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In preclinical studies, a new antituberculosis drug regimen markedly reduced the time required to achieve relapse-free cure. This study aimed to preliminarily evaluate the efficacy and safety of this four-month regimen, consisting of clofazimine, prothionamide, pyrazinamide and ethambutol, with a standard six-month regimen in patients with drug-susceptible tuberculosis. An open-label pilot randomized clinical trial was conducted among the patients with newly diagnosed bacteriologically-confirmed pulmonary tuberculosis. The primary efficacy end-point was sputum culture negative conversion. Totally, 93 patients were included in the modified intention-to-treat population. The rates of sputum culture conversion were 65.2% (30/46) and 87.2% (41/47) for short-course and standard regimen group, respectively. There was no difference on two-month culture conversion rates, time to culture conversion, nor early bactericidal activity (P > 0.05). However, patients on short-course regimen were observed with lower rates of radiological improvement or recovery and sustained treatment success, which was mainly attributed to higher percent of patients permanently changed assigned regimen (32.1% vs. 12.3%, P = 0.012). The main cause for it was drug-induced hepatitis (16/17). Although lowering the dose of prothionamide was approved, the alternative option of changing assigned regimen was chosen in this study. While in per-protocol population, sputum culture conversion rates were 87.0% (20/23) and 94.4% (34/36) for the respective groups. Overall, the short-course regimen appeared to have inferior efficacy and higher incidence of hepatitis but desired efficacy in per-protocol population. It provides the first proof-of-concept in humans of the capacity of the short-course approach to identify drug regimens that can shorten the treatment time for tuberculosis.

PurposeTo investigate the impact of trabecular bypass surgery targeted to angiographically determined high- vs. low-aqueous humor outflow areas on outflow facility (C) and intraocular pressure (IOP).DesignEx vivo comparative study.SubjectsPostmortem ex vivo porcine and human eyes.MethodsPorcine (n = 14) and human (n = 13) whole globes were acquired. In both species, anterior segments were dissected, mounted onto a perfusion chamber, and perfused using Dulbecco's phosphate buffered solution containing glucose in a constant flow paradigm to achieve a stable baseline. Fluorescein was perfused into the anterior chamber and used to identify baseline segmental high- and low-flow regions of the conventional outflow pathways. The anterior segments were divided into 2 groups, and a 5 mm needle goniotomy was performed in either a high- or low-flow area. Subsequently, C and IOP were quantitatively reassessed and compared between surgery in baseline "high-flow" and "low-flow" region eyes followed by indocyanine green angiography.Main outcome measuresOutflow facility.ResultsIn all eyes, high- and low-flow segments could be identified. Performing a 5-mm goniotomy increased outflow facility to a variable extent depending on baseline flow status. In the porcine high-flow group, C increased from 0.31 ± 0.09 to 0.39 ± 0.09 μL/mmHg/min (P = 0.12). In the porcine low-flow group, C increased from 0.29 ± 0.03 to 0.56 ± 0.10 μL/mmHg/min (P

OBJECTIVES: The objective of this study was to evaluate the influence of a long-axial field-of-view (LAFOV) on stage migration using a large single-centre retrospective cohort in lymphoma and non-small cell lung cancer (NSCLC). METHODS: A retrospective study is performed for patients undergoing PET/computed tomography (CT) on either a short-axial field-of-view (SAFOV) or LAFOV PET/CT system for the staging of known or suspected NSCLC or for therapeutic response in lymphoma. The primary endpoint was the Deauville therapy response score for patients with lymphoma for the two systems. Secondary endpoints were the American Joint Committee on Cancer stage for NSCLC, the frequency of cN3 and cM1 findings, the probability for a positive nodal staging (cN1-3) for NSCLC and the diagnostic accuracy for nodal staging in NSCLC. RESULTS: One thousand two hundred eighteen records were screened and 597 patients were included for analysis ( N  = 367 for lymphoma and N  = 291 for NSCLC). For lymphoma, no significant differences were found in the proportion of patients with complete metabolic response versus non-complete metabolic response Deauville response scores ( P  = 0.66). For NSCLC no significant differences were observed between the two scanners for the frequency of cN3 and cM1 findings, for positive nodal staging, neither the sensitivity nor the specificity. CONCLUSIONS: In this study use of a LAFOV system was neither associated with upstaging in lymphoma nor NSCLC compared to a digital SAFOV system. Diagnostic accuracy was comparable between the two systems in NSCLC despite shorter acquisition times for LAFOV.

