Exposures and Bladder Cancer Risk Among Military Veterans: A Systematic Review and Meta-analysis.

OBJECTIVES: To investigate potential carcinogenic exposures in military personnel that are implicated in the development of bladder cancer. METHODS: This systematic review aimed to evaluate the association between specific military exposures and bladder cancer risk among veterans. PubMed, Scopus, and Ovid MEDLINE databases were searched in December 2023 for relevant articles. Inclusion criteria comprised retrospective cohort studies, reviews, and observational studies documenting bladder cancer incidence among military populations exposed to specific agents. A total of 25 studies, involving 4,320,262 patients, met the inclusion criteria. Data extraction followed PRISMA guidelines, and a random-effects model was used for data synthesis. RESULTS: The meta-analysis revealed significant associations between exposure to Agent Orange (HR 1.17 [95% CI: 1.01-1.36], p < 0.00001) and depleted uranium (HR 2.13 [95% CI: 1.31-3.48], p = 0.002) with increased bladder cancer risk among veterans. Contaminated drinking water showed a trend towards increased risk (HR 1.25 [95% CI: 0.97-1.61], p = 0.08). CONCLUSION: The findings suggest a possible association between specific military exposures and heightened bladder cancer risk among veterans, emphasizing the necessity for targeted screening protocols and preventive measures. Further research is essential to identify specific carcinogenic agents and prevalence of exposures among veterans, enabling more effective prevention and management strategies.

Novel therapeutic regimens in previously untreated metastatic urothelial carcinoma: A systematic review and bayesian network meta-analysis.

Metastatic urothelial carcinoma (muC) has historically had few effective therapeutic options. Recently, immune checkpoint inhibitors (ICIs), were introduced as therapeutic options for cisplatin-ineligible patients, however, direct head-to-head trials comparing these treatments are lacking. To address this gap, this study employs a Bayesian framework to indirectly compare the performance of ICIs as first-line agents for muC. A systematic review was performed to identify randomized controlled trials evaluating different ICI for mUC. Data was inputted into Review Manager 5.4 for pairwise meta-analysis. Data was then used to build a network in R Studio. These networks were used to model 200,000 Markov Chains via MonteCarlo sampling. The results are expressed as hazard ratios (HR) with 95% credible intervals (CrI). Six studies with 5,449 patients were included, 3,255 received ICI monotherapy or combination. Moreover, a total of 3,006 had PD-L1 positive tumors and 2,362 were PD-L1 negative. Median overall survival (OS) ranged from 12.1 to 31.5 months across the studies, with the combination of enfortumab vedotin and pembrolizumab demonstrating the most substantial reduction in the risk of death (HR 0.47 [95% CrI: 0.38, 0.58]), followed by avelumab monotherapy (HR 0.69 [95% CrI: 0.56, 0.86]). The limitations of this network meta-analysis include variability in study follow-up duration, lack of standardized methods for assessing PD-L1 positivity, and potential bias introduced by control arms with poorer survival outcomes across included trials. The enfortumab vedotin/pembrolizumab combination significantly improved survival and response rates. Avelumab showed notable single-agent activity. These findings provide a valuable framework to guide clinical decision-making and highlight priority areas for future research, including biomarker refinement and novel combination strategies to enhance antitumor immunity in this challenging malignancy.

Open-Globe Injury With Globe Penetration Leading to Complex Retinal Detachment After Intraoral Anesthetic Injection.

