Treatment Sequence Research Articles

Enhancing Soil Resilience to Climatic Wetting‐Drying Cycles Through a Bio‐Mediated Approach

AbstractClimatic wetting‐drying cycles exacerbated by climate change can trigger several weakening mechanisms in surface soils, potentially leading to instability and failure of slopes and earthen structures. This study proposes a bio‐mediated approach based on microbially induced calcite precipitation (MICP) to increase soil resilience to wetting‐drying cycles. To explore its viability and the underlying mechanisms, we conducted a series of laboratory tests on clayey soil that underwent six wetting‐drying cycles. The tests were conducted with different treatment methods to investigate the effect of treatment sequence and cementation solution concentration. After MICP treatment, the initial evaporation rate, surface crack ratio during drying, and total soil weight loss during rainfall erosion were reduced by up to 32%, 85%, and 90%, respectively. Spraying the cementation solution first in the MICP treatment sequence proves more effective in improving soil water retention capacity. On the other hand, initiating the sequence with the bacterial solution demonstrates a more pronounced effect in reducing soil desiccation cracks and erosion. Microstructure analysis reveals that the content and distribution of CaCO3 precipitation are the major factors controlling the effectiveness of MICP for the cementation of clayey soil. Employing MICP can minimize the carbon footprint and contribute to developing environmentally friendly solutions for soil improvement in regions affected by climatic wetting‐drying cycles.

Histological Assessment of the Effectiveness of Microneedling Device-Assisted Filler Delivery.

Microneedling is used to enhance transcutaneous drug delivery. However, the extent to which microneedling devices impact filler delivery and whether this varies by filler type, microneedling device type, and treatment sequence is not known. To histologically assess and quantify the delivery of commonly used fillers through microneedling, using both a microneedling pen and a microneedling roller. In addition, the authors investigated whether there is a variation in filler delivery based on the sequence of microneedling in relation to topical filler application. Ex vivo human abdominal skin samples were subjected to microneedling pen or microneedling roller treatment. Black tissue marking ink, hyaluronic acid, poly- l -lactic acid, or undiluted calcium hydroxyapatite was topically applied before or immediately after microneedling treatment. Histological evaluation revealed a notable presence of black ink within channels formed by both microneedling treatments (15.5%-98.1%), whereas there was limited presence of the various filler types tested (0%-6.6%) in all settings. Topical application before microneedling treatment led to relatively higher filler/ink deposition within the channels formed by the microneedling treatments compared with topical application after microneedling. Transcutaneous delivery of fillers was not significantly helped by microneedling treatment, whereas the microneedling devices demonstrated effective delivery of an aqueous solution.

Long-term safety and efficacy of upadacitinib versus adalimumab in patients with rheumatoid arthritis: 5-year data from the phase 3, randomised SELECT-COMPARE study

ObjectivesTo assess the safety and efficacy of upadacitinib versus adalimumab from SELECT-COMPARE over 5 years.MethodsPatients with rheumatoid arthritis and inadequate response to methotrexate were randomised to receive upadacitinib 15 mg...

Attrition in the First Three Therapy Lines in Patients with Advanced Breast Cancer in the German Real-World PRAEGNANT Registry.

Background With more effective therapies for patients with advanced breast cancer (aBC), therapy sequences are becoming increasingly important. However, some patients might drop out of the treatment sequence due to deterioration of their life status. Since little is known about attrition in the real-world setting, this study assessed attrition in the first three therapy lines using a real-world registry. Methods Patients with information available on the first three therapy lines were selected from the German PRAEGNANT registry (NCT02338167). Attrition was determined for each therapy line using competing risk analyses, with the start of the next therapy line or death as endpoints. Additionally, a simple attrition rate was calculated based on the proportion of patients who completed therapy but did not start the next therapy line. Results Competitive risk analyses were performed on 3988 1st line, 2651 2nd line and 1866 3rd line patients. The probabilities of not starting the next therapy line within 5 years after initiation of 1st, 2nd and 3rd line therapy were 30%, 24% and 24% respectively. Patients with HER2-positive disease had the highest risk for attrition, while patients with HRpos/HER2neg disease had the lowest risk. Attrition rates remained similar across molecular subgroups in the different therapy lines. Conclusion Attrition affects a large proportion of patients with aBC, which should be considered when planning novel therapy concepts that specifically address the sequencing of therapies. Taking attrition into account could help understand treatment effects resulting from sequential therapies and might help develop treatment strategies that specifically aim at maintaining quality of life.