AIM: [18F]FDG PET/CT proved accurate in the diagnostic work-up of large vessel vasculitis (LVV). While a visual interpretation is currently considered adequate, several attempts have been made to integrate it with a semiquantitative evaluation. In this regard, there is the need to validate current or new thresholds for the semiquantitative parameters on long-axial field of view (LAFOV) scanners. METHODS: We retrospectively evaluated 100 patients (50 with LVV and 50 controls) who underwent [18F]FDG LAFOV PET/CT. Semiquantitative parameters (SUVmax and SUVmean) were calculated for large vessels in 3 districts (supra-aortic [SA], thoracic aorta [TA], and infra-aortic [IA]). Values were also normalized to liver activity (SUVmax/L-SUVmax, and SUVmax/L-SUVmean). RESULTS: Of the 50 patients diagnosed with LVV, SA vessels were affected in 38 (76%), TA in 42 (84%) and IA vessels in 26 (52%). To-liver normalized values had higher diagnostic accuracy than non-normalized values (AUC always ≥ 0.90 vs. 0.74-0.89). For the SA vessels, best thresholds were 0.66 for SUVmax/L-SUVmax and 0.88 for SUVmax/L-SUVmean; for the TA, 1.0 for SUVmax/L-SUVmax and 1.30 for SUVmax/L-SUVmean; finally, for IA vessels, the best threshold was 0.83 for SUVmax/L-SUVmax and 1.11 for SUVmax/L-SUVmean. CONCLUSION: LAFOV [18F]FDG-PET/CT is accurate in the diagnostic workup of LVV, but different threshold in semi-quantitative parameters than reported in literature for standard scanners should be considered.

BACKGROUND: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. MAIN BODY: This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. CONCLUSION: Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field in many aspects.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, presenting a persisting global health burden. Neutrophils have a double-edged role in tumor progression exhibiting both pro-tumor and anti-tumor functions. CD71, also known as transferrin receptor 1, performs a critical role in cellular iron uptake and is highly expressed on proliferating cells, and especially on activated immune cells. CD71 is known to be elevated in various types of solid cancers and is associated with poor prognosis, however, the expression of CD71 on neutrophils in PDAC and its potential clinical impact is still unknown. Therefore, we analyzed CD71 on circulating neutrophils in PDAC and clinical control patients and found a significant increased expression in PDAC patients. High expression of CD71 on neutrophils in PDAC patients was associated with reduced outcome compared to low expression. CD71 on neutrophils correlated positively with the levels of proinflammatory cytokines IL-6, IFN-γ, and growth factor ligands CD40-L, and BAFF in plasma of PDAC patients. Finally, we have demonstrated that high expression of CD71 on neutrophils was also associated with an increased expression of CD39 and CD25 on circulating T-cells. Based on our findings, we hypothesize that CD71 on neutrophils is associated with tumor progression in PDAC. Further studies are required to investigate the distinct functionality of CD71 expressing neutrophils and their potential clinical application.

Chronic lateral ankle instability is a relatively frequent consequence after acute ankle sprain. In case of unsuccessful conservative treatment, surgical therapy is recommended to prevent osteoarthritis of the ankle joint. To date, different surgical methods have evolved. Yet, it remains unclear which approach reveals the best results. We hypothesized that the modified Broström–Gould procedure with suture anchor ligament fixation leads to superior postoperative results compared to the Broström–Gould procedure or the periosteal flap technique.