Purpose: To report a case of a suspected open-globe injury and globe penetration complicated by a rhegmatogenous retinal detachment (RRD) after administration of intraoral anesthetic injections during an endodontic procedure. Methods: A retrospective chart review was performed. Results: A 34-year-old woman presented with acute onset of flashes, floaters, and a curtain-like shadow across her field of vision. Four days previously, she had multiple left-sided anesthetic injections during an endodontic procedure. The visual acuity (VA) in the left eye was 20/25. Ophthalmoscopy showed a suspected globe-penetration site inferiorly, associated multilayered hemorrhages, and adjacent subretinal fluid. Laser demarcation of the inferior RRD was performed at sequential clinical visits. Through 8 months, the multilayered hemorrhages improved while proliferative vitreoretinopathy-associated tissue formation over the posterior pole caused macular distortion and mild visual deterioration. The VA in the left eye was 20/40 at the last follow-up. Conclusions: Iatrogenic globe penetration during intraoral anesthesia delivery associated with an endodontic procedure may result in globe injury.

Impact of Rectal Spacer on Toxicity Reduction in Men Treated With Proton Versus Photon Therapy.

Purpose: Rectal toxicity after prostate cancer (PCa) radiation therapy (RT) may be greater with protons compared with photon intensity-modulated RT, perhaps due to lateral penumbra and end-of-range uncertainty. Rectal spacers (RSs) have been shown to mitigate RT-associated acute/late rectal toxicity in men treated with photons. The relative benefit of RS in men treated with protons versus photons is unknown. We hypothesize that RS will confer greater bowel toxicity benefits in PCa treated with protons versus photons. Materials and Methods: We conducted a single institution, retrospective review of men receiving photon intensity-modulated RT or pencil-beam scanning proton RT for localized PCa. Four cohorts were compared: photon with or without RS, and proton with or without RS. Acute (<3 months), late (≥3 months), and most recent toxicity were compared among the 4 cohorts. The cumulative incidence of physician-reported grade 1 to 2 gastrointestinal (GI) toxicity (common terminology criteria for adverse events V5.0) was compared using χ2 or Fisher exact test. Patient-reported toxicity was evaluated using the International Prostate Expanded Prostate Composite Index-Clinical Practice and compared using linear mixed modeling. Results: In total, 164 patients were eligible for analysis: 38 photons without RS, 50 photons with RS, 26 protons without RS, and 50 protons with RS. The median follow-up was 17.6 months. In proton patients, acute (6.12% vs 30.77%, P = .009) and most recent (4.26% vs 26.09%, P = .01) G1-2 GI toxicity was lower with versus without RS. In photon patients, there were no significant differences in toxicity with versus without RS. No significant differences in patient-reported outcomes were observed with versus without RS in photon or proton groups. Conclusion: The rectal spacer was associated with lower G1-2 acute and most recent GI toxicity in men treated with protons; this difference was not observed in men treated with photons. While this study is limited by sample size, a relatively greater benefit of RS with proton versus photon therapy was observed.

Ultrafiltration Patterns during Automated Peritoneal Dialysis: Findings and Insights to Peritoneal Physiology.

BACKGROUND: With the growing use of automated peritoneal dialysis (APD), it is important to improve our knowledge of the clinical patterns and physiology of APD treatment sessions. The ultrafiltration (UF) achieved during each cycle of an APD treatment is assumed to be relatively linear if the delivered prescription is the same. We set out to determine if that is indeed the case. METHODS: Single-center, cross-sectional study of prevalent PD patients. All adult APD patients (> 18 years of age), who had been on PD for >3 months, and >3 months on APD were included. Continuous ambulatory PD patients or those with peritonitis within 3 months of the consent date were excluded. Individual treatment data from 7 consecutive APD treatment sessions with consistent dialysate composition for each cycler exchange were collected for each subject. RESULTS: Thirty-nine subjects met the inclusion criteria and were enrolled. The probability of yielding a positive UF was 48.9% for cycle 1, rising to 90.5% by cycle 6. Adjusting for average dextrose concentration, dwell time, fill volume, solute transfer rate, and number of cycles, we observed that cycles 2 through 6 achieved progressively higher UF volumes than cycle 1 (p < 0.001). The first and last cycles demonstrated significantly different cycle UF volumes compared to a middle cycle (-230 ml and 277 ml, respectively, p < 0.001). CONCLUSIONS: We observed a consistent increase in UF volumes achieved per cycle over the course of an APD treatment session with numerous clinical and physiologic implications. This provides the foundation for future studies investigating peritoneal inter-cycle variations and membrane physiology.

