Exploring neonicotinoid effects on Drosophila: insights into olfactory memory, neurotransmission, and synaptic connectivity.

Neonicotinoid insecticides, the fastest-growing class in recent decades, interfere with cholinergic neurotransmission by binding to the nicotinic acetylcholine receptor. This disruption affects both targeted and non-targeted insects, impairing cognitive functions such as olfaction and related behaviors, with a particular emphasis on olfactory memory due to its ecological impact. Despite the persistent presence of these chemicals in the environment, significant research gaps remain in understanding the intricate interplay between cognitive function, development, neuronal activity, and neonicotinoid-induced toxicity. This study focuses on the fruit fly Drosophila melanogaster, chosen for its genetic tractability, well-characterized neural circuitry, and remarkable parallels with bees in neurotransmitter systems and brain structures. Our aim is to establish the fruit fly as a valuable model organism for studying the effects of neonicotinoids on behavior and neuronal circuitry, with particular attention to olfactory memory and associated brain circuitries. To achieve this aim, we conducted experiments to investigate the effects of short-term exposure to sublethal doses of the neonicotinoid imidacloprid, mimicking realistic environmental insecticide exposure, on the formation of odor memories. Additionally, we evaluated synaptic contacts and cholinergic neurotransmission within the mushroom body, the primary memory network of insects. Our results showed significant impairments in odor memory formation in flies exposed to imidacloprid, with exposure during the adult stage showing more pronounced effects than exposure during the larval stage. Additionally, functional studies revealed a decrease in synaptic contacts within the intrinsic olfactory projection neurons and the mushroom body. Furthermore, another experiment showed an odor-dependent reduction in cholinergic neurotransmission within this network. In summary, employing Drosophila as a model organism provides a robust framework for investigating neonicotinoid effects and understanding their diverse impacts on insect physiology and behavior. Our study initiates the establishment of the fruit fly as a pivotal model for exploring neonicotinoid influences, shedding light on their effects on olfactory memory, neuronal integrity, and synaptic transmission.

Conventional vs Augmented Reality-Guided Lateral Calcaneal Lengthening Simulated in a Foot Bone Model.

BACKGROUND: Acquired adult flatfoot deformity (AAFD) results in a loss of the medial longitudinal arch of the foot and dysfunction of the posteromedial soft tissues. Hintermann osteotomy (H-O) is often used to treat stage II AAFD. The procedure is challenging because of variations in the subtalar facets and limited intraoperative visibility. We aimed to assess the impact of augmented reality (AR) guidance on surgical accuracy and the facet violation rate. METHODS: Sixty AR-guided and 60 conventional osteotomies were performed on foot bone models. For AR osteotomies, the ideal osteotomy plane was uploaded to a Microsoft HoloLens 1 headset and carried out in strict accordance with the superimposed holographic plane. The conventional osteotomies were performed relying solely on the anatomy of the calcaneal lateral column. The rate and severity of facet joint violation was measured, as well as accuracy of entry and exit points. The results were compared across AR-guided and conventional osteotomies, and between experienced and inexperienced surgeons. RESULTS: Experienced surgeons showed significantly greater accuracy for the osteotomy entry point using AR, with the mean deviation of 1.6 ± 0.9 mm (95% CI 1.26, 1.93) compared to 2.3 ± 1.3 mm (95% CI 1.87, 2.79) in the conventional method (P = .035). The inexperienced had improved accuracy, although not statistically significant (P = .064), with the mean deviation of 2.0 ± 1.5 mm (95% CI 1.47, 2.55) using AR compared with 2.7 ± 1.6 mm (95% CI 2.18, 3.32) in the conventional method. AR helped the experienced surgeons avoid full violation of the posterior facet (P = .011). Inexperienced surgeons had a higher rate of middle and posterior facet injury with both methods (P = .005 and .021). CONCLUSION: Application of AR guidance during H-O was associated with improved accuracy for experienced surgeons, demonstrated by a better accuracy of the osteotomy entry point. More crucially, AR guidance prevented full violation of the posterior facet in the experienced group. Further research is needed to address limitations and test this technology on cadaver feet. Ultimately, the use of AR in surgery has the potential to improve patient and surgeon safety while minimizing radiation exposure. CLINICAL RELEVANCE: Subtalar facet injury during lateral column lengthening osteotomy represents a real problem in clinical orthopaedic practice. Because of limited intraoperative visibility and variable anatomy, it is hard to resolve this issue with conventional means. This study suggests the potential of augmented reality to improve the osteotomy accuracy.

