Prognosis of pediatric BCP-ALL with IKZF1 deletions and impact of intensive chemotherapy: Results of SCCLG-2016 study.

BACKGROUND: IKZF1 deletion (IKZF1del) is associated with poor prognosis in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). But the prognosis of IKZF1del combined with other prognostic stratification factors remains unclear. Whether intensified treatment improves BCP-ALL prognosis has not been determined. METHODS: A retrospective analysis was performed on 1291 pediatric patients diagnosed with BCP-ALL and treated with the South China Children's Leukemia 2016 protocol. Patients were stratified based on IKZF1 status for comparison of characteristics and outcome. Additionally, IKZF1del patients were further divided based on chemotherapy intensity for outcome assessments. RESULTS: The BCP-ALL pediatric patients with IKZF1del in south China showed poorer early response. Notably, the DFS and OS for IKZF1del patients were markedly lower than IKZF1wt group (3-year DFS: 88.7% [95% CI: 83.4%-94.0%] vs. 93.5% [95% CI: 92.0%-94.9%], P = .021; 3-year OS: 90.7% [95% CI: 85.8% to 95.6%] vs. 96.1% [95% CI: 95% to 97.2%, P = .003]), with a concurrent increase in 3-year TRM (6.4% [95% CI: 2.3%-10.5%] vs. 2.9% [95% CI: 1.9%-3.8%], P = .025). However, the 3-year CIR was comparable between the two groups (5.7% [95% CI: 1.8%-9.5%] vs. 3.7% [95% CI: 2.6%-4.7%], P = .138). Subgroup analyses reveal no factor significantly influenced the prognosis of the IKZF1del cohort. Noteworthy, intensive chemotherapy improved DFS from 85.7% ± 4.1% to 94.1% ± 0.7% in IKZF1del group (P = .084). Particularly in BCR::ABL positive subgroup, the 3-year DFS was remarkably improved from 53.6% ± 20.1% with non-intensive chemotherapy to 100% with intensive chemotherapy (P = .026). CONCLUSIONS: Pediatric BCP-ALL patients with IKZF1del in South China manifest poor outcomes without independent prognostic significance. While no factor substantially alters the prognosis in the IKZF1del group. Intensified chemotherapy may reduce relapse rates and improve DFS in patients with IKZF1del subset, particularly in IKZFdel patients with BCR::ABL positive.

Comparative evaluation of intensified short course regimen and standard regimen for adults TB meningitis: a protocol for an open label, multi-center, parallel arms, randomized controlled superiority trial (INSHORT trial).

BACKGROUND: Despite several incremental improvements in the management of tuberculous meningitis (TBM), the mortality rates remain high. In spite of national and international guidelines, variation in the choice, dose, and duration of drugs exist between countries and clinicians. We propose to evaluate a shorter and more effective regimen containing agents with augmented intracerebral drug exposure and anti-inflammatory approaches to improve disability-free survival among patients with TBM. Our strategy incorporates the various developments in the field of TBM over the last two decades and only few trials have evaluated a composite of these strategies in the overall outcomes of TBM. METHODS: An open label, parallel arms, randomized controlled superiority trial will be conducted among 372 participants across 6 sites in India. Eligible participants will be randomly allocated in 1:1:1 ratio into one of the three arms. The intervention arm consists of 2 months of high-dose rifampicin (25 mg/kg), moxifloxacin (400 mg), pyrazinamide, isoniazid, aspirin (150 mg), and steroids followed by rifampicin, isoniazid, and pyrazinamide for 4 months. The second intervention arm includes all the drugs as per the first arm except aspirin and the patients in the control arm will receive treatment according to the National TB Elimination Program guidelines. All participants will be followed up for 1 year after the treatment.  DISCUSSION: Current WHO regimens have agents with poor central nervous system drug exposure and is too long. It does not reflect the accumulating evidence in the field. We propose a comprehensive clinical trial incorporating the emerging evidence accrued over the last two decades to shorten the duration and improve the treatment outcomes. This multi-centric trial may generate crucial evidence with policy and practice implications in the treatment of TBM. TRIAL REGISTRATION: Clinical Trial Registry India CTRI/2023/05/053314. Registered on 31 May 2023 ( https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=ODYzMzg=&Enc=&userName=CTRI/2023/05/053314 ). CLINICALTRIALS: gov NCT05917340. Registered on 6 August 2023 ( https://classic. CLINICALTRIALS: gov/ct2/show/NCT05917340 ). PROTOCOL VERSION: Version 1.3 dated 12 July 2023.

