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Abstract Objective The piriform cortex is considered to be highly epileptogenic. Its resection during epilepsy surgery is a predictor for postoperative seizure freedom in temporal lobe epilepsy. Epilepsy is associated with a dysfunction of the blood–brain barrier. We investigated blood–brain barrier dysfunction in the piriform cortex of people with temporal lobe epilepsy using quantitative T1‐relaxometry. Methods Gadolinium‐based contrast agent was administered ictally and interictally in 37 individuals before undergoing quantitative T1‐relaxometry. Postictal and interictal images were co‐registered, and subtraction maps were created as biomarkers for peri‐ictal (∆qT1interictal‐postictal) and interictal (∆qT1noncontrast‐interictal) blood–brain barrier dysfunction. Values were extracted for the piriform cortex, hippocampus, amygdala, and the whole cortex. Results In temporal lobe epilepsy (n = 14), ∆qT1noncontrast‐interictal was significantly higher in the piriform cortex than in the whole cortex (p = 0.02). In extratemporal lobe epilepsy (n = 23), ∆qT1noncontrast‐interictal was higher in the hippocampus than in the whole cortex (p = 0.05). Across all individuals (n = 37), duration of epilepsy was correlated with ∆qT1noncontrast‐interictal (ß = 0.001, p

Abstract This study provides a detailed understanding of the preclinical pharmacokinetics and metabolism of ELP‐004, an osteoclast inhibitor in development for the treatment of bone erosion. Current treatments for arthritis, including biological disease‐modifying antirheumatic drugs, are not well‐tolerated in a substantial subset of arthritis patients and are expensive; therefore, new treatments are needed. Pharmacokinetic parameters of ELP‐004 were tested with intravenous, oral, and subcutaneous administration and found to be rapidly absorbed and distributed. We found that ELP‐004 was non‐mutagenic, did not induce chromosome aberrations, non‐cardiotoxic, and had minimal off‐target effects. Using in vitro hepatic systems, we found that ELP‐004 is primarily metabolized by CYP1A2 and CYP2B6 and predicted metabolic pathways were identified. Finally, we show that ELP‐004 inhibits osteoclast differentiation without suppressing overall T‐cell function. These preclinical data will inform future development of an oral compound as well as in vivo efficacy studies in mice.

Abstract Purpose Many cancer patients wish for complementary and integrative medicine (CIM) consultations led by their oncology physician. Within the KOKON‐KTO study, oncology physicians in the intervention group were trained in a blended learning to provide CIM consultations to their cancer patients in addition to distributing a leaflet about CIM websites. Control oncology physicians only distributed the leaflet. The training showed positive effects on the patient‐level. As of now, no consistent evidence exists on the long‐term effects of such one‐time‐only CIM consultation during cancer treatment. Methods In the KOKON‐KTO follow‐up study, cancer patients previously participating in the KOKON‐KTO study (intervention group:IG and control group: CG) received, at least 24 months later, a follow‐up questionnaire by post, evaluating long‐term effects of the KOKON‐KTO consultation using the measures provided in the original study (patient‐physician communication (EORTC‐QLQ‐COMU2), satisfaction with cancer treatment (PS‐CaTE), CIM disclosure with healthcare provider (HCP), and need for CIM consultation during cancer therapy). Results In total, 102 cancer patients participated in the follow‐up study (IG n = 62; CG n = 40). The overall reponse rate was around 36% (IG: 48.4%; CG: 23.7%). In the follow‐up study, differences between groups had increased and were still shown (EORTC‐QLQ‐COMU26, 0–100 point scale, ≥10‐point‐group difference) in some subscales: patient's active behavior (in means; IG:73.6 (95% CI, 63.8–83.5); CG:61.1 (95% CI, 52.4–69.8)); clinician‐patient relationship (IG:80.9 (95% CI, 71.8–90.0); CG:68.7 (95% CI, 59.3–78.0)). For some outcomes, differences decreased over time (e.g., EORTC‐QLQ‐COMU26 subscales “takes into account patient's preference” and “corrects misunderstandings”). More patients in the CG used CIM without oncology physicians' knowledge (IG: 13.7%, CG: 24.0%). Conclusion This study presents first findings that one‐time‐only CIM consultations may enhance patient‐physican relationship and CIM disclosure long‐term. To further support cancer patients' in their wish for CIM consultations, training programs should provide oncology physicians with CIM competencies for different cancer stages including cancer survivors.