Abstract Background Child maltreatment (CM) can have devastating and potentially lifelong effects for those affected and is a major contributor to mental health problems. To tackle public health problems it is crucial to have reliable data on CM. The aim of this study is to assess the prevalence and predictors of CM in a nationwide sample of the German population of young adults. Methods The study population (young adults aged 18 to 31 years) stems from the KiGGS Cohort study, the longitudinal branch of the German Health Interview and Examination Survey for children and adolescents. This sample meets the criteria of the United Nations Sustainable Development Goals (SDG) indicator 16.2.3. The data was collected between 2014 and 2017. CM were assessed with the Childhood Trauma Questionnaire (CTQ) in. In addition, socio-demographic variables and other known risk factors for CM were assessed. A total of 6433 (47.8% female) participants were included in the analyses. Binary logistic regression analyses were used to investigate predictors of maltreatment subtypes. Ordinal regression was used to examine their association with experience of multiple forms of CM. Results Overall, 18.4% (f: 20.9%, m: 16.1%) of the participants reported having experienced at least one type of CM; 6.7% (f: 8.8%, m: 4.8%) reported experiences of emotional abuse, 3.7% (f: 3.9%, m: 3.5%) physical abuse, 3.5% (f: 5.3%, m: 1.7%) sexual abuse, 9.0% (f: 9.9%, m: 8.2%) emotional neglect and 8.6% (f: 8.5%, m: 8.7%) physical neglect. Gender, subjective social status, education and household dysfunction (e.g. living with an individual who is using substances) emerged as significant predictors for different types of CM. Additionally, all these factors were significant risk factors for experiencing cumulative CM. Conclusions CM is common in the German population, with almost one in five people experiencing at least one type of CM. The results reveal important risk factors for the occurrence of CM. In particular, people with lower social status and those who grew up in dysfunctional households are at higher risk of CM. Greater support for this vulnerable population may reduce the prevalence of CM.

Abstract Butyl octyl magnesium solutions are important raw materials in various chemical processes but suffer from their high reactivity with even traces of water, protic solvents or oxygen and an increased viscosity in hydrocarbon solution due to the formation of polymeric structures. N 1,N 2-diphenylacenaphthylene-1,2-diimines (BIANs) have already been identified as potential candidates to reduce the viscosity of alkyl magnesium solutions and this study provides a systematic insight into the dependence of this ability on the position and structures of substituents on the BIAN. Besides the various BIANs, ZnCl2 complexes and hydrogenated derivatives were characterized and tested for their ability to reduce the viscosity. HPLC-high resolution mass spectrometry, MALDI-ToF mass spectrometry, but most important FTIR and NMR experiments under inert conditions have been used to shine light on the interaction of the different BIAN derivatives with alkyl magnesium solutions. Hydrogenated BIANs, especially those with bulky alkyl groups in the ortho position(s) have been identified as the most promising candidates. An additional benefit of the hydrogenated species is that in contrast to BIANs and BIAN-Zn complexes they do not undergo permanent chemical modification and can be reused after extraction.

Abstract Preoperative identification of intracranial meningiomas with aggressive behaviour may help in choosing the optimal treatment strategy. Radiomics is emerging as a powerful diagnostic tool with potential applications in patient risk stratification. In this study, we aimed to compare the predictive value of conventional, semantic based and radiomic analyses to determine CNS WHO grade and early tumour relapse in intracranial meningiomas. We performed a single-centre retrospective analysis of intracranial meningiomas operated between 2007 and 2018. Recurrence within 5 years after Simpson Grade I-III resection was considered as early. Preoperative T1 CE MRI sequences were analysed conventionally by two radiologists. Additionally a semantic feature score based on systematic analysis of morphological characteristics was developed and a radiomic analysis were performed. For the radiomic model, tumour volume was extracted manually, 791 radiomic features were extracted. Eight feature selection algorithms and eight machine learning methods were used. Models were analysed using test and training datasets. In total, 226 patients were included. There were 21% CNS WHO grade 2 tumours, no CNS WHO grade 3 tumour, and 25 (11%) tumour recurrences were detected in total. In ROC analysis the best radiomic models demonstrated superior performance for determination of CNS WHO grade (AUC 0.930) and early recurrence (AUC 0.892) in comparison to the semantic feature score (AUC 0.74 and AUC 0.65) and conventional radiological analysis (AUC 0.65 and 0.54). The combination of human classifiers, semantic score and radiomic analysis did not markedly increase the model performance. Radiomic analysis is a promising tool for preoperative identification of aggressive and atypical intracranial meningiomas and could become a useful tool in the future.

