The Global Experience of Laryngeal Transplantation: Series of Eleven Patients in Three Continents.

BACKGROUND: The loss of laryngeal function affects breathing, swallowing, and voice, thus severely compromises quality of life. Laryngeal transplantation has long been suggested as a solution for selected highly affected patients with complete laryngeal function loss. OBJECTIVE: To obtain insights regarding the advantages, weaknesses, and limitations of this procedure and facilitate future advances, we collected uniform data from all known laryngeal transplants reported internationally. METHODOLOGY: A case series. Patients were enrolled retrospectively by each institutional hospital or clinic. Eleven patients with complete loss of laryngeal function undergoing total laryngeal transplantation between 1998 and 2018 were recruited. RESULTS: After a minimum of 24 months follow-up, three patients had died (27%), and there were two graft explants in survivors, one total and one partial, due to chronic rejection. In the remaining cases, voice was functional in 62.5% and 50% achieved decannulation. Swallowing was initially restricted, but only one patient was gastrostomy-dependent by 6 months and all had normal or near-normal swallowing by the end of year two after transplantation. Median follow-up was 73 months. Functional (voice, swallowing, airway) recovery peaked between 12 and 24 months. CONCLUSIONS: Laryngeal transplantation is a complex procedure with significant morbidity. Significant improvements in quality of life are possible for highly selected individuals with end-stage laryngeal disorders, including laryngeal neoplasia, but further technical and pharmacological developments are required if the technique is to be more widely applicable. An international registry should be created to provide better quality pooled data for analysis of outcomes of any future laryngeal transplants. LEVEL OF EVIDENCE: IV Laryngoscope, 2024.

A biomarker of brain arousal mediates the intergenerational link between maternal and child post-traumatic stress disorder.

This study examined whether there is a biological basis in the child's resting brain activity for the intergenerational link between maternal interpersonal violence-related posttraumatic stress disorder (IPV-PTSD) and child subclinical symptoms. We used high-density EEG recordings to investigate the resting brain activity in a sample of 57 children, 34 from mothers with IPV-PTSD, and 23 from mothers without PTSD. These children were part of a prospective, longitudinal study focusing on the offspring of mothers with and without IPV-PTSD, reporting how the severity of a mother's IPV-PTSD can impact her child's emotional regulation and risk for developing mental illness. However, we had not yet looked into potential EEG biomarkers during resting state that might mediate and/or moderate effects of maternal IPV-PTSD severity on child mental health, and in particular the risk for PTSD. The alpha band spectral power as well as the aperiodic exponent of the power spectrum (PLE; power-law exponent) were examined as mediators of maternal IPV-PTSD and child PTSD. While there was no difference in alpha spectral power between the two groups, PLE was significantly reduced in children of mothers with IPV-PTSD compared to control children, indicating cortical hyper-arousal. Interestingly, child PLE was negatively correlated with the severity of maternal IPV-PTSD, suggesting an intergenerational interaction. This interpretation was reinforced by a negative correlation between child PLE and child PTSD symptoms. Finally, causal analyses using structural equation modelling indicated that child PLE mediated the relationship between maternal PTSD severity and child PTSD. Our observations suggest that maternal IPV-PTSD has an intergenerational impact on the child neurobehavioral development through a correlated abnormal marker of brain arousal (i.e. child PLE). These findings are potentially relevant to psychotherapy research and to the development of more effective psycho-neurobehavioral therapies (i.e. neurofeedback) among affected individuals.

Identifying Key Drivers of Efficient B Cell Responses: On the Role of T Help, Antigen-Organization, and Toll-like Receptor Stimulation for Generating a Neutralizing Anti-Dengue Virus Response.