Unveiling piperazine-quinoline hybrids as potential multi-target directed anti-Alzheimer's agents: design, synthesis and biological evaluation.

Multi-target directed ligands (MTDLs) have recently been popularized due to their outstanding efficacy in combating the complicated features of Alzheimer's disease. This study details the synthesis of piperazine-quinoline-based MTDLs through a multicomponent Petasis reaction, targeting multiple factors such as AChE, BuChE, metal chelation to restore metal dyshomeostasis, and antioxidant activity. Some of the synthesized compounds exhibited notable inhibitory activity against AChE and BuChE enzymes at specific concentrations. Among the synthesized compounds compound (95) containing a 4-chloroaniline moiety and a 4-methoxybenzyl group displayed the most promising inhibitory activities against AChE (IC50 3.013 µM) and BuChE (IC50 = 3.144 µM). Compound (83) featuring 2-methoxyaniline and 4-fluorobenzyl substituents, exhibited the highest BuChE inhibition (IC50 1.888 µM). Notably, compound (79) demonstrated 93-times higher selectivity for BuChE over AChE. Molecular docking and molecular dynamics simulations were also performed to explore the binding modes and stability of these compounds with the AChE amd BuChE proteins. Further, kinetics study was performed against AChE for comounds (83 and 95) which indicated mixed inhibition of the enzyme by these compounds, Amongs the synthesized compounds, nine compounds were assessed for their antioxidant activity, displaying significant antioxidant properties with IC50 values ranging from 156 µM to 310 µM. Moreover, all the compounds demonstrated metal chelating tendency with Cu+2, Zn+2, Fe+2, Fe+3 and Al+3. This study provides insights into the design of novel MTDLs, highlighting compound (95) as a potential candidate for combating Alzheimer's disease.

CLINICALLY RELEVANT POSTERIOR VITREOUS DETACHMENT STAGING USING CIRCUMPAPILLARY AND MACULAR VOLUME OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: This study was designed to investigate retinal nerve fiber layer circumpapillary optical coherence tomography to determine posterior vitreous detachment (PVD) status and to develop a clinically relevant PVD grading scale based on retinal nerve fiber layer circumpapillary optical coherence tomography to determine the incidence of PVD by age and association with vitreomacular traction disorders. METHODS: Ophthalmic images and medical records of patients with retinal diseases were retrospectively analyzed by three masked graders using retinal nerve fiber layer circumpapillary optical coherence tomography and macular optical coherence tomography. Based on PVD status, eyes were categorized into five newly defined PVD stages. RESULTS: Among 2002 eyes, PVD stages were as follows: A) 25 (1.25%); B) 725 (36.21%); C-) 248 (12.39%); C+) 151 (7.54%); D) 851 (42.51%); X) 2 (0.1%). Posterior vitreous detachment was correlated with advanced age (P < 0.0001). Limited separation or partial separation between lamella within the posterior vitreous cortex (Stage B) was noted early (68% of eyes <18 years). Overall, 34% of eyes >70 years did not exhibit complete PVD. Of 75 eyes with tractional vitreoretinal disorders, 64 (85.3%) were Stage C-/C+, identifying Stage C as the high-risk "complication" stage. CONCLUSION: Imaging analyses using retinal nerve fiber layer circumpapillary optical coherence tomography and macular optical coherence tomography scans in conjunction allow rapid assessment of the PVD stage. These techniques can assist clinicians and surgeons in counseling patients and planning surgical approaches. Observations confirmed the progression of PVD through predictable stages and the progression of PVD with age.

Towards a Customizable, SLA 3D-Printed Biliary Stent: Optimizing a Commercially Available Resin and Predicting Stent Behavior with Accurate In Silico Testing.