Failure to Undergo Resection Following Neoadjuvant Therapy for Resectable Pancreatic Cancer: A Secondary Analysis of SWOG S1505.

Neoadjuvant therapy (NT) is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC), and yet reasons for not undergoing subsequent pancreatectomy are poorly understood. Given the importance of completing multimodality therapy, we investigated factors associated with failure to undergo surgical resection following NT for PDAC. SWOG S1505 was a multicenter phase II randomized trial of preoperative mFOLFIRINOX or gemcitabine/nab-paclitaxel prior to planned pancreatectomy for patients with potentially resectable PDAC. Associations between clinical, demographic, and hospital-level characteristics and receipt of surgical resection were estimated via multiple logistic regression. Differences in overall survival from 18 weeks postrandomization (scheduled time of surgery) according to resection status were assessed via Cox regression models. Among 102 eligible patients, 73 (71.6%) underwent successful pancreatectomy, whereas 29 (28.4%) did not, primarily because of progression (n=11; 10.8%) or toxicity during NT (n=9; 8.8%). Weight loss during NT (odds ratio [OR], 0.34; 95% CI, 0.11-0.93) and the hospital's city size (small: OR, 0.24 [95% CI, 0.07-0.80] and large: OR, 0.28 [95% CI, 0.10-0.79] compared with midsize) were significantly associated with a lower probability of surgical resection in adjusted models, whereas age, sex, race, body mass index, performance status, insurance type, geographic region, treatment arm, tumor location, chemotherapy delays/modifications, and hospital characteristics were not. Surgical resection following NT was associated with improved overall survival (median, 23.8 vs 10.8 months; P<.01) even after adjusting for grade 3-5 adverse events during NT, performance status, and body mass index (hazard ratio, 0.55; 95% CI, 0.32-0.95). Failure to undergo resection following NT was relatively common among patients with potentially resectable PDAC and associated with worse survival. Although few predictive factors were identified in this secondary analysis of the SWOG S1505 randomized trial, further research must focus on risk factors for severe toxicities during NT that preclude surgical resection so that patient-centered interventions can be delivered or alternate treatment sequencing can be recommended.

Current Therapeutic Sequencing in Chronic Lymphocytic Leukemia.

The treatment landscape of chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults, is constantly changing. CLL patients can be divided into three risk categories, based on their IGHV mutational status and the occurrence of TP53 disruption and/or complex karyotype. For the first-line treatment of low- and intermediate-risk CLL, both the BCL2 inhibitor venetoclax plus obinutuzumab and the second generation BTK inhibitors (BTKi), namely acalabrutinib and zanubrutinib, are valuable and effective options. Conversely, venetoclax-based fixed duration therapies have not shown remarkable results in high-risk CLL patients, while continuous treatment with acalabrutinib and zanubrutinib displayed favorable outcomes, similar to those obtained in TP53 wild-type patients. The development of acquired resistance to pathway inhibitors is still a clinical challenge, and the optimal treatment sequencing of relapsed/refractory CLL is not completely established. Covalent BTKi-refractory patients should be treated with venetoclax plus rituximab, whereas venetoclax-refractory CLL may be treated with second generation BTKi in the case of early relapse, while venetoclax plus rituximab might be used if late relapse has occurred. On these grounds, here we provide an overview of the current state-of-the-art therapeutic algorithms for treatment-naïve patients, as well as for relapsed/refractory disease.