T help (Th), stimulation of toll-like receptors (pathogen-associated molecular patterns, PAMPs), and antigen organization and repetitiveness (pathogen-associated structural patterns, PASPs) were shown numerous times to be important in driving B-cell and antibody responses. In this study, we dissected the individual contributions of these parameters using newly developed "Immune-tag" technology. As model antigens, we used eGFP and the third domain of the dengue virus 1 envelope protein (DV1 EDIII), the major target of virus-neutralizing antibodies. The respective proteins were expressed alone or genetically fused to the N-terminal fragment of the cucumber mosaic virus (CMV) capsid protein-nCMV, rendering the antigens oligomeric. In a step-by-step manner, RNA was attached as a PAMP, and/or a universal Th-cell epitope was genetically added for additional Th. Finally, a PASP was added to the constructs by displaying the antigens highly organized and repetitively on the surface of CMV-derived virus-like particles (CuMV VLPs). Sera from immunized mice demonstrated that each component contributed stepwise to the immunogenicity of both proteins. All components combined in the CuMV VLP platform induced by far the highest antibody responses. In addition, the DV1 EDIII induced high levels of DENV-1-neutralizing antibodies only if displayed on VLPs. Thus, combining multiple cues typically associated with viruses results in optimal antibody responses.

Temporomandibular Disorders in Relation to Mandibular Advancement Devices for Treating Obstructive Sleep Apnea.

Mandibular advancement devices (MADs) keep the upper airways patent by holding the mandible and attached soft tissues forward via altered position of its condyles relative to the articulating surfaces of the temporal bones. During the first weeks of MAD therapy, pain may occur in the area of the temporomandibular joints, masticatory muscles, and/or teeth with a tendency of spontaneous resolution. In patients reporting temporomandibular disorder (TMD) symptoms prior to therapy, the MAD-related anterior condylar position during sleep may result in a reduction of TMD signs and symptoms.

Objective numeracy exacerbates framing effects from decision-making under political risk.

While Prospect Theory helps to explain decision-making under risk, studies often base frames on hypothetical events and fail to acknowledge that many individuals lack the ability and motivation to engage in complex thinking. We use an original survey of US adults (N = 2813) to test Prospect Theory in the context of the May 2023 debt ceiling negotiations in the US Congress and assess whether objective numeracy moderates framing effects. We hypothesize and find evidence to suggest that most respondents are risk-averse to potential gains and risk-accepting to potential losses; however, high numerates are more risk-averse and risk-accepting to gains and losses, respectively, than low numerates. We also find that need for cognition interacts with numeracy to moderate framing effects for prospective losses, such that higher need for cognition attenuates risk-acceptance among low numerates and exacerbates risk-acceptance among high numerates. Our results are robust to a range of other covariates and in models accounting for the interaction between political knowledge and need for cognition, indicating joint moderating effects from two knowledge domains similarly conditioned by the desire to engage in effortful thinking. Our findings demonstrate that those who can understand and use objective information may remain subjectively persuaded by certain policy frames.

Transfemoral hepatic vein catheterization reduces procedure time in double vein embolization.

BACKGROUND: Double vein embolization with simultaneous embolization of the portal and hepatic vein aims to grow the future liver remnant in preparation for major hepatectomy. Transvenous hepatic vein embolization is usually done via a transjugular access. The purpose of this study is to describe the transfemoral approach as an alternative option and to discuss potential advantages. RESULTS: Twenty-three patients undergoing hepatic vein embolization via a transjugular (n = 10) or transfemoral access (n = 13) were evaluated retrospectively. In all cases the portal vein embolization was done first. All procedures were technically successful. There were no peri-interventional complications. Only two patients were not able to proceed to surgery. Standardized future liver remnant hypertrophy was non-inferior with the transfemoral approach compared to the transjugular route. Procedure time was significantly shorter in the transfemoral access group (40 ± 13 min) compared to the transjugular group (67 ± 13 min, p < 0.001). CONCLUSION: Transfemoral hepatic vein embolization is feasible, safe, and faster due to easier catheterization, improved stability, and simpler patient preparation. These findings will need to be validated in larger studies.

