Concurrent high risk HPV35, HPV45, and HPV59 infections in prostate and bladder cancer tissues of a single patient: A case report.

Human papillomavirus (HPV) infections, primarily transmitted through sexual contact, have been linked to various cancers, including cervical, penile, anal, oropharynx, breast, and prostate cancers. This study presents a unique case of concurrent high-risk HPV35, HPV45, and HPV59 infections in both prostate and bladder cancer tissues from a single patient, representing the first documented instance worldwide with identical HPV types detected in two adjacent organs of the same individual. Employing a multiplex-PCR approach, gel electrophoresis, and Sanger sequencing, we confirmed the presence of these high-risk HPV types. Additionally, Western blot analysis using an HPV E7 antibody demonstrated the active expression of HPV oncoproteins in both cancer types. This discovery underscores the potential for HPV intra-organ transmission and necessitates further exploration of alternative transmission routes. The implications of our results offer new insights into the complex dynamics of HPV transmission in cancer pathogenesis. In conclusion our study reveals concurrent HPV infections in both prostate and bladder cancers within a single patient and highlights the potential intra-organ spread of HPV and the need for further investigation of alternative transmission routes.

Concurrent Care and use of Advanced Cardiac Therapies for Hospitalized Veterans with Heart Failure.

CONTEXT: Concurrent care allows patients to receive hospice while continuing disease-directed therapies. This treatment model is available in the Veterans Administration (VA) medical system, but its use in Veterans with heart failure (HF) is unexplored. OBJECTIVE: To compare use of advanced HF therapies 30 days post-hospitalization in Veterans on hospice versus not on hospice following admission for HF exacerbation. METHODS: We evaluated Veterans admitted for HF exacerbation to VA hospitals between Jan 2011 and June 2019 who received advanced HF therapies, hospice services, or both post-discharge. Concurrent care was defined as receiving both hospice services and advanced HF therapies. Demographics, comorbidities, and prior healthcare utilization were compared. Secondary outcomes included burdensome transitions and mortality. RESULTS: Among 317,967 HF Veterans, 18,350 (5.8%) chose hospice post-hospitalization. Only 58 hospice-enrolled Veterans (0.3%) received advanced HF therapies (i.e. concurrent care) within 30 days post-discharge. Of 299,617 Veterans not on hospice, 6,083 (2.0%) received advanced HF therapies (0.3% vs 2.0%; p<0.001). Veterans receiving concurrent care had higher six-month mortality than those receiving advanced HF therapies alone (77.6% vs. 14.9%, SMD 1.61). Hazard of burdensome transitions was similar (adjusted HR 1.44, 95% CI 0.95-2.17). CONCLUSION: Veterans with HF receiving concurrent care were few and experienced higher mortality. Rate of burdensome transitions was similar between Veterans receiving concurrent care and those not on hospice. Further research may explore why Veterans infrequently utilize concurrent care at the end of life.

Effect of Strength and Endurance Training Sequence on Endurance Performance.

This review investigates the effect of two different concurrent training sequences on endurance performance. The sequences investigated are Endurance-Resistance (ER) and Resistance-Endurance (RE). A literature search is conducted of the SPORTDiscus and Medline databases. The included studies are randomized control trials, which compare the effect of ER and RE on at least one endurance performance variable. A PEDro scale is used to assess the methodological quality of the articles in this review. Of a total of 152 articles identified during the initial screening, 15 studies meet the inclusion criteria. These studies include 426 participants (298 males and 128 females), with 212 of the participants training with ER and 214 with RE. The results are presented as the percentage change of the mean from pre- to post-test. All the studies show an improvement in endurance from pre to post for both interventions, except for the RE group in one study. This review finds small and non-conclusive sequence effects between ER and RE, suggesting that the sequence of concurrent training is not of great importance in relation to endurance performance.

A longitudinal assessment of major mouthwashes used in alleviating pain and xerostomia among advanced nasopharyngeal carcinoma patients receiving chemoradiotherapy.