Abstract Introduction Neurosurgery is considered the mainstay of treatment for pediatric low‐grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long‐term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies. Patients and Methods Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1‐5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1‐status, sex, and age. Results The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p

Background The purpose of this study was to investigate a therapeutic approach targeting the inflammatory response and consequent remodeling from ischemic myocardial injury. Methods and Results Coronary thrombus aspirates were collected from patients at the time of ST‐segment–elevation myocardial infarction and subjected to array‐based proteome analysis. Clinically indistinguishable at myocardial infarction (MI), patients were stratified into vulnerable and resilient on the basis of 1‐year left ventricular ejection fraction and death. Network analysis from coronary aspirates revealed prioritization of tumor necrosis factor‐α signaling in patients with worse clinical outcomes. Infliximab, a tumor necrosis factor‐α inhibitor, was infused intravenously at reperfusion in a porcine MI model to assess whether infliximab‐mediated immune modulation impacts post‐MI injury. At 3 days after MI (n=7), infliximab infusion increased proregenerative M2 macrophages in the myocardial border zone as quantified by immunofluorescence (24.1%±23.3% in infliximab versus 9.29%±8.7% in sham; P

Abstract Characterizing patterns of genetic connectivity in marine species is of critical importance given the anthropogenic pressures placed on the marine environment. For sessile species, population connectivity can be shaped by many processes, such as pelagic larval duration, oceanographic boundaries and currents. This study combines restriction‐site associated DNA sequencing (RADseq) and passive particle dispersal modelling to delineate patterns of population connectivity in the pink sea fan, Eunicella verrucosa, a temperate octocoral. Individuals were sampled from 20 sites covering most of the species' northeast Atlantic range, and a site in the northwest Mediterranean Sea to inform on connectivity across the Atlantic‐Mediterranean transition. Using 7510 neutral SNPs, a geographic cline of genetic clusters was detected, partitioning into Ireland, Britain, France, Spain (Atlantic), and Portugal and Spain (Mediterranean). Evidence of significant inbreeding was detected at all sites, a finding not detected in a previous study of this species based on microsatellite loci. Genetic connectivity was characterized by an isolation by distance pattern (IBD) (r2 = 0.78, p

Abstract Sea turtles are critical components of marine ecosystems, and their conservation is important for Ocean Governance and Global Planet Health. However, there is limited knowledge of their ecology in the Gulf of Guinea. To fill this knowledge gap, this study presents the first integrative assessment of green and hawksbill turtles in the region, combining nesting surveys over 9 years and telemetry data, to offer insights into these population dynamics, and behaviours, including nesting preferences, morphological and reproductive parameters, diving patterns and inter‐nesting core‐use areas. Both green and hawksbill turtles are likely making a recovery on São Tomé, potentially driven by sustained conservation efforts. There are preliminary indications of recovery, but we interpret this cautiously. Coupled with satellite tracking, this study estimated that 482 to 736 green turtles and 135 to 217 hawksbills nest on the beaches of São Tomé. Their movements overlap significantly with a proposed Marine Protected Area (MPA), which suggests they may be well placed for conservation if managed appropriately. However, the presence of artisanal fisheries and emerging threats, such as sand mining and unregulated tourism, highlight the urgent need for robust management strategies that align global conservation objectives with local socioeconomic realities. This study significantly enhances our understanding of the ecology and conservation needs of the green and hawksbill turtles in the Gulf of Guinea. The insights gleaned here can contribute to the development of tailored conservation strategies that benefit these populations and the ecosystem services upon which they depend.

Abstract Modulation of autophagy, specifically its inhibition, stands to transform the capacity to effectively treat a broad range of cancers. However, the clinical efficacy of autophagy inhibitors has been inconsistent. To delineate clinical and epidemiological features associated with autophagy inhibition and a positive oncological clinical response, a retrospective analysis of patients is conducted treated with hydroxychloroquine, a known autophagy inhibitor. A direct correlation between smoking status and inhibition of autophagy with hydroxychloroquine is identified. Recognizing that smoking is associated with elevated circulating levels of carbon monoxide (CO), it is hypothesized that supplemental CO can amplify autophagy inhibition. A novel, gas‐entrapping material containing CO in a pre‐clinical model is applied and demonstrated that CO can dramatically increase the cytotoxicity of autophagy inhibitors and significantly inhibit the growth of tumors when used in combination. These data support the notion that safe, therapeutic levels of CO can markedly enhance the efficacy of autophagy inhibitors, opening a promising new frontier in the quest to improve cancer therapies.

