Dose Of Therapy Research Articles

Impact of oral melatonin supplementation on urine and serum melatonin concentrations and quality-of-life measures in persons with relapsing multiple sclerosis

IntroductionMelatonin is an antioxidant and anti-inflammatory agent that modulates the immune system by scavenging free radicals, reducing the upregulation of pro-inflammatory cytokines, and reducing transendothelial cell migration. Therefore, melatonin may play a role in regulating multiple sclerosis (MS) disease activity. However, little is known about how melatonin supplementation effects individuals with MS. ObjectiveDetermine if there was a dose-dependent elevation in urine and serum melatonin concentrations. Determine if melatonin supplementation had an impact on patient reported outcomes. MethodsThis was a randomized, dose-blinded exploratory study. Adults (age 18–65) with relapsing forms of multiple sclerosis (RMS) treated with a stable dose of oral disease modifying therapy for at least 6 months were randomized into melatonin 3 mg or 5 mg daily. Urinary and serum melatonin levels and modified fatigue impact scale (MFIS), multiple sclerosis impact scale (MSIS-29), and Pittsburgh sleep quality index (PSQI), patient determined disease steps (PDDS) and performance scales (PS) were measured at baseline, 3, 6, and 12 months. Urinary and serum melatonin analyses was performed to estimate mean concentrations and their differences between treatment arms over time by a repeated measures linear mixed model. The model included treatment, assessment time, and treatment × time interaction. ResultsThirty patients, randomized 1:1, were analyzed in an intent to treat population. Twenty-three completed the study. The repeated measures linear mixed model analysis of all timepoints revealed higher melatonin concentrations in patients on 5 mg compared to 3 mg melatonin for both urinary 6-SMT (p = 0.03) and serum melatonin (p = 0.04). MFIS, MSIS-29, PSQI, and PDSS-PS scores did not significantly change from baseline to month 12. No significant differences in these measures were seen between the two doses. Five patients stopped melatonin (three on 5 mg and two on 3 mg) due to adverse events, including one patient who developed focal spongiotic dermatitis. One patient experienced three consecutive serious adverse events that were unrelated to melatonin supplementation. ConclusionsThe 5 mg melatonin supplementation group had higher concentrations of urinary 6-SMT and serum melatonin compared to the 3 mg group over 12 months of treatment. There was a correlation between 6-SMT and serum melatonin concentrations. This suggests that measuring serum melatonin is a reliable alternative to measuring urinary 6-SMT. However, no differences in clinical benefit between the two dosage groups were demonstrated in the patient reported outcomes. Trial Registration NumberNCT03498131

Potential of Fasting C-peptide to Glucose Ratio and Triglyceride Glucose Index as Markers for β-Cell Dysfunction and Insulin Resistance in Patients With Type 2 Diabetes on Insulin Therapy.

Pathogenesis of type 2 diabetes mellitus (T2DM) is combined from initial insulin resistance (IR) and subsequent β-cell dysfunction. Insulin therapy can replace β-cell function in advanced stages. However excessive insulin therapy increases IR and may expose the patients to risk of cardiovascular disease. We aim to assess β-cell function and IR in patients with type 2 diabetes on insulin therapy by fasting C-peptide to glucose ratio (FCPGR), and triglyceride glucose (TyG) index respectively to support treatment plans. A cross-sectional study was conducted at the Galiawa Diabetes and Endocrinology Teaching Center in Erbil City, Iraq,from June 2023 to January 2024. A convenient sample of 100 patients with T2DM on insulin-based therapy were included after obtaining informed written consent and excluding conditions such as acute illness,uncertain type of diabetes, etc. Each patient was evaluated for anthropometric parameters and current treatment details. Biochemical tests were then carried out to calculate metabolic syndrome (MetS) index score, FCPGR, and TyG index. Finally, patients were divided into four subgroups according to their FCPGR and TyG index and the data were analyzed statistically. The data showed those patients with sufficient β-cell function were 60(60%), and patients withhigh TyG index were 95 (95%). There was a significant negative correlation betweenFCPGR and hemoglobin A1c (HbA1c) (p-value=0.001), while there was a positive correlation between TyG index and HbA1C (p-value=0.001). None of these markers were correlated with BMI (p-value=0.297, and 0.976), duration of T2DM (p-value=0.258, and 0.458), and dose of insulin therapy (p-value=0.901, and 0.477). Patients with sufficient β-cell function and high TyG index had the lowest HbA1C. The study provides valuable insights into the utility of FCPGR and TyG index as biomarkers for β-cell function and insulin resistance in T2DM patients on insulin therapy. The significant correlation with HbA1C underscores their potential in clinical practice. However, the lack of correlation with BMI, disease duration, and insulin dose suggests that further investigation is needed to fully understand these biomarkers' implications across diverse patient profiles.

