Routine Approach Research Articles

Vitamin A supplementation coverage and associated factors for children aged 6 to 59 months in integrated and campaign-based delivery systems in four sub-Saharan African countries

BackgroundVitamin A deficiency (VAD) is a leading contributor to the poor health and nutrition of young children in sub-Saharan Africa. Funding constraints are compelling many countries to shift from longstanding campaigns to integrating vitamin A supplementation (VAS) into routine health services. We assessed child VAS coverage and associated factors for integrated delivery systems in Mozambique, Senegal, and Sierra Leone and for a campaign-based delivery strategy in Tanzania.MethodsData were obtained using representative household surveys administered to primary caregivers of N = 16,343 children aged 6–59 months (Mozambique: N = 1,659; Senegal: N = 7,254; Sierra Leone: N = 4,149; Tanzania: N = 3,281). Single-dose VAS coverage was assessed and bivariate and multivariable associations were examined for child VAS receipt with respect to rural or urban residence; child age and sex; maternal age, education, and VAS program knowledge; and household wealth.ResultsVAS coverage for children aged 6–59 months was 42.8% (95% CI: 40.2, 45.6) in Mozambique, 46.1% (95% CI: 44.9, 47.4) in Senegal, 86.9% (95% CI: 85.8, 87.9) in Sierra Leone, and 42.4% (95% CI: 40.2, 44.6) in Tanzania and was significantly higher for children 6–11 vs. 24–59 months in Mozambique, Senegal, and Tanzania. In Sierra Leone, children aged 12–23 months (aOR = 1.86; 95% CI: 1.20, 2.86) and 24–59 months (aOR = 1.55; 95% CI: 1.07, 2.25) were more likely to receive VAS, compared to those 6–11 months. Maternal awareness of VAS programs was associated with higher uptake in Mozambique (aOR = 4.00; 95% CI: 2.81, 5.68), Senegal (aOR = 2.72; 95% CI: 2.35, 3.15), and Tanzania (aOR = 14.50; 95% CI: 10.98, 19.17). Increased household wealth was associated with a higher likelihood of child VAS in Senegal and Tanzania.ConclusionsOur findings indicate routine delivery approaches for VAS are not achieving the level of coverage needed for public health impact in these settings. Intensive outreach efforts contributed to the higher coverage in Sierra Leone and highlight the importance of reducing the burdens associated with seeking supplementation at health facilities. As countries move towards incorporating VAS into routine health services, the essentiality of informed communities and potential losses for older children and socio-economically disadvantaged populations are key considerations in the sub-Saharan African context.

Exploring research progress in studying serum exosomal miRNA-21 as a molecular diagnostic marker for breast cancer.

Breast cancer is one of the most prevalent malignancies affecting women globally and poses a significant public health challenge. Early clinical detection plays a pivotal role in providing optimal treatment opportunities and favorable prognoses, crucial for reducing breast cancer mortality and enhancing patients' quality of life. Therefore, the timely identification and diagnosis of breast cancer are imperative. Conventional tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA15-3), serve as reliable methods for actively monitoring disease progression and have become a routine auxiliary diagnostic approach in clinical settings. However, these biomarkers exhibit limitations in sensitivity and specificity, particularly in the early screening and diagnosis of tumors, often yielding results inconsistent with clinical manifestations. In recent years, research has increasingly focused on exosomes released by tumor cells as potential new biomarkers for early stage breast cancer screening. Exosomes carry various components, including tumor-derived proteins, nucleic acids, and lipids. This paper delves into the specific utilization of serum exosomal microRNA-21 (miR-21) as a biomarker for early detection and diagnosis of breast cancer, evaluating its efficacy within this framework.

Extracellular Vesicles as Surrogates for the Regulation of the Drug Transporters ABCC2 (MRP2) and ABCG2 (BCRP).

Drug efflux transporters of the ATP-binding-cassette superfamily play a major role in the availability and concentration of drugs at their site of action. ABCC2 (MRP2) and ABCG2 (BCRP) are among the most important drug transporters that determine the pharmacokinetics of many drugs and whose overexpression is associated with cancer chemoresistance. ABCC2 and ABCG2 expression is frequently altered during treatment, thus influencing efficacy and toxicity. Currently, there are no routine approaches available to closely monitor transporter expression. Here, we developed and validated a UPLC-MS/MS method to quantify ABCC2 and ABCG2 in extracellular vesicles (EVs) from cell culture and plasma. In this way, an association between ABCC2 protein levels and transporter activity in HepG2 cells treated with rifampicin and hypericin and their derived EVs was observed. Although ABCG2 was detected in MCF7 cell-derived EVs, the transporter levels in the vesicles did not reflect the expression in the cells. An analysis of plasma EVs from healthy volunteers confirmed, for the first time at the protein level, the presence of both transporters in more than half of the samples. Our findings support the potential of analyzing ABC transporters, and especially ABCC2, in EVs to estimate the transporter expression in HepG2 cells.

