Barbed suture in neck dissection: a randomized clinical study on efficacy, safety and aesthetic outcome.

PURPOSE: The resection of lymph nodes/neck dissection is a typical part of the surgical treatment of head and neck malignancies. The aim of this study was to compare subcutaneous closure using single knotted, braided suture (VicrylTM, standard arm) with continuous self-locking, monofilament barbed suture (V-LocTM, experimental arm). METHODS: Neck Lock was a randomized clinical trial at a single tertiary referral center. It was conducted from 2016 till 2022 with a follow-up period of 3 months. Assessment of safety and aesthetic outcome was double-blinded. 68 patients were randomized after application of exclusion criteria. Subcutaneous wound closure was performed in an intrapatient randomized fashion for suture technique. The primary endpoint was the duration of subcutaneous sutures. Wound healing and scar formation were recorded at multiple postoperative intervals as secondary endpoints. RESULTS: The median age was 61 years, 89.7% were male. 92.6% suffered from a squamous cell carcinoma. There was a significant difference in median subcutaneous suture time (p = 0.024) between the experimental (6:11 ± 2:30 min) and standard (7:01 ± 2.42 min) arms. There was no significant difference in safety when assessing adverse events (AEs). At least one AE occurred in 14.7% vs. 5.9%, for barbed and smooth sutures respectively (p = 0.16). CONCLUSION: For neck dissection of head and neck malignancies, subcutaneous wound closure with self-locking sutures offers significant time savings over the single knot technique with similar safety and aesthetic results. TRIAL REGISTRATION INFORMATION: The trial was registered with WHO acknowledged primary registry "German Clinical Trials Register" under the ID DRKS00025831 ( https://drks.de/search/de/trial/DRKS00025831 ).

A qualitative study of stakeholders' experiences with and acceptability of a technology-supported health coaching intervention (SHARE-S) delivered in coordination with cancer survivorship care.

PURPOSE: Healthy cancer survivorship involves patients' active engagement with preventative health behaviors and follow-up care. While clinicians and patients have typically held dual responsibility for activating these behaviors, transitioning some clinician effort to technology and health coaches may enhance guideline implementation. This paper reports on the acceptability of the Shared Healthcare Actions & Reflections Electronic systems in survivorship (SHARE-S) program, an entirely virtual multicomponent intervention incorporating e-referrals, remotely-delivered health coaching, and automated text messages to enhance patient self-management and promote healthy survivorship. METHODS: SHARE-S was evaluated in single group hybrid implementation-effectiveness pilot study. Patients were e-referred from the clinical team to health coaches for three health self-management coaching calls and received text messages to enhance coaching. Semi-structured qualitative interviews were conducted with 21 patient participants, 2 referring clinicians, and 2 health coaches to determine intervention acceptability (attitudes, appropriateness, suitability, convenience, and perceived effectiveness) and to identify important elements of the program and potential mechanisms of action to guide future implementation. RESULTS: SHARE-S was described as impactful and convenient. The nondirective, patient-centered health coaching and mindfulness exercises were deemed most acceptable; text messages were less acceptable. Stakeholders suggested increased flexibility in format, frequency, timing, and length of participation, and additional tailored educational materials. Patients reported tangible health behavior changes, improved mood, and increased accountability and self-efficacy. CONCLUSIONS: SHARE-S is overall an acceptable and potentially effective intervention that may enhance survivors' self-management and well-being. Alterations to tailored content, timing, and dose should be tested to determine impact on acceptability and outcomes.

A Multidisciplinary Curriculum to Standardize Chest Procedures Training for Trainees in General Surgery, Emergency Medicine, and Critical Care.