Abstract Progressive gait impairment is common among aging adults. Remote phenotyping of gait during daily living has the potential to quantify gait alterations and evaluate the effects of interventions that may prevent disability in the aging population. Here, we developed ElderNet, a self-supervised learning model for gait detection from wrist-worn accelerometer data. Validation involved two diverse cohorts, including over 1000 participants without gait labels, as well as 83 participants with labeled data: older adults with Parkinson's disease, proximal femoral fracture, chronic obstructive pulmonary disease, congestive heart failure, and healthy adults. ElderNet presented high accuracy (96.43 ± 2.27), specificity (98.87 ± 2.15), recall (82.32 ± 11.37), precision (86.69 ± 17.61), and F1 score (82.92 ± 13.39). The suggested method yielded superior performance compared to two state-of-the-art gait detection algorithms, with improved accuracy and F1 score (p

Abstract Background The COVID-19 pandemic has increased worldwide mental health conditions, substantially affecting the demand and provision of mental health services. To continue services and safeguard the health and well-being of mental health service users, service providers have responded to the pandemic with the adoption of remote services. The objective of our study was to identify and compare the promoters and challenges of the adoption of remote mental health services experienced by service users in Finland and the Netherlands during the COVID-19 pandemic with help of the FITTE framework. Methods The study adopted a qualitative descriptive approach, consisting of in-depth semi-structured interviews with mental health service users in Finland (n = 12) and the Netherlands (n = 13) during the COVID-19 pandemic. Qualitative content analysis with both inductive and deductive approach was utilized, and the extended FITTE framework was applied to identify the factors related to the fit between individual, task, technology, and environment that influenced the adoption of remote services. Results Overall, the adoption of remote mental health services during the COVID-19 pandemic involved several promoters related to easy access to mental health services, support for mental health and well-being, and benefits of the home environment such as not having to leave outside for services and having less risk of getting the corona virus. Most of the challenges were related to lack of non-verbal communication, difficulties with expressing oneself and interpreting others, technological issues, the organization of remote services, usability and suitability of services, affinity of the health professional with the provision of remote services, and the safety and security of remote services. Conclusions While remote services are accessible, support our well-being and mental health and protect us against the coronavirus, our findings also show that face-to-face contact was often indispensable when adopting mental health services. Therefore, the design of future mental health services should include both remote and face-to-face delivery. Further research should be done on blended approaches and on ways in which the challenges and development needs which emerged from this study can be tackled to improve remote mental health services.

Abstract The coherent continental-wide speleothem water isotope records are accompanied by regionally inconsistent moisture patterns within the Asian summer monsoon (ASM) region, leaving a disputed explanation of monsoonal hydroclimate variability at the orbital timescale. Here, the transient simulation forced by orbital parameters during the past 300,000 years in an isotope-enabled fully coupled model shows that the complex ASM response can be understood as a grand dipole pattern of oxygen isotope and rainfall between South Asia and Japan, with South China lying in a hybrid transition region. While the dipole monsoon rainfall change between South Asia and Japan is related to the large-scale circulation adjustment in response to Northern Hemisphere summer insolation, the dipole oxygen isotope pattern is associated with the changing contribution of moisture sources. Our results provide new clues to reconcile ASM hydroclimate patterns at orbital timescale as revealed by the water isotope records and other hydrological proxies.

Abstract Accurate estimates of CO2 emissions from anthropogenic land-use change (E LUC) and of the natural terrestrial CO2 sink (S LAND) are crucial to precisely know how much CO2 can still be emitted to meet the goals of the Paris Agreement. In current carbon budgets, E LUC and S LAND stem from two model families that differ in how CO2 fluxes are attributed to environmental and land-use changes, making their estimates conceptually inconsistent. Here we provide consistent estimates of E LUC and S LAND by integrating environmental effects on land carbon into a spatially explicit bookkeeping model. We find that state-of-the-art process-based models overestimate S LAND by 23% (min: 8%, max: 33%) in 2012–2021, as they include hypothetical sinks that in reality are lost through historical ecosystem degradation. Additionally, E LUC increases by 14% (8%, 23%) in 2012–2021 when considering environmental effects. Altogether, we find a weaker net land sink, which makes reaching carbon neutrality even more ambitious. These results highlight that a consistent estimation of terrestrial carbon fluxes is essential to assess the progress of net-zero emission commitments and the remaining carbon budget.

