their inception to October 15, 2023, to collect randomized controlled trials (RCTs) related to acupuncture therapies for treating DED. The risk of bias was assessed using the revised Cochrane risk of bias tool (ROB 2.0). Network meta-analysis was conducted using R 4.1.2 and Stata 17.0. The Confidence in Network Meta-Analysis (CINeMA) tool was used to evaluate the certainty of evidence. ResultsA total of 41 studies with 2931 participants were included. The network meta-analysis results showed that conventional acupuncture combined with thumbtack needle had the best efficacy in improving tear break-up time (TBUT) (MD = 2.95, 95 % CI [1.49, 4.39]) and Schirmer's test (MD = 3.34, 95 % CI [0.90, 5.79]). In terms of improving the corneal fluorescein staining score, conventional acupuncture combined with electroacupuncture demonstrated the best efficacy (SMD = -0.80, 95 % CI [-1.40, -0.18]). The confidence ratings of different treatment comparisons were judged as very low to low. Eight studies reported adverse effects, none of which were serious. ConclusionThe NMA results support the use of acupuncture for treating DED. Among the therapies, conventional acupuncture combined with thumbtack needle and conventional acupuncture combined with electroacupuncture have higher priority. However, before widespread adoption, more multicenter, randomized, double-blind, and placebo-controlled clinical trials are needed to confirm these findings.

Procedural Outcomes With Femoral, Radial, Distal Radial, and Ulnar Access for Coronary Angiography: A Network Meta-Analysis.

Radial artery access for coronary angiography or percutaneous coronary intervention (PCI) reduces the risk of death, bleeding, and vascular complications and is preferred over femoral artery access, leading to a class 1 indication by clinical practice guidelines. However, alternate upper extremity access such as distal radial and ulnar access are not mentioned in the guidelines despite randomized trials. We aimed to evaluate procedural outcomes with femoral, radial, distal radial, and ulnar access sites in patients undergoing coronary angiography or PCI. PubMed, EMBASE, and clinicaltrials.gov databases were searched for randomized clinical trials that compared at least 2 of the 4 access sites in patients undergoing PCI or angiography. Primary outcomes were major bleeding and access site hematoma. Intention-to-treat mixed treatment comparison meta-analysis was performed. From 47 randomized clinical trials that randomized 38 924 patients undergoing coronary angiography or PCI, when compared with femoral access, there was a lower risk of major bleeding with radial access (odds ratio [OR], 0.46 [95% CI, 0.35-0.59]) and lower risk of access site hematoma with radial (OR, 0.34 [95% CI, 0.24-0.48]), distal radial (OR, 0.33 [95% CI, 0.20-0.56]), and ulnar (OR, 0.50 [95% CI, 0.31-0.83]) access. However, when compared with radial access, there was higher risk of hematoma with ulnar access (OR, 1.48 [95% CI, 1.03-2.14]). Data from randomized trials support guideline recommendation of class 1 for the preference of radial access over femoral access in patients undergoing coronary angiography or PCI. Moreover, distal radial and ulnar access can be considered as a default secondary access site before considering femoral access. URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: 42024512365.

Comparison of systemic treatments for previously treated patients with unresectable colorectal liver metastases: a systematic review and network meta-analysis.

There is limited evidence of comparative results among different treatments for patients with unresectable colorectal liver metastases (CRLM) who have failed at least one line of previous systemic therapy. We aimed to compare the efficacy of systemic treatments among these patients through this investigation. We collected randomized controlled trials (RCTs) reported in English up until July 2023, from databases including PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and prominent conference databases, for this Bayesian network meta-analysis. Phase II or III trials that evaluated at least two therapeutic regimens were included. Primary outcome was overall survival (OS), secondary outcome was progression-free survival (PFS). Hazards ratios (HRs) with 95% confidence intervals (CIs) were used as effect size. Subgroup analysis was performed based on metastatic sites. The current systematic review protocol was registered on PROSPERO (CRD42023420498). 30 RCTs were included, with a total of 13,511 patients. Compared to chemotherapy, multi-targeted therapy (HR 0.57, 95% CI 0.37-0.87) and targeted therapy plus chemotherapy (HR 0.78, 95% CI 0.67-0.91) show significant advantages. Targeted therapy (HR 0.92, 95% CI 0.54-1.57) and local treatment plus chemotherapy (HR 1.03, 95% CI 0.85-1.23) had comparable performance. For patients with liver metastases, TAS-102 plus bevacizumab, aflibercept plus fluorouracil-based combination chemotherapy (CTFU), and bevacizumab plus capecitabine-based combination chemotherapy (CTCA) showed the best outcomes in terms of OS. Bevacizumab plus intensified CTFU, bevacizumab plus CTCA, and HAI followed by single-agent chemotherapy (SingleCT) performed the best regarding PFS. For patients with liver-limited metastases, aflibercept plus CTFU is the optimal choice in OS. For PFS, the best options were HAI followed by SingleCT, aflibercept plus CTFU, and panitumumab plus CTFU. For patients with multiple-site metastases, the best treatments were TAS-102 plus bevacizumab, bevacizumab plus CTCA, bevacizumab plus CTFU, and aflibercept plus CTFU. Multi-targeted therapy and targeted therapy plus chemotherapy are the best treatment mechanisms. TAS-102 plus bevacizumab is superior in OS, the combination of anti-VEGF drugs like bevacizumab and aflibercept with standard chemotherapy is the preferred option for CRLM patients.