Introduction: Critical care, emergency medicine, and surgical trainees frequently perform surgical and Seldinger-technique tube thoracostomy, thoracentesis, and thoracic ultrasound. However, approaches to teaching these skills are highly heterogeneous. Over 10 years, we have developed a standardized, multidisciplinary curriculum to teach these procedures. Methods: Emergency medicine residents, surgical residents, and critical care fellows, all in the first year of their respective programs, underwent training in surgical and Seldinger chest tube placement and securement, thoracentesis, and thoracic ultrasound. The curriculum included preworkshop instructional videos and 45-minute in-person practice stations (3.5 hours total). Sessions were co-led by faculty from emergency medicine, thoracic surgery, and pulmonary/critical care who performed real-time formative assessment with standardized procedural steps. Postcourse surveys assessed learners' confidence before versus after the workshop in each procedure, learners' evaluations of faculty by station and specialty, and the workshop overall. Results: One hundred twenty-three trainees completed course evaluations, demonstrating stable and positive responses from learners of different backgrounds taught by a multidisciplinary group of instructors, as well as statistically significant improvement in learner confidence in each procedure. Over time, we have made incremental changes to our curriculum based on feedback from instructors and learners. Discussion: We have developed a unique curriculum designed, revised, and taught by a multidisciplinary faculty over many years to teach a unified approach to the performance of common chest procedures to surgical, emergency medicine, and critical care trainees. Our curriculum can be readily adapted to the needs of institutions that desire a standardized, multidisciplinary approach to thoracic procedural education.

Bladder tumour focused adaptive radiotherapy: Clinical outcomes of a phase I dose escalation study.

PURPOSE/OBJECTIVES: We determine the maximum tolerated tumour focused dose (MTD) for the radical treatment of muscle invasive bladder cancer (MIBC) enabled by image guided adaptive radiotherapy (IGART) and long-term clinical outcomes. MATERIALS/METHODS: Fifty-nine patients with T2-T4aN0M0 unifocal urothelial MIBC suitable for daily radical radiotherapy were recruited prospectively to an ethics approved protocol (XX). The uninvolved bladder (PTVbladder) was planned to 52Gy in 32 fractions (f). The bladder tumour (PTVtumour) was planned to an assigned dose level of 68, 70, 72, or 74Gy. If organ at risk (OAR) dose constraints were violated, then PTVtumour was planned to 64Gy. Dose level allocation was determined by concurrent toxicity assessment of all previous patients recruited. Acute toxicity was evaluated using CTCAE v3.0; late toxicity was evaluated using RTOG criteria. The MTD was predefined as the highest dose level with estimated probability of ≤ 15% ≥G3 late toxicity and observed rate <50% acute G3 and <10% acute G4 toxicity. RESULTS: Twenty-six patients were assigned to 68Gy, of whom 6 were planned to 64Gy; 29 patients were assigned to 70Gy of whom 1 was planned to 68Gy, 2 patients were assigned and planned to 72Gy; no patients were assigned to 74Gy. Three patients did not complete treatment as planned, of whom only 1 patient stopped treatment because dose limiting toxicity occurred. The MTD was 70Gy. Acute genitourinary (GU) and gastrointestinal (GI) G3 acute toxicity was seen in 19% and 7% patients respectively. No grade 4 GU or GI toxicity was seen. Late toxicity (any) G3 and G4 was seen in 14% and 2% patients respectively. The 5-year overall survival was 58% (95% CI 44-71%). The bladder preservation rate was 89% (95% CI, 88 to 96%) with 6 patients not retaining native bladder function. CONCLUSION: Bladder tumour focused dose escalation to 70Gy using IGART is feasible with acceptable toxicity. This dose level has been evaluated in a phase II randomised control trial (XXXXX).

Single-cell topographical profiling of the immune synapse reveals a biomechanical signature of cytotoxicity.

Immune cells have intensely physical lifestyles characterized by structural plasticity and force exertion. To investigate whether specific immune functions require stereotyped mechanical outputs, we used super-resolution traction force microscopy to compare the immune synapses formed by cytotoxic T cells with contacts formed by other T cell subsets and by macrophages. T cell synapses were globally compressive, which was fundamentally different from the pulling and pinching associated with macrophage phagocytosis. Spectral decomposition of force exertion patterns from each cell type linked cytotoxicity to compressive strength, local protrusiveness, and the induction of complex, asymmetric topography. These features were validated as cytotoxic drivers by genetic disruption of cytoskeletal regulators, live imaging of synaptic secretion, and in silico analysis of interfacial distortion. Synapse architecture and force exertion were sensitive to target stiffness and size, suggesting that the mechanical potentiation of killing is biophysically adaptive. We conclude that cellular cytotoxicity and, by implication, other effector responses are supported by specialized patterns of efferent force.