Trends in the treatment of human papillomavirus-associated oropharyngeal carcinoma in Slovakia.

The optimal treatment of oropharyngeal cancer (OPC) associated with human papillomavirus (HPV) is currently a subject of clinical research. This questionnaire study investigated current trends in the treatment of HPV-associated (HPV+) OPC in Slovakia with the incorporation of deintensification of oncological treatment into routine clinical practice outside of clinical trials. The Slovak Cooperative Head and Neck Cancer Group (SCHNCG) developed a questionnaire aimed at identifying trends in the oncological treatment of HPV+ OPC intended for all radiation oncology (RO) facilities in Slovakia. Specialists in the field of RO responded to general questions about the character of their individual institutions as well as to 4 theoretical clinical scenarios (case reports) regarding the treatment of HPV+ OPC, focusing primarily on the applied dose of radiotherapy (RT), the extent of target volumes, and the type of concurrent chemotherapy (CHT). The questionnaire study involved 35 RO specialists from 14 institutions in Slovakia. Regarding primary chemoradiotherapy (CRT) in T1N1M0 HPV+ OPC, 16 respondents (45.7%) would consider de-escalation of the RT dose to <70 Gy. In the case of postoperative RT in pT1pN1M0 HPV+ OPC with negative resection margins (R0) and absent extracapsular extension (ECE), 4 physicians (11.4%) would consider de-escalation of the RT dose to <60 Gy in the tumor bed area, while the majority of the treating specialists (n=19, 54.3%) would omit concurrent CHT. In the case of primary RT in elderly patient with T2N1M0 HPV+ OPC, the same number of physicians (n=16, 45.7%) would consider de-escalation of the RT dose to <70 Gy, and 14 respondents (40.0%) would completely omit CHT. In a high-risk patient with T2N3M0 HPV+ OPC with a complete response after 3 cycles of induction chemotherapy (iCHT), none of the respondents would indicate a reduction in the RT dose to the area of the original tumor and lymphadenopathy to <60 Gy. The doses and extent of irradiated volumes in the treatment of HPV+ OPC in Slovakia vary among different institutions. The tendency to de-escalate RT doses and reduce doses of concurrent systemic therapy in Slovakia is high and there was also an observed trend to reduce the extent of radiation treatment fields.

Extracellular vesicles as the next-generation modulators of pharmacokinetics and pharmacodynamics of medications and their potential as adjuvant therapeutics.

Pharmacokinetics (PK) and pharmacodynamics (PD) are central concepts to guide the dosage and administration of drug therapies and are essential to consider for both healthcare professionals and researchers in therapeutic planning and drug discovery. PK/PD properties of a drug significantly influence variability in response to treatment, including therapeutic failure or excessive medication-related harm. Furthermore, suboptimal PK properties constitute a significant barrier to further development for some candidate treatments in drug discovery. This article describes how extracellular vesicles (EVs) affect different aspects of PK and PD of medications and their potential to modulate PK and PD properties to address problematic PK/PD profiles of drugs. We reviewed EVs' intrinsic effects on cell behaviours and medication responses. We also described how surface and cargo modifications can enhance EV functionalities and enable them as adjuvants to optimise the PK/PD profile of conventional medications. Furthermore, we demonstrated that various bioengineering strategies can be used to modify the properties of EVs, hence enhancing their potential to modulate PK and PD profile of medications. This review uncovers the critical role of EVs in PK and PD modulation and motivates further research and the development of assays to unfold EVs' full potential in solving PK and PD-related problems. However, while we have shown that EVs play a vital role in modulating PK and PD properties of medications, we postulated that it is essential to define the context of use when designing and utilising EVs in pharmaceutical and medical applications. Existing solutions for pharmacokinetics and pharmacodynamics modulation are limited. Extracellular vesicles can optimise pharmacokinetics as a drug delivery vehicle. Biogenesis and administration of extracellular vesicles can signal cell response. The pharmaceutical potential of extracellular vesicles can be enhanced by surface and cargo bioengineering. When using extracellular vesicles as modulators of pharmacokinetics and pharmacodynamics, the 'context of use' must be considered.