Abstract Objective Pediatric epilepsy surgery yields cure from epilepsy or complete seizure control with continued medication in many patients early in life. This study aimed to evaluate the long‐term (>10 years) psychosocial and socioeconomic outcomes of pediatric epilepsy surgery and examine the role of comorbid disability, type of surgery, seizure freedom, and age at surgery. Methods A novel ad hoc parent/patient questionnaire was used to assess educational and occupational attainment, marital/familial status, mobility, and other outcomes in patients who underwent unilobar or multilobar surgery for drug‐refractory epilepsy during their childhood. The questionnaire also captured information on comorbid disability. Results Of the 353 eligible patients, 203 could still be contacted and 101 of these (50%) returned appropriately filled‐in questionnaires (follow‐up intervals: 11‐30 [mean: 19.6] years). The cure from epilepsy rate was 53%. Type of surgery was strongly confounded by comorbid disability. Patients with comorbid disabilities had significantly lower rates of regular school degrees, gainful employment, marriage, and driving license (N = 29; 12%, 4%, 0%, 3%) compared with non‐disabled patients (N = 69; 89%, 80%, 43%, and 67%, respectively). Patients achieved lower school degrees than their siblings and parents. Non‐disabled seizure‐free patients had better employment and mobility outcomes compared with non‐seizure‐free patients. Age at surgery (

Abstract Background Cancer patients often search for information about their health conditions online. Cancer patient narratives have established themselves as a way of providing information and education but also as an effective approach to improving coping with the disease. Objective We investigated how people affected by cancer perceive cancer patient narratives and whether such stories can potentially improve coping during their own cancer journeys. Additionally, we reflected on whether our co‐creative citizen science approach can contribute to gaining knowledge about cancer survival stories and providing peer support. Design, Setting and Stakeholders We applied a co‐creative citizen science approach by using quantitative and qualitative research methods with stakeholders (i.e., cancer patients, their relatives, friends and health professionals). Main Outcome Measures Understandability and perceived benefits of cancer survival stories, coping, emotional reactions to the stories and helpful characteristics of the stories. Results Cancer survival stories were considered intelligible and beneficial, and they potentially support positive emotions and coping in people affected by cancer. Together with the stakeholders, we identified four main characteristics that evoked positive emotions and that were considered especially helpful: (1) positive attitudes towards life, (2) encouraging cancer journeys, (3) individual coping strategies for everyday challenges and (4) openly shared vulnerabilities. Conclusions Cancer survival stories potentially support positive emotions and coping in people affected by cancer. A citizen science approach is suitable for identifying relevant characteristics of cancer survival stories and may become a helpful educational peer support resource for people coping with cancer. Patient or Public Contributions We adopted a co‐creative citizen science approach, wherein citizens and researchers were equally involved throughout the entire project.

Abstract Objective Endotracheal intubation is a common procedure in the medical intensive care unit (MICU), but it carries risk of complications including, but not limited to, subglottic stenosis (SGS) and tracheal stenosis (TS). Current literature suggests identifiable risk factors for the development of airway complications. This study is a comprehensive evaluation of potential risk factors in patients who developed SGS and TS following endotracheal intubation in our MICU. Methods Patients intubated in our MICU were identified from 2013 to 2019. Diagnoses of SGS or TS within 1 year of MICU admission were identified. Data extracted included age, sex, body measurements, comorbidities, bronchoscopies, endotracheal tube size, tracheostomy, social history, and medications. Patients with prior diagnosis of airway complication, tracheostomy, or head and neck cancer were excluded. Univariate and multivariate logistic regressions were performed. Results A total of 136 patients with TS or SGS were identified out of a sample of 6603 patients intubated in the MICU. Cases were matched to controls who did not develop airway stenosis based on identical Charlson Comorbidity Index scores. Eighty six controls were identified with a complete record of endotracheal/tracheostomy tube size, airway procedures, sociodemographic data, and medical diagnosis. Regression analysis showed that SGS or TS were associated with tracheostomy, bronchoscopy, chronic obstructive pulmonary disease, current tobacco use, gastroesophageal reflux disease, systemic lupus erythematosus, pneumonia, bronchitis, and numerous medication classes. Conclusion Various conditions, procedures, and medications are associated with an increased risk of developing SGS or TS. Level of evidence 4.