A Comprehensive Review of Taxane Treatment in Breast Cancer: Clinical Perspectives and Toxicity Profiles.

Taxanes, such as paclitaxel and docetaxel, have transformed the landscape of breast cancer treatment, playing pivotal roles in chemotherapy protocols for both early-stage and advanced/metastatic diseases. While these agents have demonstrated remarkable efficacy in enhancing patient outcomes, they are also linked to a range of adverse effects that can impact treatment tolerability and quality of life. This comprehensive review offers an in-depth exploration of taxane therapy in breast cancer, with a focus on clinical perspectives and toxicity profiles. We delineate the mechanisms of action of taxanes, their clinical effectiveness across various breast cancer subtypes, and the prevalent adverse effects encountered in clinical practice. Moreover, we deliberate on strategies for mitigating taxane-associated toxicity and optimizing treatment selection and sequencing based on individual patient characteristics and therapeutic objectives. Finally, we underscore areas for future research and advancement, encompassing the development of novel formulations, the identification of predictive biomarkers for treatment response, and the exploration of combination therapies to bolster therapeutic outcomes. By amalgamating existing evidence and clinical insights, this review aims to apprise clinicians and researchers of the current status of taxane treatment in breast cancer and steer endeavors towardfurther enhancing patient care and outcomes.

Treatment sequencing and impact of number of treatment lines on survival in follicular lymphoma: A national population-based study.

Follicular lymphoma (FL) is a clinically heterogeneous disease. The need for treatment, treatment sequencing, number of treatment lines, and its association with survival have not been described in a population-based setting. We identified all patients diagnosed with FL in the Swedish Lymphoma register from 2007 to 2014, followed until 2020, with detailed data on progression/relapse, transformation, and 2nd and further lines of therapy. During a median follow-up of 6.8 years, 1226 patients (69%) received 1st systemic treatment, 358 patients (20%) were managed with watch-and-wait (WaW) only, and 188 (10%) patients were treated with radiotherapy and did not require additional therapy during the study period. Among patients starting systemic treatment, 496 (40%), 224 (18%), and 88 (7%) received 2nd-, 3rd-, or 4th-line therapy, respectively. The 10-year cause-specific cumulative incidence of transformation was 13%. Among patients managed with 1st line R-single, R-CHOP, or BR, 54%, 33%, and 29% required 2nd line, respectively. The cumulative probability of starting subsequent treatment within 2 years was 26% after 1st line and 35% after 2nd line treatment. Two-year OS following 1st, 2nd, 3rd, and 4th line systemic treatment was 84%, 70%, 52%, and 36%, respectively, and remained similar when excluding transformations. We conclude that a substantial proportion of FL patients can be managed with WaW for a long period of time, while patients who require multiple treatment lines constitute a group with a large clinical unmet need. These results constitute valuable real-world reference data for FL.

Investigation on high cycle fatigue performance of additively manufactured Alloys: Synergistic effects of surface finishing and Post-Heat treatment

The high-cycle fatigue (HCF) behavior of additively manufactured (AM) materials in structural applications remains insufficiently explored when contrasted with conventionally fabricated alloys. Addressing this research gap, we systematically investigate the potential to enhance HCF performance in AM alloys through a strategic interplay of surface finishing and post-heat treatment design. Concentrating on laser powder bed fusion, we evaluate surface roughness and post-heat treatment effects on HCF life across a300to1000 MPa stress range. Findings show that, at700to1000 MPa, surface finishing significantly extends HCF life by mitigating crack initiation. Paradoxically, at300to700 MPa, it shortens HCF life due to induced local residual stress on the sample surface. Additionally, post-aging finishing moderately enhances HCF life compared to pre-aging. This underscores the crucial role of sequence in surface finishing and heat treatment, emphasizing their collective impact on fatigue properties. Our study advances the understanding of post-processing factors influencing AM alloy fatigue properties, providing valuable insights for enhancing mechanical performance.