The high FKBP1A expression in WBCs as a potential screening biomarker for pancreatic cancer

Given the limitation of current routine approaches for pancreatic cancer screening and detection, the mortality rate of pancreatic cancer cases is still critical. The development of blood-based molecular biomarkers for pancreatic cancer screening and early detection which provide less-invasive, high-sensitivity, and cost-effective, is urgently needed. The goal of this study is to identify and validate the potential molecular biomarkers in white blood cells (WBCs) of pancreatic cancer patients. Gene expression profiles of pancreatic cancer patients from NCBI GEO database were analyzed by CU-DREAM. Then, mRNA expression levels of three candidate genes were determined by quantitative RT-PCR in WBCs of pancreatic cancer patients (N = 27) and healthy controls (N = 51). ROC analysis was performed to assess the performance of each candidate gene. A total of 29 upregulated genes were identified and three selected genes were performed gene expression analysis. Our results revealed high mRNA expression levels in WBCs of pancreatic cancer patients in all selected genes, including FKBP1A (p < 0.0001), PLD1 (p < 0.0001), and PSMA4 (p = 0.0002). Among candidate genes, FKBP1A mRNA expression level was remarkably increased in the pancreatic cancer samples and also in the early stage (p < 0.0001). Moreover, FKBP1A showed the greatest performance to discriminate patients with pancreatic cancer from healthy individuals than other genes with the 88.9% sensitivity, 84.3% specificity, and 90.1% accuracy. Our findings demonstrated that the alteration of FKBP1A gene in WBCs serves as a novel valuable biomarker for patients with pancreatic cancer. Detection of FKBP1A mRNA expression level in circulating WBCs, providing high-sensitive, less-invasive, and cost-effective, is simple and feasible for routine clinical setting that can be applied for pancreatic cancer screening and early detection.

Cultivation and characterization of functional-yet-uncultivable phenanthrene degraders by stable-isotope-probing and metagenomic-binning directed cultivation (SIP-MDC)

High-throughput identification and cultivation of functional-yet-uncultivable microorganisms is a fundamental goal in environmental microbiology. It remains as a critical challenge due to the lack of routine and effective approaches. Here, we firstly proposed an approach of stable-isotope-probing and metagenomic-binning directed cultivation (SIP-MDC) to isolate and characterize the active phenanthrene degraders from petroleum-contaminated soils. From SIP and metagenome, we assembled 13 high-quality metagenomic bins from 13C-DNA, and successfully obtained the genome of an active PHE degrader Achromobacter (genome-MB) from 13C-DNA metagenomes, which was confirmed by gyrB gene comparison and average nucleotide/amino identity (ANI/AAI), as well as the quantification of PAH dioxygenase and antibiotic resistance genes. Thereinto, we modified the traditional cultivation medium with antibiotics and specific growth factors (e.g., vitamins and metals), and separated an active phenanthrene degrader Achromobacter sp. LJB-25 via directed isolation. Strain LJB-25 could degrade phenanthrene and its identity was confirmed by ANI/AAI values between its genome and genome-MB (>99 %). Our results hinted at the feasibility of SIP-MDC to identify, isolate and cultivate functional-yet-uncultivable microorganisms (active phenanthrene degraders) from their natural habitats. Our findings developed a state-of-the-art SIP-MDC approach, expanded our knowledge on phenanthrene biodegradation mechanisms, and proposed a strategy to mine functional-yet-uncultivable microorganisms.

Combined Calcaneal Osteotomy and Achilles Tendon Lengthening in the Treatment of Rigid Heel Varus Deformity: A Novel Approach

Calcaneal sliding osteotomy is a frequently preferred procedure in the treatment of rigid heel varus deformity. The routine approach for calcaneal osteotomy is the lateral approach. However, wound problems, risk of iatrogenic injury to medial neurovascular structures, and difficulty in the management of the deformity are the main problems of this approach. In this article, we describe a new surgical approach, consisting of Achilles tendon lengthening in addition to calcaneal osteotomy, facilitating the intervention of other flexor tendon components and posterior structures in the correction of rigid heel varus deformity. Level of Evidence: Diagnostic Level V.