Abstract Purpose To assess the effectiveness and safety of acupuncture for the prevention of chemotherapy‐induced nausea and vomiting (CINV), with a specific intention on exploring sources of between‐study variation in treatment effects. Methods MEDLINE, EMBASE, Cochrane CENTRAL, CINAHL, Chinese Biomedical Literature Database, VIP Chinese Science and Technology Periodicals Database, China National Knowledge Infrastructure, and Wanfang were searched to identify randomized controlled trials (RCTs) that compared acupuncture to sham acupuncture or usual care (UC). The main outcome is complete control (no vomiting episodes and/or no more than mild nausea) of CINV. GRADE approach was used to rate the certainty of evidence. Results Thirty‐eight RCTs with a total of 2503 patients were evaluated. Acupuncture in addition to UC may increase the complete control of acute vomiting (RR, 1.13; 95% CI, 1.02 to 1.25; 10 studies) and delayed vomiting (RR, 1.47; 95% CI, 1.07 to 2.00; 10 studies) when compared with UC only. No effects were found for all other review outcomes. The certainty of evidence was generally low or very low. None of the predefined moderators changed the overall findings, but in an exploratory moderator analysis we found that an adequate reporting of planned rescue antiemetics might decrease the effect size of complete control of acute vomiting (p = 0.035). Conclusion Acupuncture in addition to usual care may increase the complete control of chemotherapy‐induced acute vomiting and delayed vomiting but the certainty of evidence was very low. Well‐designed RCTs with larger sample sizes, standardized treatment regimens, and core outcome measures are needed.

Abstract Objectives Bipolar disorder (BD) and major depressive disorder (MDD) are characterized by specific alterations of mood. In both disorders, alterations in cognitive domains such as impulsivity, decision‐making, and risk‐taking have been reported. Identification of similarities and differences of these domains in BD and MDD could give further insight into their etiology. The present study assessed impulsivity, decision‐making, and risk‐taking behavior in BD and MDD patients from bipolar multiplex families. Methods Eighty‐two participants (BD type I, n = 25; MDD, n = 26; healthy relatives (HR), n = 17; and healthy controls (HC), n = 14) underwent diagnostic interviews and selected tests of a cognitive battery assessing neurocognitive performance across multiple subdomains including impulsivity (response inhibition and delay aversion), decision‐making, and risk behavior. Generalized estimating equations (GEEs) were used to analyze whether the groups differed in the respective cognitive domains. Results Participants with BD and MDD showed higher impulsivity levels compared to HC; this difference was more pronounced in BD participants. BD participants also showed lower inhibitory control than MDD participants. Overall, suboptimal decision‐making was associated with both mood disorders (BD and MDD). In risk‐taking behavior, no significant impairment was found in any group. Limitations As sample size was limited, it is possible that differences between BD and MDD may have escaped detection due to lack of statistical power. Conclusions Our findings show that alterations of cognitive domains—while present in both disorders—are differently associated with BD and MDD. This underscores the importance of assessing such domains in addition to mere diagnosis of mood disorders.

Abstract Objectives The Salivary Gland Committee of the American Academy of Otolaryngology‐Head and Neck Surgery seeks to standardize terminology and technique for ultrasonograpy used in the evaluation and treatment of salivary gland disorders. Methods Development of expert opinion obtained through interaction with international practitioners representing multiple specialties. This committee work includes a comprehensive literature review with presentation of case examples to propose a standardized protocol for the language used in ultrasound salivary gland assessment. Results A multiple segment proposal is initiated with this focus on the submandibular gland. We provide a concise rationale for recommended descriptive language highlighted by a more extensive supplement that includes an extensive literature review with additional case examples. Conclusion Recommendations are provided to improve consistency both in performing and reporting submandibular gland ultrasound.

Abstract Impranil® DLN‐SD is a poly(ester‐urethane) (PEU) that is widely used as coating material for textiles to fine‐tune and improve their properties. Since coatings increase the complexity of such plastic materials, they can pose a hindrance for sustainable end‐of‐life solutions of plastics using enzymes or microorganisms. In this study, we isolated Halopseudomonas formosensis FZJ due to its ability to grow on Impranil DLN‐SD and other PEUs as sole carbon sources. The isolated strain was exceptionally thermotolerant as it could degrade Impranil DLN‐SD at up to 50°C. We identified several putative extracellular hydrolases of which the polyester hydrolase Hfor_PE‐H showed substrate degradation of Impranil DLN‐SD and thus was purified and characterized in detail. Hfor_PE‐H showed moderate temperature stability (Tm = 53.9°C) and exhibited activity towards Impranil DLN‐SD as well as polyethylene terephthalate. Moreover, we revealed the enzymatic release of monomers from Impranil DLN‐SD by Hfor_PE‐H using GC‐ToF‐MS and could decipher the associated metabolic pathways in H. formosensis FZJ. Overall, this study provides detailed insights into the microbial and enzymatic degradation of PEU coatings, thereby deepening our understanding of microbial coating degradation in both contained and natural environments. Moreover, the study highlights the relevance of the genus Halopseudomonas and especially the novel isolate and its enzymes for future bio‐upcycling processes of coated plastic materials.