OBJECTIVE: This longitudinal study aimed to evaluate the overall efficacy of mouthwashes in oral mucositis pain and mucositis xerostomia in advanced nasopharyngeal carcinoma (NPC) patients undergoing concurrent chemoradiotherapy (CCRT) at different phases throughout treatment. METHODS: A longitudinal study enrolled 79 advanced NPC subjects receiving CCRT. The subjects were interviewed prospectively three times over 7 weeks for pain and xerostomia scores based on the various types of mouthwash used. The median pain score difference and median xerostomia score difference were utilised to determine mouthwash superiority. RESULTS: Participants completed three interviews, during which 480 instances of mouthwash use were observed throughout different phases of the treatment period. The results showed that the median pain scores between mouthwashes differed significantly, H-Stat(3) = 30.0, 25.7 and 26.0, respectively, with p < 0.001 for all three interviews. The pain score reductions of lidocaine mouthwash (median = 2, interquartile range (IQR) = 3, 2 and 2.75 over the three interviews, respectively) were significantly higher than those of benzydamine and sodium bicarbonate mouthwashes. There were no significant differences between the studied mouthwashes in their xerostomia score reductions. CONCLUSIONS: Lidocaine mouthwash was superior in managing oral mucositis pain at all phases throughout the entire chemoradiotherapy treatment for advanced NPC patients. There was insufficient evidence to determine the preferred mouthwash for treating oral mucositis xerostomia.

Safety and Immunogenicity of Respiratory Syncytial Virus Prefusion F Protein Vaccine when Co-administered with Adjuvanted Seasonal Quadrivalent Influenza Vaccine in Older Adults: A Phase 3 Randomized Trial.

BACKGROUND: We evaluated co-administration of adjuvanted seasonal quadrivalent influenza vaccine (FLU-aQIV) and respiratory syncytial virus (RSV) prefusion F protein-based vaccine (RSVPreF3 OA) in ≥65-year-olds. METHODS: This phase 3, open-label trial randomized ≥65-year-olds to receive FLU-aQIV and RSVPreF3 OA concomitantly (Co-Ad) or sequentially, 1 month apart (Control). Primary objectives were to demonstrate the non-inferiority of FLU-aQIV and RSVPreF3 OA co-administration versus sequential administration in terms of hemagglutination inhibition (HI) titers for each FLU-aQIV strain and RSV-A and RSV-B neutralization titers, 1 month post-vaccination. Reactogenicity and safety were also assessed. RESULTS: Overall, 1045 participants were vaccinated (Co-Ad: 523; Control: 522). Non-inferiority of FLU-aQIV and RSVPreF3 OA co-administration versus sequential administration was demonstrated in terms of HI titers for the A/Victoria(H1N1), B/Victoria, and B/Yamagata influenza strains and RSV-A neutralization titers (upper limits [ULs] of 95% confidence intervals [CIs] for adjusted geometric mean titer [GMT] ratios [Control/Co-Ad] ≤1.50) but not for A/Darwin(H3N2) HI titers (95% CI UL = 1.53). The immune response to A/Darwin(H3N2) was further assessed post-hoc using a microneutralization assay; the post-vaccination adjusted GMT ratio (Control/Co-Ad) was 1.23 (95% CI: 1.06-1.42, ie, UL ≤1.50), suggesting an adequate immune response to A/Darwin(H3N2) following co-administration. RSV-B neutralization titers were comparable between groups (95% CI UL for adjusted GMT ratio ≤1.50). Solicited adverse events were mostly mild or moderate and transient; unsolicited and serious adverse event rates were balanced between groups. CONCLUSIONS: Adjuvanted FLU-aQIV and RSVPreF3 OA had acceptable reactogenicity/safety profiles when co-administered in ≥65-year-olds, without clinically relevant interference with the immune responses to either vaccine. CLINICAL TRIALS REGISTRATION: NCT05568797.

The addition of nimotuzumab during concurrent chemoradiotherapy improved survival outcomes in locally advanced nasopharyngeal carcinoma patients with optimal response to induction chemotherapy.