Assessment of spasticity-related pain in cerebral palsy and the efficacy of its treatment with incobotulinumtoxin A (literature review)

Pain in cerebral palsy (CP) occurs in 30–60% of cases. Pain associated with spasticity (PAS) is one of the most common causes of pain syndrome in cerebral palsy, which is often associated with impairment of the child’s daily life. Recently, more studies have been published on the use of botulinum toxin type A preparations to control PAS. The review article presents the results of a special pooled analysis of data on the analgesic effect of the drug Xeomin (incobotulinumtoxin A) in the treatment of PAS based on data from three phase III multicentre prospective comparative studies in children and adolescents with spastic forms of cerebral palsy. To evaluate PAS and the effect of incobotulinumtoxin A on it, a special questionnaire (Questionnaire on Pain caused by Spasticity, QPS) was used in these studies. The QPS reflects the child's pain associated with spasticity, which can be observed at rest and during various activities of the child.It was found that the children included in these studies reported the presence of PAS in more than 80% of cases with lower limb spasticity and in almost 70% of cases with upper limb spasticity. Parents or caregivers of these children observed an even higher prevalence of PAS. The use of incobotulinumtoxin A showed not only a pronounced antispastic effect, but also a significant reduction in the frequency and intensity of PAS in children and adolescents with cerebral palsy during normal daily activities, and during strenuous activities such as physical exercise and rehabilitation treatment. With repeated injection cycles of incobotulinumtoxin A, PAS continued to decrease, ensuring a reduction in pain even when physical activity became more difficult. Nowadays, injections with incobotulinumtoxin A can be considered as a routine therapeutic approach for the treatment of spasticity and increased muscle tone, but it is certainly an innovative method for effective pain reduction in cerebral palsy patients with lower and upper limb spasticity accompanied by PAS.

Is inadequate risk stratification diluting hazard ratio estimates in randomized clinical trials?

In randomized clinical trials, analyses of time-to-event data without risk stratification, or with stratification based on pre-selected factors revealed at the end of the trial to be at most weakly associated with risk, are quite common. We caution that such analyses are likely delivering hazard ratio estimates that unwittingly dilute the evidence of benefit for the test relative to the control treatment. To make our case, first, we use a hypothetical scenario to contrast risk-unstratified and risk-stratified hazard ratios. Thereafter, we draw attention to the previously published 5-step stratified testing and amalgamation routine (5-STAR) approach in which a pre-specified treatment-blinded algorithm is applied to survival times from the trial to partition patients into well-separated risk strata using baseline covariates determined to be jointly strongly prognostic for event risk. After treatment unblinding, a treatment comparison is done within each risk stratum and stratum-level results are averaged for overall inference. For illustration, we use 5-STAR to reanalyze data for the primary and key secondary time-to-event endpoints from three published cardiovascular outcomes trials. The results show that the 5-STAR estimate is typically smaller (i.e. more in favor of 5-STAR the test treatment) than the originally reported (traditional) estimate. This is not surprising because 5-STAR mitigates the presumed dilution bias in the traditional hazard ratio estimate caused by no or inadequate risk stratification, as evidenced by two detailed examples. Pre-selection of stratification factors at the trial design stage to achieve adequate risk stratification for the analysis will often be challenging. In such settings, an objective risk stratification approach such as 5-STAR, which is partly aligned with guidance from the US Food and Drug Administration on covariate-adjustment in clinical trials, is worthy of consideration.