Respiratory gating improves correlation between pulse wave transit time and pulmonary artery pressure in experimental pulmonary hypertension.

Objective. Since pulse wave transit time (PWTT) shortens as pulmonary artery pressure (PAP) increases it was suggested as a potential non-invasive surrogate for PAP. The state of tidal lung filling is also known to affect PWTT independently of PAP. The aim of this retrospective analysis was to test whether respiratory gating improved the correlation coefficient between PWTT and PAP.Approach. In each one of five anesthetized and mechanically ventilated pigs two high-fidelity pressure catheters were placed, one directly behind the pulmonary valve, and the second one in a distal branch of the pulmonary artery. PAP was raised using the thromboxane A2 analogue U46619 and animals were ventilated in a pressure controlled mode (I:E ratio 1:2, respiratory rate 12/min, tidal volume of 6 ml kg-1). All signals were recorded using the multi-channel platform PowerLab®. The arrival of the pulse wave at each catheter tip was determined using a MATLAB-based modified hyperbolic tangent algorithm and PWTT calculated as the time interval between these arrivals.Main results. Correlation coefficient for PWTT and mean PAP wasr= 0.932 for thromboxane. This correlation coefficient increased considerably when heart beats either at end-inspiration (r= 0.978) or at end-expiration (r= 0.985) were selected (=respiratory gating).Significance. The estimation of mean PAP from PWTT improved significantly when taking the respiratory cycle into account. Respiratory gating is suggested to improve for the estimation of PAP by PWTT.

A Smaller Tibiotalar Sector Is a Risk Factor for Recurrent Anterolateral Ankle Instability after a Modified Broström-Gould Procedure.

BACKGROUND: Several demographic and clinical risk factors for recurrent ankle instability have been described. The main objective of this study was to investigate the potential influence of morphologic characteristics of the ankle joint on the occurrence of recurrent instability and the functional outcomes following a modified Broström-Gould procedure for chronic lateral ankle instability. METHODS: Fifty-eight ankles from 58 patients (28 males and 30 females) undergoing a modified Broström-Gould procedure for chronic lateral ankle instability between January 2014 and July 2021 were available for clinical and radiological evaluation. Based on the preoperative radiographs, the following radiographic parameters were measured: talar width (TW), tibial anterior surface (TAS) angle, talar height (TH), talar radius (TR), tibiotalar sector (TTS), and tibial lateral surface (TLS) angle. The history of recurrent ankle instability and the functional outcome using the Karlsson Score were assessed after a minimum follow-up of 2 years. RESULTS: Recurrent ankle instability was reported in 14 patients (24%). The TTS was significantly lower in patients with recurrent ankle instability (69.8 degrees vs 79.3 degrees) (P < .00001). The multivariate logistic regression model confirmed the TTS as an independent risk factor for recurrent ankle instability (OR = 1.64) (P = .003). The receiver operating characteristic curve analysis revealed that patients with a TTS lower than 72 degrees (=low-TTS group) had an 82-fold increased risk for recurrent ankle instability (P = .001). The low-TTS group showed a significantly higher rate of recurrent instability (58% vs 8%; P = .0001) and a significantly lower Karlsson score (65 points vs 85 points; P < .00001). CONCLUSION: A smaller TTS was found to be an independent risk factor for recurrent ankle instability and led to poorer functional outcomes after a modified Broström-Gould procedure. LEVEL OF EVIDENCE: Level IV, retrospective cohort study.

Ten-Year Minimum Follow-up Study of First Metatarsophalangeal Joint Fusion in Young vs Old Patients.