Inflammation of the bile ducts and surrounding tissues can impede bile flow from the liver into the intestines. If this occurs, a plastic or self-expanding metal (SEM) stent is placed to restore bile drainage. United States (US) Food and Drug Administration (FDA)-approved plastic biliary stents are less expensive than SEMs but have limited patency and can occlude bile flow if placed spanning a duct juncture. Recently, we investigated the effects of variations to post-processing and autoclaving on a commercially available stereolithography (SLA) resin in an effort to produce a suitable material for use in a biliary stent, an FDA Class II medical device. We tested six variations from the manufacturer's recommended post-processing and found that tripling the isopropanol (IPA) wash time to 60 min and reducing the time and temperature of the UV cure to 10 min at 40 °C, followed by a 30 min gravity autoclave cycle, yielded a polymer that was flexible and non-cytotoxic. In turn, we designed and fabricated customizable, SLA 3D-printed polymeric biliary stents that permit bile flow at a duct juncture and can be deployed via catheter. Next, we generated an in silico stent 3-point bend test to predict displacements and peak stresses in the stent designs. We confirmed our simulation accuracy with experimental data from 3-point bend tests on SLA 3D-printed stents. Unfortunately, our 3-point bend test simulation indicates that, when bent to the degree needed for placement via catheter (~30°), the peak stress the stents are predicted to experience would exceed the yield stress of the polymer. Thus, the risk of permanent deformation or damage during placement via catheter to a stent printed and post-processed as we have described would be significant. Moving forward, we will test alternative resins and post-processing parameters that have increased elasticity but would still be compatible with use in a Class II medical device.

Efficacy and Safety of Intrathecal Morphine for Cesarean Delivery: A Narrative Review.

PURPOSE OF REVIEW: Pain management is a critical aspect of care during and following a cesarean delivery. Without proper control of pain, individuals can experience poor mobility, increased thromboembolic events, and difficulty caring for the neonate in the postpartum period. There have been multiple methods for pain management for cesarean delivery and intrathecal morphine (ITM) has emerged as a prominent option for post-operative analgesia due to its efficacy, safety, and potential benefits over other treatments. This review analyzes data on efficacy, side effects, and safety of ITM and the pain control alternatives. RECENT FINDINGS: A comprehensive literature review was conducted to compare ITM with other analgesic techniques in post-cesarean patients. ITM was found to be as effective or better than other analgesic options, including bilateral quadratus lumborum block (QLB), opioid-free epidural analgesia (CSEA-EDA), and intravenous fentanyl. One study found that both ITM and oral analgesia were effective in pain control and that ITM caused fewer breakthrough pain events but had a longer duration and a greater rate of side effects than oral opioid analgesia. Commonly observed side effects of intrathecal opioids include nausea, vomiting, pruritus, and urinary retention, and it is thought that the adverse effects from intrathecal administration of opioids are short-lived. ITM may provide a decreased risk of DVT and coagulation by decreasing lower extremity weakness and numbness, thereby decreasing recovery time and increasing mobility. ITM is a safe and effective option for post-cesarean analgesia, with comparable pain relief to alternative forms of pain control, and side effects that are generally manageable. Further research is warranted to explore beneficial combinations with other methods of pain management and optimal dosing strategies.

Optical perturbation of Agtr1a-containing neurons and afferents within the caudal nucleus of the solitary tract modulates sodium intake.