Abstract Dual use crops are becoming popular as resources like land and water become scarcer. Annual peanuts are an important food crop grown worldwide that can also be used as forage or hay. Replicated trials evaluated the late season (≥15 weeks after planting) forage accumulations and nutritive values (acid detergent fiber, carbon content, crude protein, invitro true digestibility, neutral detergent fiber, nitrogen content, and relative feed value) of four market types near Clovis, NM and El Reno, OK in 2019 and 2020. Statistical analyses (p ≤ .05) showed all traits were affected by the interaction between market type and growing environment. Overall, forage accumulations for all market types ranged from 2.7 to 6.5 Mg ha−1 with relative feed values of 107–155. The location average across sites was 4.45 Mg ha−1 with relative feed value of 132. The Virginia market types produced large amounts of biomass. However, the Valencia market type generated the greatest nutritive values. This study indicates harvesting late‐season biomass of peanuts for hay may be an option that allows producers to generate more income from limited land and water resources. However, both market type and environmental factors, such as rainfall/irrigation, play important roles in production and forage nutritive values of peanut forage.

Abstract Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disorder. With the availability of treatment and renal replacement therapy, nephropathic cystinosis has evolved from an early fatal disease to a chronic, progressive disorder with potentially high impairment. We aim to review the literature on the health‐related quality of life and identify appropriate patient‐reported outcome measurements to assess the health‐related quality of life of patients with cystinosis. For this review, we conducted a literature search in PubMed and Web of Science in September 2021. Inclusion and exclusion criteria for the selection of articles were defined a priori. We identified 668 unique articles through the search and screened them based on title and abstract. The full texts of 27 articles were assessed. Finally, we included five articles (published between 2009 and 2020) describing the health‐related quality of life in patients with cystinosis. All studies, apart from one, were conducted in the United States, and no condition‐specific measurement was used. Patients with cystinosis reported a lower health‐related quality of life (for certain dimensions) than healthy subjects. Few published studies address the health‐related quality of life of patients with cystinosis. Such data must be collected standardized and follow the FAIR (Findable, Accessible, Interoperable, and Reusable) principles. To gain a comprehensive understanding of the impact of this disorder on health‐related quality of life, it is necessary to use generic and condition‐specific instruments to measure this, preferably in large samples from longitudinal studies. A cystinosis‐specific instrument for measuring health‐related quality of life has yet to be developed.

Abstract Pulmonary hypertension (PH) is the most severe complication in preterm infants with bronchopulmonary dysplasia (BPD) and associated with significant mortality. Diagnostic and treatment strategies, however, still lack standardization. By the use of a survey study (PH in BPD), we assessed clinical practice (diagnosis, treatment, follow‐up) in preterm infants with early postnatal persistent pulmonary hypertension of the newborn (PPHN) as well as at risk for or with established BPD‐associated PH between 06/2018 and 10/2020 in two‐thirds of all German perinatal centers with >70 very low birthweight infants/year including their cardiology departments and outpatient units. Data were analyzed descriptively by measures of locations and distributional shares. In routine postnatal care, clinical presentation and echocardiography were reported as the main diagnostic modalities to screen for PPHN in preterm infants, whereas biomarkers brain natriuretic peptide/N‐terminal pro b‐type natriuretic peptide were infrequently used. For PPHN treatment, inhaled nitric oxide was used in varying frequency. The majority of participants agreed to prescribe diuretics and steroids (systemic/inhaled) for infants at risk for or with established BPD‐associated PH and strongly agreed on recommending respiratory syncytial virus immunization and the use of home monitoring upon discharge. Reported oxygen saturation targets, however, varied in these patients in in‐ and outpatient care. The survey reveals shared practices in diagnostic and therapeutic strategies for preterms with PPHN and BPD‐associated PH in Germany. Future studies are needed to agree on detailed echo parameters and biomarkers to diagnose and monitor disease next to a much‐needed agreement on the use of pulmonary vasodilators, steroids, and diuretics as well as target oxygen saturation levels.