National Cancer Database analysis of radiation therapy consolidation modality and dose for inoperable endometrial cancer

We utilized the National Cancer Database (NCDB) to evaluate trends and assess outcomes in radiation therapy (RT) boost modality and total dose among medically inoperable endometrial cancer (EC) patients with locoregional disease. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage I - IIIC2 inoperable EC treated with RT ± chemotherapy were analyzed. Practice patterns compared external beam RT (EBRT) versus high-dose-rate brachytherapy (BT) boost and total RT dose (palliative: ≤3000 cGy, definitive low dose [DLD]: 4500 - 6249 cGy, definitive high dose [DHD]: ≥6250 cGy) over time. Kaplan-Meier method evaluated overall survival (OS) and Cox proportional hazard modeling assessed variables associated with OS. NCDB included 1755 total cases, of which 1209 received a radiotherapy boost. From 2004 to 2019, boost modality rates differed with increasing utilization of BT consolidation and a decreasing rate of palliation. Predictors of a palliative dose were stage III disease, Black race, N2 disease, and poorly or undifferentiated grade. Multivariable analysis found BT boost was associated with lower mortality compared to EBRT (HR: 0.81, CI: 0.68-0.97; p = 0.019). Mortality rates were higher for palliation versus DHD. Additional factors associated with inferior survival were increasing age, worse Charlson-Deyo score, higher T stage, higher N stage, and moderately, poorly, or undifferentiated grade. Utilization of BT boost for locoregionally confined, medically inoperable EC has increased since 2004. Brachytherapy consolidation remains an effective RT modality for medically inoperable EC, associated with lower mortality compared to EBRT consolidation.

Endocrine, gender dysphoria, and sexual function benefits of gender-affirming bilateral orchiectomy: patient outcomes and surgical technique.

Gender-affirming bilateral orchiectomy (GABO) may be completed as either a standalone procedure (sGABO) or at the same time as gender-affirming vaginoplasty (vGABO). GABO is postulated to decrease gender-affirming hormone therapy (GAHT) dosages and reduce gender dysphoria, but these phenomena are not empirically described in the medical literature. The primary aim of this study was to describe changes in GAHT dosages after sGABO and vGABO. A secondary aim was to assess sGABO patients' preoperative decision-making priorities and postoperative satisfaction. A retrospective chart review identified 204 patients who completed GABO as either a standalone procedure (64% of patients) or at the same time as vaginoplasty (36%). Patient demographic data, surgical outcomes, and pre- and postoperative GAHT dosage data were recorded. Patients completed an opinion questionnaire to assessed decision-making priorities, as well as postoperative satisfaction and changes in quality-of-life measures. Primary outcomes included pre- and postoperative dosages of estradiol, progesterone, and spironolactone. Secondary outcomes included sGABO patient priorities, satisfaction with sGABO, changes in quality-of-life measures between sGABO and vGABO patients, and sGABO recommendations to future patients. The sGABO and vGABO patients experienced a statistically significant dosage reduction in all three GAHT assessed: estradiol, progesterone, and spironolactone (P < .05). All patients discontinued spironolactone postoperatively. Zero complications related to GABO were recorded for patients in either group. The patient questionnaire revealed that sGABO patients prioritize decreasing endogenous testosterone and reducing their GAHT as most important in their decision to undergo sGABO prior to vaginoplasty. A majority of sGABO patients reported improvement in all nine quality-of-life indices. None of the sGABO patients would recommend against sGABO to a friend who is waiting for vaginoplasty. For patients who are interested in vaginoplasty, sGABO may serve as a more immediate, low-risk, intermediary step that comes with the benefits of GABO, including significant GAHT medication reduction and gender dysphoria relief. This study offers a comprehensive evaluation of the impact of GABO on patients, combining empirical data with subjective patient feedback. Limitations include the retrospective design and the use of unvalidated survey questions. Prevaginoplasty GABO is a viable option to more immediately alleviate gender dysphoria and reduce GAHT medications for patients who are interested in gender-affirming vaginoplasty.

Association Between Periodontal Diseases and Hypothyroidism: A Case-Control Study.

Periodontal diseases are chronic inflammatory disorders influenced by systemic health of the individual. This study aimed to investigate the association between hypothyroidism and periodontal disease in a cohort of adult Saudi population. This case-control study included 201 adults with hypothyroidism on hormone replacement therapy and 188 healthy controls. The medical files of patients were reviewed to check thyroid stimulation hormone (TSH) and free thyroxine (FT4) levels. Participants completed a questionnaire on demographic and health information, followed by a comprehensive periodontal examination. Pearson chi-square and binary logistic regression analyses determined associations, with a significance set at p ≤0.05. Gingivitis was found in 20.9% of cases and 58% of controls. Periodontitis stages I, II, III and IV were in general higher in cases compared to controls (23.4%, 27.9%, 21.9%, 6% in cases versus 13.8%, 17%, 9.6%, 1.6% in controls, respectively). Mean PPD and CAL values were higher in cases (5.54 ± 2.5 and 3.88 ± 3.1) than in controls (4.03 ± 1.6 and 1.72 ± 2.4). Significant associations between periodontal status and hypothyroidism were found (p < 0.0001). The periodontal status in hypothyroid cases correlated significantly with hormone replacement therapy dose and duration (p < 0.0001). The findings of the current study showed that, in a cohort of adult Saudi subjects, patients with hypothyroidism have higher prevalence and more severe periodontal disease symptoms compared to controls, suggesting significant association.