Health and Productivity Benefits with Early Intensified Treatment in Patients with Type 2 Diabetes: Results from Korea.

The available evidence suggests positive health outcomes associated with early treatment intensification in Type 2 diabetes mellitus (T2DM). Our study estimated the productivity effects arising from improved health correlated with early intensified treatment in T2DM in Korea. Using a recently published methodology and model, we investigated the association between early intensified treatment and the probability of experiencing fewer diabetes-related complication events. Treatment strategies leading to better health outcomes are expected to be associated with social value through increased participation in paid and unpaid work activities. Therefore, we translated the lower incidence of complications into monetary terms related to productivity for the Korean population. We quantified productivity by considering (a) absenteeism, (b) presenteeism, (c) permanent loss of labor force, and (d) activity restriction. Deterministic and probabilistic sensitivity analyses in the base case parameter were performed. Approximately, 1.7 thousand (standard deviation [SD] ±580 events) micro- and macrovascular complication events could potentially be avoided by early treatment intensification. This led to a societal gain attributed to increased productivity of 23 million USD (SD ± $8.2 million). This article demonstrates the likelihood of achieving better health and productivity through early intensified treatment in diabetes.

Programmable activation of berbamine and photosensitizers for enhanced photodynamic therapy using emission-switchable upconversion nanoparticles.

Photodynamic therapy (PDT) shows great potential in precision tumor treatment. However, its efficacy is inhibited by the antioxidant defense capacities of tumor cells. To address this challenge, a near-infrared light-controlled nanosystem (UCNPs@mSiO2@Azo@ZnPc&BBM, PB@UA) was developed using emission-switchable upconversion nanoparticles (UCNPs) to independently and precisely control the release of berbamine (BBM) and activation of photosensitizer for enhanced PDT in deep tissues. Firstly, BBM release was triggered by exciting PB@UA at 980 nm. The BBM could inhibit the activities of antioxidant enzymes and disrupt calcium ion regulation, making the tumor cells more susceptible to ROS-induced cell death in the following PDT treatment. The PDT was initiated by irradiating the photosensitizers of ZnPc on PB@UA at 808 nm and achieved a tumor inhibition rate of 80.91 % in vivo, which is significantly higher than that of unique PDT (31.78 %) or BBM (11.29 %) treatment and demonstrates the potential of our strategy for improved cancer treatment.

The IDEAL (Insulin therapy DE-intensificAtion with iglarLixi) Randomised Controlled Trial-Study Design and Protocol.

INTRODUCTION: Multiple daily injection insulin regimen (MDI) represents the most intensive insulin regimen used in the management of people with type 2 diabetes (PwT2D). Its efficacy regarding glycaemic control is counterbalanced by the increased risk of hypoglycaemia, frequently observed tendency to weight gain and necessity for frequent glucose monitoring. Recent introduction of novel antidiabetic medications with pleiotropic effects reaching far beyond the reduction of glycaemia (HbA1c), such as the glucagon-like peptide 1 receptor agonist (GLP-1 RA), has significantly widened the therapeutic options available for management of T2D. Consequently, there is currently a substantial number of PwT2D for whom the MDI regimen was initiated at a time when no other options were available. Yet, in present times, these individuals could benefit from simplified insulin regimens ideally taking advantage of the beneficial effects of the novel classes of antidiabetic medications. iGlarLixi (Suliqua®) is a once-daily fixed-ratio combination of basal insulin analogue glargine 100 U/ml and a GLP-1 RA lixisenatide. METHODS: Insulin therapy DE-intensificAtion with iglarLixi (IDEAL) is a six-centre, open-label, parallel-group, active comparator, phase IV randomised controlled trial with a 24-week active treatment period examining the efficacy and safety of MDI regimen de-intensification with once-daily administration of iGlarLixi versus MDI regimen continuation in PwT2D on a backgroud therapy with metformin ± sodium-glucose cotransporter 2 inhibitor. PLANNED OUTCOMES: The primary objective is to compare the effects of MDI therapy de-intensification with iGlarLixi versus MDI regimen continuation regarding glycaemic control (HbA1c). Secondary objectives include detailed evaluation of the effects of MDI regimen de-intensification with iGlarLixi on glycaemic control using standardised continuous glucose monitoring (CGM) metrics and self-monitoring of plasma glucose. Furthermore, body weight and body composition analysis, quality of life and safety profile are evaluated. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT04945070.

Deciphering Metabolic Pathways in High-Seeding-Density Fed-Batch Processes for Monoclonal Antibody Production: A Computational Modeling Perspective.