Abstract Eocene hyperthermal events reflect profound perturbations of the global carbon cycle. Most of our knowledge about their onset, timing, and rates originates from marine records. Hence, the pacing and magnitude of hyperthermal continental warming remains largely unaccounted for due to a lack of high-resolution climate records. Here we use terrestrial biomarkers and carbon isotopes retrieved from varved lake deposits of the UNESCO World Heritage site ‘Messel Fossil Pit’ (Germany) to quantify sub-millennial to millennial-scale temperature and carbon isotope changes across hyperthermal event C21n-H1 (47.2 million years ago). Our results show maximum warming of ca. 3.5 °C during C21n-H1. We propose that two components are responsible for the warming pattern across the hyperthermal: (1) the massive release of greenhouse gases into the atmosphere-ocean system and (2) half-precession orbital forcing indicated by ~12.000-year temperature cycles. The carbon isotope record of bulk organic matter indicates a sharp, 7‰ decrease at the peak of the hyperthermal, corresponding to increased organic carbon content and a shift in the lake algal community. Collectively, our proxy data reveal the structure of continental temperature response during the hyperthermal event that is characterized by overall warming with a superimposed pattern of sub-orbital scale temperature fluctuations.

Abstract For many years, ventilation has been an essential part of advanced life support (ALS) in cardiopulmonary resuscitation (CPR). Nevertheless, there is little evidence about the best method of ventilation during resuscitation for both out-of-hospital cardiac arrest (OHCA) and inhospital cardiac arrest (IHCA) patients. Effective ventilation is one of the two main keys to successful resuscitation. In this context, the question always arises as to which airway management, along with which ventilation mode, constitutes the best strategy. Conventional ventilation modes are not designed for cardiac arrest and show important limitations that must be considered when used in CPR. Manual ventilation without the use of an automated transport ventilator (ATV) could be shown to be uncontrolled in applied volumes and pressures and should be avoided. Mechanical ventilation with an ATV is therefore superior to manual ventilation, but both volume- and pressure-controlled ventilation modes are significantly influenced by chest compressions. With the newly designed chest compression synchronized ventilation (CCSV), a special ventilation mode for resuscitation is available. Further research should be conducted to obtain more evidence of the effect of ventilation during CPR on outcomes following OHCA and not only about how to secure the airway for ventilation during CPR.

Even though it has been established that a hyetograph's shape affects the results of hydrological simulations, common engineering practice does not always account for this fact. Instead, a single design storm is often considered sufficient for designing a urban drainage system. This study examines the impact that this design paradigm, combined with the uncertainty introduced by subjective choices made during the design process, has on the robustness of a designed system. To do so, we evaluated a set of individual designs created by engineering students using the same Chicago hyetograph as a design storm. We then created ensembles of hyetographs with the same precipitation volume and duration as the Chicago hyetograph and evaluated the designs' hydrological responses. The results showed that designs, which performed equally well for the initial design storm, triggered varying responses for the storms in the ensembles and, consequently, showed different levels of robustness, hinting at a need to adapt the current design approach. HIGHLIGHTS Designing an urban drainage system (UDS) using a single design storm does not produce a robust result.; Storms with the same total precipitation volume but different temporal patterns can expose different vulnerabilities in an UDS.; Designer subjectivity introduces uncertainty to the performance of a UDS.;

Abstract Molecules involved in solvation shells have properties differing from those of the bulk solvent, which can in turn affect reactivity. Among key properties of these molecules are their nature and electronic structure. Widely used tools to characterize this type of property are X-ray-based spectroscopies, which, however, usually lack the capability to selectively probe the solvation-shell molecules. A class of X-ray triggered “non-local” processes has the recognized potential to provide this selectivity. Intermolecular Coulombic decay (ICD) and related processes involve neighbouring molecules in the decay of the X-ray-excited target, and are thus naturally sensitive to its immediate environment. Applying electron spectroscopy to aqueous solutions, we explore the resonant flavours of ICD and demonstrate how it can inform on the first solvation shell of excited solvated cations. One particular ICD process turns out to be a potent marker of the formation of ion pairs. Another gives a direct access to the electron binding energies of the water molecules in the first solvation shell, a quantity previously elusive to direct measurements. The resonant nature of the processes makes them readily measurable, providing powerful new spectroscopic tools.