Optimal Treatment Order With Fibula-Free Flap Reconstruction, Oncologic Treatment, and Dental Implants: A Systematic Review and Meta-Analysis.

Head and neck cancer (HNC) patients benefit from craniofacial reconstruction, but no clear guidance exists for rehabilitation timing. This meta-analysis aims to clarify the impact of oncologic treatment order on implant survival. An algorithm to guide placement sequence is also proposed in this paper. PubMed, Embase, and Web of Science were searched for studies on HNC patients with ablative and fibula-free flap (FFF) reconstruction surgeries and radiotherapy (RTX). Primary outcomes included treatment sequence, implant survival rates, and RTX dose. Of 661 studies, 20 studies (617 implants, 199 patients) were included. Pooled survival rates for implants receiving >60Gy RTX were significantly lower than implants receiving < 60Gy (82.8% versus 90.1%, P =0.035). Placement >1 year after RTX completion improved implant survival rates (96.8% versus 82.5%, P =0.001). Implants receiving pre-placement RTX had increased survival with RTX postablation versus before (91.2% versus 74.8%, P <0.001). One hundred seventy-seven implants were placed only in FFF with higher survival than implants placed in FFF or native bone (90.4% versus 83.5%, P =0.035). Radiotherapy is detrimental to implant survival rates when administered too soon, in high doses, and before tumor resection. A novel evidence-based clinical decision-making algorithm was presented for utilization when determining the optimal treatment order for HNC patients. The overall survival of dental prostheses is acceptable, reaffirming their role as a key component in rehabilitating HNC patients. Considerations must be made regarding RTX dosage, timing, and implant location to optimize survival rates and patient outcomes for improved functionality, aesthetics, and comfort.

Sequencing of Anti-CD19 Therapies in the Management of Diffuse Large B-Cell Lymphoma.

Several second- and third-line immunotherapeutic options for patients with relapsed or refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplant are directed against the B-cell antigen cluster of differentiation 19 (CD19). The anti-CD19 monoclonal antibody tafasitamab, paired with the immunomodulator lenalidomide, mediates antibody-dependent cellular toxicity and phagocytosis; the antibody-drug conjugate loncastuximab tesirine delivers the DNA cross-linking agent tesirine via CD19 binding and internalization; and CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) products are engineered from autologous T cells. Although CD19 expression is assessed at diagnosis, clinically relevant thresholds of CD19 expression-which may not be detectable using current routine methodologies-have not been defined and may vary between CD19-directed treatment modalities. Determining optimal treatment sequencing strategies for CD19-directed therapy is hampered by the exclusion of patients who have received prior CD19-directed therapies from major clinical trials. Antigen escape, which is attributed to mechanisms including epitope loss and defective cell surface trafficking of CD19, is an important cause of CAR-T failure. Limited data suggest that CD19 expression may be maintained after non-CAR-T CD19-directed therapy, and retrospective analyses indicate that some patients with disease relapse after CAR-T may benefit from subsequent CD19-directed therapy. To date, clinical evidence on the effect of anti-CD19 therapy prior to CAR-T has been limited to small case series. Prospective studies and detailed analyses are needed to understand how pretreatment and posttreatment CD19 expression correlates with clinical responses to subsequent CD19-directed therapy to fully maximize treatment strategies.

Immune Therapies in AL Amyloidosis-A Glimpse to the Future.

Light-chain (AL) amyloidosis is a rare plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains in target organs, leading to multi-organ dysfunction. Treatment approaches have historically mirrored but lagged behind those of multiple myeloma (MM). Recent advancements in MM immunotherapy are gradually being evaluated and adopted in AL amyloidosis. This review explores the current state of immunotherapeutic strategies in AL amyloidosis, including monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cell therapy. We discuss the unique challenges and prospects of these therapies in AL amyloidosis, including the exposure of frail AL amyloidosis patients to immune-mediated toxicities such as cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS), as well as their efficacy in promoting rapid and deep hematologic responses. Furthermore, we highlight the need for international initiatives and compassionate programs to provide access to these promising therapies and address critical unmet needs in AL amyloidosis management. Finally, we discuss future directions, including optimizing treatment sequencing and mitigating toxicities, to improve outcomes for AL amyloidosis patients.