OBJECTIVE: To investigate the impact of response to induction chemotherapy (IC) on survival outcomes in patients with locally advanced nasopharyngeal carcinoma (LANPC) and evaluate the efficacy of adding nimotuzumab to concurrent chemoradiotherapy (CCRT) based on different responses to IC. METHODS: We retrospectively included patients with stage III-IVA NPC who underwent IC with and without nimotuzumab during CCRT. Statistical analysis included the chi-square test, propensity score matching, Kaplan-Meier survival analysis, and Cox proportional hazards model. RESULTS: Among 383 identified patients, 216 (56.4%) received nimotuzumab during CCRT, while 167 (43.6%) did not. Following IC, 269 (70.2%) patients showed a complete response (CR) or partial response (PR), and 114 (29.8%) had stable disease (SD) or progressive disease (PD). The response to IC independently influenced disease-free survival (DFS) and overall survival (OS). Patients achieving CR/PR demonstrated significantly higher 3-year DFS (80.3% vs. 70.6%, P = 0.031) and OS (90.9% vs. 83.2%, P = 0.038) than those with SD/PD. The addition of nimotuzumab during CCRT significantly improved DFS (P = 0.006) and OS (P = 0.037) for CR/PR patients but not for those with SD/PD. CONCLUSIONS: This study emphasizes the importance of IC response in LANPC and highlights the potential benefits of nimotuzumab during CCRT for improving survival outcomes in CR/PR patients. Tailored treatment approaches for SD/PD patients warrant further investigation.

Concurrent Validity of the Anxiety Disorders Section of the Anxiety Disorder Interview Schedule- Autism Spectrum Addendum (ADIS-ASA) in Autistic Youth.

PURPOSE: Examine the concurrent validity of specific Anxiety Disorders Section of the Anxiety Disorder Interview Schedule for DSM-IV-Autism Spectrum Addendum (ADIS-ASA)-Parent Interview in a sample of 167 autistic youth who met diagnostic criteria for an anxiety-related disorder (Mage = 9.91; 78.4% male; 82% non-Hispanic; 77.67% White). METHODS: Concurrent validity of Diagnostic and Statistical Manual (DSM)-defined ADIS-ASA anxiety disorder diagnostic caseness was examined via relations with (a) parent-reported dimensions of youth anxiety symptomology and (b) dimensional measures of youth anxiety-related functional impairment, respectively, using logistic regression models and point-biserial correlations. RESULTS: Significant relations were found between separation anxiety disorder and social anxiety disorder (but not generalized anxiety disorder nor obsessive-compulsive disorder) caseness, respectively, and theoretically consistent facets of dimensional youth anxiety symptomology. Relations between ADIS-ASA diagnostic caseness and youth functional impairment-related variables revealed that only separation anxiety disorder demonstrated robust evidence of convergent validity. CONCLUSION: Despite mixed findings concerning relations between ADIS-ASA anxiety disorder diagnostic caseness and dimensional measures of anxiety severity and anxiety-related impairment, the present findings provide further support for the status of the ADIS-ASA as a gold standard for assessment of anxiety in autistic youth. This work also highlights the importance of continuing to improve precision in measurement of anxiety symptomology in autistic youth, with implications for clinical assessment.

American society for metabolic and bariatric surgery: intra-operative care pathway for minimally invasive Roux-en-Y gastric bypass.

BACKGROUND: Clinical care pathways help guide and provide structure to clinicians and providers to improve healthcare delivery and quality. The Quality Improvement and Patient Safety Committee (QIPS) of the American Society for Metabolic and Bariatric Surgery (ASMBS) has previously published care pathways for the performance of laparoscopic sleeve gastrectomy (LSG) and pre-operative care of patients undergoing Roux-en-Y gastric bypass (RYGB). OBJECTIVE: This current RYGB care pathway was created to address intraoperative care, defined as care occurring on the day of surgery from the preoperative holding area, through the operating room, and into the postanesthesia care unit (PACU). METHODS: PubMed queries were performed from January 2001 to December 2019 and reviewed according to Level of Evidence regarding specific key questions developed by the committee. RESULTS: Evidence-based recommendations are made for care of patients undergoing RYGB including the pre-operative holding area, intra-operative management and performance of RYGB, and concurrent procedures. CONCLUSIONS: This document may provide guidance based on recent evidence to bariatric surgeons and providers for the intra-operative care for minimally invasive RYGB.

MonARCh: an actor based architecture for dynamic linked data monitoring.