Due to their high specificity, monoclonal antibodies (mAbs) have garnered significant attention in recent decades, with advancements in production processes, such as high-seeding-density (HSD) strategies, contributing to improved titers. This study provides a thorough investigation of high seeding processes for mAb production in Chinese hamster ovary (CHO) cells, focused on identifying significant metabolites and their interactions. We observed high glycolytic fluxes, the depletion of asparagine, and a shift from lactate production to consumption. Using a metabolic network and flux analysis, we compared the standard fed-batch (STD FB) with HSD cultivations, exploring supplementary lactate and cysteine, and a bolus medium enriched with amino acids. We reconstructed a metabolic network and kinetic models based on the observations and explored the effects of different feeding strategies on CHO cell metabolism. Our findings revealed that the addition of a bolus medium (BM) containing asparagine improved final titers. However, increasing the asparagine concentration in the feed further prevented the lactate shift, indicating a need to find a balance between increased asparagine to counteract limitations and lower asparagine to preserve the shift in lactate metabolism.

Predictors of Survival, Treatment Modalities, and Clinical Outcomes of Diffuse Large B-Cell Lymphoma in Patients Older Than 70 Years Still an Unmet Medical Need in 2024 Based on Real-World Evidence.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) especially affects the older population. Old (≥60 years) and very old age (≥80 years) DLBCL patients often present high-risk molecular alterations, lower tolerability to conventional immunochemotherapy, and poor clinical outcomes. In this scenario, attenuated therapeutic strategies, such as the R-MiniCHOP and R-MiniCHOP of the elderly regimens, have emerged for this particularly fragile population. However, the responses, clinical outcomes, and toxicities of these regimens currently remain poorly understood, mainly because these individuals are not usually included in controlled clinical trials. METHODS: This retrospective, observational, and single-center real-world study included 185 DLBCL, NOS patients older than 70 years treated at the largest oncology center in Latin America from 2009 to 2020. We aimed to assess the outcomes, determine survival predictors, and compare responses and toxicities between three different primary therapeutic strategies, including the conventional R-CHOP regimen and the attenuated R-MiniCHOP and R-MiniCHOP of the elderly protocols. RESULTS: The median age at diagnosis was 75 years (70-97 years), and 58.9% were female. Comorbidities were prevalent, including 19.5% with immobility, 28.1% with malnutrition, and 24.8% with polypharmacy. Advanced clinical stage was observed in 72.4%, 48.6% had bulky disease ≥7 cm, 63.2% had B-symptoms, and 67.0% presented intermediate-high/high-risk IPI. With a median follow-up of 6.3 years, the estimated 5-year OS and PFS were 50.2% and 44.6%, respectively. The R-MiniCHOP of the elderly regimen had a lower ORR (p = 0.040); however, patients in this group had higher rates of unfavorable clinical and laboratory findings, including hypoalbuminemia (p = 0.001), IPI ≥ 3 (p = 0.013), and NCCN-IPI ≥ 3 (p = 0.002). Although associated with higher rates of severe neutropenia (p = 0.003), the R-CHOP regimen promoted increased OS (p = 0.003) and PFS (p = 0.005) in comparison to the attenuated protocols. Additionally, age ≥ 75 years, high levels of LDH, B-symptoms, advanced clinical stage (III/IV), neutrophilia, and low lymphocyte/monocyte ratio were identified as poor prognostic factors in this cohort. CONCLUSIONS: In this large and real-life Latin American cohort, we demonstrated that patients with DLBCL, NOS older than 70 years still do not have satisfactory clinical outcomes in 2024, with half of cases not reaching 5 years of life expectancy after diagnosis. Although the conventional R-CHOP offers response and survival advantages over attenuated regimens, its myelotoxicity is not negligible. Therefore, the outcomes reported and the prognostic factors here identified may assist clinicians in the appropriate selection of therapeutic strategies adapted to the risk for old and very old DLBCL patients.

Biochars assisted phytoremediation of polycyclic aromatic hydrocarbons contaminated agricultural soil: Dynamic responses of functional genes and microbial community.