Development of a novel dosing paradigm to model diazepam rescue therapy in preclinical seizure and epilepsymodels.

Diazepam is a cornerstone immediate-use antiseizure rescue therapy that may extend the duration between seizure clusters in people living with epilepsy. However, our mechanistic understanding of intermittent rescue therapy on disease progression is limited by the lack of suitable preclinical models. Specifically, the pharmacokinetics of diazepam varies widely between humans and laboratory animals. Here, we developed a novel repeat rescue therapy dosing paradigm in rats to maintain prolonged therapeutic concentrations seen in humans. Rats received three diazepam doses separated by 1 h (0.75, 1.5, or 3 mg/kg, intraperitoneal); plasma and brains were collected at 10 min and 1, 3, or 6 h following the last dose. Plasma and brain concentrations followed a dose-dependent increase with peak concentrations following the repeat 3 mg/kg paradigm (180 ng/mL) being equivalent to plasma levels observed in human studies with diazepam nasal spray. Increased brain-to-plasma ratios in this paradigm indicate that diazepam accumulation in the brain may be long-acting at the site of action. Overall, our repeat diazepam dosing paradigm mimics drug concentrations and accumulation seen in humans, offering a preclinical tool to study the impact of benzodiazepine rescue therapy on seizure-cluster biology in rodent models of epilepsy. PLAIN LANGUAGE SUMMARY: There is more to learn about how diazepam works in the brains of people who use it only when they have two or more seizures in 24 h (this is called a seizure cluster). Ethical studies in animals can be used to learn more about medicines in the body. In this study, we showed that three doses of diazepam in rats give about the same amount of the drug as one dose for a person. We can now test rats with epilepsy to see how the drug might work in people who take it when needed for seizure clusters.

Shedding more than weight: Metabolic and bariatric surgery and the journey to insulin independence in insulin-treated type 2 diabetes

BackgroundType 2 diabetes (T2D) imposes a significant health burden, necessitating lifelong pharmacological interventions, with insulin being one of the cornerstone therapies. However, these regimens are associated with health risks and psychological stressors. This study aimed to examine the rates of insulin-treated T2D remission and cessation or reduction in the dosage of insulin therapy after metabolic and bariatric surgery (MBS). MethodsThis was a retrospective analysis of patients with a preoperative diagnosis of insulin-treated T2D who underwent primary laparoscopic sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion with duodenal switch (BPD/DS) with a minimum of 3 and up to 5 years of follow-up. The average daily dose for each type of insulin, measured in units, was calculated at annual intervals. ResultsAmong 287 patients included, 201 (70%) underwent RYGB, 66 (23%) underwent SG, and 20 (7%) underwent BPD/DS. The average follow-up period was 4.6 ± 0.7 years. At 5 years follow-up, the mean total weight loss was the highest in the BPD/DS subgroup at 37.5% ± 11.6%. Insulin usage decreased significantly from complete dependency at baseline to 36.2% just 1 year postoperatively, and the use of noninsulin antidiabetic drugs decreased from 79.4% initially to 26.1%. These results were sustained throughout the study period. The subgroup analysis indicated that, 5 years after surgery, T2D remission was the highest after BPD/DS (73.7%) compared with RYGB (43.2%) and SG (23.3%) (P < .001). ConclusionMBS is a transformative approach for achieving significant remission in insulin-treated T2D and reducing insulin requirements. Our findings reinforce the efficacy of these surgical interventions, particularly highlighting the promising potential of procedures that bypass the proximal small intestine, such as BPD/DS and RYGB.

Treatment adjustment in biologic therapies for moderate-to-severe plaque psoriasis: a German retrospective chart review (TABU).

Flexible biologic therapy dosing regimens in psoriasis management are common, but data from routine care in Germany are scarce. This study evaluated treatment adjustments for biologic therapies commonly prescribed in Germany. Charts for up to 100 consecutive patients treated at 29centers were reviewed. Data were extracted for adults (aged 18-65years) with moderate-to-severe plaque psoriasis treated with adalimumab, guselkumab, ixekizumab, secukinumab, or ustekinumab for ≥36weeks. The primary endpoint was time to first treatment adjustment. Secondary endpoints included frequency of and reasons for treatment adjustments. Time to treatment adjustment was analyzed using Kaplan-Meier methods. Among 982 patients, 297 treatment adjustments in 240 (24.4%) patients were identified. The mean (median; interquartile range) time to first treatment adjustment (n=223) was 8.4 (4.0; 2.0-12.0) months (secukinumab: 14.1 [10.0; 4.0-21.0], adalimumab: 11.0 [7.0; 3.0-14.5], ustekinumab: 11.0 [6.0; 2.0-16.0], ixekizumab: 5.8 [3.0; 2.0-8.5], guselkumab: 5.1 [3.0; 2.0-7.0]). The most frequent adjustment type was starting concomitant treatment(s) (10.4% of patients); insufficient skin effectiveness was the most frequent reason for adjustment. Biological treatment adjustments are frequent in moderate-to-severe psoriasis; flexible dosing regimens would support optimal management.