BACKGROUND: Painful degenerative joint disease (DJD) of the first metatarsophalangeal joint (MTP I), or hallux rigidus, mainly occurs in later stages of life. For end-stage hallux rigidus, MTP I arthrodesis is considered the gold standard. As young and active patients are affected considerably less frequently, it currently remains unclear, whether they benefit to the same extent. We hypothesized that MTP I arthrodesis in younger patients would lead to an inferior outcome with decreased rates of overall with lower rates of patient postoperative pain and function compared to an older cohort. METHODS: All patients aged <50 years who underwent MTP I arthrodesis at our institution between 1995 and 2012 were included in this study. This group was then matched and compared with a group of patients aged >60 years. Minimum follow-up was 10 years. Outcome measures were Tegner activity score (TAS), a "Virtual Tegner activity score" (VTAS), the visual analog scale (VAS), and the Foot Function index (FFI). RESULTS: Sixty-one MTP I fusions (n = 28 young, n = 33 old) in 46 patients were included in our study at an average of 14 years after surgery. Younger patients experienced significantly more pain relief as reflected by changes in VAS and FFI Pain subscale scores. No difference in functional outcomes was found with change in the FFI function subscale or in the ability to have desired functional outcomes using the ratio of TAS to VTAS. Revision rate did not differ between the two groups apart from hardware removal, which was significantly more likely in the younger group. CONCLUSION: In patients below the age of 50 years with end-stage DJD of the first metatarsal joint, MTP I arthrodesis not only yielded highly satisfactory postoperative results at least equal outcome compared to an older cohort of patients aged >60 years at an average 14 years' follow-up. Based on these findings, we consider first metatarsal joint fusion even for young patients is a valid option to treat end-stage hallux rigidus. LEVEL OF EVIDENCE: Level III, a case-control study.

The Unloading Effect of Supramalleolar Versus Sliding Calcaneal Osteotomy for Treatment of Osteochondral Lesions of the Medial Talus: A Biomechanical Study.

Background: In patients with osteochondral lesion, defects of the medial talus, or failed cartilage surgery, a periarticular osteotomy can unload the medial compartment. Purpose: To compare the effects of supramalleolar osteotomy (SMOT) versus sliding calcaneal osteotomy (SCO) for pressure redistribution and unloading of the medial ankle joint in normal, varus-aligned, and valgus-aligned distal tibiae. Study Design: Controlled laboratory study. Methods: Included were 8 cadaveric lower legs with verified neutral ankle alignment (lateral distal tibial angle [LDTA] = 0°) and hindfoot valgus within normal range (0°-10°). SMOT was performed to modify LDTA between 5° valgus, neutral, and 5° varus. In addition, a 10-mm lateral SCO was performed and tested in each position in random order. Axial loading (700 N) of the tibia was applied with the foot in neutral alignment in a customized testing frame. Pressure distribution in the ankle joint and subtalar joint, center of force, and contact area were recorded using high-resolution Tekscan pressure sensors. Results: At neutral tibial alignment, SCO unloaded the medial joint by a mean of 10% ± 10% or 66 ± 51 N (P = .04) compared with 6% ± 12% or 55 ± 72 N with SMOT to 5° valgus (P = .12). The achieved deload was not significantly different (ns) between techniques. In ankles with 5° varus alignment at baseline, SMOT to correct LDTA to neutral insufficiently addressed pressure redistribution and increased medial load by 6% ± 9% or 34 ± 33 N (ns). LDTA correction to 5° valgus (10° SMOT) unloaded the medial joint by 0.4% ± 14% or 20 ± 75 N (ns) compared with 9% ± 11% or 36 ± 45 N with SCO (ns). SCO was significantly superior to 5° SMOT (P = .017) but not 10° SMOT. The subtalar joint was affected by both SCO and SMOT, where SCO unloaded but SMOT loaded the medial side. Conclusion: SCO reliably unloaded the medial compartment of the ankle joint for a neutral tibial axis. Changes in the LDTA by SMOT did not positively affect load distribution, especially in varus alignment. The subtalar joint was affected by SCO and SMOT in opposite ways, which should be considered in the treatment algorithm. Clinical Relevance: SCO may be considered a reliable option for beneficial load-shifting in ankles with neutral alignment or 5° varus malalignment.