Angiotensin-II (Ang-II) production is driven by deviations in blood volume and osmolality, and serves the role of regulating blood pressure and fluid intake to maintain cardiovascular and hydromineral homeostasis. These actions are mediated by Ang-II acting on its type 1a receptor (AT1aR) within the central nervous system and periphery. Of relevance, AT1aR are expressed on sensory afferents responsible for conveying cardiovascular information to the nucleus of the solitary tract (NTS). We have previously determined that optical excitation of neurons and vagal afferents within the NTS that express AT1aR (referred to as NTSAT1aR) mimics the perception of increased vascular stretch and induces compensatory responses to restore blood pressure. Here, we test whether NTSAT1aR are also involved in the modulation of water and sodium intake. We directed the light-sensitive excitatory channelrhodopsin-2 (ChR2) or inhibitory halorhodopsin (Halo) to Agtr1a-containing neurons and measured water and sodium chloride (NaCl) intake in the presence and absence of optical stimulation within the NTS during various challenges to fluid homeostasis. Optical perturbation of NTSAT1aR modulates NaCl intake, such that excitation attenuates, whereas inhibition increases intake. This effect is only observed in the water-deprived condition, suggesting that NTSAT1aR are involved in the regulation of sodium intake during an imbalance in both the intracellular and extracellular fluid compartments. Furthermore, optical excitation of NTSAT1aR increases c-Fos expression within oxytocinergic neurons of the paraventricular nucleus of the hypothalamus (PVN), indicating that the regulation of sodium intake by NTSAT1aR may be mediated by oxytocin. Collectively, these results reveal that NTSAT1aR are sufficient and necessary to modulate sodium intake relative to perceived changes in vascular stretch.

Biochemical Relapse-Free Survival in Postprostatectomy Patients Receiving 18F-Fluciclovine-Guided Prostate Bed-Only Radiation: Post Hoc Analysis of a Prospective Randomized Trial.

PURPOSE: Whole-pelvis (WP) radiation therapy (radiation) improved biochemical relapse-free survival (bRFS) compared with prostate bed (PB)-only radiation in the Radiation Therapy Oncology Group 0534, but was performed in an era prior to positron emission tomography (PET) staging. Separately, 18F-fluciclovine PET/CT-guided postprostatectomy radiation improved 3-year bRFS versus radiation guided by conventional imaging alone. We hypothesized that patients who were changed from WP to PB-only radiation after PET would have bRFS that was: (a) no higher than patients initially planned for PB-only radiation; and (b) lower than patients planned for WP radiation without PET guidance. METHODS AND MATERIALS: We conducted a post hoc analysis of a prospective, randomized trial comparing conventional (arm 1) versus PET-guided (arm 2) postprostatectomy radiation. In arm 2, pre-PET treatment field decisions were recorded and post-PET fields were defined per protocol; pathologic node negative (pN0) without pelvic or extrapelvic PET uptake received PB-only radiation. Three-year bRFS was compared in patients planned for WP with change to PB-only radiation (arm 2 [WP:PB]) vs arm 2 patients planned for PB-only with final radiation to PB-only (arm 2 [PB:PB]) and arm 1 pN0 patients treated with WP radiation (arm 1 [WP]) using the Z test and log-rank test. Demographics were compared using the chi-square test, Fisher exact test, or analysis of variance, as appropriate. RESULTS: We identified 10 arm 2 (WP:PB), 31 arm 2 (PB:PB) and 11 arm 1 (WP) patients. Androgen deprivation was used in 50.0% of arm 2 (WP:PB) and 3.2% of arm 2 (PB:PB) patients, P < .01. Median preradiation prostate-specific antigen was higher in arm 2 (WP:PB) vs arm 2 (PB:PB) patients (0.4 vs 0.2 ng/mL, P = .03); however, there were no significant differences in T stage, Gleason score, or margin positivity. Three-year bRFS was 80% in arm 2 (WP:PB) vs 87.4% in arm 2 (PB:PB), P = .47, respectively. Arm 1(WP) patients had significantly worse 3-year (23%) bRFS vs arm 2 (WP:PB), P < .01. CONCLUSIONS: Patients initially planned for WP radiation with field decision change to PB-only radiation after PET showed (1) no significant difference in 3-year bRFS compared with patients initially planned for PB-only radiation; and (2) improved bRFS compared with patients receiving WP radiation without PET guidance. PET-guided volume de-escalation in selected patients may be 1 approach to mitigating toxicity without compromising outcomes.