Who was at risk of trauma-related injuries during the COVID-19 pandemic? A retrospective study from a level 1 trauma centre in Switzerland.

INTRODUCTION: During the first wave of the COVID-19 pandemic, increasingly strict restrictions were imposed on the activities of the Swiss population, with a peak from 21 March to 27 April 2020. Changes in trauma patterns during the pandemic and the lockdown have been described in various studies around the world, and highlight some particularly exposed groups of people. The objective of this study was to assess changes in trauma-related presentations to the emergency department (ED) during the first wave of the COVID-19 pandemic, as compared to the same period in the previous year, with a particular focus on vulnerable populations. MATERIALS AND METHODS: All trauma-related admissions to our ED in the first half of 2019 and 2020 were included. Patient demographics, trauma mechanism, affected body region, injury severity and discharge type were extracted from our hospital information system. Trauma subpopulations, such as interpersonal violence, self-inflicted trauma, geriatric trauma and sports-related trauma were analysed. RESULTS: A total of 5839 ED presentations were included in our study, of which 39.9% were female. Median age was 40 years (interquartile range: 27-60). In comparison to 2019, there was a 15.5% decrease in trauma-related ED presentations in the first half of 2020. This decrease was particularly marked in the 2-month March/April period, with a drop of 36.8%. In 2020, there was a reduction in injuries caused by falls of less than 3 metres or by mechanical force. There was a marked decrease in sports-related trauma and an increase in injuries related to pedal cycles. Geriatric trauma, self-harm and assault-related injuries remained stable. CONCLUSION: This study described changes in trauma patterns and highlighted populations at risk of trauma during the pandemic in Switzerland in the context of previous international studies.These results may contribute to resource management in a future pandemic.

Accuracy between prehospital and hospital diagnosis in helicopter emergency medical services and its consequences for trauma care.

PURPOSE: For optimal prehospital trauma care, it is essential to adequately recognize potential life-threatening injuries in order to correctly triage patients and to initiate life-saving measures. The aim of the present study was to determine the accuracy of prehospital diagnoses suspected by helicopter emergency medical services (HEMS). METHODS: This retrospective multicenter study included patients from the Swiss Trauma Registry with ISS ≥ 16 or AIS head ≥ 3 transported by Switzerland's largest HEMS and subsequently admitted to one of twelve Swiss trauma centers from 01/2020 to 12/2020. The primary outcome was the comparison of injuries suspected prehospital with the final diagnoses obtained at the hospital using the abbreviated injury scale (AIS) per body region. As secondary outcomes, prehospital interventions were compared to corresponding relevant diagnoses. RESULTS: Relevant head trauma was the most commonly injured body region and was identified in 96.3% (95% CI: 92.1%; 98.6%) of the cases prehospital. Relevant injuries to the chest, abdomen, and pelvis were also common but less often identified prehospital [62.7% (95% CI: 54.2%; 70.6%), 45.5% (95% CI: 30.4%; 61.2%), and 61.5% (95% CI: 44.6%; 76.6%)]. Overall, 7 of 95 (7.4%) patients with pneumothorax received a chest decompression and in 22 of 39 (56.4%) patients with an instable pelvic fracture a pelvic binder was applied prehospital. CONCLUSION: Approximately half of severe chest, abdominal, and pelvic diagnoses made in hospital went undetected in the challenging prehospital environment. This underlines the difficult circumstances faced by the rescue teams. Potentially life-saving interventions such as prehospital chest decompression and increased use of a pelvic binder were identified as potential improvements to prehospital care.

Influence of artificial intelligence on the diagnostic performance of endoscopists in the assessment of Barrett's esophagus: a tandem randomized and video trial.