Monitoring the data sources for possible changes is an important consumption requirement for applications running in interaction with the Web of Data. In this article, MonARCh which is an architecture for monitoring the result changes of registered SPARQL queries in the Linked Data environment, is proposed. MonARCh can be comprehended as a publish/subscribe system in the general sense. However, it differs in how communication with the data sources is realized. Data sources in the Linked Data environment do not publish the changes in the data. MonARCh provides the necessary communication infrastructure between the data sources and the consumers for the notification of changes. Users subscribe SPARQL queries to the system which are then converted to federated queries. MonARCh periodically checks for updates by re-executing SERVICE clauses and notifying users in case of any result change. In addition, to provide scalability, MonARCh takes the advantage of concurrent computation of the actor model. The parallel join algorithm utilized speeds up query execution and result generation processes. The design science methodology is used during the design, implementation and evaluation of the architecture. When compared to the literature MonARCh meets all the sufficient requirements from the linked data monitoring and state of the art perspectives while having many outstanding features from both points of view. The evaluation results show that even while working under the limited two-node cluster setting MonARCh could reach from 300 to 25,000 query monitoring capacity according to the diverse query selectivities executed within our test bench.

Usefulness of pre- and post-treatment volumetric PET/CT parameters in predicting prognosis and evaluating recurrence for chemoradiotherapy-treated hypopharyngeal cancer.

OBJECTIVE: To investigate the usefulness of pre- and post-treatment metabolic tumor volume (MTV) obtained from positron emission tomography (PET) in predicting prognosis and evaluating recurrence in patients with hypopharyngeal cancer (HPC). MATERIALS AND METHODS: Forty-three consecutive HPC patients treated with chemoradiotherapy were retrospectively analyzed. Maximum standard uptake value (SUVmax) and MTV of tumor (T) and lymph node (N) were analyzed. RESULTS: On multivariate analysis using pre-treatment parameters, MTV-T (p = 0.049) and MTV-TN (p = 0.043) were significantly associated with local control (LC), and MTV-N (p = 0.049) was significantly associated with disease-specific survival (DSS). Post-treatment MTV-TN was also significantly associated with prognosis (p < 0.001 in LC; p = 0.002 in DSS) and recurrence (area under curve 0.95). Neither pre- nor post-treatment SUVmax was significantly associated with prognosis. CONCLUSION: Pre- and post-treatment MTV appears useful for predicting prognosis and evaluating recurrence.

Effects of concurrent optical and magnetic stimulation in hard-to-heal wounds: a real-world evidence case series.

OBJECTIVE: This work explores concurrent optical and magnetic stimulation (COMS) effects on hard-to-heal wounds in real-world settings. METHOD: In this case series, participants received COMS 1-3 times per week for up to 12 weeks alongside standard wound care. RESULTS: A total of 27 patients (18 female and nine male) were included. Mean age was 72 years. Participants' wounds that were unresponsive to standard wound care included: venous leg ulcers (VLUs, n=13); mixed leg ulcers (MLUs, n=4); diabetic foot ulcers (DFUs, n=1); pressure ulcers (PUs, n=5); and traumatic wounds (TWs, n=4). On average, COMS was applied twice a week, resulting in an overall mean wound area reduction of 69%. In 24 participants, COMS was used primarily to achieve wound closure by the end of the 12-week period, of which: 12 were classified as complete wound closure (50%; VLUs=8, PUs=3 and TW=1); four as likely-to-heal (17%; VLUs=2 and MLUs=2); four as 'improved' (17%; MLU=1, DFU=1 and TWs=2); and four as 'non-responding' (17%; VLUs=3 and MLU=1). The best results were achieved in PUs and VLUs (respectively 100% and 62% categorised as completely healed). When used in participants where its purpose was other than that of achieving wound closure, COMS was successfully used to debride two PUs, and for wound bed preparation in one TW. CONCLUSION: In this case series, COMS showed positive effects and appeared to be beneficial in healing different types of hard-to-heal wounds in community health and homecare settings. Novel COMS therapy aspects emerged: (1) positive outcomes for PU and VLU treatment; (2) COMS as a potential debridement tool when sharp debridement is unfeasible; and (3) COMS as a promising method to prepare wound beds for subsequent skin grafting or skin replacement procedures.