The impact of ischemic stroke on bone marrow microenvironment and extracellular vesicles: A study on inflammatory and molecular changes.

An ischemic stroke (IS) is caused due to the lack of blood flow to cerebral tissue. Most of the studies have focused on how stroke affects the localized tissue, but it has been observed that a stroke can cause secondary complications in distant organs, such as Bone Marrow (BM). Our study focused on the effect of ischemic strokes on the bone marrow microenvironment. Bone marrow (BM) is a vital organ that maintains inflammatory homeostasis and aids in the repair of damaged tissue after injury/IS. We used the middle cerebral artery occlusion (MCAO) model of ischemic stroke on adult mice (6 months) and investigated the changes in the BM environment. BM cells were used for western blot and RT-PCR, and the BM supernatant was used for cytokine analysis and extracellular vesicle (EVs) isolation. We observed a significant increase in the total cell number within the BM and an increase in TNF-alpha and MCP-1, which are known for inducing a pro-inflammatory environment. Western blots analysis on the whole BM cell lysate demonstrated elevated levels of inflammatory factors (IL-6, TNF-alpha, and TLR-4) and senescence markers (p21 p16). EVs isolated from the BM supernatant showed no change in size or concentration; however, we found that the EVs carried increased miRNA-141-3p and miRNA-34a. Proteomic analysis on BM-derived EVs showed an alteration in the protein cargo of IS. We observed an increase in FgB, C3, Fn1, and Tra2b levels. The signaling pathway analysis showed mitochondrial function is most affected within the bone marrow. Our study demonstrated that IS induces changes in the BM environment and EVs secreted in the BM.

MANAGEMENT OF LARGE FULL-THICKNESS MACULAR HOLES: Long-Term Outcomes of Internal Limiting Membrane Flaps and Internal Limiting Membrane Peels.

BACKGROUND/PURPOSE: To determine and compare the efficacy of a surgical internal limiting membrane (ILM) flap technique with the traditional ILM peel on long-term visual and anatomical outcomes for large (>400 µm) full-thickness macular holes. METHODS: From October 2016 to July 2022, patients undergoing initial full-thickness macular hole repair with the ILM flap or ILM peel technique were reviewed. Final outcomes were recorded and based on size in microns: 401 to 800, 801 to 1,200, and >1,200. RESULTS: Patients treated with ILM flap (n = 52, 94.2% closure rate) or ILM peel (n = 407, 93.6% closure rate) were followed with a mean follow-up time of 15.0 ± 10.2 and 20.0 ± 13.4 months, respectively. Success rates for ILM flaps and ILM peels were compared for full-thickness macular holes of 401 to 800 (100%, 95.8%, P = 0.39), 801 to 1,200 (95%, 93%, P = 0.74), and >1,200 (86.7%, 86.7%, P = 1.0) µm. Mean best-recorded logarithm of the minimal angle of resolution visual acuity for ILM flaps and ILM peels, respectively, was 1.02 ± 0.46 and 0.87 ± 0.47 preoperatively, with follow-up acuity of 0.48 ± 0.32 (P < 0.03) and 0.39 ± 0.42 (P < 0.01) at Year 3. CONCLUSION: Both techniques provide a similar anatomical closure rate and functional improvement in vision. Comparisons should be cautiously made based on difference in preoperative hole size.

Stability-Indicating TLC-Densitometric and HPLC Methods for Simultaneous Determination of Teneligliptin and Pioglitazone in Pharmaceutical Dosage Forms with Eco-Friendly Assessment.