Abstract Radiotherapy (RT) plays a critical role in the management of rhabdomyosarcoma (RMS), the prevalent soft tissue sarcoma in childhood. The high risk PAX3-FOXO1 fusion-positive subtype (FP-RMS) is often resistant to RT. We have recently demonstrated that inhibition of class-I histone deacetylases (HDACs) radiosensitizes FP-RMS both in vitro and in vivo. However, HDAC inhibitors exhibited limited success on solid tumors in human clinical trials, at least in part due to the presence of off-target effects. Hence, identifying specific HDAC isoforms that can be targeted to radiosensitize FP-RMS is imperative. We, here, found that only HDAC3 silencing, among all class-I HDACs screened by siRNA, radiosensitizes FP-RMS cells by inhibiting colony formation. Thus, we dissected the effects of HDAC3 depletion using CRISPR/Cas9-dependent HDAC3 knock-out (KO) in FP-RMS cells, which resulted in Endoplasmatic Reticulum Stress activation, ERK inactivation, PARP1- and caspase-dependent apoptosis and reduced stemness when combined with irradiation compared to single treatments. HDAC3 loss-of-function increased DNA damage in irradiated cells augmenting H2AX phosphorylation and DNA double-strand breaks (DSBs) and counteracting irradiation-dependent activation of ATM and DNA-Pkcs as well as Rad51 protein induction. Moreover, HDAC3 depletion hampers FP-RMS tumor growth in vivo and maximally inhibits the growth of irradiated tumors compared to single approaches. We, then, developed a new HDAC3 inhibitor, MC4448, which showed specific cell anti-tumor effects and mirrors the radiosensitizing effects of HDAC3 depletion in vitro synergizing with ERKs inhibition. Overall, our findings dissect the pro-survival role of HDAC3 in FP-RMS and suggest HDAC3 genetic or pharmacologic inhibition as a new promising strategy to overcome radioresistance in this tumor.

Abstract Background Orthogeriatric co-management (OGCM) addresses the special needs of geriatric fracture patients. Most of the research on OGCM focused on hip fractures while results concerning other severe fractures are rare. We conducted a health-economic evaluation of OGCM for pelvic and vertebral fractures. Methods In this retrospective cohort study, we used German health and long-term care insurance claims data and included cases of geriatric patients aged 80 years or older treated in an OGCM (OGCM group) or a non-OGCM hospital (non-OGCM group) due to pelvic or vertebral fractures in 2014–2018. We analyzed life years gained, fracture-free life years gained, healthcare costs, and cost-effectiveness within 1 year. We applied entropy balancing, weighted gamma and two-part models. We calculated incremental cost-effectiveness ratios and cost-effectiveness acceptability curves. Results We included 21,036 cases with pelvic (71.2% in the OGCM, 28.8% in the non-OGCM group) and 33,827 with vertebral fractures (72.8% OGCM, 27.2% non-OGCM group). 4.5–5.9% of the pelvic and 31.8–33.8% of the vertebral fracture cases were treated surgically. Total healthcare costs were significantly higher after treatment in OGCM compared to non-OGCM hospitals for both fracture cohorts. For both fracture cohorts, a 95% probability of cost-effectiveness was not exceeded for a willingness-to-pay of up to €150,000 per life year or €150,000 per fracture-free life year gained. Conclusion We did not obtain distinct benefits of treatment in an OGCM hospital. Assigning cases to OGCM or non-OGCM group on hospital level might have underestimated the effect of OGCM as not all patients in the OGCM group have received OGCM.