Urologists’ Approach to Nocturia: Routine vs. Standardized Approach

Objective: We aimed to compare the effect of urologists’ routine approach and standardized approach on disease management and treatment results in patients suffering from nocturia. Material and Methods: The study was designed as a non-randomized prospective cohort study between March and July 2023. In the first stage, the routine clinical approach of 6 urology specialists was evaluated. Demographic data, comorbidities, baseline nocturia number, quality of life, and multidisciplinary approach preference of the patients were recorded (Group 1). In the second stage, the patients’ demographic data, comorbidities, and additionally the voiding diary and “Targeting the individual’s Aetiology of Nocturia to Guide Outcomes” (TANGO) questionnaire were questioned (Group 2). All patients were re-evaluated in the first month of the treatments/recommendations given. The difference in the multidisciplinary approach and the change in the number of nocturia and the quality of life of the patients were compared between the two approaches. Results: Forty-seven patients were included in each group. The demographic and clinical characteristics of the patients in both groups were statistically similar. Charlson’s comorbidity index was higher in Group 2 (p=0.01). The multidisciplinary treatment approach was at a higher level in Group 2 (59.6% vs 8.5%, p=0.001). While the average number of nocturia decreased from 4.6 to 2.19 in group 1, it decreased from 5.15 to 1.21 in group 2. In the first month, the number of nocturia and quality of life scores were lower in group 2. The decrease in the average number of nocturia and quality of life in group 2 was statistically significantly higher than in group 1. Conclusion: In the approach to nocturia, questioning comorbidities and applying multidisciplinary management provides more meaningful results in nocturia treatment and increase the quality of life.

Preventing and Managing Iatrogenic Dry Eye Disease during the Entire Surgical Pathway: A Study Focusing on Patients Undergoing Cataract Surgery

Patient expectations for cataract surgery are continuously increasing, and dry eye disease (DED) represents a major cause of patient dissatisfaction in eye surgery. The present opinion paper aims to provide useful insights to improve the entire pathway of a patient undergoing cataract surgery, from the preoperative setting to the postoperative one. The available evidence from main clinical trials published on this topic is presented in association with experience-based points of view by the authors. Ocular surface disease (OSD) is common in patients presenting for cataract surgery, and more than half of these patients have DED and meibomian gland dysfunction (MGD), even in the absence of symptoms. Therefore, there is a need to encourage preoperative assessments for the risk of DED development or worsening in all patients as a routine approach to cataract surgery. New all-in-one diagnostic machines allow for fast and noninvasive screening of the ocular surface status. Once a preoperative diagnosis of DED/OSD is reached, ocular surface optimization should be obtained before surgery. In the case of unresolved OSD, the decision to delay surgery should be considered. The surgical procedure can be optimized by avoiding large incisions, limiting microscope light intensity and exposure, and avoiding an aspirating speculum or preserved eye drops. Postoperatively, the continued avoidance of preserved agents is advisable, as well as a limited exposure to epitheliotoxic antibiotics and nonsteroidal anti-inflammatory drugs. Short-term, preservative-free, soft corticosteroids may be useful for patients with extensive or persistent inflammation.

Determinants and impacts of rural crime victimization: Evidence from a case study in Southeast Asia

We use a panel dataset of around 3500 rural households from Southeast Asia and investigate evidence on crime victimization. More concretely, we ask (1) to what extent are rural people affected by crime? (2) What factors determine rural crime victimization? And (3) what are the impacts of crime victimization on welfare of rural households? We use the routine activity approach as the theoretical framework and apply different logit models to identify determinants of crime victimization. We find that 5.46% of the rural households have been victimized, mainly by theft, over the last 12 months, some of them even more than once. Living in a rural region with higher levels of inequality is positively correlated with the likelihood of theft victimization. Households with higher levels of crop commercialization are associated with a higher victimization risk, while households with more livestock and being more specialized in specific livestock species are associated with a lower risk. Moreover, past victimization and exposure to weather shocks are positively associated with the likelihood of being affected by crime. With respect to the impacts, we use the heteroscedasticity-based instrumental variable approach to account for endogeneity and find highly significant negative effects of agricultural theft victimization on food consumption and child health outcomes. We conclude that rural crime requires attention although overall incidence is low in rural Thailand and Vietnam. Guardianship should be promoted, especially in times of weather shocks. Finally, reducing inequality helps preventing theft.

Hapsolutely: a user-friendly tool integrating haplotype phasing, network construction, and haploweb calculation.