Echocardiographic Functional Outcomes Following Regional Nodal Irradiation for Breast Cancer Using Volumetric Modulated Arc Therapy

Regional nodal irradiation (RNI) for breast cancer yields improvements in disease outcomes, yet comprehensive target coverage often increases cardiac radiation therapy (RT) dose. Volumetric modulated arc therapy (VMAT) may mitigate high-dose cardiac exposure, although it often increases the volume of low-dose exposure. The cardiac implications of this dosimetric configuration (in contrast to historic 3D conformal techniques) remain uncertain. Eligible patients receiving adjuvant RNI using VMAT for locoregional breast cancer were prospectively enrolled in an IRB-approved study. Echocardiograms were performed prior to RT, at the conclusion of RT, and 6 months following RT. Echocardiographic parameters were measured by a single reader and measures were compared pre- and post-RT via the signed-rank test. Changes in echocardiographic parameters over time were compared to mean and max heart doses via the Spearman correlation test. Among 19 evaluable patients (median age 38 years), 89% (n = 17) received doxorubicin and 37% (n = 7) received trastuzumab/pertuzumab combination therapy. All patients received VMAT-based whole-breast/chest wall and RNI. The average mean heart dose was 456 cGy (range, 187-697 cGy) and the average max heart dose was 3001 cGy (1560-4793 cGy). Among salient echocardiographic parameters, no significant decrement in cardiac function was observed when comparing pre-RT to 6 months post-RT: mean left ventricular ejection fraction (LVEF) was 61.8% (SD 4.4%) pre-RT and 62.7% (SD 3.8%) 6 months post-RT (P = .493); mean global longitudinal strain (GLS) was -19.3% (SD 2.2%) pre-RT and -19.6% (SD 1.8%) 6 months post-RT (P = .627). No individual patient exhibited reduced LVEF or sustained decrement in GLS. No correlations were observed for changes in LVEF or GLS when compared to mean or maximum heart doses (P > .1 for all). VMAT for left-sided RNI yielded no significant early decrement in echocardiographic parameters of cardiac function, including LVEF and GLS, within this limited cohort. No patient exhibited significant LVEF changes, and none exhibited sustained decrements in GLS. VMAT may be a reasonable approach to cardiac avoidance in patients requiring RNI, including those receiving anthracyclines and HER2-directed therapy. Larger cohorts with longer follow-ups will be needed to validate these findings.

AP-1 Mediates Cellular Adaptation and Memory Formation During Therapy Resistance.

Cellular responses to environmental stimuli are typically thought to be governed by genetically encoded programs. We demonstrate that melanoma cells can form and maintain cellular memories during the acquisition of therapy resistance that exhibit characteristics of cellular learning and are dependent on the transcription factor AP-1. We show that cells exposed to a low dose of therapy adapt to become resistant to a high dose, demonstrating that resistance was not purely selective. The application of therapy itself results in the encoding of transient gene expression into cellular memory and that this encoding occurs for both transiently induced and probabilistically arising expression. Chromatin accessibility showed concomitant persistence. A two-color AP-1 reporter system showed that these memories are encoded in cis, constituting an example of activating cis epigenetics. Our findings establish the formation and maintenance of cellular memories as a critical aspect of gene regulation during the development of therapy resistance.

The effect of a psychological scare on the dynamics of the tumor-immune interaction with optimal control strategy

Contracting cancer typically induces a state of terror among the individuals who are affected. Exploring how chemotherapy and anxiety work together to affect the speed at which cancer cells multiply and the immune system’s response model is necessary to come up with ways to stop the spread of cancer. This paper proposes a mathematical model to investigate the impact of psychological scare and chemotherapy on the interaction of cancer and immunity. The proposed model is accurately described. The focus of the model’s dynamic analysis is to identify the potential equilibrium locations. According to the analysis, it is possible to establish three equilibrium positions. The stability analysis reveals that all equilibrium points consistently exhibit stability under the defined conditions. The bifurcations occurring at the equilibrium sites are derived. Specifically, we obtained transcritical, pitchfork, and saddle-node bifurcation. Numerical simulations are employed to validate the theoretical study and ascertain the minimum therapy dosage necessary for eradicating cancer in the presence of psychological distress, thereby mitigating harm to patients. Fear could be a significant contributor to the spread of tumors and weakness of immune functionality.