Abstract Background Tucatinib (TUC), a HER2-directed tyrosine kinase inhibitor, is the first targeted drug demonstrating intracranial efficacy and significantly prolonged survival in metastatic HER2-positive breast cancer (BC) patients with brain metastases. Current treatments for brain metastases often include radiotherapy, but little is known about the effects of combination treatment with TUC. Therefore, we examined the combined effects of irradiation and TUC in human HER2-overexpressing BC, non-small cell lung cancer (NSCLC), and colorectal cancer (CRC) cell lines. For the latter two, a standard therapy successfully targeting HER2 is yet to be established. Methods Nine HER2-overexpressing (BC: BT474, ZR7530, HCC1954; CRC: LS411N, DLD1, COLO201; NSCLC: DV90, NCI-H1781) and three control cell lines (BC: MCF7, HCC38; NSCLC: NCI-H2030) were examined. WST-1 assay (metabolic activity), BrdU ELISA (proliferation), γH2AX assay (DNA double-strand breaks (DSB), Annexin V assay (apoptosis), and clonogenic assay (clonogenicity) were performed after treatment with TUC and/or irradiation (IR). The relevance of the treatment sequence was analyzed exemplarily. Results In BC, combinatorial treatment with TUC and IR significantly decreased metabolic activity, cell proliferation, clonogenicity and enhanced apoptotis compared to IR alone, whereby cell line-specific differences occurred. In the PI3KCA-mutated HCC1954 cell line, addition of alpelisib (ALP) further decreased clonogenicity. TUC delayed the repair of IR-induced DNA damage but did not induce DSB itself. Investigation of treatment sequence indicated a benefit of IR before TUC versus IR after TUC. Also in CRC and NSCLC, the combination led to a stronger inhibition of metabolic activity, proliferation, and clonogenic survival (only in NSCLC) than IR alone, whereby about 10-fold higher concentrations of TUC had to be applied than in BC to induce significant changes. Conclusion Our data indicate that combination of TUC and IR could be more effective than single treatment strategies for BC. Thereby, treatment sequence seems to be an important factor. The lower sensitivity to TUC in NSCLC and particularly in CRC (compared to BC) implicates, that tumor promotion there might be less HER2-related. Combination with inhibitors of other driver mutations may aid in overcoming partial TUC resistance. These findings are of high relevance to improve long-time prognosis especially in brain-metastasized situations given the intracranial activity of TUC.

Introduction: Fibrolamellar carcinoma (FLC) displays upregulation of several oncogenes, including HER2, and multiple immune-suppressive mechanisms. We investigated the efficacy and safety of the pan-HER tyrosine kinase inhibitor neratinib as monotherapy (SUMMIT phase 2 basket study) or with immune checkpoint and/or mammalian target of rapamycin (mTOR) inhibitors (compassionate-use program) in patients with FLC. Methods: Patients received neratinib 240 mg/day orally in SUMMIT, or as doublet or triplet combinations with pembrolizumab 2 mg/kg intravenously every 3 weeks, nivolumab 240 mg intravenously every 2 weeks, everolimus 7.5 mg/day orally, or sunitinib 37.5 mg/day orally under compassionate use. The primary endpoint in SUMMIT was objective response rate; safety was a secondary endpoint. Results: Fifteen patients with FLC received neratinib monotherapy in SUMMIT. The objective response rate was 5% (95% confidence interval [CI]: 0–21.8) and the disease control rate was 13.3% (95% CI: 1.7–40.5). Upon progression, five had added immune checkpoint inhibitors with or without everolimus or sunitinib. Two additional patients received neratinib-based combinations outside of SUMMIT, for a total of 17 neratinib-treated patients. One patient who received neratinib plus pembrolizumab had a confirmed partial response, one treated with neratinib plus everolimus had stable disease lasting 6 months, and one who received neratinib plus pembrolizumab plus sunitinib had stable disease lasting 16 months. Grade 3/4 adverse events with neratinib monotherapy occurred in 10 (66.7%)/2 (13.3%) patients, respectively. Grade 3 adverse events with neratinib-based combinations were hyperglycemia (n = 1; neratinib plus pembrolizumab), hepatic failure, and anaphylaxis (n = 1 each, neratinib plus pembrolizumab plus everolimus). There were no grade 4 adverse events with combination therapy. Conclusion: In patients with FLC, single-agent neratinib had limited efficacy, but clinical benefit was observed with neratinib in combination with immunotherapy and/or mTOR-targeted agents.