Haplotype networks are a routine approach to visualize relationships among alleles. Such visual analysis of single-locus data is still of importance, especially in species diagnosis and delimitation, where a limited amount of sequence data usually are available and sufficient, along with other datasets in the framework of integrative taxonomy. In diploid organisms, this often requires separating (phasing) sequences with heterozygotic positions, and typically separate programs are required for phasing, reformatting of input files, and haplotype network construction. We therefore developed Hapsolutely, a user-friendly program with an ergonomic graphical user interface that integrates haplotype phasing from single-locus sequences with five approaches for network/genealogy reconstruction. Among the novel options implemented, Hapsolutely integrates phasing and graphical reconstruction steps of haplotype networks, supports input of species partition data in the common SPART and SPART-XML formats, and calculates and visualizes haplowebs and fields for recombination, thus allowing graphical comparison of allele distribution and allele sharing among subsets for the purpose of species delimitation. The new tool has been specifically developed with a focus on the workflow in alpha-taxonomy, where exploring fields for recombination across alternative species partitions may help species delimitation. Hapsolutely is written in Python, and integrates code from Phase, SeqPHASE, and PopART in C++ and Haxe. Compiled stand-alone executables for MS Windows and Mac OS along with a detailed manual can be downloaded from https://www.itaxotools.org; the source code is openly available on GitHub (https://github.com/iTaxoTools/Hapsolutely).

Comparison of the deformity reduction device (DRD) mini and the Slocum jig in the precision of torsional correction during distal femoral osteotomies in small to medium breed dogs.

Previous studies have compared the use of the Slocum- jig to the deformity reduction device (DRD) jig for the correction of distal femoral deformities of varying degrees in the frontal plane. The objective of the current study is to further investigate the use of the mini DRD jig in comparison to the Slocum jig for correction of varying degrees of torsional deformities of the distal femur. Femoral models (n = 60) were developed based on a CT scan of an approximately 16.5 kg normal canine femur. Models were created with a standard varus deformity of 15 degrees, and external torsional deformities of 15, 20, or 30 degrees. Using center of rotation of angulation (CORA) methodology, corrective osteotomies were planned and performed on each of the 3D printed models based on the group assigned. Modeling clay was applied the proximal femur to mimic visualization of a routine lateral surgical approach, while retaining the ability to palpate surgical landmarks. Post-correction anatomic lateral distal femoral angle (aLDFA) and femoral torsion angle (FTA) were measured and recorded. The mean post-correction FTA of groups using the DRD jig for correction were consistently closer to the ideal value compared to those using the Slocum jig, although these differences were not always statistically significant. Correction of external torsion between the DRD jig and the Slocum jig was significantly different in groups 1 and 2 (P = 0.026 and P = 0.046), but not in group 3. For the correction of varus deformity, no significant difference was found between the two jig types in any group. Results of this study suggest jig selection during distal femoral osteotomy for correction of torsional deformity may result in varying precision of post-correction alignment. Clinical significance of this variance remains unclear, and intra-operative visual assessment of alignment should be implemented to guide corrections.

Effects of multidisciplinary team continuous care model on psychological behavior and quality of life in children with β-thalassemia major.

To explore the effects of a multidisciplinary team (MDT) continuous care model on psychological behavior and quality of life in children with β-thalassemia major (β-TM). A retrospective study was conducted on 90 children with β-TM who were hospitalized in the Department of Pediatrics, Affiliated Hospital of Youjiang Medical University for Nationalities from October 2021 to May 2022. According to nursing methods, the children were divided into a routine group and an experimental group, with 45 cases in each group. The routine group was intervened with routine nursing approaches, and the experimental group was intervened with the MDT continuous nursing mode on the basis of the control group. The psychological behavior [Positive and Negative Affect Scale for Children (PANAS-C)], quality of life (QoL) [Pediatric Quality of Life Inventory TM (PedsQLTM)] and satisfaction were compared between the two groups before and 6 months after intervention. The hemoglobin level and ferritin level of children after 3 months and 6 months of intervention were measured. The occurrence of complications and nursing satisfaction were recorded. The prognostic factors were further analyzed. After the intervention, the positive emotion score, QoL score, hemoglobin level, satisfaction score in the experimental group were all higher than those in the conventional group, and the negative emotion score and ferritin level in the experimental group were all lower than those in the conventional group (all P < 0.05). The results of Cox analysis showed that the use of iron-removing drugs and arrhythmia/heart rate failure were risk factors affecting the prognosis of children with β-TM, while the MDT continuous nursing mode was a protective factor (all P < 0.05). The MDT continuous care model can effectively promote mental health in children with β-TM, improve their quality of life, medical satisfaction, ameliorate the degree of anemia in children, reduce the incidence of complications and improve the prognosis; thus, it is worthy of wide clinical application.

Keyhole Craniotomy and Closure for Trigeminal Neuralgia and Facial Spasms

Facial spasms and trigeminal neuralgia are functional diseases, which have alternative treatment options. The working space for each pathology can be obtained by a routine approach to the caudal and rostral sides of the cerebellum and can be provided through a small craniotomy, because CSF drainage provides sufficient space for manipulation. However, it is necessary to expose fully the structures that define the operative field, such as the margins of the venous sinuses. Familiarity with the muscular anatomy required for exposure is also important.