Abstract Background Gunshot emissions contain toxic elements that can harm those frequently exposed, such as police officers. Several years ago, police indoor firing ranges were closed by the Berlin municipality in response to police officer health complaints, and an investigation was launched into the possible respiratory health risks of frequent gunshot emission exposure. We, therefore, conducted an exploratory cross‐sectional study to investigate clinical and functional parameters of respiratory health as well as the burden of trace elements in policemen with long‐term high exposure to indoor gunshot emissions, compared to low‐exposure and control groups. Methods We conducted lung function tests and collected blood and urine samples from Berlin police officers and government employees who were divided into three subject groups based on exposure to gunshot emissions: high exposure (n = 53), low exposure (n = 94) and no exposure (n = 76). Lung function was examined using body plethysmography. Blood and urine samples were tested via inductively coupled plasma mass spectrometry for the presence of common gunshot powder elements (antimony, lead and manganese). Exposure and symptoms were assessed using records as well as questionnaires. Results Higher exposure was associated with more respiratory symptoms during gun shooting practice (64% vs. 21%, P

Abstract Despite considerable investment into potential therapeutic approaches for Alzheimer's disease (AD), currently approved treatment options are limited. Predictive modeling using quantitative systems pharmacology (QSP) can be used to guide the design of clinical trials in AD. This study developed a QSP model representing amyloid beta (Aβ) pathophysiology in AD. The model included mechanisms of Aβ monomer production and aggregation to form insoluble fibrils and plaques; the transport of soluble species between the compartments of brain, cerebrospinal fluid (CSF), and plasma; and the pharmacokinetics, transport, and binding of monoclonal antibodies to targets in the three compartments. Ordinary differential equations were used to describe these processes quantitatively. The model components were calibrated to data from the literature and internal studies, including quantitative data supporting the underlying AD biology and clinical data from clinical trials for anti‐Aβ monoclonal antibodies (mAbs) aducanumab, crenezumab, gantenerumab, and solanezumab. The model was developed for an apolipoprotein E (APOE) ɛ4 allele carrier and tested for an APOE ɛ4 noncarrier. Results indicate that the model is consistent with data on clinical Aβ accumulation in untreated individuals and those treated with monoclonal antibodies, capturing increases in Aβ load accurately. This model may be used to investigate additional AD mechanisms and their impact on biomarkers, as well as predict Aβ load at different dose levels for mAbs with known targets and binding affinities. This model may facilitate the design of scientifically enriched and efficient clinical trials by enabling a priori prediction of biomarker dynamics in the brain and CSF.

Chemotherapy resistance is a persistent clinical problem in relapsed high‐risk neuroblastomas. We tested a panel of 15 drugs for sensitization of neuroblastoma cells to the conventional chemotherapeutic vincristine, identifying tariquidar, an inhibitor of the transmembrane pump P‐glycoprotein (P‐gp/ABCB1), and the ERBB family inhibitor afatinib as the top resistance breakers. Both compounds were efficient in sensitizing neuroblastoma cells to vincristine in trypan blue exclusion assays and in inducing apoptotic cell death. The evaluation of ERBB signaling revealed no functional inhibition, that is, dephosphorylation of the downstream pathways upon afatinib treatment but direct off‐target interference with P‐gp function. Depletion of ABCB1, but not ERRB4, sensitized cells to vincristine treatment. P‐gp inhibition substantially broke vincristine resistance in vitro and in vivo (zebrafish embryo xenograft). The analysis of gene expression datasets of more than 50 different neuroblastoma cell lines (primary and relapsed) and more than 160 neuroblastoma patient samples from the pediatric precision medicine platform INFORM (Individualized Therapy For Relapsed Malignancies in Childhood) confirmed a pivotal role of P‐gp specifically in neuroblastoma resistance at relapse, while the ERBB family appears to play a minor part.