The combination of teneligliptin hydrobromide hydrate and pioglitazone hydrochloride in pharmaceutical formulations has improved type 2 diabetes management. Two chromatographic methods TLC-densitometry and RP-HPLC were developed for simultaneous quantification of teneligliptin hydrobromide hydrate and pioglitazone hydrochloride in pharmaceutical formulations, ensuring accuracy and stability assessment. The TLC method uses a mobile phase of methanol, toluene, ethyl acetate and triethylamine (1:7:2:0.1, v/v/v/v) on TLC silica gel plates, scanned at 268 nm. The RP-HPLC method employs isocratic elution with acetonitrile and sodium acetate buffer (adjust pH 3.6 with glacial acetic acid, 60:40 v/v) on a shimpack C18 column (250 × 4.6 mm i.d., 5 µm), detected at 235 nm. Both methods offer high accuracy and reliability, making them valuable for pharmaceutical quality control. Additionally, an environmental impact assessment was conducted using eco-scale, Analytical Greenness Metric Approach, Green Analytical Procedure Index, and national environmental method index to evaluate solvent consumption, waste generation and energy usage. Statistical comparisons (t-tests and F-tests) validate the outcomes of both methods, ensuring their effectiveness in drug formulation analysis. These methods can enhance pharmaceutical quality control while fulfilling environmental responsibilities.

Donor types and outcomes of transplantation in myelofibrosis: a CIBMTR study.

ABSTRACT: We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)-HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

Adaptive Proton Therapy Using CBCT-Guided Digital Twins.

This study aims to develop a digital twin (DT) framework to enhance adaptive proton stereotactic body radiation therapy (SBRT) for prostate cancer. Prostate SBRT has emerged as a leading option for external beam radiotherapy due to its effectiveness and reduced treatment duration. However, interfractional anatomy variations can impact treatment outcomes. This study seeks to address these uncertainties using DT concept, with the goal of improving treatment quality, potentially revolutionizing prostate radiotherapy to offer personalized treatment solutions. Our study presented a pioneering approach that leverages DT technology to enhance adaptive proton SBRT. The framework improves treatment plans by utilizing patient-specific CTV setup uncertainty, which is usually smaller than conventional clinical setups. This research contributes to the ongoing efforts to enhance the efficiency and efficacy of prostate radiotherapy, with ultimate goals of improving patient outcomes and life quality.

Postoperative Delirium Screening Characteristics in Pediatric Intestinal, Liver, and Renal Transplant Recipients: Single-Center Retrospective Cohort Study.

OBJECTIVES: To describe and compare the results of delirium screening in the immediate post-transplant PICU admission for pediatric intestinal, liver, and renal transplant recipients. We also examined associations with known and suspected risk factors for pediatric delirium (PD). DESIGN: Retrospective analysis of a single-center cohort, 2016-2022. SETTING: Twenty-four-bed PICU in a high-volume transplant center. PATIENTS: All intestinal, liver, and renal transplant recipients under 23 years old admitted between July 2016 and August 2022. MEASUREMENTS AND MAIN RESULTS: We identified 211 pediatric transplant recipients: intestinal (n = 36), liver (n = 78), and renal (n = 97). Results of the Cornell Assessment for PD during the immediate post-transplant PICU admission were reviewed and patients were categorized into screen positive, screen negative, and unscreened. Corresponding data on known and suspected risk factors for PD were also collected. Data on delirium subtypes were not collected. Screens were available for 156 of 211 patients (74%) who were included in the final analysis. The prevalence of a positive screen by transplant category was: intestine 80% (24/30), liver 75% (47/63), and renal 14% (9/63). A positive screen was associated with younger age, greater duration of mechanical ventilation, and greater PICU length of stay (LOS) in bivariate analysis. In multivariable analysis, age and PICU LOS remained strongly correlated with a positive screen (p < 0.05). Deep sedation and agitation as categorized by the State Behavioral Scale was associated with a positive screen, as was significant iatrogenic withdrawal symptoms (p < 0.05). Most patients screened positive by post-transplant days 2 and 3 (58/80 [72%] and 64/80 [80%], respectively). CONCLUSIONS: In our 2016 to 2022 experience, we found a high prevalence of positive PD screens in pediatric intestinal and liver transplant recipients in the immediate post-transplant PICU admission. A positive screen was associated with younger age and greater PICU LOS.