BACKGROUND: This study evaluated the effect of an artificial intelligence (AI)-based clinical decision support system on the performance and diagnostic confidence of endoscopists in their assessment of Barrett's esophagus (BE). METHODS: 96 standardized endoscopy videos were assessed by 22 endoscopists with varying degrees of BE experience from 12 centers. Assessment was randomized into two video sets: group A (review first without AI and second with AI) and group B (review first with AI and second without AI). Endoscopists were required to evaluate each video for the presence of Barrett's esophagus-related neoplasia (BERN) and then decide on a spot for a targeted biopsy. After the second assessment, they were allowed to change their clinical decision and confidence level. RESULTS: AI had a stand-alone sensitivity, specificity, and accuracy of 92.2%, 68.9%, and 81.3%, respectively. Without AI, BE experts had an overall sensitivity, specificity, and accuracy of 83.3%, 58.1%, and 71.5%, respectively. With AI, BE nonexperts showed a significant improvement in sensitivity and specificity when videos were assessed a second time with AI (sensitivity 69.8% [95%CI 65.2%-74.2%] to 78.0% [95%CI 74.0%-82.0%]; specificity 67.3% [95%CI 62.5%-72.2%] to 72.7% [95%CI 68.2%-77.3%]). In addition, the diagnostic confidence of BE nonexperts improved significantly with AI. CONCLUSION: BE nonexperts benefitted significantly from additional AI. BE experts and nonexperts remained significantly below the stand-alone performance of AI, suggesting that there may be other factors influencing endoscopists' decisions to follow or discard AI advice.

Longitudinal analysis of caloric requirements in critically ill trauma patients: a retrospective cohort study.

PURPOSE: Nutrition is of paramount importance in critically ill trauma patients. However, adequate supply is difficult to achieve, as caloric requirements are unknown. This study investigated caloric requirements over time, based on indirect calorimetry, in critically ill trauma patients. METHODS: Retrospective cohort study at a tertiary trauma center including critically ill trauma patients who underwent indirect calorimetry 2012-2019. Caloric requirements were assessed as resting energy expenditure (REE) during the intensive care unit stay up to 28 days and analyzed in patient-clustered linear regression analysis. RESULTS: A total of 129 patients were included. Median REE per day was 2376 kcal. The caloric intake did not meet REE at any time with a median daily deficit of 1167 kcal. In univariable analysis, ISS was not significantly associated with REE over time (RC 0.03, p = 0.600). Multivariable analysis revealed a significant REE increase (RC 0.62, p < 0.001) and subsequent decrease (RC - 0.03, p < 0.001) over time. Age < 65 years (RC 2.07, p = 0.018), male sex (RC 4.38, p < 0.001), and BMI ≥ 35 kg/m2 (RC 6.94, p < 0.001) were identified as independent predictors for higher REE over time. Severe head trauma was associated with lower REE over time (RC - 2.10, p = 0.030). CONCLUSION: In critically ill trauma patients, caloric requirements significantly increased and subsequently decreased over time. Younger age, male sex and higher BMI were identified as independent predictors for higher caloric requirements, whereas severe head trauma was associated with lower caloric requirements over time. These results support the use of IC and will help to adjust nutritional support in critically ill trauma patients.

The CD4 Versus CD8 T Cell Fate Decision: A Multiomics-Informed Perspective.

The choice of developing thymocytes to become CD8+ cytotoxic or CD4+ helper T cells has been intensely studied, but many of the underlying mechanisms remain to be elucidated. Recent multiomics approaches have provided much higher resolution analysis of gene expression in developing thymocytes than was previously achievable, thereby offering a fresh perspective on this question. Focusing on our recent studies using CITE-seq (cellular indexing of transcriptomes and epitopes) analyses of mouse thymocytes, we present a detailed timeline of RNA and protein expression changes during CD8 versus CD4 T cell differentiation. We also revisit our current understanding of the links between T cell receptor signaling and expression of the lineage-defining transcription factors ThPOK and RUNX3. Finally, we propose a sequential selection model to explain the tight linkage between MHC-I versus MHC-II recognition and T cell lineage choice. This model incorporates key aspects of previously proposed kinetic signaling, instructive, and stochastic/selection models.