Unusual Synchronous Multiple Primary Early-Stage Lung Adenocarcinoma with Concomitant MET Exon 14 Skipping, PIK3CA and KRAS Mutations: A Case Report.

Instruction: Synchronous multiple primary lung cancer (sMPLC) constitutes a distinct subtype of NSCLC, where accurate diagnosis and prognostic evaluation remain challenging. Case Presentation: The case involves a 70-year-old male patient admitted to the hospital due to bilateral pulmonary nodules. The patient underwent staged resection. Molecular pathological examination revealed that tumor A harbored concurrent mutations in MET exon 14 skipping and PIK3CA (p.E545K), while tumor B exhibited a KRAS exon 2 (p.G12S/D) mutation. Postoperatively, the patient demonstrated a favorable recovery, with no evidence of recurrence for 1 year. Conclusion: This study presents a case of sMPLC in early-stage lung cancer, illustrating the genetic heterogeneity in early-stage lung adenocarcinoma and underscoring the significance of precise evaluation of sMPLC and intrapulmonary metastases.

Exploring the Role of Masturbation as a Coping Strategy in Women.

Objectives: Recent findings suggest that individuals tend to engage in masturbation more frequently when experiencing elevated levels of psychological stress, and there appears to be distinguishable effects on stress response based on clitoral and vaginal stimulation. In this concurrent mixed-method study, we aimed to investigate this association in more detail using a convenience sample of 370 women. Methods: Quantitative data were used to examine whether higher psychological distress was associated with higher levels of masturbation frequency depending on the mode of stimulation, while qualitative data gave further insight into this association. Results: In regression analysis, higher levels of general and subscale-specific psychological distress were significantly associated with higher clitoral, but not combined clitoral and vaginal masturbation frequency. Qualitative content analysis showed that masturbation was used as a reliable coping strategy and self-care strategy which induced positive affective states, such as happiness and relaxation. Very few women reported negative feelings associated with masturbation. Mixed-method analysis revealed that women who indicated to use of masturbation for coping or self-care or who reported negative feelings did not differ in their level of psychological distress from women who did not report using it. The positive effects of masturbation were not related to the mode of stimulation. Conclusions: Results showed the complexity of how psychological distress is related to sexual activity and point to the potential benefits of masturbation for dealing with psychological distress and for enhancing general well-being. Our results have various implications for researchers, clinicians, and society.

Concurrent chemoradiotherapyof different radiation doses and different irradiation fields for locally advanced thoracic esophageal squamous cell carcinoma: A randomized, multicenter, phase III clinical trial.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal radiotherapy regimen, particularly in terms of total dose and planned range of irradiation field, remains unclear. This phase III clinical trial aimed to compare the survival benefits between different radiation doses and different target fields. METHODS: This trial compared two aspects of radiation treatment, total dose and field, using a two-by-two factorial design. The high-dose (HD) group received 59.4 Gy radiation, and the standard-dose (SD) group received 50.4 Gy. The involved field irradiation (IFI) group and elective nodal irradiation (ENI) group adopted different irradiation ranges. The participants were assigned to one of the four groups (HD+ENI, HD+IFI, SD+ENI and SD+IFI). The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS). The synergy indexwas used to measure the interaction effect between dose and field. RESULTS: The interaction analysis did not reveal significant synergistic effects between the dose and irradiation field. In comparison to the target field, patients in IFI or ENI showed similar OS (hazard ratio [HR] = 0.99, 95% CI: 0.80-1.23, p = 0.930) and PFS (HR = 1.02, 95% CI: 0.82-1.25). The HD treatment did not show significantly prolonged OS compared with SD (HR = 0.90, 95% CI: 0.72-1.11, p = 0.318), but it suggested improved PFS (25.2 months to 18.0 months). Among the four groups, the HD+IFI group presented the best survival, while the SD+IFI group had the worst prognosis. No significant difference in the occurrence of severe adverse events was found in dose or field comparisons. CONCLUSIONS: IFI demonstrated similar treatment efficacy to ENI in CCRT of ESCC. The HD demonstrated improved PFS, but did not significantly improve OS. The dose escalation based on IFI (HD+IFI) showed better therapeutic efficacy than the current recommendation (SD+ENI) and is worth further validation.