[Three-dimensional analysis of posttraumatic tibial shaft malunion and correction based on the healthy, contralateral leg]. / 3-D-Analyse von posttraumatischen Tibiaschaftfehlstellungen und deren Korrektur anhand der gesunden Gegenseite.

OBJECTIVE: Three-dimensional (3D) analysis and implementation with patient-specific cutting and repositioning blocks enables correction of complex tibial malunions. Correction can be planned using the contralateral side or a statistical model. Patient-specific 3D-printed cutting guide blocks enable a precise osteotomy and reduction guide blocks help to achieve anatomical reduction. Depending on the type and extent of correction, fibula osteotomy may need to be considered to achieve the desired reduction. CONTRAINDICATIONS: a) Poor soft tissue (flap surgery, adherent skin in field of operation); b) infection; c) peripheral artery disease (stage III and IV classified according to Fontaine, critical transcutaneous oxygen partial pressure, TcPO2); d) general contraindication to surgery. SURGICAL TECHNIQUE: Before surgery, a 3D model of both lower legs is created based on computed tomography (CT) scans. Analysis of the deformity based on the contralateral side in a 3D computer model (CASPA) and planning of the osteotomy. If the contralateral side also has a deformity, a statistical model can be used. Printing of patient-specific guides made of nylon (PA2200) for the osteotomy and reduction. Surgery is performed in supine position, antibiotic prophylaxis, thigh tourniquet, which is used as needed. Ventrolateral approach to the tibia. Attachment of the patient-specific osteotomy guide, performance of the osteotomy. Reduction using the guide. Fibula osteotomy through a lateral approach is performed if the reduction of the tibia is hindered by the fibula. This can be performed freehand or with patient-specific guides. Wound closure. POSTOPERATIVE MANAGEMENT: Compartment monitoring. Passive mobilization of the ankle in the cast as soon as the wound healing has progressed. Partial weightbearing in a lower leg cast for at least 6-12 weeks, depending on the routinely performed radiographic assessment 6 weeks postoperatively. Thromboprophylaxis with low molecular weight heparin until cast removal. RESULTS: Patient-specific correction of malunions are generally good. This could be confirmed for distal tibial corrections. For tibial shaft deformities, the final results are still pending. Preliminary results, however, show good feasibility with a pseudarthrosis rate of 10% without postoperative infection.

Pressure- vs. volume-controlled ventilation and their respective impact on dynamic parameters of fluid responsiveness: a cross-over animal study.

BACKGROUND AND GOAL OF STUDY: Pulse pressure variation (PPV) and stroke volume variation (SVV), which are based on the forces caused by controlled mechanical ventilation, are commonly used to predict fluid responsiveness. When PPV and SVV were introduced into clinical practice, volume-controlled ventilation (VCV) with tidal volumes (VT) ≥ 10 ml kg- 1 was most commonly used. Nowadays, lower VT and the use of pressure-controlled ventilation (PCV) has widely become the preferred type of ventilation. Due to their specific flow characteristics, VCV and PCV result in different airway pressures at comparable tidal volumes. We hypothesised that higher inspiratory pressures would result in higher PPVs and aimed to determine the impact of VCV and PCV on PPV and SVV. METHODS: In this self-controlled animal study, sixteen anaesthetised, paralysed, and mechanically ventilated (goal: VT 8 ml kg- 1) pigs were instrumented with catheters for continuous arterial blood pressure measurement and transpulmonary thermodilution. At four different intravascular fluid states (IVFS; baseline, hypovolaemia, resuscitation I and II), ventilatory and hemodynamic data including PPV and SVV were assessed during VCV and PCV. Statistical analysis was performed using U-test and RM ANOVA on ranks as well as descriptive LDA and GEE analysis. RESULTS: Complete data sets were available of eight pigs. VT and respiratory rates were similar in both forms. Heart rate, central venous, systolic, diastolic, and mean arterial pressures were not different between VCV and PCV at any IVFS. Peak inspiratory pressure was significantly higher in VCV, while plateau, airway and transpulmonary driving pressures were significantly higher in PCV. However, these higher pressures did not result in different PPVs nor SVVs at any IVFS. CONCLUSION: VCV and PCV at similar tidal volumes and respiratory rates produced PPVs and SVVs without clinically meaningful differences in this experimental setting. Further research is needed to transfer these results to humans.