Neoadjuvant Exercise Therapy in Prostate Cancer

Observational data have shown that postdiagnosis exercise is associated with reduced risk of prostate cancer death. The feasibility and tumor biological activity of exercise therapy is not known. To identify recommended phase 2 dose of exercise therapy for patients with prostate cancer. This single-center, phase 1a dose-finding trial was conducted at a tertiary cancer center using a patientcentric, decentralized platform and included 53 inactive men with treatment-naive localized prostate cancer scheduled to undergo surgical resection between June 2019 and January 2023. Data were analyzed in June 2024. Six escalated exercise therapy dose levels ranging from 90 to 450 minutes per week of individualized, moderate-intensity treadmill walking, allocated using adaptive continual reassessment. All exercise therapy sessions were conducted remotely with real-time monitoring. Feasibility was evaluated by relative exercise dose intensity (REDI). A dose level was considered feasible if 70% or more of patients achieved an REDI of 75% or greater. Activity end points were changes in tumor cell proliferation (Ki67) and plasma prostate-specific antigen levels between pretreatment and postintervention. Safety and changes in patient physiology were also assessed. A total of 53 men were enrolled (median [IQR] age, 61 [56-66] years). All dose levels were feasible (≥75% REDI). The mean (95% CI) changes in Ki67 were 5.0% (-4.3% to 14.0%) for 90 minutes per week, 2.4% (-1.3% to 6.2%) for 150 minutes per week, -1.3% (-5.8% to 3.3%) for 225 minutes per week, -0.2% (-4.0% to 3.7%) for 300 minutes per week, -2.6% (-9.2% to 4.1%) for 375 minutes per week, and 2.2% (-0.8% to 5.1%) for 450 minutes per week. Changes in prostate-specific antigen levels were 1.0 ng/mL (-1.8 to 3.8) for 90 minutes per week, 0.2 ng/mL (-1.1 to 1.5) for 150 minutes per week, -0.5 ng/mL (-1.2 to 0.3) for 225 minutes per week, -0.2 (-1.7 to 1.3) for 300 minutes per week, -0.7 ng/mL (-1.7 to 0.4) for 375 minutes per week, and -0.9 ng/mL (-2.4 to 0.7) for 450 minutes per week. No serious adverse events were observed. Overall, 225 minutes per week (approximately 45 minutes per treatment at 5 times weekly) was selected as the recommended phase 2 dose. The results of this nonrandomized clinical trial suggest that neoadjuvant exercise therapy is feasible and safe with promising activity in localized prostate cancer. ClinicalTrials.gov Identifier: NCT03813615.

Early and long-term responses of intestinal microbiota and metabolites to 131I treatment in differentiated thyroid cancer patients

BackgroundMultiple high doses of 131I therapy in patients with differentiated thyroid cancer (DTC) might disrupt the balance of gut microbiota and metabolites. This study aimed to investigate the alterations of intestinal bacteria and metabolism over two courses of 131I therapy, explore the interactions, and construct diagnostic models reflecting enteric microecology based on 131I therapy.MethodsA total of 81 patients were recruited for the first 131I therapy (131I-1st), among whom 16 received a second course (131I-2nd) after half a year. Fecal samples were collected 1 day before (Pre-131I-1st/2nd) and 3 days after (Post-131I-1st/2nd) 131I therapy for microbiome (16S rRNA gene sequencing) and metabolomic (LC–MS/MS) analyses.ResultsA total of six microbial genera and 11 fecal metabolites enriched in three pathways were identified to show significant differences between Pre-131I-1st and other groups throughout the two courses of 131I treatment. In the Post-131I-1st group, the beneficial bacteria Bifidobacterium, Lachnoclostridium, uncultured_bacterium_f_Lachnospiraceae, and Lachnospiraceae_UCG004 were abundant and the radiation-sensitive pathways of linoleic acid (LA), arachidonic acid, and tryptophan metabolism were inhibited compared with the Pre-131I-1st group. Compared with the Pre-131I-1st group, the Pre-131I-2nd group exhibited a reduced diversity of flora and differentially expressed metabolites, with a low abundance of beneficial bacteria and dysregulated radiation-sensitive pathways. However, less significant differences in microbiota and metabolites were found between the Pre/Post-131I-2nd groups compared with those between the Pre/Post-131I-1st groups. A complex co-occurrence was observed between 6 genera and 11 metabolites, with Lachnoclostridium, Lachnospiraceae_UCG004, Escherichia-Shigella, and LA-related metabolites contributing the most. Furthermore, combined diagnostic models of charactered bacteria and metabolites answered well in the early, long-term, and dose-dependent responses for 131I therapy.ConclusionsDifferent stages of 131I therapy exert various effects on gut microecology, which play an essential role in regulating radiotoxicity and predicting the therapeutic response.