Utilization of Point-of-Care Ultrasound as an Imaging Modality in the Emergency Department: A Systematic Review and Meta-Analysis.

Point-of-care ultrasound (POCUS) is an imaging modality that has become a fundamental part of clinical care provided in the emergency department (ED). The applications of this tool in the ED have ranged from resuscitation, diagnosis, and therapeutic to procedure guidance. This review aims to summarize the evidence on the use of POCUS for diagnosis and procedure guidance. To achieve this, CrossRef, PubMed, Cochrane Library, Web of Science, and Google Scholar databases were extensively searched for studies published between January 2000 and November 2023. Additionally, the risk of bias assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies 2 (for studies on the diagnostic role of POCUS) and Cochrane Risk of Bias tool (for studies on the use of POCUS for procedure guidance). Furthermore, diagnostic accuracy outcomes were pooled using STATA 16 software (StatCorp., College Station, TX, USA), while outcomes related to procedure guidance were pooled using the Review Manager software. The study included 81 articles (74 evaluating the diagnostic application of POCUS and seven evaluating the use of POCUS in guiding clinical procedures). In our findings sensitivities and specificities for various conditions were as follows: appendicitis, 65% and 89%; hydronephrosis, 82% and 74%; small bowel obstruction, 93% and 82%; cholecystitis, 75% and 96%; retinal detachment, 94% and 91%; abscess, 95% and 85%; foreign bodies, 67% and 97%; clavicle fractures, 93% and 94%; distal forearm fractures, 97% and 94%; metacarpal fractures, 94% and 92%; skull fractures, 91% and 97%; and pleural effusion, 91% and 97%. A subgroup analysis of data from 11 studies also showed that the two-point POCUS has a sensitivity and specificity of 89% and 96%, while the three-point POCUS is 87% sensitive and 92% specific in the diagnosis of deep vein thrombosis. In addition, the analyses showed that ultrasound guidance significantly increases the overall success rate of peripheral venous access (p = 0.02) and significantly reduces the number of skin punctures (p = 0.01) compared to conventional methods. In conclusion, POCUS can be used in the ED to diagnose a wide range of clinical conditions accurately. Furthermore, it can be used to guide peripheral venous access and central venous catheter insertion.

CD70-Targeted Allogeneic CAR T-Cell Therapy for Advanced Clear Cell Renal Cell Carcinoma.

Therapeutic approaches for clear cell renal cell carcinoma (ccRCC) remain limited; however, chimeric antigen receptor (CAR) T-cell therapies may offer novel treatment options. CTX130, an allogeneic CD70-targeting CAR T-cell product, was developed for the treatment of advanced or refractory ccRCC. We report that CTX130 showed favorable preclinical proliferation and cytotoxicity profiles and completely regressed RCC xenograft tumors. We also report results from 16 patients with relapsed/refractory ccRCC who received CTX130 in a phase I, multicenter, first-in-human clinical trial. No patients encountered dose-limiting toxicity, and disease control was achieved in 81.3% of patients. One patient remains in a durable complete response at 3 years. Finally, we report on a next-generation CAR T construct, CTX131, in which synergistic potency edits to CTX130 confer improved expansion and efficacy in preclinical studies. These data represent a proof of concept for the treatment of ccRCC and other CD70+ malignancies with CD70- targeted allogeneic CAR T cells. Significance: Although the role of CAR T cells is well established in hematologic malignancies, the clinical experience in solid tumors has been disappointing. This clinical trial demonstrates the first complete response in a patient with RCC, reinforcing the potential benefit of CAR T cells in the treatment of solid tumors.