Decision-making Algorithm for the Surgical Treatment of Degenerative Lumbar Spondylolisthesis of L4/L5.

STUDY DESIGN: A retrospective analysis of prospectively collected data. OBJECTIVE: To report the decision-making process for decompression alone (DA) and decompression and fusion (DF) at a tertiary orthopedic center and compare the operative outcomes between both groups. BACKGROUND: Controversy exists around the optimal operative treatment for DLS, either with DF or DA. Although previous studies tried to establish specific indications, clinical decision-making algorithms are needed. MATERIALS AND METHODS: Patients undergoing spinal surgery for DLS at L4/5 were retrospectively analyzed. A survey of spine surgeons was performed to identify factors influencing surgical decision-making, and their association with the surgical procedure was tested in the clinical data set. We then developed a clinical score based on the statistical analysis and survey results. The predictive capability of the score was tested in the clinical data set with a receiver operating characteristic (ROC) analysis. To evaluate the clinical outcome, two years follow-up postoperative Oswestry Disability Index (ODI), postoperative low back pain (LBP) (Numeric Analog Scale), and patient satisfaction were compared between the DF and DA groups. RESULTS: A total of 124 patients were included in the analysis; 66 received DF (53.2%) and 58 DA (46.8%). Both groups showed no significant differences in postoperative ODI, LBP, or satisfaction. The degree of spondylolisthesis, facet joint diastasis and effusion, sagittal disbalance, and severity of LBP were identified as the most important factors for deciding on DA or DF. The area under the curve of the decision-making score was 0.84. At a cutoff of three points indicating DF, the accuracy was 80.6%. CONCLUSIONS: The two-year follow-up data showed that both groups showed similar improvement in ODI after both procedures, validating the respective decision. The developed score shows excellent predictive capabilities for the decision processes of different spine surgeons at a single tertiary center and highlights relevant clinical and radiographic parameters. Further studies are needed to assess the external applicability of these findings.

Preoperative imaging in third molar surgery - A prospective comparison of X-ray-based and radiation-free magnetic resonance orthopantomography.

This study aimed to compare preoperative data relevant to third molar surgery based on radiographic orthopantomography (OPG) and orthopantomogram-like MR images (MR-OPG), using five different MR protocols. X-ray-based OPG and OPG-like MRI reconstructions from DESS, SPACE-STIR, SPACE-SPAIR, T1-VIBE-Dixon, and UTE sequences were acquired in 11 patients undergoing third molar surgery, using a 15-channel mandibular coil. Qualitative (image quality, susceptibility to artifacts, positional relationship, contact/non-contact of the inferior alveolar nerve (IAN), relationship to maxillary sinus, IAN continuity, root morphology) and quantitative (tooth length, retromolar distance, distance to the IAN, and distance to the mandible margin) parameters of the maxillary and mandibular third molars were assessed regarding inter-reader agreement and quantitative discrepancies by three calibrated readers. Radiation-free MR-OPGs generated within clinically tolerable acquisition times, which exhibited high image quality and low susceptibility to artifacts, showed no significant differences compared with X-ray-based OPGs regarding the assessment of quantitative parameters. UTE MR-OPGs provided radiographic-like images and were best suited for assessing qualitative preoperative data (positional relationship, nerve contact/non-contact, and dental root morphology) relevant to third molar surgery. For continuous and focal nerve imaging, DESS MR-OPG was superior. MR-OPGs could represent a shift towards indication-specific and modality-oriented perioperative imaging in high-risk oral and maxillofacial surgery.

Injury patterns and outcomes in motorcycle driver crashes in the United States: The effect of helmet use.