Prediction of Radiation Therapy Dose Distribution Using Random Forest Algorithm in Volumetric Modulated Arc Therapy Technique for Brain Cancer

Optimization of radiation dose distribution in clinical planning using a Treatment Planning System (TPS) for radiotherapy patients is crucial to achieving a balance between therapeutic effectiveness and patient safety. However, this process is time-consuming and relies heavily on the expertise of medical physicists. In this study, dose prediction using machine learning was performed on the Planning Target Volume (PTV) and Organ at Risk (OAR) for brain cancer cases using the Volumetric Modulated Arc Therapy (VMAT) planning technique. The planning DICOM data were extracted for radiomic and dosiomic values, which were then used as input and output in this study using a random forest algorithm model. Model evaluation results indicated that the random forest model's performance in predicting dose had a Mean Square Error (MSE) value of 0.018. The Homogeneity Index (HI) and Conformity Index (CI) values for the clinical data were 0.136±0.134 and 0.939±0.131 respectively, while the predicted results were 0.136±0.039 and 0.949±0.006, with p-values for PTV and OAR features &gt; 0.05. Thus, it can be concluded that the random forest model is effective in predicting dose for PTV brain cancer and OAR and can function as a reference in the planning process.

Evaluating therapeutic potential of NR2E3 doses in the rd7 mouse model of retinal degeneration

Retinitis Pigmentosa is a leading cause of severe vision loss. Retinitis Pigmentosa can present with a broad range of phenotypes impacted by disease age of onset, severity, and progression. This variation is influenced both by different gene mutations as well as unique variants within the same gene. Mutations in the nuclear hormone receptor 2 family e, member 3 are associated with several forms of retinal degeneration, including Retinitis Pigmentosa. In our previous studies we demonstrated that subretinal administration of one Nr2e3 dose attenuated retinal degeneration in rd7 mice for at least 3 months. Here we expand the studies to evaluate the efficacy and longitudinal impact of the NR2E3 therapeutic by examining three different doses administered at early or intermediate stages of retinal degeneration in the rd7 mice. Our study revealed retinal morphology was significantly improved 6 months post for all doses in the early-stage treatment groups and for the low and mid doses in the intermediate stage treatment groups. Similarly, photoreceptor function was significantly improved in the early stage for all doses and intermediate stage low and mid dose groups 6 months post treatment. This study demonstrated efficacy in multiple doses of NR2E3 therapy.

Prophylactic Dose of Rivaroxaban Versus Warfarin for the Treatment of Isolated Calf Muscle Vein Thrombosis: A Retrospective Propensity Score-Matched Analysis

BackgroundProphylactic dose of rivaroxaban is often used in treatment of isolated calf muscle vein thrombosis (ICMVT), nevertheless, its effect is less reported. This study aims to evaluate short-term outcomes in patients with ICMVT who received prophylactic dose of rivaroxaban or warfarin therapy. MethodsA retrospective analysis of 472 ICMVT patients who received two different treatment regimens was undertaken. Propensity score matching method was used to balance the confounding effect of baseline clinical data. Chi-squared test and logistic regression analysis were used to compare outcomes (venous thromboembolism events, bleeding events, complete clot resolution) according to the type of treatment regimens before and after propensity score matching. Univariate and multivariable analysis were used to investigate risk factors for incomplete clot resolution of ICMVT after propensity score matching. Results242 ICMVT patients received prophylactic dose of rivaroxaban (rivaroxaban group, RG), and 230 received warfarin (warfarin group, WG). After propensity score matching, 156 patients were included in each group; Venous thromboembolism (VTE) events occurred in 14 (9.0%) patients in the RG and 10 (6.4%) in the WG (P = 0.395); No major bleeding events occurred in each group, and clinically relevant non-major bleeding events occurred in 5 (3.2%) patients in the RG and 10 (6.4%) in the WG (P = 0.186); Complete clot resolution at 3 months occurred in 80 (51.3%) patients in the RG and 100 (64.1%) in the WG (P = 0.022). Logistic regression analysis showed that there were no significant differences between RG and WG in VTE events (odds ratio 1.439, 95% confidence interval 0.619 to 3.347, P = 0.397) and clinically relevant non-major bleeding events (odds ratio 0.483, 95% confidence interval 0.161 to 1.449, P = 0.194); it revealed that complete clot resolution rate at 3 months was different in the two groups (odds ratio 0.589, 95% confidence interval 0.375 to 0.928, P = 0.022). Treatment regimens (prophylactic dose of rivaroxaban), thrombosis (maximum diameter >7 mm) and risk factors for VTE (non-surgery risk factors, mainly referring to active malignancy) were risk factors for incomplete clot resolution of ICMVT (P < 0.05). ConclusionsIn this retrospective study with a short-term follow-up, ICMVT patients who received prophylactic dose of rivaroxaban had no significant differences in VTE and bleeding events compared to those who received warfarin therapy (the overall INR > 2.0 for >50% of the time); but it was not conducive to complete clot resolution.