[Cardiovascular treatment in chronic kidney disease]. / Kardiovaskuläre Therapie bei chronischer Nierenerkrankung.

Patients with combined cardiac and renal diseases are particularly challenging in the routine clinical practice due to the substantial risk profile for increased morbidity and mortality. As cardiorenal patients have often been underrepresented in randomized, controlled interventional trials, guideline recommendations regarding the choice of treatment are often weaker for these individuals than for cardiovascular patients without chronic kidney disease. Furthermore, there are limitations in the approval of certain medications depending on the kidney function. This review addresses some considerations in crucial treatment areas for patients with cardiovascular diseases, whose treatment is significantly influenced by concomitant chronic kidney disease.

Effects of apparatus dead space on volumetric capnograms in neonates with healthy lungs: a simulation study.

BACKGROUND: Volumetric capnography in healthy ventilated neonates showed deformed waveforms, which are supposedly due to technological limitations of flow and carbon dioxide sensors. AIMS: This bench study analyzed the role of apparatus dead space on the shape of capnograms in simulated neonates with healthy lungs. METHODS: We simulated mechanical breaths in neonates of 2, 2.5, and 3 kg of body weight using a neonatal volumetric capnography simulator. The simulator was fed by a fixed amount of carbon dioxide of 6 mL/kg/min. Such simulator was ventilated in a volume control mode using fixed ventilatory settings with a tidal volume of 8 mL/kg and respiratory rates of 40, 35, and 30 breaths per minute for the 2, 2.5 and 3 kg neonates, respectively. We tested the above baseline ventilation with and without an additional apparatus dead space of 4 mL. RESULTS: Simulations showed that adding the apparatus dead space to baseline ventilation increased the amount of re-inhaled carbon dioxide in all neonates: 0.16 ± 0.01 to 0.32 ± 0.03 mL (2 kg), 0.14 ± 0.02 to 0.39 ± 0.05 mL (2.5 kg), and 0.13 ± 0.01 to 0.36 ± 0.05 mL (3 kg); (p < .001). Apparatus dead space was computed as part of the airway dead space, and therefore, the ratio of airway dead space to tidal volume increased from 0.51 ± 0.04 to 0.68 ± 0.06, from 0.43 ± 0.04 to 0.62 ± 0.01 and from 0.38 ± 0.01 to 0.60 ± 0.02 in the 2, 2.5 and 3 kg simulated neonates, respectively (p < .001). Compared to baseline ventilation, adding apparatus dead space decreased the ratio of the volume of phase III to VT size from 31% to 11% (2 kg), from 40% to 16% (2.5 kg) and from 50% to 18% (3 kg); (p < .001). CONCLUSIONS: The addition of a small apparatus dead space artificially deformed the volumetric capnograms in simulated neonates with healthy lungs.

Defining the landscape of circular RNAs in neuroblastoma unveils a global suppressive function of MYCN.