Lipiodol emulsion as a dual chemoradiation-sensitizer for pancreatic cancer treatment.

Pancreatic ductal adenocarcinoma (PDAC) has a low survival rate and limited treatment options. Concurrent chemoradiotherapy is considered beneficial to improve tumor control, but the low drug bioavailability at tumor site and the low radiation tolerance of surrounding healthy organs greatly limits its effectiveness. Lipiodol, a natural drug carrier used in clinical transarterial chemoembolization, has shown potential as a radiosensitizer due to its high Z element iodine composition. Thus, this study aims to repurpose lipiodol as a sensitizer to simultaneously enhance chemo- and radiotherapy for PDAC. To this end, a stable lipiodol emulsion (IOE) loaded with gemcitabine is designed using clinically approved surfactants. At in vivo level, IOE demonstrates better radiotherapeutic effect than existing nanoradiosensitizers and enhanced drug bioavailability over free drug, leading to significant tumor inhibition and improved survival rates under concurrent chemo-radiotherapy. This may due to the sustained drug release, homogenous spatial distribution, and long-term retention ability of IOE in solid PDAC tumor. Furthermore, to better understand the functioning mechanism of drug-loaded IOE, in vitro study is conducted to reveal the ROS- and DNA damage-related therapeutic pathways. Lastly, a comprehensive toxicity assessment also proves the good biocompatibility and safety of as-prepared IOE. This study offers a clinically feasible sensitizer for simultaneous chemoradiotherapy and holds potential for other types of cancer treatment in clinics.

Induction plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy in elderly patients with locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND: The effectiveness and safety of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) in elderly patients with locoregionally advanced nasopharyngeal carcinomas (LANPCs) remain subjects of debate. This study evaluated the efficacy of IC+CCRT compared to CCRT alone in elderly LANPC patients. MATERIALS AND METHODS: This retrospective, single-center study analyzed 335 elderly patients diagnosed with stage III or IVa NPC who received CCRT with or without IC between 2010 and 2016. Kaplan-Meier analysis and log-rank tests were used to estimate and compare survival rates. Multivariate analysis using Cox proportional hazards regression model was conducted to assess prognostic risk factors. Toxicities were compared using the χ2 test. RESULTS: The median follow-up duration was 69.3 months (interquartile range: 42.7-72.6). Baseline clinical characteristics were well-balanced between groups. No significant differences were observed between IC+CCRT and CCRT for any survival-related endpoints, including overall survival (hazard ratio [HR] = 1.26, 95 % confidence interval [CI]: 0.89-1.77, p = 0.188), locoregional relapse-free survival (HR=1.03, 95 % CI: 0.56-1.91, p = 0.913), distant metastasis-free survival (HR=1.39, 95 % CI: 0.90-2.16, p = 0.139), and failure-free survival (HR = 1.25, 95 % CI: 0.85-1.83, p = 0.255). However, the incidence and severity of acute and late toxicities were significantly higher in the IC+CCRT group compared to the CCRT group. CONCLUSION: In elderly LANPC patients, the addition of IC to CCRT did not improve survival outcomes, but was associated with significant toxicities.

Accelerated Radiotherapy Alone Versus Chemoradiation in Locally Advanced Carcinoma Cervix: Long-Term Outcomes.