A Novel Macrophage Subpopulation Conveys Increased Genetic Risk of Coronary Artery Disease.

BACKGROUND: Coronary artery disease (CAD), the leading cause of death worldwide, is influenced by both environmental and genetic factors. Although over 250 genetic risk loci have been identified through genome-wide association studies, the specific causal variants and their regulatory mechanisms are still largely unknown, particularly in disease-relevant cell types such as macrophages. METHODS: We utilized single-cell RNA-seq and single-cell multiomics approaches in primary human monocyte-derived macrophages to explore the transcriptional regulatory network involved in a critical pathogenic event of coronary atherosclerosis-the formation of lipid-laden foam cells. The relative genetic contribution to CAD was assessed by partitioning disease heritability across different macrophage subpopulations. Meta-analysis of single-cell RNA-seq data sets from 38 human atherosclerotic samples was conducted to provide high-resolution cross-referencing to macrophage subpopulations in vivo. RESULTS: We identified 18 782 cis-regulatory elements by jointly profiling the gene expression and chromatin accessibility of >5000 macrophages. Integration with CAD genome-wide association study data prioritized 121 CAD-related genetic variants and 56 candidate causal genes. We showed that CAD heritability was not uniformly distributed and was particularly enriched in the gene programs of a novel CD52-hi lipid-handling macrophage subpopulation. These CD52-hi macrophages displayed significantly less lipoprotein accumulation and were also found in human atherosclerotic plaques. We investigated the cis-regulatory effect of a risk variant rs10488763 on FDX1, implicating the recruitment of AP-1 and C/EBP-ß in the causal mechanisms at this locus. CONCLUSIONS: Our results provide genetic evidence of the divergent roles of macrophage subsets in atherogenesis and highlight lipid-handling macrophages as a key subpopulation through which genetic variants operate to influence disease. These findings provide an unbiased framework for functional fine-mapping of genome-wide association study results using single-cell multiomics and offer new insights into the genotype-environment interactions underlying atherosclerotic disease.

Impact of clinical frailty on surgical and non-surgical complications after major emergency abdominal surgery.

BACKGROUND: Major emergency abdominal surgery is associated with a high risk of morbidity and mortality. Given the ageing and increasingly frail population, understanding the impact of frailty on complication patterns after surgery is crucial. The aim of this study was to evaluate the association between clinical frailty and organ-specific postoperative complications after major emergency abdominal surgery. METHODS: A prospective cohort study including all patients undergoing major emergency abdominal surgery at Copenhagen University Hospital Herlev, Denmark, from 1 October 2020 to 1 August 2022, was performed. Clinical frailty scale scores were determined for all patients upon admission and patients were then analysed according to clinical frailty scale groups (scores of 1-3, 4-6, or 7-9). Postoperative complications were registered until discharge. RESULTS: A total of 520 patients were identified. Patients with a low clinical frailty scale score (1-3) experienced fewer total complications (120 complications per 100 patients) compared with patients with clinical frailty scale scores of 4-6 (250 complications per 100 patients) and 7-9 (277 complications per 100 patients) (P < 0.001). A high clinical frailty scale score was associated with a high risk of pneumonia (P = 0.009), delirium (P < 0.001), atrial fibrillation (P = 0.020), and infectious complications in general (P < 0.001). Patients with severe frailty (clinical frailty scale score of 7-9) suffered from more surgical complications (P = 0.001) compared with the rest of the cohort. Severe frailty was associated with a high risk of 30-day mortality (33% for patients with a clinical frailty scale score of 7-9 versus 3.6% for patients with a clinical frailty scale score of 1-3, P < 0.001). In a multivariate analysis, an increasing degree of clinical frailty was found to be significantly associated with developing at least one complication. CONCLUSION: Patients with frailty have a significantly increased risk of postoperative complications after major emergency abdominal surgery, especially atrial fibrillation, delirium, and pneumonia. Likewise, patients with frailty have an increased risk of mortality within 90 days. Thus, frailty is a significant predictor for adverse events after major emergency abdominal surgery and should be considered in all patients undergoing major emergency abdominal surgery.