BACKGROUND: Motorcycle crashes pose a persistent public health problem with disproportionate rates of severe injuries and mortality. This study aims to analyze injury patterns and outcomes with regard to helmet use. We hypothesized that helmet use is associated with fewer head injuries and does not increase the risk of cervical spine injuries. METHODS: The National Trauma Data Bank was queried for all motorcycle driver crashes between 2007-2017. Univariable analysis was used to compare demographics, clinical data, injury patterns using abbreviated injury scale, and outcomes between helmeted motorcycle drivers and non-helmeted motorcycle drivers who were injured in traffic crashes. Independent factors associated with mortality were determined by regression analysis after adjustment for potential confounders. RESULTS: A total of 315,258 patients were included for analysis, 66 % of these patients were helmeted. The sample was 92.5 % male and the median age was 41 years. Non-helmeted motorcycle drivers were more likely to sustain severe head trauma (head abbreviated injury scale ≥ 3: 28.5 % vs. 13.3 %, p < 0.001), had higher intensive care unit-admission (38 % vs. 30.2 %, p<0.001), mechanical ventilation (20.1 % vs. 13 %, p<0.001) and overall mortality rates (6.2 % vs. 3.9 %, p<0.001). Cervical spine injuries occurred in 10.6 % of non-helmeted motorcycle drivers and in 9.5 % of helmeted motorcycle drivers (p<0.001). Helmet use was identified as an independent factor associated with lower mortality [OR 0.849 (0.809-0.891), p<0.001]. CONCLUSION: Helmet use is protective for severe head injuries and associated with decreased mortality. Helmet use was not associated with increased rates of cervical spine injuries. On the contrary, fewer injuries were observed in helmeted motorcycle drivers. Public health initiatives should be aimed at enforcement of universal helmet laws within the United States and across the world.

Risk factors for thromboembolic complications in isolated severe head injury.

PURPOSE: Patients with traumatic brain injury (TBI) are at high risk for venous thromboembolism (VTE). The aim of the present study is to identify factors independently associated with VTE events. Specifically, we hypothesized that the mechanism of penetrating head trauma might be an independent factor associated with increased VTE events when compared with blunt head trauma. METHODS: The ACS-TQIP database (2013-2019) was queried for all patients with isolated severe head injuries (AIS 3-5) who received VTE prophylaxis with either unfractionated heparin or low-molecular-weight heparin. Transfers, patients who died within 72 h and those with a hospital length of stay < 48 h were excluded. Multivariable analysis was used as the primary analysis to identify independent risk factors for VTE in isolated severe TBI. RESULTS: A total of 75,570 patients were included in the study, 71,593 (94.7%) with blunt and 3977 (5.3%) with penetrating isolated TBI. Penetrating trauma mechanism (OR 1.49, CI 95% 1.26-1.77), increasing age (age 16-45: reference; age > 45-65: OR 1.65, CI 95% 1.48-1.85; age > 65-75: OR 1.71, CI 95% 1.45-2.02; age > 75: OR 1.73, CI 95% 1.44-2.07), male gender (OR 1.53, CI 95% 1.36-1.72), obesity (OR 1.35, CI 95% 1.22-1.51), tachycardia (OR 1.31, CI 95% 1.13-1.51), increasing head AIS (AIS 3: reference; AIS 4: OR 1.52, CI 95% 1.35-1.72; AIS 5: OR 1.76, CI 95% 1.54-2.01), associated moderate injuries (AIS = 2) of the abdomen (OR 1.31, CI 95% 1.04-1.66), spine (OR 1.35, CI 95% 1.19-1.53), upper extremity (OR 1.16, CI 95% 1.02-1.31), lower extremity (OR 1.46, CI 95% 1.26-1.68), craniectomy/craniotomy or ICP monitoring (OR 2.96, CI 95% 2.65-3.31) and pre-existing hypertension (OR 1.18, CI 95% 1.05-1.32) were identified as independent risk factors for VTE complications in isolated severe head injury. Increasing GCS (OR 0.93, CI 95% 0.92-0.94), early VTE prophylaxis (OR 0.48, CI 95% 0.39-0.60) and LMWH compared to heparin (OR 0.74, CI 95% 0.68-0.82) were identified as protective factors for VTE complications. CONCLUSION: The identified factors independently associated with VTE events in isolated severe TBI need to be considered in VTE prevention measures. In penetrating TBI, an even more aggressive VTE prophylaxis management may be justified as compared to that in blunt.