A biochar-intensified phytoremediation experiment was designed to investigate the dynamic effects of different biochars on polycyclic aromatic hydrocarbon (PAH) removal in ryegrass rhizosphere contaminated soil. Maize and wheat straw biochar pyrolyzed at 300 °C and 500 °C were amended into PAH-contaminated soil, and then ryegrass (Lolium multiflorum L.) was planted for 90 days. Spearman's correlations among PAH removal, enzyme activity, abundance of PAH-ring hydroxylating dioxygenase (PAH-RHDα), and fungal and bacterial community structure were analyzed to elucidate the microbial degradation mechanisms during the combined remediation process. The results showed that 500 °C wheat straw biochar had higher surface area and more nutrients, and significantly accelerated the phytoremediation of PAHs (62.5 %), especially for high molecular weight PAH in contaminated soil. The activities of urease and dehydrogenase and the abundance of total and PAH-degrading bacteria, which improved with time by biochar and ryegrass, had a positive correlation with the removal rate of PAHs. Biochar enhanced the abundance of gram-negative (GN) PAH-RHDα genes. The GN PAH-degraders, Sphingomonas, bacteriap25, Haliangium, and Dongia may play vital roles in PAH degradation in biochar-amended rhizosphere soils. Principal coordinate analysis indicated that biochar led to significant differences in fungal community structures before 30 days, while the diversity of the bacterial community composition depended on planting ryegrass after 60 days. These findings imply that the structural reshaping of microbial communities results from incubation time and the selection of biochar and ryegrass in PAH-contaminated soils. Applying 500 °C wheat straw biochar could enhance the rhizoremediation of PAH-contaminated soil and benefit the soil microbial ecology.

Critical pulse in multi-shot femtosecond laser ablation on metallic surfaces.

Thermal effect remains a thorny issue for femtosecond-laser surface engineering and nanostructuring on metallic targets with high pulse energies or high repetition rates, which needs to be paid adequate attentions. Herein, we have experimentally investigated the heat diffusion and accumulations during single-shot and multi-shot femtosecond laser ablation on metallic surfaces. We have for the first time observed a novel phenomenon that the thermal effect was intensified abruptly when the laser-pulse number goes over a threshold (approximately between 10 and 20 for aluminum alloy with laser fluence of 6 J cm-2), accompanied with a dramatic reduction of ablated depth and complicated plasma dynamics. Based on both optical and thermodynamic analysis, we introduced a defocusing-dominated plasma-assistant model for this abnormal thermal effect. This work explored the critical experimental parameters for femtosecond-laser surface modification and processing in micro-scale engineering applications.

Intensified conditioning regimens with total marrow irradiation/etoposide/cyclophosphamide and busulfan/etoposide/cyclophosphamide overcome the impact of pre-transplant minimal residual disease on outcomes in high-risk acute lymphoblastic leukemia patients in complete remission.

PURPOSE: Among high-risk acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), those with positive minimal residual disease (MRD) are susceptible to poor outcomes. Therefore, it is necessary to determine the most suitable preparatory regimen for these patients. METHODS: Data were analyzed from 141 patients who received allo-HSCT and were diagnosed with high-risk ALL. These patients underwent intensified conditioning regimens, including either total marrow and lymphoid irradiation (TMLI)-etoposide (VP16)-cyclophosphamide (CY) or busulfan (BU)-VP16-CY between October 2016 and November 2022. A total of 141 individuals were in complete remission (CR) before transplantation and, among all patients, 90 individuals exhibited a negative MRD status and 51 patients had a positive MRD status. RESULTS: In patients who tested negative for MRD, the incidence of relapse within a 2-year timeframe was 25.0% (24.8%-25.5%), compared with 32.2% (31.2%-33.2%) in MRD-positive patients; however, this difference was not statistically significant. There were no significant differences in the 2-year disease-free survival (DFS) and 2-year overall survival (OS) rates between the MRD-negative and MRD-positive groups (DFS: 67.2% (57.9%-78.1%) vs. 55.5% (42.6%-72.3%); OS: 69.0% (61.9%-88.2%) vs. 66.7% (53.9%-82.5%)). Furthermore, no notable variations were observed in the occurrence of transplant-related mortality (TRM) and graft-versus-host disease (GVHD) across the two groups. CONCLUSION: This study reveals the benefits of TMLI-VP16-CY and BU-VP16-CY conditioning regimens in high-risk ALL patients with CR and MRD-positive status. A large-scale prospective clinical trial is warranted in the future.

Treatment of auricular pseudocysts using enhanced negative drainage: a prospective study of 21 cases.

OBJECTIVE: Auricular pseudocysts are rare, painless, benign intracartilaginous cysts of the auricle that are not lined by epithelium and have no known aetiology. METHOD: This was a prospective study conducted in an ENT department from January 2020 to June 2022. In 21 patients, complete aspiration of the pseudocyst with enhanced negative drainage was performed. They were followed for a minimum of six months. RESULTS: All patients completely responded to the negative drainage treatment. No cases of recurrence or obvious deformities were observed. CONCLUSION: Aspiration with intensified negative drainage was associated with a positive response in patients with auricular pseudocysts. Complete resolution of the swelling can be achieved without any serious complications. Thus, it appears to be a simple and effective method for managing the condition.