Blood biomarkers of neurodegeneration associate differently with amyloid deposition, medial temporal atrophy, and cerebrovascular changes in APOE ε4-enriched cognitively unimpaired elderly.

BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß (Aß) plaques, neurofibrillary tau tangles, and neurodegeneration in the brain parenchyma. Here, we aimed to (i) assess differences in blood and imaging biomarkers used to evaluate neurodegeneration among cognitively unimpaired APOE ε4 homozygotes, heterozygotes, and non-carriers with varying risk for sporadic AD, and (ii) to determine how different cerebral pathologies (i.e., Aß deposition, medial temporal atrophy, and cerebrovascular pathology) contribute to blood biomarker concentrations in this sample. METHODS: Sixty APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) ranging from 60 to 75 years, were recruited in collaboration with Auria biobank (Turku, Finland). Participants underwent Aß-PET ([11C]PiB), structural brain MRI including T1-weighted and T2-FLAIR sequences, and blood sampling for measuring serum neurofilament light chain (NfL), plasma total tau (t-tau), plasma N-terminal tau fragments (NTA-tau) and plasma glial fibrillary acidic protein (GFAP). [11C]PiB standardized uptake value ratio was calculated for regions typical for Aß accumulation in AD. MRI images were analysed for regional volumes, atrophy scores, and volumes of white matter hyperintensities. Differences in biomarker levels and associations between blood and imaging biomarkers were tested using uni- and multivariable linear models (unadjusted and adjusted for age and sex). RESULTS: Serum NfL concentration was increased in APOE ε4 homozygotes compared with non-carriers (mean 21.4 pg/ml (SD 9.5) vs. 15.5 pg/ml (3.8), p = 0.013), whereas other blood biomarkers did not differ between the groups (p > 0.077 for all). From imaging biomarkers, hippocampal volume was significantly decreased in APOE ε4 homozygotes compared with non-carriers (6.71 ml (0.86) vs. 7.2 ml (0.7), p = 0.029). In the whole sample, blood biomarker levels were differently predicted by the three measured cerebral pathologies; serum NfL concentration was associated with cerebrovascular pathology and medial temporal atrophy, while plasma NTA-tau associated with medial temporal atrophy. Plasma GFAP showed significant association with both medial temporal atrophy and Aß pathology. Plasma t-tau concentration did not associate with any of the measured pathologies. CONCLUSIONS: Only increased serum NfL concentrations and decreased hippocampal volume was observed in cognitively unimpaired APOEε4 homozygotes compared to non-carriers. In the whole population the concentrations of blood biomarkers were affected in distinct ways by different pathologies.

Increase in acute mastoiditis at the end of the COVID-19 pandemic.

PURPOSE: Common respiratory infections were significantly reduced during the COVID-19 pandemic due to general protective and hygiene measures. The gradual withdrawal of these non-pharmaceutical interventions (NPI) was associated with a notable increase in these infections, particularly in pediatric and adult otorhinolaryngology. The aim of this retrospective monocentric study was to evaluate the impact of NPI during the COVID-19 pandemic on the incidence and severity of acute mastoiditis (AM). METHODS: Pre-pandemic clinical data of AM cases from 2011 to 2019 were compared with infection counts from January 2020 to June 2023 for seasonal periodicity, age-specific differences, pathogens, and complication rates in a German third-level hospital. RESULTS: Out of 196 patients with AM 133 were children, the majority between 1 and 5 years of age. Complications of AM, such as meningitis, brain abscess, and sinus vein thrombosis, were more common in adults (87%) than in children (17%). Morbidity and mortality rates were similar before, during and after the pandemic. Pneumococci were the most common pathogen in both age groups, with a post-pandemic cumulation of Streptococcus pyogenes infections in children. While pre-pandemic cases clustered in spring, seasonality was absent in all age groups during the main phase of the pandemic. The cessation of NPI caused a steep rise in AM cases in both age groups starting from December 2022. CONCLUSION: NPI during the COVID-19 pandemic reduced the incidence of AM. Their reversal led to a substantial increase in the incidence of AM during the post-pandemic period, which may be due to a general increase in viral respiratory infections and an insufficiently trained immune system.