Ruminal methane emission and lactational performance of cows fed rapeseed cake and oats on a grass silage–based diet

The objective of this experiment was to investigate the effect of lipid from rapeseed cake and oats on ruminal CH4 emission and lactational performance of dairy cows. Twelve lactating Nordic Red cows, of which 4 were primiparous, and averaging (±SD) 48 ± 22.9 DIM, 37.8 ± 7.14 kg/d milk yield were enrolled in a switch-back design experiment with 3 periods of 4 wk each. The cows were assigned into 6 pairs based on parity, DIM, milk yield, and BW at the beginning of the experiment. The experimental treatments were (1) rapeseed cake and oats (RSC+O), and (2) rapeseed meal and barley (RSM+B) as the concentrate feeds. Cows in each pair were randomly assigned to 1 of the 2 groups, which received the treatments in 2 different sequences (i.e., group 1 received RSC+O in period 1 and 3, and RSM+B in period 2, whereas group 2 was fed RSM+B in period 1 and 3, and RSC+O in period 2). The diets consisted of a partially mixed ration with grass silage mixed with either oats or barley, according to the treatment sequence, and the rapeseed cake or meal being mixed into a pellet with either oats or barley according to the treatments, and a mineral mix. The pellet was delivered at a fixed amount (i.e., 6 kg/d for multiparous and 5 kg/d for the primiparous cows) from the milking robot. The actual forage to concentrate ratios for RSC+O and RSM+B were 51:49 and 52:48, respectively, with NDF concentrations of 41.5% and 36.0% and CP concentrations of 17.0% and 16.7% of diet DM. Dry matter intake, milk yield, and gas exchange (with a GreenFeed system attached to the milking robot) were recorded daily, and milk composition and spot fecal samples were collected during the last week of each period. Based on feed analysis, and DMI of the cows during the experiment, the total fat content of the experimental diets was 4.1% and 2.7% of DM for RSC+O and RSM+B diets, respectively. Dry matter intake was 1.6 kg/d lower, and milk yield tended to be 1.0 kg/d greater for RSC+O versus RSM+B. There were no differences in ECM yield and milk composition between the treatments, whereas milk ME efficiency was greater for cows fed RSC+O than RSM+B. Methane yield (g/kg DMI) did not differ between treatments, but CH4 production (g/d) was 9.4% and CH4 intensity as g/kg ECM was 11.7% lower for RSC+O versus RSM+B. The lower CH4 production was likely caused by the lower DMI and fiber digestibility, observed with the RSC+O diet. In addition, the greater lipid intake also contributed to lower rate of fermentation and subsequent decrease in CH4 production. Overall, feeding rapeseed cake with oats in a grass silage-based diet increased feed efficiency while decreasing CH4 emission intensity in lactating cows. This provides a practical way of mitigating ruminal CH4 emission from dairy operations while maintaining milk production with commonly used feedstuffs in Nordic conditions.

Asymmetric Allylation of Aldoxime Derivatives with β‐Amidoallylboronate in Water and Its Application to Divergent Synthesis of N‐Hydroxy‐γ‐Lactam and 1,2‐Oxazinan‐6‐one

AbstractA new application involving a water–stable amido–functionalized allylboronate has been developed for 1,2‐addition to carbon–nitrogen double bonds. The process achieves highly enantioselective allylation of aldoxime derivatives in water, by employing O‐Boc oximes as substrates under Zn(OH)2–chiral aminophenol catalysis. This process affords the corresponding homoallylic amines with 91–96 % ee. The products could be transformed into N‐hydroxy‐γ‐lactam or 1,2‐oxazinan‐6‐one, through an acidic or a protection‐acidic treatment sequence, respectively, almost without enantiopurity loss.