Abstract Background Lynch syndrome is one of the most common cancer predisposition syndromes. It is caused by inherited changes in the mismatch repair pathway. With current diagnostic approaches, a causative genetic variant can be found in less than 50% of cases. A correct diagnosis is important for ensuring that an appropriate surveillance program is used and that additional high‐risk family members are identified. Methods We used clinical genome sequencing on DNA from blood and subsequent transcriptome sequencing for confirmation. Data were analyzed using the megSAP pipeline and classified according to basic criteria in diagnostic laboratories. Segregation analyses in family members were conducted via breakpoint PCR. Results We present a family with the clinical diagnosis of Lynch syndrome in which standard diagnostic tests, such as panel or exome sequencing, were unable to detect the underlying genetic variant. Genome sequencing in the index patient confirmed the previous diagnostic results and identified an additional complex rearrangement with intronic breakpoints involving MLH1 and its neighboring gene LRRFIP2. The previously undetected structural variant was classified as medically relevant. Segregation analysis in the family identified additional at‐risk individuals which were offered intensified cancer screening. Discussion and Conclusions This case illustrates the advantages of clinical genome sequencing in detecting structural variants compared with current diagnostic approaches. Although structural variants are rare in Lynch syndrome families, they seem to be underreported, in part because of technical challenges. Clinical genome sequencing offers a comprehensive genetic characterization detecting a wide range of genetic variants.

Abstract Objectives/hypothesis To identify sociodemographic factors associated with the development of airway stenosis (AS) among intubated medical intensive care unit (MICU) patients. Study design Retrospective cohort study. Methods A retrospective review of adult MICU intubated patients from 2013 to 2019 at a single academic institution was performed. Univariate and multivariate analysis with logistic regression examined associations between the development of AS and subsite abnormalities such as posterior glottic stenosis (PGS), subglottic stenosis (SGS), tracheal stenosis (TS), vocal fold immobility (VFI), and posterior glottic granuloma (PGG) with age, body mass index (BMI), height, weight, race, ethnicity, sex, rurality, Appalachian status, length of admission, distance to hospital, and median household income. Results Of an overall sample of 6603 MICU patients, 449 intubated patients were included in the study, and 204 patients were found to have AS. AS was statistically associated with decreased driving distance to the hospital and increases in BMI. PGS was statistically associated with increases in age. TS was statistically associated with increases in admission duration and not having residence status in Appalachia. VFI was statistically associated with decreases in driving distance to the hospital and not having residence status in Appalachia. Additionally, black patients had a higher odds of developing VFI compared to Caucasian patients. Conclusion AS is associated with sociodemographic factors such as age, BMI, shorter distance to hospital, admission duration, and no Appalachian status. These data demonstrate the need to further investigate the impact of social determinants of health on airway pathology and outcomes. Level of evidence 4.

Abstract Tumor hypoxia drives resistance to many cancer therapies, including radiotherapy and chemotherapy. Methods that increase tumor oxygen pressures, such as hyperbaric oxygen therapy and microbubble infusion, are utilized to improve the responses to current standard‐of‐care therapies. However, key obstacles remain, in particular delivery of oxygen at the appropriate dose and with optimal pharmacokinetics. Toward overcoming these hurdles, gas‐entrapping materials (GeMs) that are capable of tunable oxygen release are formulated. It is shown that injection or implantation of these materials into tumors can mitigate tumor hypoxia by delivering oxygen locally and that these GeMs enhance responsiveness to radiation and chemotherapy in multiple tumor types. This paper also demonstrates, by comparing an oxygen (O2)‐GeM to a sham GeM, that the former generates an antitumorigenic and immunogenic tumor microenvironment in malignant peripheral nerve sheath tumors. Collectively the results indicate that the use of O2‐GeMs is promising as an adjunctive strategy for the treatment of solid tumors.

Abstract Objective Direct pathogenic effects of autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GAD65) in autoimmune limbic encephalitis (LE) have been questioned due to its intracellular localization. We therefore hypothesized a pathogenic role for T cells. Methods We assessed magnet resonance imaging, neuropsychological and peripheral blood, and CSF flow cytometry data of 10 patients with long‐standing GAD65‐LE compared to controls in a cross‐sectional manner. These data were related to each other within the GAD65‐LE group and linked to neuropathological findings in selective hippocampectomy specimen from another two patients. In addition, full‐resolution human leukocyte antigen (HLA) genotyping of all patients was performed. Results Compared to controls, no alteration in hippocampal volume but impaired memory function and elevated fractions of activated HLADR+ CD4+ and CD8+ T cells in peripheral blood and cerebrospinal fluid were found. Intrathecal fractions of CD8+ T cells negatively correlated with hippocampal volume and memory function, whereas the opposite was true for CD4+ T cells. Consistently, antigen‐experienced CD8+ T cells expressed increased levels of the cytotoxic effector molecule perforin in peripheral blood, and perforin‐expressing CD8+ T cells were found attached mainly to small interneurons but also to large principal neurons together with wide‐spread hippocampal neurodegeneration. 6/10 LE patients harbored the HLA‐A*02:01 allele known to present the immunodominant GAD65114–123 peptide in humans. Interpretation Our data suggest a pathogenic effect of CD8+ T cells and a regulatory effect of CD4+ T cells in patients with long‐standing GAD65‐LE.