In silico model development and optimization of in vitro lung cell population growth.

Tissue engineering predominantly relies on trial and error in vitro and ex vivo experiments to develop protocols and bioreactors to generate functional tissues. As an alternative, in silico methods have the potential to significantly reduce the timelines and costs of experimental programs for tissue engineering. In this paper, we propose a methodology to formulate, select, calibrate, and test mathematical models to predict cell population growth as a function of the biochemical environment and to design optimal experimental protocols for model inference of in silico model parameters. We systematically combine methods from the experimental design, mathematical statistics, and optimization literature to develop unique and explainable mathematical models for cell population dynamics. The proposed methodology is applied to the development of this first published model for a population of the airway-relevant bronchio-alveolar epithelial (BEAS-2B) cell line as a function of the concentration of metabolic-related biochemical substrates. The resulting model is a system of ordinary differential equations that predict the temporal dynamics of BEAS-2B cell populations as a function of the initial seeded cell population and the glucose, oxygen, and lactate concentrations in the growth media, using seven parameters rigorously inferred from optimally designed in vitro experiments.

Ex Vivo Immune Function and Modulatory Effects of Calcitriol in Dogs with Naturally Occurring Diabetes Mellitus.

Human patients with type 1 diabetes mellitus (T1DM) are susceptible to several long-term complications that are related to glycemic control and immune dysregulation. Immune function remains relatively unexplored in dogs with naturally occurring diabetes mellitus (NODM). Calcitriol improves various aspects of immune function in a variety of species, but its effect in diabetic dogs remains unexplored. Therefore, the objectives of this study were to (i) evaluate immune function in dogs with NODM and determine if differences exist based on the level of clinical control and (ii) assess the immunomodulatory effects of calcitriol. Twenty diabetic dogs (clinically controlled, n = ten, not controlled, n = ten) and 20 non-diabetic, healthy control dogs were included in this prospective, case-control study. Whole blood was incubated with calcitriol (10-7 M) or negative control, after which the samples were divided for phagocytosis and leukocyte cytokine response experiments. The phagocytosis of opsonized Escherichia coli (E. coli) was evaluated with flow cytometry. The samples for leukocyte cytokine response evaluations were stimulated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or phosphate buffer solution (PBS; negative control), and tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and IL-10 were measured in supernatant using a canine-specific multiplex bead-based assay. The leukocytes from diabetic dogs produced higher concentrations of IL-10 (p = 0.01), IL-6 (p < 0.0001), and IL-8 (p < 0.0001) than the control dogs while controlling for the intervention and stimulant. Calcitriol decreased the supernatant concentrations of TNF-α (p < 0.001) and IL-8 (p = 0.04) with concomitant increases in IL-6 (p = 0.005). Diabetic dogs had a lower percentage of leukocytes undergoing phagocytosis (p < 0.0001) but a higher number of bacteria phagocytized per cell (p = 0.001) when compared to the control dogs. Calcitriol had no effect on phagocytic capacity. Lastly, the status of clinical control in diabetic dogs did not yield differences in immune function. These results support that dogs with NODM exhibit immune dysregulation and warrant additional investigation.

Management of Congenital Hernias in Adults: Foramen of Morgagni Hernia.

Morgagni hernias may range from asymptomatic incidental findings to surgical emergencies. An abdominal approach is ideal in the majority of cases, although surgeons should understand alternatives for repair.

Injection Laryngoplasty for Children with Dysphagia after Cardiac Surgery.