Insight into the stabilization/solidification of Cd, Pb and Zn in MSWI FA by three stages: Vulcanization, precipitation and bio-oxidation

Bio-oxidation has been perceived as a promising treatment for the solidification/stabilization (S/S) of heavy metals (HMs) in mining soils. Nonetheless, no research exists on the integration of the iron-sulfur oxidizing bacterium Acidithiobacillus ferrooxidans as a microbial agent into the treatment of municipal solid waste incineration-fly ash (MSWI-FA). The effect of vulcanization (Stage I), precipitation (Stage II) and bio-oxidation (Stage III) on the stabilization of HMs in MSWI-FA was unexplored. This study investigated the stabilization effects of Stage I and Stage II by utilizing Na2S and FeSO4 to adjust the Fe/S ratio. The findings contributed to identifying suitable methods to enhance the stabilization effect of the microbial agent on MSWI-FA (Stage III). The results indicated that the vulcanization (Stage I) increased the compressive strength of MSWI-FA to 1.87 MPa when the concentration of Na2S reached 0.03 mM. The leaching toxicity of Cd, Pb, and Zn at 28 days after Stage II was 0.12 mg/L, 0.99 mg/L, and 356 mg/L, respectively, which improved by 96.3%, 94.8%, and 26.9% compared to the untreated samples. The compressive strength of the samples peaked at 1.97 MPa when the Fe/S ratio was 0.25 (precipitation (Stage II)). Despite the inhibitory effect of MSWI-FA on microbial activity, the leaching toxicity of Cd, Pb, and Zn in the presence of Acidithiobacillus ferrooxidans decreased to 0.07 mg/L, 0.17 mg/L and 97.3 mg/L at 28 days after Stage III, with no significant further increase in compressive strength. This study suggested that bio-oxidation utilizing iron sources may change the formation of iron oxides, thereby impacting the mechanical and chemical properties of MSWI-FA-based materials. The treatment sequence of vulcanization, precipitation and bio-oxidation proved effective in immobilizing HMs, particularly Pb, Cd, and Zn in MSWI FA. This research highlighted the potential of employing this technique to treat MSWI FA, yet it is essential to identify suitable reaction systems with appropriate additives to further enhance the long-term effectiveness and mechanical properties of MSWI-FA-based materials.

The Real-Life Impact of Primary Tumor Resection of Synchronous Metastatic Colorectal Cancer-From a Clinical Oncologic Point of View.

The complex medical care of synchronous metastatic colorectal (smCRC) patients requires prudent multidisciplinary planning and treatments due to various challenges caused by the primary tumor and its metastases. The role of primary tumor resection (PTR) is currently uncertain; strong arguments exist for and against it. We aimed to define its effect and find its best place in our therapeutic methodology. We performed retrospective data analysis to investigate the clinical course of 449 smCRC patients, considering treatment modalities and the location of the primary tumor and comparing the clinical results of the patients with or without PTR between 1 January 2013 and 31 December 2018 at the Institute of Oncotherapy of the University of Pécs. A total of 63.5% of the 449 smCRC patients had PTR. Comparing their data to those whose primary tumor remained intact (IPT), we observed significant differences in median progression-free survival with first-line chemotherapy (mPFS1) (301 vs. 259 days; p < 0.0001; 1 y PFS 39.2% vs. 26.6%; OR 0.56 (95% CI 0.36-0.87)) and median overall survival (mOS) (760 vs. 495 days; p < 0.0001; 2 y OS 52.4 vs. 26.9%; OR 0.33 (95% CI 0.33-0.53)), respectively. However, in the PTR group, the average ECOG performance status was significantly better (0.98 vs. 1.1; p = 0.0456), and the use of molecularly targeted agents (MTA) (45.3 vs. 28.7%; p = 0.0005) and rate of metastasis ablation (MA) (21.8 vs. 1.2%; p < 0.0001) were also higher, which might explain the difference partially. Excluding the patients receiving MTA and MA from the comparison, the effect of PTR remained evident, as the mOS differences in the reduced PTR subgroup compared to the reduced IPT subgroup were still strongly significant (675 vs. 459 days; p = 0.0009; 2 y OS 45.9 vs. 24.1%; OR 0.37 (95% CI 0.18-0.79). Further subgroup analysis revealed that the site of the primary tumor also had a major impact on the outcome considering only the IPT patients; shorter mOS was observed in the extrapelvic IPT subgroup in contrast with the intrapelvic IPT group (422 vs. 584 days; p = 0.0026; 2 y OS 18.2 vs. 35.9%; OR 0.39 (95% CI 0.18-0.89)). Finally, as a remarkable finding, it should be emphasized that there were no differences in OS between the smCRC PTR subgroup and metachronous mCRC patients (mOS 760 vs. 710 days, p = 0.7504, 2 y OS OR 0.85 (95% CI 0.58-1.26)). The role of PTR in smCRC is still not professionally justified. Our survey found that most patients had benefited from PTR. Nevertheless, further prospective trials are needed to clarify the optimal treatment sequence of smCRC patients and understand this cancer disease's inherent biology.