The reproducibility of dendritic cell and T cell counts to a 30-min high-intensity cycling protocol as a tool to highlight overtraining.

Heavy training has been reported to be immunosuppressive in athletes and lead to blunted cortisol responses to exercise. Cortisol elevates the number of dendritic cells (DCs), key antigen-presenting cells that interact with T cells to initiate an immune response. Reproducible cortisol responses to a 30-min cycle test have been identified but were based on percentage of work rate maximum. To ensure physiological consistency, submaximal anchors, that is, ventilatory threshold (VT1 ) should prescribe intensity. This study aims to assess the reproducibility of the DC and T cell responses to an adapted stress test to assess its usefulness in assessing DC dysfunction with intensified training. Twelve males cycled for 1 min at 20% below VT1 and 4 min at 50% between VT1 and V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}\max }$ , for 30 min (20/50), with blood samples pre-, post- and 30 min post-exercise. This was repeated twice, 2-7 days apart. Flow cytometry assessed total DCs, plasmacytoid DCs, myeloid DCs, total T cells, T helper cells and T cytotoxic cells. No significant trial or interaction effects were found for any variable. A significant main effect of time for all variables was found; immune cells increased from pre- to post-exercise and decreased to baseline 30 min post-exercise, apart from plasmacytoid DCs, which remained elevated 30 min post-exercise. Intraclass correlation coefficients showed overall good-to-excellent reliability for all immune cells, with smallest real difference and Bland-Altman analysis verifying high reproducibility between trials. These results suggest that the 20/50 exercise test induces reproducible DC and T cell count changes, which, implemented before and after a period of intensified training, may highlight the negative states of overtraining.

Developing an ultra-intensified fed-batch cell culture process with greatly improved performance and productivity.

Intensified fed-batch (IFB), a popular cell culture intensification strategy, has been widely used for productivity improvement through high density inoculation followed by fed-batch cultivation. However, such an intensification strategy may counterproductively induce rapidly progressing cell apoptosis and difficult-to-sustain productivity. To improve culture performance, we developed a novel cell culture process intermittent-perfusion fed-batch (IPFB) which incorporates one single or multiple cycles of intermittent perfusion during an IFB process for better sustained cellular and metabolic behaviors and notably improved productivity. Unlike continuous perfusion or other semi-continuous processes such as hybrid perfusion fed-batch with only early-stage perfusion, IPFB applies limited times of intermittent perfusion in the mid-to-late stage of production and still inherits bolus feedings on nonperfusion days as in a fed-batch culture. Compared to IFB, an average titer increase of ~45% was obtained in eight recombinant CHO cell lines studied. Beyond IPFB, ultra-intensified IPFB (UI-IPFB) was designed with a markedly elevated seeding density of 20-80 × 106 cell/mL, achieved through the conventional alternating tangential flow filtration (ATF) perfusion expansion followed with a cell culture concentration step using the same ATF system. With UI-IPFB, up to ~6 folds of traditional fed-batch and ~3 folds of IFB productivity were achieved. Furthermore, the application grounded in these two novel processes showed broad-based feasibility in multiple cell lines and products of interest, and was proven to be effective in cost of goods reduction and readily scalable to a larger scale in existing facilities.

The TB Surge intervention: an optimized approach to TB case-finding in Nigeria.

INTRODUCTION: TB remains one of the leading causes of death in Nigeria, and despite progress in treatment coverage, a 56% gap in national case notifications remains. This gap is attributable in part to underdiagnosis due to missed cases in health facilities. The TB Surge intervention presented an opportunity to address barriers to optimal case detection in public health facilities. METHODS: KNCV Nigeria implemented the TB Surge intervention under the USAID-funded TB-LON Project in 1,041 public facilities from June 2020 to September 2022. Trained ad-hoc staff screened hospital attendees, linked identified presumptive TB cases to diagnosis and confirmed TB cases to treatment. Data were reported using the Commcare application. Robust project monitoring was used to address gaps. RESULTS: Of a total of 12,195,874 hospital attendees screened for TB, 729,369 identified as presumptive TB were tested and 65,029 TB cases were diagnosed; 8% of the TB cases were children. Overall TB yield was 9%. Medical ward service delivery point had the highest TB yield of 21%. The number needed to test was 11 and the number needed to screen was 188. CONCLUSION: The TB Surge intervention was of strategic importance in addressing missed cases and barriers to prompt TB diagnosis in health facilities.