Objective: To determine whether injection laryngoplasty (IL) resolves thin liquid aspiration among children with unilateral vocal cord paralysis (UVCP) after cardiac surgery. Study Design: Retrospective case-control. Setting: Tertiary children's hospital. Methods: Consecutive children (<5 years) between 2012 and 2022 with UVCP after cardiac surgery were included. Resolution of thin liquid aspiration after IL versus observation was determined for children obtaining videofluoroscopic swallow studies (VFSS). Results: A total of 32 children with left UVCP after cardiac surgery met inclusion. Initial surgeries were N = 9 (28%) patent ductus arteriosus ligations, N = 7 (22%) aortic arch surgeries, N = 9 (28%) surgeries for hypoplastic left heart syndrome, and N = 7 (22%) other cardiac surgeries. The mean age at initial surgery was 1.8 months (SD: 3.7). All children had a VFSS obtained after surgery that confirmed aspiration. There were 17 children that obtained an IL at 33.6 months (SD: 20.9) after cardiac surgery and 15 children observed without IL procedure. No surgical complications after IL were noted. The rate of aspiration resolution based on postoperative VFSS was N = 14 (82%) for the IL group and N = 9 (60%) for the control group P = .24. Documented VFSS aspiration resolution after cardiac surgery occurred by 9.6 months (SD: 10.0) in the observation group and 47.4 months (SD: 24.1) in the IL group (P < .001). Conclusion: IL can help treat aspiration in children with UVCP after cardiac surgery but the benefit beyond observation remains unclear. Future studies should continue to explore the utility for IL in managing dysphagia in this pediatric population.

Sex differences in Alzheimer's disease blood biomarkers in a Caribbean population of African ancestry: The Tobago Health Study.

INTRODUCTION: Alzheimer's disease (AD) is increasing in the Caribbean, especially for persons of African ancestry (PAA) and women. However, studies have mostly utilized surveys without AD biomarkers. METHODS: In the Tobago Health Study (n = 309; 109 women, mean age 70.3 ± 6.6), we assessed sex differences and risk factors for serum levels of phosphorylated tau-181 (p-tau181), amyloid-beta (Aß)42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Blood samples were from 2010 to 2013 for men and from 2019 to 2023 for women. RESULTS: Women were more obese, hypertensive, and sedentary but reported less smoking and alcohol use than men (age-adjusted p < 0.04). Compared to men, women had worse levels of AD biomarkers, with higher p-tau181 and lower Aß42/40, independent of covariates (p < 0.001). In sex-stratified analyses, higher p-tau181 was associated with older age in women and with hypertension in men. GFAP and NfL did not differ by sex. DISCUSSION: Women had worse AD biomarkers than men, unexplained by age, cardiometabolic diseases, or lifestyle. Studying risk factors for AD in PAA is warranted, especially for women earlier in life.

Risk Factors Associated with Chemotherapy-Induced Nausea and Vomiting Among Women with Breast Cancer Receiving Highly Emetogenic Chemotherapy: Individual Patient-Based Analysis of Three Prospective Antiemetic Trials.

Purpose: Although risk factors related to chemotherapy-induced nausea and vomiting (CINV) have been identified in previous studies, only a few studies have evaluated the risk factors associated with contemporary antiemetic prophylaxis, including olanzapine/aprepitant- or NEPA-containing regimens. This study aimed to identify the risk factors associated with CINV development in Chinese breast cancer patients receiving doxorubicin and cyclophosphamide chemotherapy. Methods: Data from 304 patients enrolled in 3 previously reported prospective antiemetic studies were included. Multivariate logistic regression models were used to predict risk factors associated with CINV occurrence. Additionally, the likelihood of treatment failure in relation to the number of risk factors in individual patients was evaluated. Results: Multivariate analysis of the entire study group revealed that obesity status (defined as body mass index/= 25.0 kg/m2) and the use of olanzapine/aprepitant- or NEPA-containing anti-emetic regimens were associated with a high likelihood, while a history of motion sickness was associated with a lower likelihood, complete response (CR), and "no nausea" in the overall phase. A history of vomiting during pregnancy was also associated with a lower likelihood of an overall CR. Patients with an increasing number of risk factors had a higher likelihood of treatment failure and shorter time to first vomiting. Those who did not achieve CR and "no nausea" in the first cycle were less likely to achieve these parameters in the subsequent cycle of chemotherapy. Conclusion: The present study confirmed previously reported risk factors for CINV in Chinese breast cancer patients receiving doxorubicin and cyclophosphamide. Further optimization of CINV control is required for patients with identifiable risk factors; olanzapine/aprepitant- or NEPA- containing prophylaxis are the preferred contemporary anti-emetics regimens for Chinese breast cancer patients undergoing doxorubicin and cyclophosphamide chemotherapy.