ОБОСНОВАНИЯ ПО ПРИМЕНЕНИЮ ОПЫТА ПРОТИВОТУБЕРКУЛЁЗНОЙ СЛУЖБЫ ДЛЯ АДЕКВАТНОГО РЕАГИРОВАНИЯ В ПЕРИОД ПАНДЕМИИ COVID-19

Objective: To summarize the experience of the anti-tuberculosis care (ATC) units of the Republic of Tajikistan (RT) to optimize medical aid to the population during potential outbreaks of respiratory infectious diseases. Methods: This study examines the experience and lessons learned after the COVID-19 pandemic in the RT, as well as the main provisions recommended for the partial reorganization of the ATC to ensure its readiness to function during outbreaks of respiratory infections. The standards and rules of antituberculosis infection control were used to develop preventive measures against the nosocomial spread of aerogenic infections in healthcare facilities and society. Results: The analysis revealed that maintaining of a sanitary and anti-epidemic regimen in healthcare institutions primarily involved a routine approach to the disinfection of medical facilities. However, in respiratory infections, adopting the experience of ATC RT was beneficial. It included strict adherence to infection control rules, social distancing, avoidance of crowded public places, restriction of unnecessary migration and public events, and the rigorous use of means of personal protection. The ATC also pioneered innovative approaches through various software, which have proven effective even under the restrictions imposed during the COVID-19 pandemic. Conclusion: ATC can serve as a coordinating link and an excellent example of how to prepare the healthcare system for various potential outbreaks of respiratory infections. It is necessary to integrate the ATC with other relevant institutions of the healthcare system, both functionally and structurally, to increase the effectiveness of preventive measures against the transmission of respiratory infections. Keywords: TB care, health care facilities, COVID-19, respiratory infections.

Augmented wound healing potential of photosensitive GelMA hydrogel incorporating antimicrobial peptides and MXene nanoparticles.

Introduction: Wound healing is a delicate and complex process influenced by many factors. The treatment of skin wounds commonly involves the use of wound dressings, which remain a routine approach. An ideal dressing can provide protection and a suitable environment for wound surfaces by maintaining moisture and exhibiting good biocompatibility, mechanical strength, and antibacterial properties to promote healing and prevent infection. Methods: We encapsulated tick-derived antibacterial polypeptides (Os) as a model drug within a methylacrylyl gelatin (GelMA) hydrogel containing MXene nanoparticles. The prepared composite hydrogels were evaluated for their wound dressing potential by analyzing surface morphology, mechanical properties, swelling behavior, degradation properties, antibacterial activity, and cytocompatibility. Results: The results demonstrated excellent mechanical strength, swelling performance, degradation behavior, and antibacterial activity of the prepared composite hydrogels, effectively promoting cell growth, adhesion, and expression of antibacterial peptide activity. A full-thickness rat wound model then observed the wound healing process and surface interactions between the composite hydrogels and wounds. The composite hydrogel significantly accelerated wound closure, reduced inflammation, and sped epithelial formation and maturation. Discussion: Incorporating antibacterial peptides into GelMA provides a feasible strategy for developing excellent antibacterial wound dressings capable of tissue repair. In conclusion, this study presents a GelMA-based approach for designing antibacterial dressings with strong tissue regenerative ability.

Unraveling the potential of segment scan mass spectral acquisition for chemical isotope labeling LC-MS-based metabolome analysis: Performance assessment across different types of biological samples