INTRODUCTION: La TB reste l'une des principales causes de décès au Nigeria et, malgré les progrès réalisés en matière de couverture thérapeutique, il subsiste un écart de 56% dans la déclaration des cas à l'échelon national. Cet écart s'explique en partie par le sous-diagnostic dû aux cas manqués dans les centres de santé. L'intervention TB Surge a permis de lever les obstacles à la détection optimale des cas dans les centres de santé publique. MÉTHODES: KNCV Nigeria a mis en œuvre l'intervention TB Surge dans le cadre du projet TB-LON financé par l'USAID dans 1 041 centres publics de juin 2020 à septembre 2022. Le personnel ad hoc formé a dépisté les personnes présentes à l'hôpital, lié les cas de TB présomptifs identifiés au diagnostic et les cas de TB confirmés au traitement. Les données ont été communiquées à l'aide de l'application Commcare. Un suivi rigoureux du projet a permis de combler les lacunes. RÉSULTATS: Sur un total de 12 195 874 patients hospitalisés ayant fait l'objet d'un dépistage de la TB, 729 369 cas présumés de TB ont été testés et 65 029 cas de TB ont été diagnostiqués ; 8% des cas de TB étaient des enfants. Le rendement global de la TB était de 9%. Le point de prestation de services du service médical a enregistré le taux de TB le plus élevé (21%). Le nombre de tests nécessaires était de 11 et le nombre de dépistages nécessaires de 188. CONCLUSION: L'intervention TB Surge a été d'une importance stratégique pour traiter les cas non détectés et les entraves à un diagnostic rapide de la TB dans les centres de santé.

Infliximab Induction Strategies in Corticosteroid-Refractory Acute Severe Ulcerative Colitis: A Case Series and Literature Review.

Acute severe ulcerative colitis (ASUC) is an emergent medical condition and particularly challenging to treat efficaciously. Infliximab is one of the medical salvage treatment options after corticosteroid refractoriness, but the best induction strategy is not yet defined. With this case series, the authors intend to describe three corticosteroid-refractory ASUC cases with different intensified/accelerated infliximab induction approaches and review the literature on this topic. The first case describes an 18-year-old girl with ASUC at disease onset with rapid progression to toxic megacolon, complicated also with anemia, hypoalbuminemia, and coagulopathy. After corticosteroid failure, both accelerated and intensified (10 mg/kg) infliximab regimen was completed within 11 days, with solid clinical response and colon imaging normalization. Second, we present a 26-year-old male with left-sided ulcerative colitis known for 2 years, under mesalazine, who developed a moderate flare and was started on infliximab after partial and inconsistent response to corticosteroids. During the induction period, he presented this time an ASUC episode, which motivated an early and intensified third dose with good clinical response. Finally, we describe the case of a 78-year-old man with ulcerative proctitis for 12 years presenting ASUC with proximal disease extension as well. After unsatisfactory response to corticosteroids, infliximab was initiated on an accelerated induction regimen, completed in 13 days, with the standard dose, achieving clinical remission. Accelerated or intensified infliximab induction plans are becoming current clinical practice in corticosteroid-refractory ASUC. Current guidelines refer to the possibility of this type of strategies, not determining the optimal regimen due to lack of solid evidence. Literature is mainly based on retrospective studies, not randomized, with heterogeneous groups according to disease severity, and the effect on colectomy rates, mainly on the long term, is not clear. Additional well-supported studies are needed on this subject in order to seek a more widely uniform approach.

A agudização grave de colite ulcerosa é uma emergência médica, particularmente difícil de tratar de forma eficaz. O infliximab é uma das opções de tratamento médico de resgate após refractariedade aos corticosteróides, porém a melhor estratégia de indução ainda não está definida. Com este relato de série de casos, os autores pretendem descrever três casos de agudização grave de colite ulcerosa refratária a corticosteróides com diferentes abordagens de indução intensificada/acelerada de infliximab e rever a literatura sobre este tópico. O primeiro caso descreve uma jovem de 18 anos com agudização grave de colite ulcerosa, à apresentação da doença, com rápida progressão para megacólon tóxico, complicada também com anemia, hipoalbuminemia e coagulopatia. Após ausência de resposta a corticosteróides, foi iniciado regime acelerado e intensificado (10 mg/kg) de infliximab, concluído em 11 dias, com resposta clínica e normalização das alterações imagiológicas do cólon. Em segundo lugar, apresentamos um homem de 26 anos com colite ulcerosa esquerda conhecida há 2 anos, sob messalazina, que apresentou uma agudização moderada da doença e iniciou infliximab após resposta parcial e inconsistente aos corticosteróides. Durante o período de indução, apresentou desta vez um episódio de agudização grave, o que motivou uma terceira dose precoce e intensificada com boa resposta clínica. Por fim, descrevemos o caso de um homem de 78 anos com proctite ulcerosa há 12 anos apresentando agudização grave de colite ulcerosa, também com extensão proximal da doença. Após resposta insatisfatória a corticosteróides, foi iniciado infliximab em regime de indução acelerada, completado em 13 dias, com a dose padrão, obtendo remissão clínica. Os esquemas de indução de infliximab acelerados ou intensificados têm vindo a tornar-se prática clínica habitual nos casos de agudização grave de colite ulcerosa refratária a corticosteróides. As diretrizes atuais referem a possibilidade deste tipo de estratégias, não indicando qual o regime ideal por falta de evidência sólida. A literatura baseia-se principalmente em estudos retrospetivos, não randomizados, com heterogeneidade de grupos de estudo de acordo com a gravidade da doença e o efeito nas taxas de colectomia, sobretudo a longo prazo, não é claro. Estudos mais fundamentados são necessários sobre esta matéria de modo a que seja possível uma abordagem amplamente mais uniforme.