Partial recovery of peripheral blood monocyte subsets in head and neck squamous cell carcinoma patients upon radio(chemo)therapy is associated with decreased plasma CXCL11.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) represents a common and heterogeneous malignancy of the oral cavity, pharynx and larynx. Surgery and radio(chemo)therapy are the standard treatment options and also have great influence on the composition of the tumor microenvironment and immune cell functions. However, the impact of radio(chemo)therapy on the distribution and characteristics of circulating monocyte subsets in HNSCC are not fully understood. METHODS: Expression patterns of adhesion molecules and chemokine receptors CD11a (integrin-α L; LFA-1), CD11b (integrin-α M; Mac-1), CD11c (integrin-α X), CX3CR1 (CX3CL1 receptor) and checkpoint molecule PD-L1 (programmed cell death ligand-1) were investigated upon radio(chemo)therapeutic treatment using flow cytometry. Furthermore, comprehensive analysis of plasma cytokines was performed before and after treatment using ELISA measurements. RESULTS: Our data reveal a partial recovery of circulating monocytes in HNSCC patients upon radio(chemo)therapeutic treatment, with differential effects of the individual therapy regimen. PD-L1 expression on non-classical monocytes significantly correlates with the individual plasma levels of chemokine CXCL11 (C-X-C motif chemokine 11). CONCLUSIONS: Further comprehensive investigations on larger patient cohorts are required to elucidate the meaningfulness of peripheral blood monocyte subsets and chemokine CXCL11 as potential bioliquid indicators in HNSCC with regard to therapy response and the individual immunological situation.

Establishment of the deuterium oxide dilution method as a new possibility for determining the transendothelial water permeability.

Increase in transendothelial water permeability is an essential etiological factor in a variety of diseases like edema and shock. Despite the high clinical relevance, there has been no precise method to detect transendothelial water flow until now. The deuterium oxide (D2O) dilution method, already established for measuring transepithelial water transport, was used to precisely determine the transendothelial water permeability. It detected appropriate transendothelial water flow induced by different hydrostatic forces. This was shown in four different endothelial cell types. The general experimental setup was verified by gravimetry and absorbance spectroscopy. Determination of transendothelial electrical resistance (TEER) and immunocytochemical staining for proteins of the cell-cell contacts were performed to ensure that no damage to the endothelium occurred because of the measurements. Furthermore, endothelial barrier function was modulated. Measurement of transendothelial water flux was verified by measuring the TEER, the apparent permeability coefficient and the electrical capacity. The barrier-promoting substances cyclic adenosine monophosphate and iloprost reduced TEER and electrical capacity and increased permeability. This was accompanied by a reduced transendothelial water flux. In contrast, the barrier-damaging substances thrombin, histamine and bradykinin reduced TEER and electrical capacity, but increased permeability. Here, an increased water flow was shown. This newly established in vitro method for direct measurement of transendothelial water permeability was verified as a highly precise technique in various assays. The use of patient-specific endothelial cells enables individualized precision medicine in the context of basic edema research, for example regarding the development of barrier-protective pharmaceuticals.

The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis.

Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl-) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise. Here, we show that partial inhibition of ClC-1 with an orally bioavailable small molecule (NMD670) can restore muscle function in rat models of MG and in patients with MG. In severely affected MG rats, ClC-1 inhibition enhanced neuromuscular transmission, restored muscle function, and improved mobility after both single and prolonged administrations of NMD670. On this basis, NMD670 was progressed through nonclinical safety pharmacology and toxicology studies, leading to approval for testing in clinical studies. After successfully completing phase 1 single ascending dose in healthy volunteers, NMD670 was tested in patients with MG in a randomized, placebo-controlled, single-dose, three-way crossover clinical trial. The clinical trial evaluated safety, pharmacokinetics, and pharmacodynamics of NMD670 in 12 patients with mild MG. NMD670 had a favorable safety profile and led to clinically relevant improvements in the quantitative myasthenia gravis (QMG) total score. This translational study spanning from single muscle fiber recordings to patients provides proof of mechanism for ClC-1 inhibition as a potential therapeutic approach in MG and supports further development of NMD670.