Introduction Chemoradiation (CRT) is the standard of care for the treatment of carcinoma cervix, more benefits of CRT are seen in the early stage as compared to a locally advanced stage. Altered fractionation such as accelerated radiotherapy (ART) in locally advanced carcinoma cervix has not been explored much. Here, we have reported the long-term outcome of ART in comparison to conventional CRT in locally advanced cervical cancer patients. Methods From September 2011 to January 2014, 191 patients with locally advanced squamous cell carcinoma of the uterine cervix, FIGO stage IIB - IIIB were included in this study. They were randomized into two arms: the CRT arm (95 patients) versus the ART arm (96 patients). During external beam radiotherapy (EBRT), the patients in the CRT arm received conventional radiotherapy 50 Gy/25 fractions, 2 Gy/fraction, 5 fractions/week with cisplatin 40 mg/m2/week while patients in the ART arm received 50 Gy/25 fractions, 2 Gy/fraction, 6 fractions per week (Monday to Saturday) radiation alone. This was followed by three insertions of 6.5 Gy per fraction of high dose rate (HDR) brachytherapy at one-week intervals in both arms to keep the total treatment time 50 days in the CRT arm versus 45 days in the ART arm. Results The median follow-up of the study population was 57 months (range: 4-108 months). The patients with no residual disease (NRD) after EBRT and complete response (CR) at first follow-up were statistically less in the ART arm as compared to the CRT arm (30.2% versus 53.7% and 42.7% versus 63.2%; p = 0.006 and p = 0.024, respectively). However, there was no statistical difference in response at six months. High-grade acute toxicities hematological (9.5%) and gastrointestinal (15.8%) were more prevalent in the CRT arm in comparison to the ART arm, with no statistical significance (p>0.05) and Grade 1/2 genitourinary toxicity was significantly higher in the CRT arm. Late toxicities in both groups were equivalent. Recurrence, distant type of recurrence, and time to recurrence were similar in both groups. Five-year rates of overall survival (OS) and disease-free survival (DFS) were 51.2% versus 37.2% (p = 0.087) and 57.1% versus 46.3% (p = 0.223) in the CRT arm versus ART arm, respectively. Conclusion ART is a compelling alternative to concurrent chemoradiotherapy for locally advanced cervical cancer, particularly in patients with significant comorbidities, elderly women, and those in higher stages where concurrent chemotherapy's efficacy diminishes. It should be strongly considered when chemotherapy is contraindicated.

Dose-dependent target engagement of a clinical iTBS protocol: An interleaved TMS-fMRI study in healthy subjects.

BACKGROUND: Intermittent theta burst stimulation (iTBS) of the dorsolateral prefrontal cortex (DLPFC) is widely applied as therapeutic intervention in mental health, however understanding of its mechanisms is still incomplete. Prior MRI studies have mainly used offline iTBS or short sequences in concurrent TMS-fMRI. This study investigated a full 600 stimuli iTBS protocol using interleaved TMS-fMRI in comparison with two control conditions in healthy subjects. METHODS: In a crossover design, 18 participants underwent three sessions of interleaved iTBS-fMRI: 1) left DLPFC at 40% resting motor threshold (rMT) intensity, 2) left DLPFC at 80% rMT intensity, and 3) left primary motor cortex (M1) at 80% rMT intensity. We compared immediate blood-oxygen-level-dependent (BOLD) responses during interleaved iTBS-fMRI across these conditions including correlations between individual fMRI BOLD activation and iTBS induced electric field (E-field) strength at the target sites. RESULTS: Whole-brain analysis showed increased activation in several regions following iTBS. Specifically, left DLPFC, as well as bilateral M1, anterior cingulate cortex, and insula showed increased activation during 80% rMT left DLPFC stimulation. Increased BOLD activity in the left DLPFC was not observed with 40% rMT left DLPFC stimulation nor left M1 80% rMT iTBS, whereas activation in other regions was found to overlap between conditions. Of note, BOLD activation and E-field intensities were only correlated for M1 stimulation, but not for the DLPFC conditions. CONCLUSIONS: The study showed dosage and target specific BOLD activation during interleaved TMS-fMRI with 600 stimuli iTBS in healthy subjects. Future studies may use our approach for demonstrating target engagement.

Treatment Comparisons in Adaptive Platform Trials Adjusting for Temporal Drift.

An adaptive platform trial (APT) is a multi-arm trial in the context of a single disease where treatment arms are allowed to enter or leave the trial based on some decision rule. If a treatment enters the trial later than the control arm, there exist non-concurrent controls who were not randomized between the two arms under comparison. As APTs typically take long periods of time to conduct, temporal drift may occur, which requires the treatment comparisons to be adjusted for this temporal change. Under the causal inference framework, we propose two approaches for treatment comparisons in APTs that account for temporal drift, both based on propensity score weighting. In particular, to address unmeasured confounders, one approach is doubly robust in the sense that it remains valid so long as either the propensity score model is correctly specified or the time effect model is correctly specified. Simulation study shows that our proposed approaches have desirable operating characteristics with well controlled type I error rates and high power with or without unmeasured confounders.