Highly Transparent, Yet Photoluminescent: 2D CdSe/CdS Nanoplatelet-Zeolitic Imidazolate Framework Composites Sensitive to Gas Adsorption.

In this work, thin composite films of zeolitic imidazolate frameworks (ZIFs) and colloidal two-dimensional (2D) core-crown CdSe/CdS nanoplatelet (NPL) emitters with minimal scattering are formed by a cycled growth method and yield highly transparent coatings with strong and narrow photoluminescence of the NPLs at 546 nm (FWHM: 25 nm) in a solid-state composite structure. The porous ZIF matrix acts as functional encapsulation for the emitters and enables the adsorption of the guest molecules water and ethanol. The adsorption and desorption of the guest molecules is then characterized by a reversable photoluminescence change of the embedded NPLs. The transmittance of the composite films exceeds the values of uncoated glass at visible wavelengths where the NPL emitters show no absorption (>540 nm) and renders them anti-reflective coatings. At NPL absorption wavelengths (440-540 nm), the transmittance of the thin composite film-coated glass lies close to the transmittance of uncoated glass. The fast formation of innovative, smooth NPL/ZIF composite films without pre-polymerizing the colloidal 2D nanostructures first provides a powerful tool toward application-oriented photoluminescence-based gas sensing.

Early kinetics of C reactive protein for cancer-agnostic prediction of therapy response and mortality in patients treated with immune checkpoint inhibitors: a multicenter cohort study.

BACKGROUND: C reactive protein (CRP) kinetics have recently been suggested as predictive biomarkers for the efficacy of immune checkpoint inhibitor (ICI) therapy in selected cancer types. The aim of this study was to characterize early CRP kinetics as a tumor-agnostic biomarker for ICI treatment outcomes. METHODS: In this multicenter retrospective cohort study, two independent cohorts of patients with various cancer types undergoing palliative ICI treatment at Austrian academic centers served as the discovery (n=562) and validation cohort (n=474). Four different patterns of CRP kinetics in the first 3 months of ICI therapy were defined (CRP-flare responders, CRP-responders, CRP non-responders, patients with all-normal CRP). Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were defined as coprimary endpoints. Univariable and multivariable logistic regression, landmark analysis and Cox regression including CRP kinetics as time-dependent variable were performed. RESULTS: The ORR in patients with all-normal CRP, CRP responders, CRP flare-responders and CRP non-responders was 41%, 38%, 31% and 12%, respectively. The median OS and PFS estimates were 24.5 months (95% CI 18.5 to not reached) and 8.2 months (95% CI 5.9 to 12.0) in patients with all-normal CRP, 16.1 months (95% CI 12.6 to 19-8) and 6.1 months (95% CI 4.9 to 7.2) in CRP-responders, 14.0 months (95% CI 8.5 to 19.4) and 5.7 months (95% CI 4.1 to 8.5) in CRP flare-responders and 8.1 months (95% CI 5.8 to 9.9) and 2.3 months (95% CI 2.2 to 2.8) in CRP non-responders (log-rank p for PFS and OS<0.001). These findings prevailed in multivariable analysis and could be fully confirmed in our validation cohort. Pooled subgroup analysis suggested a consistent predictive significance of early CRP kinetics for treatment efficacy and outcome independent of cancer type. CONCLUSION: Early CRP kinetics represent a tumor-agnostic predictor for treatment response, progression risk and mortality in patients with cancer undergoing ICI therapy.

Impact of Modern Low Dose Involved Site Radiation Therapy on Normal Tissue Toxicity in Cervicothoracic Non-Hodgkin Lymphomas: A Biophysical Study.