Abstract Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. More than a third of patients do not respond to standard therapy and urgently require alternative treatment options. Due to a high degree of inter‐ and intra‐tumoural genomic heterogeneity and complexity, recurrent molecular alterations that could serve as prognostic predictors or therapeutic targets are still lacking in osteosarcoma. Copy number (CN) gains involving the IGF1R gene, however, have been suggested as a potential surrogate marker for treating a subset of patients with IGF1R inhibitors. In this study, we screened a large set of osteosarcomas and found specific CN gains of the IGF1R gene in 18 of 253 (7.1%) cases with corresponding IGF1R overexpression. Despite the discouraging results observed in clinical trials in other tumours so far, focusing only on selected patients with osteosarcoma that show evidence of IGF pathway activation might represent a promising new and innovative treatment approach.

Abstract Disentangling the factors underlying the diversification of geographically variable species with a wide geographical range is essential to understanding the initial stages and drivers of the speciation process. The Amazilia Hummingbird, Amazilis amazilia, is found along the Pacific coast from northern Ecuador down to the Nazca Valley of Peru, and is currently classified as six phenotypically differentiated subspecies. We aimed to resolve the evolutionary relationships of the six subspecies, to assess the geographical pattern and extent of evolutionary divergence, and to test for introgression using both a mtDNA marker and a genome‐by‐sequencing dataset from 86 individuals from across the species range. The consensus phylogenetic tree separated the six subspecies into three distinct clades, corresponding with the Ecuador lowlands (A. amazilia dumerilii), the Ecuador highlands (A. amazilia alticola and A. amazilia azuay), and the Peruvian coast (A. amazilia leucophoea, A. amazilia amazilia, and A. amazilia caeruleigularis). However, an unresolved mtDNA network suggests that the diversification of the subspecies was recent and rapid. We found evidence of gene flow among the subspecies A. amazilia dumerilii, A. amazilia alticola, and A. amazilia leucophoea, with strong genetic isolation of the subspecies A. amazilia azuay in the isolated Yunguilla Valley of Ecuador. Finally, environmental data from each subspecies’ capture locations were concordant with the three distinct clades. Overall, our results suggest that both expansions into new habitats and geographic isolation shaped the present‐day phylogeny and range of the A. amazilia subspecies, and that A. amazilia azuay may be genetically divergent enough to be considered a separate species.

Abstract As part of the Post‐2020 Biodiversity Framework, nations are assessing progress over the past decade in addressing the underlying drivers that influence direct pressures on biodiversity and formulating new policies and strategies for the decade to come. For marine conservation, global marine protected area (MPA) coverage is still falling short of the 10% target set in 2010. Here we show that while this reflects a lack of progress in many low‐ and middle‐income countries, a few of these nations have met or exceeded international commitments. To provide an in‐depth explanation of how this was achieved in Gabon, we summarize the lessons learnt by our consortium of policy makers and practitioners who helped implement a comprehensive and ecologically representative network of 20 MPAs. We show the importance of creating a national framework, building long‐term stakeholder support, and focusing on research that guides implementation and policy; and outline a four‐step approach that countries and donors could use as an example to help meet international commitments. By responding to calls to share lessons learned to inform future Convention on Biological Diversity targets, we show how Gabon's experiences could inform change elsewhere.

Abstract Introduction Objective of this study was to examine if the Interlocking Finger Test (ILFT) is a suitable bedside screening test for visuospatial functions and/or dementia in Parkinson's disease (PD) patients aiming to facilitate the diagnosis of a dementia syndrome associated with posterior cortical and temporal lobe dysfunction according to the dual syndrome hypothesis (frontostriatal vs. posterior cortical cognitive impairment). Methods Forty‐seven PD patients were assessed with the ILFT and an extensive cognitive test battery. The ILFT was carried out in the original version as well as in three modified versions of the test including a fifth figure and/or a more complex rating system, leading to four different ILFT scores (named after the maximum achievable scoring result: ILFT 4, ILFT 5, ILFT 12, and ILFT 15). We conducted a correlation analysis to reveal associations between the ILFT scores and cognitive as well as motor impairments. Receiver operating curve (ROC) analyses were calculated to evaluate the ability of the ILFT scores to predict visuospatial impairments and dementia. Results ILFT scores correlated significantly with global cognition, visuospatial functions, memory, attention, and age (p