Circular RNAs (circRNAs) are a regulatory RNA class. While cancer-driving functions have been identified for single circRNAs, how they modulate gene expression in cancer is not well understood. We investigate circRNA expression in the pediatric malignancy, neuroblastoma, through deep whole-transcriptome sequencing in 104 primary neuroblastomas covering all risk groups. We demonstrate that MYCN amplification, which defines a subset of high-risk cases, causes globally suppressed circRNA biogenesis directly dependent on the DHX9 RNA helicase. We detect similar mechanisms in shaping circRNA expression in the pediatric cancer medulloblastoma implying a general MYCN effect. Comparisons to other cancers identify 25 circRNAs that are specifically upregulated in neuroblastoma, including circARID1A. Transcribed from the ARID1A tumor suppressor gene, circARID1A promotes cell growth and survival, mediated by direct interaction with the KHSRP RNA-binding protein. Our study highlights the importance of MYCN regulating circRNAs in cancer and identifies molecular mechanisms, which explain their contribution to neuroblastoma pathogenesis.

Hydroxyproline metabolism enhances IFN-γ-induced PD-L1 expression and inhibits autophagic flux.

The immune checkpoint protein PD-L1 plays critical roles in both immune system homeostasis and tumor progression. Impaired PD-1/PD-L1 function promotes autoimmunity and PD-L1 expression within tumors promotes immune evasion. If and how changes in metabolism or defined metabolites regulate PD-L1 expression is not fully understood. Here, using a metabolomics activity screening-based approach, we have determined that hydroxyproline (Hyp) significantly and directly enhances adaptive (i.e., IFN-γ-induced) PD-L1 expression in multiple relevant myeloid and cancer cell types. Mechanistic studies reveal that Hyp acts as an inhibitor of autophagic flux, which allows it to regulate this negative feedback mechanism, thereby contributing to its overall effect on PD-L1 expression. Due to its prevalence in fibrotic tumors, these findings suggest that hydroxyproline could contribute to the establishment of an immunosuppressive tumor microenvironment and that Hyp metabolism could be targeted to pharmacologically control PD-L1 expression for the treatment of cancer or autoimmune diseases.

A prospective, randomized, controlled, multicentre trial for secondary prevention in patients with chronic coronary syndrome using a smartphone application for digital therapy: the CHANGE study protocol.

Aims: Coronary artery disease (CAD) remains the leading cause of death worldwide. 'Stable' CAD is a chronic progressive condition, which recent European guidelines recommend referring to as 'chronic coronary syndrome' (CCS). Despite therapeutic advances, morbidity and mortality among patients with CCS remain high. Optimal secondary prevention in patients with CCS includes optimization of modifiable risk factors with behavioural changes and pharmacological therapy. The CHANGE study aims to provide evidence for optimization of secondary prevention in CCS patients by using a smartphone application (app). Methods and results: The CHANGE study is designed as a prospective, randomized, controlled trial with a 1:1 allocation ratio, which is currently performed in nine centres in Germany in a parallel group design. 210 patients with CCS will be randomly allocated either to the control group (standard-of-care) or to the intervention group, who will be provided the VantisTherapy* app in addition to standard-of-care to incorporate secondary prevention into their daily life. The study will be performed in an open design. Outcomes will be assessed using objective data from three in-person visits (0, 12, and 24 weeks). Primary outcomes will involve adherence to secondary prevention recommendations and quality of life (QoL). The recruitment process started in July 2022. Conclusion: The CHANGE study will investigate whether a smartphone-guided secondary prevention app, combined with a monitor function compared with standard-of-care, has beneficial effects on overall adherence to secondary prevention guidelines and QoL in patients with CCS. Trial registration: The study is listed at the German study registry (DRKS) under the registered number DRKS00028081.

Non-canonical Biosynthesis of the Brexane-Type Bishomosesquiterpene Chlororaphen through Two Consecutive Methylation Steps in Pseudomonas chlororaphis O6 and Variovorax boronicumulans PHE5-4.

A non-canonical biosynthetic pathway furnishing the first natural brexane-type bishomosesquiterpene (chlororaphen, C17 H28 ) was elucidated in the γ-proteobacterium Pseudomonas chlororaphis O6. A combination of genome mining, pathway cloning, in vitro enzyme assays, and NMR spectroscopy revealed a three-step pathway initiated by C10 methylation of farnesyl pyrophosphate (FPP, C15 ) along with cyclization and ring contraction to furnish monocyclic γ-presodorifen pyrophosphate (γ-PSPP, C16 ). Subsequent C-methylation of γ-PSPP by a second C-methyltransferase furnishes the monocyclic α-prechlororaphen pyrophosphate (α-PCPP, C17 ), serving as the substrate for the terpene synthase. The same biosynthetic pathway was characterized in the ß-proteobacterium Variovorax boronicumulans PHE5-4, demonstrating that non-canonical homosesquiterpene biosynthesis is more widespread in the bacterial domain than previously anticipated.