Single-Grating Monolithic Spatial Heterodyne Raman Spectrometer: An Investigation on the Effects of Detector Selection.

Spatial heterodyne Raman spectrometers (SHRSs) are modified forms of Michelson interferometers, except the mirrors in a Michelson interferometer are replaced with stationary diffraction gratings. This design removes the need for an entrance slit, as is the case in a dispersive spectrometer, and removes the need to scan the spectrum by using a moving mirror in a modern Michelson interferometer. In previous studies, various SHRS variants, such as free-standing two-grating SHRS, single-grating SHRS (1g-SHRS), monolithic SHRS (mSHRS), and single-grating mSHRS (1g-mSHRS), have been evaluated. However, the present study exclusively focuses on the 1g-mSHRS configuration. The 1g-mSHRS and 1g-SHRS increase the spectral range at fixed grating line density while trading off spectral resolution and resolving power. The mSHRS benefits from increased rigidity, lack of moving parts, and reduced footprint. In this study, we investigate how the choice of detector impacts the performance of the 1g-mSHRS system, with a specific focus on evaluating the performance of three types of cameras: charged-coupled device (CCD), intensified CCD (ICCD), and complementary metal-oxide-semiconductor (CMOS) cameras. These systems were evaluated using geological, organic, and inorganic samples using a 532 nm continuous wave laser for the CMOS and CCD cameras, and a 532 nm neodymium-doped yttrium aluminum garnet pulsed laser for the ICCD camera. The footprint of the 1g-mSHRS was 3.5 × 3.5 × 2.5 cm3 with a mass of 272 g or 80 g, depending on whether the monolith housing is included or not. We found that increasing the number of pixels utilized along the x-axis of the camera increases fringe visibility (FV) and optimizes the resolution (by capturing the entirety of the grating and magnifying the fringes). The number of pixels utilized in the y-axis, chip size, and dimensions, affect the signal-to-noise ratio of the systems. Additionally, we discuss the effect of pixel pitch on the recovery of Fizeau fringes, including the relationship between the Nyquist frequency, aliasing, and FV.

An idiosyncratic MIMBO-NBRF based automated system for child birth mode prediction.

Predicting the mode of child birth is still remains one of the most complex and challenging tasks in ancient times. Also, there is no such strong methodologies are developed in the conventional works for birth mode prediction. Therefore, the proposed work objects to develop a novel and distinct optimization based machine learning technique for creating the child birth mode prediction system. This framework includes the modules of data imputation, feature selection, classification, and prediction. Initially, the data imputation process is performed to improve the quality of dataset by normalizing the attributes and filling the missed fields. Then, the Multivariate Intensified Mine Blast Optimization (MIMBO) technique is implemented to choose the best set of features by estimating the optimal function. After that, an integrated Naïve Bayes - Random Forest (NBRF) technique is developed by incorporating the functions of conventional NB and RF techniques. The novel contribution of this technique, a Bird Mating (BM) optimization technique is used in NBRF classifier for estimating the likelihood parameter to generate the Bayesian rules. The main idea of this paper is to develop a simple as well as efficient automated system with the use of hybrid machine learning model for predicting the mode of child birth. For this purpose, advanced algorithms such as MIMBO based feature selection, and NBRF based classification are implemented in this work. Due to the inclusion of MIMBO and BM optimization techniques, the performance of classifier is greatly improved with low computational burden and increased prediction accuracy. Moreover, the combination of proposed MIMBO-NBRF technique outperforms the existing child birth prediction methods with superior results in terms of average accuracy up to 99 %. In addition, some other parameters are also estimated and compared with the existing techniques for proving the overall superiority of the proposed framework.