Novel ultrasensitive immunoassay for the selective quantification of tau oligomers and related soluble aggregates.

INTRODUCTION: Tau aggregation into paired helical filaments and neurofibrillary tangles is characteristic of Alzheimer's disease (AD) and related disorders. However, biochemical assays for the quantification of soluble, earlier-stage tau aggregates are lacking. We describe an immunoassay that is selective for tau oligomers and related soluble aggregates over monomers. METHODS: A homogeneous (single-antibody) immunoassay was developed using a novel anti-tau monoclonal antibody and validated with recombinant and brain tissue-derived tau. RESULTS: The assay signals were concentration dependent for recombinant tau aggregates in solution but not monomers, and recognized peptides within, but not outside, the aggregation-prone microtubule binding region. The signals in inferior and middle frontal cortical tissue homogenates increased with neuropathologically determined Braak staging, and were higher in insoluble than soluble homogenized brain fractions. Autopsy-verified AD gave stronger signals than other neurodegenerative diseases. DISCUSSION: The quantitative oligomer/soluble aggregate-specific assay can identify soluble tau aggregates, including oligomers, from monomers in human and in vitro biospecimens. HIGHLIGHTS: The aggregation of tau to form fibrils and neurofibrillary tangles is a key feature of Alzheimer's disease. However, biochemical assays for the quantification of oligomers/soluble aggregated forms of tau are lacking. We developed a new assay that preferentially binds to soluble tau aggregates, including oligomers and fibrils, versus monomers. The assay signal increased corresponding to the total protein content, Braak staging, and insolubility of the sequentially homogenized brain tissue fractions in an autopsy-verified cohort. The assay recognized tau peptides containing the microtubule binding region but not those covering the N- or C-terminal regions only.

Does complete pathological response increase perioperative morbidity risk in rectal cancer?

AIM: The optimal management of patients with clinical complete response after neoadjuvant treatment for rectal cancer is controversial. The aim of this study is to compare the morbidity between patients with locally advanced rectal cancer who have had a pathological complete response (pCR) or not after neoadjuvant chemoradiotherapy (NCRT) and total mesorectal excision (TME). The study hypothesis was that pCR may impact the surgical complication rate. METHOD: A retrospective cohort study was conducted of a prospectively maintained database in Australia and New Zealand, the Binational Colorectal Cancer Audit, that identified patients with locally advanced rectal cancer (<15 cm from anal verge) from 1 January 2007 to 31 December 2019. Patients were included if they had locally advanced rectal cancer and had undergone NCRT and proceeded to surgical resection. RESULTS: There were 4584 patients who satisfied the inclusion criteria, 65% being male. The mean age was 63 years and 11% had a pCR (ypT0N0). TME with anastomosis was performed in 67.8% of patients, and the majority of the cohort received long-course radiotherapy (81.7%). Both major and minor complications were higher in the TME without anastomosis group (17.3% vs. 14.7% and 30.6% vs. 20.8%, respectively), and the 30-day mortality was 1.31%. In the TME with anastomosis group, pCR did not contribute to higher rates of surgical complications, but male gender (p < 0.0012), age (p < 0.0001), preoperative N stage (p = 0.0092) and American Society of Anesthesologists (ASA) score ≥3 (p < 0.0002) did. In addition, pCR had no significant effect (p = 0.44) but male gender (p = 0.0047) and interval to surgery (p = 0.015) contributed to higher rates of anastomotic leak. In the TME without anastomosis cohort, the only variable that contributed to higher rates of complications was ASA score ≥3 (p = 0.033). CONCLUSION: Patients undergoing TME dissection for rectal cancer following NCRT showed no difference in complications whether they had achieved pCR or not.