Development of a Novel Infant Volumetric Capnography Simulator: Making the Invisible Visible Improves Understanding and Safety.

METHODS: An infant lung simulator was fed with CO2 supplied by a mass flow controller (VCO2-IN) and ventilated using standard settings. A volumetric capnograph was placed between the endotracheal tube and the ventilatory circuit. We simulated ventilated babies of different body weights (2, 2.5, 3, and 5 kg) with a VCO2 ranging from 12 to 30 mL/min. The correlation coefficient (r2), bias, coefficient of variation (CV = SD/x × 100), and precision (2 × CV) between the VCO2-IN and the elimination of CO2 recorded by the capnograph (VCO2-OUT) were calculated. The quality of the capnogram's waveforms was compared with real ones belonging to anesthetized infants using an 8-point scoring system, where 6 points or greater meant that the simulated capnogram showed good, 5 to 3 points acceptable, and less than 3 points an unacceptable shape. RESULTS: The correlation between VCO2-IN and VCO2-OUT was r2 = 0.9953 (P < 0.001), with a bias of 0.16 (95% confidence intervals from 0.12 to 0.20) mL/min. The CV was 5% or less and the precision was 10% or less. All simulated capnograms showed similar shapes compared with real babies, scoring 6 points for 3 kg and 6.5 points for 2-, 2.5-, and 5-kg babies. CONCLUSIONS: The simulator of volumetric capnograms was reliable, accurate, and precise for simulating the CO2 kinetics of ventilated infants.

Identification of two unannotated miRNAs in classic Hodgkin lymphoma cell lines.

MicroRNAs (miRNAs) are small non coding RNAs responsible for posttranscriptional regulation of gene expression. Even though almost 2000 precursors have been described so far, additional miRNAs are still being discovered in normal as well as malignant cells. Alike protein coding genes, miRNAs may acquire oncogenic properties in consequence of altered expression or presence of gain or loss of function mutations. In this study we mined datasets from miRNA expression profiling (miRNA-seq) of 7 classic Hodgkin Lymphoma (cHL) cell lines, 10 non-Hodgkin lymphoma (NHL) cell lines and 56 samples of germinal center derived B-cell lymphomas. Our aim was to discover potential novel cHL oncomiRs not reported in miRBase (release 22.1) and expressed in cHL cell lines but no other B-cell lymphomas. We identified six such miRNA candidates in cHL cell lines and verified the expression of two of them encoded at chr2:212678788-212678849 and chr5:168090507-168090561 (GRCh38). Interestingly, we showed that one of the validated miRNAs (located in an intron of the TENM2 gene) is expressed together with its host gene. TENM2 is characterized by hypomethylation and open chromatin around its TSS in cHL cell lines in contrast to NHL cell lines and germinal centre B-cells respectively. It indicates an epigenetic mechanism responsible for aberrant expression of both, the TENM2 gene and the novel miRNA in cHL cell lines. Despite the GO analysis performed with the input of the in silico predicted novel miRNA target genes did not reveal ontologies typically associated with cHL pathogenesis, it pointed to several interesting candidates involved in i.e. lymphopoiesis. These include the lymphoma related BCL11A gene, the IKZF2 gene involved in lymphocyte development or the transcription initiator GTF2H1.

Ulcer occurrence on adjacent toes and hallux valgus deformity after amputation of the second toe in diabetic patients.