Invited review: Total solids concentration in milk or milk replacer for dairy calves.

Restricting milk or milk replacer (MR) fed to dairy calves to 10% of body weight at 12.5% total solids (TS) concentration is a common feeding strategy that promotes early weaning and lowers total feed costs for raising young calves. However, this strategy has been associated with inferior performance and compromised welfare. Because a restricted liquid nutrition plan limits calf growth due to limited supply of nutrients, research on increased supply of nutrients from liquid has shown improved growth, health, and welfare of calves. Nutrient supply may be increased by feeding larger amounts of milk or MR averaging 12.5% TS, or by increasing TS above the usual 12.5% TS by increasing MR TS concentration alone (TS+), or by increasing TS concentration and volume simultaneously (TSV+). The objective of this review is to discuss liquid nutrition plans with greater TS concentration in MR or in milk diets, considering the effects of such strategies on performance and digestive tract development before weaning and the future performance of dairy calves. This review will focus on liquid nutrition plans that are based on increased TS concentration (i.e., TS+ or TSV+); therefore, enhanced liquid nutrition plans based only on increased volumes will not be the discussed. Improved growth rates have been observed in calves fed TSV+ programs. However, reduced starter intake preweaning can also have negative effects on dry matter intake, average daily gain, and digestibility postweaning. Feeding a TS+ program may reduce impairment of starter intake and therefore have positive effects on performance, nutrient digestibility, and health. When considering an accelerated nutrition plan with TS+ or TSV+, it is important to consider osmolality of the liquid diet. Further studies are necessary to confirm this hypothesis and the cost-benefit of alternative liquid nutrition plans, as well as the optimal TS concentration of milk or MR fed to dairy calves.

Improved endotoxin removal using ecofriendly detergents for intensified plasmid capture.

Increasing plasmid demand for both production of viral and gene therapies as well as nucleic acid based vaccines has highlighted bottlenecks in production. One bottleneck is traditional bead-based chromatography as a capture step. To meet the needs of fast-growing markets, new production solutions are needed. These solutions must enable efficient capture of a diverse range of plasmid types and excellent clearance of bacterial host impurities, such as endotoxin. Enhanced endotoxin clearance during chromatographic purification has previously been demonstrated with detergents such as Triton™ X-100. However, degradation products of Triton™ X-100 are known to have a negative environmental impact, and more sustainable, environmentally benign alternatives have been identified. This work establishes an efficient, intensified plasmid capture using convective anion exchange (AEX) chromatography. The feasibility of the intensified capture approach was assessed with different membrane and a monolith AEX supports. Various detergents from different physico-chemical classes were evaluated with different AEX technologies. Purification efficiency evaluated endotoxin and host cell protein (HCP) clearance, plasmid yield, potential interference of the detergents with analytical in-process control assays, and overall process compatibility. This comprehensive screening approach provides valuable insights to intensified plasmid production.

The Production of Intensified Qu and Its Microbial Communities and Aroma Variation during the Fermentation of Huangjiu (Chinese Rice Wine).

In recent years, intensified Qu (IQ) has been gradually applied to brewing in order to improve the aroma of Huangjiu (Chinese rice wine). In this study, Saccharomyces cerevisiae and Wickerhamomyces anomalus solutions were added to Fengmi Qu (FMQ) from Fangxian, China to produce IQ, and brewing trial was conducted. High-throughput sequencing (HTS) was used to analyze the microbial community in fermentation broth of IQ (IQFB). Headspace solid-phase microextraction (HS-SPME) combined with gas chromatography-mass spectrometry (GC-MS) and sensory evaluation were performed to analyze volatile aroma compounds (VACs) in sample without Qu and both fermentation broths. The results showed that Pediococcus, Cronobacter, Enterococcus, Weissella, and Acinetobacter and Saccharomycopsis, Wickerhamomyces, and Saccharomyces were dominant bacterial and fungal groups, respectively. A total of 115 VACs were detected, and the content of esters including ethyl acetate, isoamyl acetate, and so on was noticeably higher in IQFB. The finding of sensory evaluation reflected that adding pure yeast to Qu could enhance fruit and floral aromas. Correlation analysis yielded 858 correlations between significant microorganisms and different VACs. In addition, prediction of microbial community functions in IQFB revealed global and overview maps and carbohydrate metabolism to be the main one. This study is advantageous for further regulation of the fermentation process of Huangjiu by microbial means.