Did we personalize? Assessing personalization by an online reinforcement learning algorithm using resampling.

There is a growing interest in using reinforcement learning (RL) to personalize sequences of treatments in digital health to support users in adopting healthier behaviors. Such sequential decision-making problems involve decisions about when to treat and how to treat based on the user's context (e.g., prior activity level, location, etc.). Online RL is a promising datadriven approach for this problem as it learns based on each user's historical responses and uses that knowledge to personalize these decisions. However, to decide whether the RL algorithm should be included in an "optimized" intervention for real-world deployment, we must assess the data evidence indicating that the RL algorithm is actually personalizing the treatments to its users. Due to the stochasticity in the RL algorithm, one may get a false impression that it is learning in certain states and using this learning to provide specific treatments. We use a working definition of personalization and introduce a resampling-based methodology for investigating whether the personalization exhibited by the RL algorithm is an artifact of the RL algorithm stochasticity. We illustrate our methodology with a case study by analyzing the data from a physical activity clinical trial called HeartSteps, which included the use of an online RL algorithm. We demonstrate how our approach enhances data-driven truth-in-advertising of algorithm personalization both across all users as well as within specific users in the study.

Phage-antibiotic combinations in various treatment modalities to manage MRSA infections.

Introduction: The emergence of antibiotic resistance is a significant challenge in the treatment of bacterial infections, particularly in patients in the intensive care unit (ICU). Phage-antibiotic combination therapy is now being utilized as a preferred therapeutic option for infections that are multi-drug resistant in nature. Methods: In this study, we examined the combined impact of the staph phage vB_Sau_S90 and four antibiotics on methicillin-resistant Staphylococcus aureus (MRSA). We conducted experiments on three different treatment sequences: a) administering phages before antibiotics, b) administering phages and antibiotics simultaneously, and c) administering antibiotics before phages. Results: When the media was supplemented with sub-inhibitory concentrations of 0.25μg/mL and 1μg/mL, the size of the plaque increased from 0.5 ± 0.1mm (in the control group with only the phage) to 4 ± 0.2mm, 1.6 ± 0.1mm, and 1.6 ± 0.4mm when fosfomycin, ciprofloxacin, and oxacillin were added, respectively. The checkerboard analysis revealed a synergistic effect between the phages and antibiotics investigated, as indicated by a FIC value of less than 0.5. The combination treatment of phages and antibiotics demonstrated universal efficacy across all treatments. Nevertheless, the optimal effectiveness was demonstrated when the antibiotics were delivered subsequent to the phages. Utilizing the Galleria mellonella model, in vivo experiments showed that the combination of phage-oxacillin effectively eliminated biofilm-infected larvae, resulting in a survival rate of up to 80% in the treated groups. Discussion: Our findings highlight the advantages of using a combination of phage and antibiotic over using phages alone in the treatment of MRSA infections.