BackgroundChemical isotope labeling (CIL) LC-MS is a powerful tool for metabolome analysis with high metabolomic coverage and quantification accuracy. In CIL LC-MS, the overall metabolite detection efficiency using Orbitrap MS can be further improved by employing a segment scan method where the full m/z range is divided into multiple segments for spectral acquisition with a significant increase in the in-spectrum dynamic range. Considering the metabolic complexity in different types of biological samples (e.g., feces, urine, serum/plasma, cell/tissue extracts, saliva, etc.), we report the development and evaluation of the segment scan method for metabolome analysis of different sample types. ResultsIt was found that sample complexity significantly influenced the performance of the segment scan method. In metabolically complex samples such as feces and urine, the method yielded a substantial increase (up to 94 %) in detected peak pairs or metabolites, compared to conventional full scan. Conversely, less complex samples like saliva exhibited more modest gains (approximately 25 %). Based on the observations, a 120-m/z segment scan method was determined as a routine approach for CIL LC-Orbitrap-MS-based metabolomics with good compatibility with different types of biological samples. For this method, a further investigation on relative quantification accuracy was done. The peak area ratios of 12C-/13-labeled metabolites were slightly reduced with 72%–84 % of peak pairs falling within the ±25 % range of the anticipated peak ratio of 1.0 among different samples, as opposed to 81%–90 % in the full scan, which was attributed to the inclusion of more low-abundance peak pairs within the narrow MS segments. However, the overall peak ratio measurement precision was not significantly affected by the segment scan. Significance and noveltyThe segment scan method was found to be useful for CIL LC-Orbitrap-MS-based metabolome analysis of different types of samples with significant improvement in metabolite detectability (25–94 % increase), compared to the conventional full scan method.

Sample size calculation for multi-arm parallel design with restricted mean survival time.

With the recent advances in oncology treatment, restricted mean survival time (RMST) is increasingly being used to replace the routine approach based on hazard ratios in randomized controlled trials for time-to-event outcomes. While RMST has been widely applied in single-arm and two-arm designs, challenges still exist in comparing RMST in multi-arm trials with three or more groups. In particular, it is unclear in the literature how to compare more than one intervention simultaneously or perform multiple testing based on RMST, and sample size determination is a major obstacle to its penetration to practice. In this paper, we propose a novel method of designing multi-arm clinical trials with right-censored survival endpoint based on RMST that can be applied in both phase II/III settings using a global test as well as a modeling-based multiple comparison procedure. The framework provides a closed-form sample size formula built upon a multi-arm global test and a sample size determination procedure based on multiple-comparison in the phase II dose-finding study. The proposed method enjoys strong robustness and flexibility as it requires less a priori set-up than conventional work, and obtains a smaller sample size while achieving the target power. In the assessment of sample size, we also incorporate practical considerations, including the presence of non-proportional hazards and staggered patient entry. We evaluate the validity of our method through simulation studies under various scenarios. Finally, we demonstrate the accuracy and stability of our method by implementing it in the design of two real clinical trial examples.

Feasibility and Safety of the Routine Distal Transradial Approach in the Anatomical Snuffbox for Coronary Procedures: The ANTARES Randomized Trial.

The distal transradial approach (dTRA) through the anatomical snuffbox is hypothesized to offer greater benefits than the conventional transradial access (cTRA) for patients undergoing coronary procedures. Our goal was to assess the safety and efficacy of dTRA. Out of 465 consecutive Caucasian patients, 400 were randomized (1:1) to dTRA or cTRA in a prospective single-center trial. Clinical and ultrasound follow-ups were obtained at 24 h and 60 days post-procedure. The primary combined endpoint consisted of access crossover, access-related complications, and major adverse cardiovascular events (MACE). Secondary endpoints included clinical success endpoints (puncture success, crossover, and access time), access-site complications endpoints, and MACE at 60 days. The primary endpoint was significantly higher in the dTRA [odds ratio (OR): 2.31, 95% confidence interval (CI): 1.38-3.86, p = 0.001]. Clinical success endpoints, namely crossover (10% vs. 3.5%, p < 0.05) and access-time [median: 140s (85-322) vs. 80s (58-127), p < 0.001], did not favor the dTRA, despite a similar success rate in radial artery puncture between the dTRA and cTRA (99.5% vs. 99%). Radial artery spasm (19% vs. 4.5%, p < 0.0001), physical discomfort during access, and transient thumb numbness after the procedure occurred more frequently with the dTRA. However, early (2.5% vs. 4.5%, p = 0.41) and mid-term (2.5% vs. 3%, p = 0.98) forearm radial artery occlusion rates were comparable between the dTRA and cTRA. Randomization to the dTRA, lower forearm radial pulse volume, higher body mass index, and lower body surface area independently predicted the primary endpoint in multivariate analysis. In the interaction effect analysis, only diabetes increased the incidence of the primary endpoint with the dTRA (OR: 18.67, 95% CI: 3.96-88.07). The dTRA was a less favorable strategy than cTRA during routine coronary procedures due to a higher incidence of arterial spasm and the necessity for access crossover. The majority of local complications following the dTRA were clinically minor complications. Individuals with diabetes were particularly susceptible to complications associated with the dTRA.