BACKGROUND: Amputation of the second toe is associated with destabilization of the first toe. Possible consequences are hallux valgus deformity and subsequent pressure ulcers on the lateral side of the first or on the medial side of the third toe. The aim of this study was to investigate the incidence and possible influencing factors of interdigital ulcer development and hallux valgus deformity after second toe amputation. METHODS: Twenty-four cases of amputation of the second toe between 2004 and 2020 (mean age 68 ± 12 years; 79% males) were included with a mean follow-up of 36 ± 15 months. Ulcer development on the first, third, or fourth toe after amputation, the body mass index (BMI) and the amputation level (toe exarticulation versus transmetatarsal amputation) were recorded. Pre- and postoperative foot radiographs were evaluated for the shape of the first metatarsal head (round, flat, chevron-type), the hallux valgus angle, the first-second intermetatarsal angle, the distal metatarsal articular angle and the hallux valgus interphalangeal angle by two orthopedic surgeons for interobserver reliability. RESULTS: After amputation of the second toe, the interdigital ulcer rate on the adjacent toes was 50% and the postoperative hallux valgus rate was 71%. Neither the presence of hallux valgus deformity itself (r = .19, p = .37), nor the BMI (r = .09, p = .68), the shape of the first metatarsal head (r = - .09, p = .67), or the amputation level (r = .09, p = .69) was significantly correlated with ulcer development. The interobserver reliability of radiographic measurements was high, oscillating between 0.978 (p = .01) and 0.999 (p = .01). CONCLUSIONS: The interdigital ulcer rate on the first or third toe after second toe amputation was 50% and hallux valgus development was high. To date, evidence on influencing factors is lacking and this study could not identify parameters such as the BMI, the shape of the first metatarsal head or the amputation level as risk factors for the development of either hallux valgus deformity or ulcer occurrence after second toe amputation. TRIAL REGISTRATION: BASEC-Nr. 2019-01791.

Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis.

Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). We characterize 58 primary human RS samples by genome-wide DNA methylation and whole-transcriptome profiling. Our comprehensive approach determines RS DNA methylation profile and unravels a CLL epigenetic imprint, allowing CLL-RS clonal relationship assessment without the need of the initial CLL tumor DNA. DNA methylation- and transcriptomic-based classifiers were developed, and testing on landmark DLBCL datasets identifies a poor-prognosis, activated B-cell-like DLBCL subset in 111/1772 samples. The classification robustly identifies phenotypes very similar to RS with a specific genomic profile, accounting for 4.3-8.3% of de novo DLBCLs. In this work, RS multi-omics characterization determines oncogenic mechanisms, establishes a surrogate marker for CLL-RS clonal relationship, and provides a clinically relevant classifier for a subset of primary "RS-type DLBCL" with unfavorable prognosis.

Ventilation Induces Changes in Pulse Wave Transit Time in the Pulmonary Artery.

Pulse wave transit time (PWTT) shortens as pulmonary artery pressure (PAP) increases and was therefore suggested as a surrogate parameter for PAP. The aim of this analysis was to reveal patterns and potential mechanisms of ventilation-induced periodic changes in PWTT under resting conditions. To measure both PWTT and PAP in five healthy pigs, two pulmonary artery Mikro-Tip™ catheters were inserted into the pulmonary vasculature: one with the tip placed in the pulmonary artery trunk, and a second one placed in a distal segment of the pulmonary artery. Animals received pressure-controlled mechanical ventilation. Ventilation-dependent changes were seen in both variables, PWTT and mean PAP; however, changes in PWTT were not synchronous with changes in PAP. Thus, plotting the value of PWTT for each heartbeat over the respective PAP revealed a characteristic hysteresis. At the beginning of inspiration, PAP rose while PWTT remained constant. During further inspiration, PWTT started to decrease rapidly as mPAP was about to reach its plateau. The same time course was observed during expiration: while mPAP approached its minimum, PWTT increased rapidly. During apnea this hysteresis disappeared. Thus, non-synchronous ventilation-induced changes in PWTT and PAP were found with inspiration causing a significant shortening of PWTT. Therefore, it is suggested that the respiratory cycle should be considered when using PWTT as a surrogate for PAP.