Purpose: The aim of this study was to evaluate the development of the worldwide survival rate of primary total hip arthroplasty (THA). The hypothesis was that survival improved over the last decade in worldwide arthroplasty registers. Methods: THA registers were screened in 2022 and compared between different countries with respect to the number of primary implantations per inhabitant, age, fixation type, and survival rate, and compared to similar data from 2009. The data from these reports were analyzed in terms of number, age distribution, and procedure type of primary THAs. Survival curves and a comparative analysis with respect to the development over time were calculated. Results: We identified nine hip arthroplasty registers that contained sufficient data to be included. A large variation was found in the annual number of primary THA implantations per inhabitant, with more than the factor 4 for all age groups across regions. The procedure type varied strongly as well, e.g. in Sweden, 50% were cemented THAs, whereas in Emilia-Romagna (Italy), 96% of THAs were implanted cementless. We found an improved survival rate of 5%, with 90% of survival after 15 years in the cohorts from 2021 compared to 85% in the cohorts from 2009. Conclusion: The present study revealed a significant improvement in the survival of THA in worldwide arthroplasty registers within different countries and regions over the period of one decade. We believe that it is safe to state that the success of THA is still rising with respect to this main outcome.

Abstract Upwelling-induced productivity in the Arabian Sea infers an out-of-phase relation between the Indian summer monsoon and Northern Hemisphere summer insolation at the precession band but an in-phase relation at the obliquity band. These records contrast speleothem oxygen records showing an in-phase relation between the monsoon and summer insolation in two bands, leaving the driving mechanism for the Indian summer monsoon still unknown. Here we use an isotope-enabled Community Earth System Model, showing that the Indian summer monsoon rainfall and water isotopes respond directly to Northern Hemisphere summer insolation in two bands. This contrasts with the Arabian Sea upwelling which is weakened at precessional minimum but strengthened at obliquity maximum by a stronger northward shift of the monsoon wind due to the stronger summer insolation at precessional minimum compared with obliquity maximum. This paper resolves the longstanding question, supporting the Northern Hemisphere-driving mechanism for the Indian summer monsoon at orbital timescale.

Abstract Sensorineural hearing loss (SNHL) is the most common sensory deficit worldwide. Due to the heterogeneity of causes for SNHL, effective treatment options remain scarce, creating an unmet need for novel drugs in the field of otology. Cochlear implantation (CI) currently is the only established method to restore hearing function in profound SNHL and deaf patients. The cochlear implant bypasses the non-functioning sensory hair cells (HCs) and electrically stimulates the neurons of the cochlear nerve. CI also benefits patients with residual hearing by combined electrical and auditory stimulation. However, the insertion of an electrode array into the cochlea induces an inflammatory response, characterized by the expression of pro-inflammatory cytokines, upregulation of reactive oxygen species, and apoptosis and necrosis of HCs, putting residual hearing at risk. Here, we characterize the small molecule AC102, a pyridoindole, for its protective effects on residual hearing in CI. In a gerbil animal model of CI, AC102 significantly improves the recovery of hearing thresholds across multiple frequencies and confines the cochlear trauma to the directly mechanically injured area. In addition, AC102 significantly preserves auditory nerve fibers and inner HC synapses throughout the whole cochlea. In vitro experiments in an ethanol challenged HT22 cell-line revealed significant and dose-responsive anti-apoptotic effects following the treatment of with AC102. Further, AC102 treatment resulted in significant downregulation of the expression of pro-inflammatory cytokines in an organotypic ex vivo model of electrode insertion trauma (EIT). These results suggest that AC102’s effects are likely elicited during the inflammatory phase of EIT and mediated by anti-apoptotic and anti-inflammatory properties, highlighting AC102 as a promising compound for hearing preservation during CI. Moreover, since the inflammatory response in CI shares similarities to that in other etiologies of SNHL, AC102 may be inferred as a potential general treatment option for various inner ear conditions.