This biophysical study aimed to determine fitting parameters for the Lyman-Kutcher-Burman (LKB) dose-response model for normal tissue complication probability (NTCP) calculations of acute side effects and to investigate the impact of reduced radiation doses on the probability of their occurrence in supradiaphragmatic non-Hodgkin lymphoma (NHL) irradiation. A cohort of 114 patients with NHL in the cervicothoracic region, treated between 2015 and 2021 at the University Hospitals of Münster, Hamburg, and Essen, with involved site radiation therapy (ISRT), were included. Among them, 68 patients with aggressive NHL (a-NHL) received consolidative radiation therapy with 24-54 Gy following (R-)CHOP chemotherapy. Additionally, 46 patients with indolent NHL (i-NHL) underwent radiotherapy with 22.5-45.0 Gy. Two treatment plans were prospectively created for each patient (a-NHL: 30.0/40.0 Gy; i-NHL: 24.0/30.0 Gy). NTCP were then calculated using the optimized LKB model. The adapted dose-response models properly predicted the patient's probability of developing acute side effects when receiving doses ≤ 50 Gy. In addition, it was shown that reduced radiation doses can influence the NTCP of acute side effects depending on the aggressiveness of NHL significantly. This study provided a foundation to prospectively assess the probability of adverse side effects among today's reduced radiation doses in the treatment of NHL.

His-Purkinje Conduction System Pacing Optimized Trial of Cardiac Resynchronization Therapy vs Biventricular Pacing: HOT-CRT Clinical Trial.

BACKGROUND: His-Purkinje conduction system pacing (HPCSP) using His bundle pacing (HBP) or left bundle branch pacing (LBBP) has emerged as an alternative to biventricular pacing (BVP) in patients requiring cardiac resynchronization therapy (CRT). OBJECTIVES: The aim of the study was to compare the feasibility and clinical efficacy of HOT-CRT (His-Purkinje conduction system pacing Optimized Trial of Cardiac Resynchronization Therapy) with BVP in patients with heart failure, reduced ejection fraction, and indication for CRT. METHODS: This was a prospective, randomized, controlled trial of HOT-CRT and BVP in patients with LVEF <50% and indications for CRT. If HPCSP resulted in incomplete electrical resynchronization, a coronary sinus (CS) lead was added. The primary outcome was the change in left ventricular ejection fraction (LVEF) at 6 months. The primary safety endpoint was freedom from major complications. RESULTS: A total of 100 patients (female 31%, aged 70 ± 12 years, LVEF 31.5% ± 9.0%) were randomized. HOT-CRT was successful in 48 of 50 (96%) and BVP-CRT in 41 of 50 (82%) patients (P = 0.03). QRS duration significantly decreased from 164 ± 26 ms to 137 ± 20 ms with HOT-CRT and 166 ± 28 ms to 141 ± 19 ms with BVP. Fluoroscopy results (18.8 ± 12.4 min vs 23.8 ± 12.4 min, P = 0.05) and procedure duration (119 ± 42 min vs 114 ± 36 min, P = 0.5) were similar. The primary outcome of change in LVEF at 6 months was greater in HOT-CRT than in BVP (12.4% ± 7.3% vs 8.0% ± 10.1%, P = 0.02). The primary safety endpoint was similar (98% vs 94%, P = 0.62). Echocardiographic response of improvement in LVEF >5% occurred in 80% vs 61% (P = 0.06). Complications occurred in 3 (6%) in HOT-CRT vs 10 (20%) in BVP (P = 0.03). CONCLUSIONS: HPCSP-guided CRT resulted in greater change in LVEF compared with BVP. Randomized clinical trials with long-term follow-up are necessary. (His-Purkinje Conduction System Pacing Optimized Trial of Cardiac Resynchronization Therapy [HOT-CRT]; NCT04561778).