The use of Moringa Oleifera and Salvia Hispanica as auxiliaries in the solar disinfection water treatment process by Sodis

Solar Water Disinfection, known as SODIS, is a treatment method involving the exposure of water to solar radiation (UVA light and heat) to eliminate pathogenic microorganisms. Organic coagulants extracted from Moringa oleifera (T1) and Salvia hispanica (T2) were used in conjunction with the filtration process as auxiliaries. This process included sand filters with particle sizes ranging from 0.25 mm to 0.850 mm and a non-woven geotextile placed at its base. After undergoing the coagulation/flocculation/sedimentation/filtration process, the samples were exposed to sunlight in a solar concentrator using bottles painted on half of their surface (PR) and unpainted bottles (BR). The analyzed parameters included physicochemical properties such as pH, electrical conductivity, turbidity, and apparent color, as well as microbiological parameters, including E. coli and total coliforms. The results of physicochemical analyses demonstrated the superiority of T1 in terms of turbidity and apparent color. Regarding microbiological analyses, they showed the effective removal of E. coli and total coliforms, with 100% inactivation observed in the samples. It was observed that the applied treatment sequence significantly reduced the microbiological load of the samples; however, it cannot be stated with certainty whether the coagulants exerted any influence on this result. Keywords: coagulants, coliforms, filtration, microorganisms.

Premastectomy Radiotherapy and Immediate Breast Reconstruction

Premastectomy radiotherapy (PreMRT) is a new treatment sequence to avoid the adverse effects of radiotherapy on the final breast reconstruction while achieving the benefits of immediate breast reconstruction (IMBR). To evaluate outcomes among patients who received PreMRT and regional nodal irradiation (RNI) followed by mastectomy and IMBR. This was a phase 2 single-center randomized clinical trial conducted between August 3, 2018, and August 2, 2022, evaluating the feasibility and safety of PreMRT and RNI (including internal mammary lymph nodes). Patients with cT0-T3, N0-N3b breast cancer and a recommendation for radiotherapy were eligible. This trial evaluated outcomes after PreMRT followed by mastectomy and IMBR. Patients were randomized to receive either hypofractionated (40.05 Gy/15 fractions) or conventionally fractionated (50 Gy/25 fractions) RNI. The primary outcome was reconstructive failure, defined as complete autologous flap loss. Demographic, treatment, and outcomes data were collected, and associations between multiple variables and outcomes were evaluated. Analysis was performed on an intent-to-treat basis. Fifty patients were enrolled. Among 49 evaluable patients, the median age was 48 years (range, 31-72 years), and 46 patients (94%) received neoadjuvant systemic therapy. Twenty-five patients received 50 Gy in 25 fractions to the breast and 45 Gy in 25 fractions to regional nodes, and 24 patients received 40.05 Gy in 15 fractions to the breast and 37.5 Gy in 15 fractions to regional nodes, including internal mammary lymph nodes. Forty-eight patients underwent mastectomy with IMBR, at a median of 23 days (IQR, 20-28.5 days) after radiotherapy. Forty-one patients had microvascular autologous flap reconstruction, 5 underwent latissimus dorsi pedicled flap reconstruction, and 2 had tissue expander placement. There were no complete autologous flap losses, and 1 patient underwent tissue expander explantation. Eight of 48 patients (17%) had mastectomy skin flap necrosis of the treated breast, of whom 1 underwent reoperation. During follow-up (median, 29.7 months [range, 10.1-65.2 months]), there were no locoregional recurrences or distant metastasis. This randomized clinical trial found PreMRT and RNI followed by mastectomy and microvascular autologous flap IMBR to be feasible and safe. Based on these results, a larger randomized clinical trial of hypofractionated vs conventionally fractionated PreMRT has been started (NCT05774678). ClinicalTrials.gov Identifier: NCT02912312.