ANTIBIOTICS CONSUMPTION AMONG HOSPITALIZED PATIENTS IN INTENSIVE CARE UNITS AT SANA’A CITY, YEMEN

Background: Monitoring antibiotic consumption is crucial to addressing antimicrobial resistance. The aim of current study was to investigate the use and consumption of antibiotics in an intensive care unit in Sana'a, Yemen using DDD and DOT methods, and to our knowledge it is the first of its kind to study this topic. Methods: A retrospective study on data from the ICU register. The study was carried out from September 2021 to February 2022 on hospitalized patients of five ICUs of main hospitals at 2020. Antimicrobial consumption data were mostly collected manually. Data were analyzed and presented as defined daily dose (DDD) and days of therapy (DOT) per 1000 patient-days. Results: A total of 1970 patients were included in this study and the overall consumption of antibiotics in ICUs was as high as 18,017.91 DDD per 1000 patient-days and as high as 17448.73 DOT per 1000 patient-days. The study results found that ceftriaxone, vancomycin, and meropenem were most frequently consumed using DDD and DOT methods among ICU patients, with results by DDDs per 1000 patient-days being 2479.23, 2124.55, and 1830.54, respectively, and results by DOTs per 1,000 patient days being 2,112.69. 2055.33 and 1890.86. The highest amount of antibiotics consumption among WHO AWaRe classification was for "watch" group of 26267.4 and 14674.5 DDDs per 1000 patient per day. Conclusions: A high consumption of antimicrobial agents such as ceftriaxone, vancomycin and meropenem was found in ICUs of five selected hospitals. There was a significant increasing in “Watch” group antibiotics use and about three-fourths of the prescribed antibiotics were from this group. The study results can be used as a basis before designing any intervention aimed at improving antibiotic use in hospital intensive care units. Peer Review History: Received 21 March 2024; Revised 4 May 2024; Accepted 26 June; Available online 15 July 2024 Academic Editor: Dr. Rola Jadallah, Arab American University, Palestine, rola@aauj.edu Average Peer review marks at initial stage: 5.5/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Dr. Mahmut Yıldıztekin, Muğla Sıtkı Koçman University, Turkey, mahmutyildiztekin@mu.edu.tr Dr. Masoumeh Divar, Shiraz University, Shiraz, Iran, zhaledivar@gmail.com

Can input reconstruction be used to directly estimate uncertainty of a dose prediction U-Net model?

The reliable and efficient estimation of uncertainty in artificial intelligence (AI) models poses an ongoing challenge in many fields such as radiation therapy. AI models are intended to automate manual steps involved in the treatment planning workflow. We focus in this study on dose prediction models that predict an optimal dose trade-off for each new patient for a specific treatment modality. They can guide physicians in the optimization, be part of automatic treatment plan generation or support decision in treatmentindication. Most common uncertainty estimation methods are based on Bayesian approximations, like Monte Carlo dropout (MCDO) or Deep ensembling (DE). These two techniques, however, have a high inference time (i.e., require multiple inference passes) and might not work for detecting out-of-distribution (OOD) data (i.e., overlapping uncertainty estimate for in-distribution (ID) and OOD). In this study, we present a direct uncertainty estimation method and apply it for a dose prediction U-Net architecture. It can be used to flag OOD data and give information on the quality of the doseprediction. Our method consists in the addition of a branch decoding from the bottleneck which reconstructs the CT scan given as input. The input reconstruction error can be used as a surrogate of the model uncertainty. For the proof-of-concept, our method is applied to proton therapy dose prediction in head and neck cancer patients. A dataset of 60 oropharyngeal patients was used to train the network using a nested cross-validation approach with 11 folds (training: 50 patients, validation: 5 patients, test: 5 patients). For the OOD experiment, we used 10 extra patients with a different head and neck sub-location. Accuracy, time-gain, and OOD detection are analyzed for our method in this particular application and compared with the popular MCDO andDE. The additional branch did not reduce the accuracy of the dose prediction model. The median absolute error is close to zero for the target volumes and less than 1% of the dose prescription for organs at risk. Our input reconstruction method showed a higher Pearson correlation coefficient with the prediction error (0.620) than DE (0.447) and MCDO (between 0.599 and 0.612). Moreover, our method allows an easier identification of OOD (no overlap for ID and OOD data and a Z-score of 34.05). The uncertainty is estimated simultaneously to the regression task, therefore requires less time and computationalresources. This study shows that the error in the CT scan reconstruction can be used as a surrogate of the uncertainty of the model. The Pearson correlation coefficient with the dose prediction error is slightly higher than state-of-the-art techniques. OOD data can be more easily detected and the uncertainty metric is computed simultaneously to the regression task, therefore faster than MCDO or DE. The code and pretrained model are available on the gitlab repository: https://gitlab.com/ai4miro/ct-reconstruction-for-uncertainty-quatification-of-hdunet.