Lenalidomide induced pneumonitis.

INTRODUCTION: Iatrogenic lung injury is a very rare, albeit serious complication with antineoplastic therapy, including immunomodulatory drugs. Pneumonitis typically presents clinically with symptoms such as cough, dyspnea, fever, and hypoxemia. Radiographic evaluation often demonstrates diffuse, patchy infiltrates and ground-glass opacities. CASE REPORT: We present a case in which therapy from an immunomodulatory drug, lenalidomide, elicited a pneumonitis in the form of a 9 cm lung mass. An exhaustive workup was completed to rule out viral, bacterial, and fungal infections as well as malignant causes. Lenalidomide-induced lung injury was suspected. MANAGEMENT AND OUTCOME: Lenalidomide was discontinued and corticosteroid therapy was initiated. This resulted in a complete clinical and radiographic resolution of symptoms. DISCUSSION: Several case reports of pneumonitis have been associated with immunomodulatory drug therapy, and while most of these exhibit diffuse ground-glass opacities radiographically, our patient presented with a 9 cm lung mass. Our findings stress the importance of a thorough medication review while ruling out other potential causes of lung injury.

Development and validation of a questionnaire to measure the severity of pain, functional limitations, and reduction of sports ability for german-speaking patients with osteochondral lesions of the ankle (OCLA-G).

BACKGROUND: There is no patient-reported functional scale specific for osteochondral lesion of the ankle (OCLA). Therefore, the objectives of this study were to develop a questionnaire that measures symptom severity, function, and sports capacity in patients with osteochondral lesions of the ankle and to determine the psychometric properties of the tool in German language (OCLA-G). METHODS: The OCLA-G questionnaire was developed according to the COSMIN guidelines. Scalable items were generated from a literature search, based on an evaluation of 71 own OCLA patients, and from expert opinions. Following a twofold item reduction the questionnaire underwent explorative data analysis and principal component analysis. Validity and reliability were analysed in four groups of participants (40 patients with OCLA, 40 patients with other foot and ankle injuries, 40 asymptomatic athletes serving as a population at risk, and 40 asymptomatic persons playing sports not at risk). The minimum age for participation in the study was set at 18 years. The mean age was 39.3 ± 15.1 years. RESULTS: The final OCLA-G questionnaire consists of eight and five questions to mirror activities of daily life (ADL) and sports, respectively. Excellent internal consistency (Cronbach's α = 0.950 for the ADL subscore and 0.965 for the sport subscale, respectively) was found. Spearman's rank correlation coefficients for test-retest reliability were 0.992 for the ADL subscore and 0.999 for the sport subscale (p < 0.001). The results of the exploratory and confirmatory factor analyses indicated that item difficulty was between 23.4 and 62.8. The Pearson correlation for the OCLA subscales ADL and sport was 0.853 (p < 0.001). Construct validity as tested against the SF-12 questionnaire subscales (Physical and Mental component scale) were r = -0.164 to -0.663 (p < 0.05). Statistically, there was no ADL and sport OCLA mean score difference between OCLA patients and patients with other foot and ankle injuries (p = 0.993 and 0.179, respectively), but both groups differed from the uninjured control groups (p < 0.001). There were no ceiling or floor effects. CONCLUSIONS: The OCLA-G was successfully developed as the first patient reported and injury specific outcome scale to measure the impact of OCLA induced symptoms on activities of daily living and sport. This study provides evidence for the reliability and validity of the OCLA-G assessing patients with OCLA. TRIAL REGISTRATION: The registration trial number is DRKS00009401 on DRKS. 'Retrospectively registered'. Date of registration: 10/12/2015.

Differences in mobile food market customer outcomes between 2019 and 2021.

OBJECTIVES: To evaluate the outcomes of increasing mobile market service from mostly biweekly in 2019 to weekly in 2021. DESIGN: Repeated, cross-sectional customer intercept surveys. SAMPLE: Mobile market customers in Summers 2019 (N = 302) and 2021 (N = 72). INTERVENTION: Mobile food markets bring affordable, high-quality foods to communities that lack such access. MEASURES/ANALYSIS: Outcomes included food security, fruit/vegetable intake, and food-related characteristics and behaviors. General linear and logistic regression models were used to assess associations between outcomes and survey year and length of mobile market shopping. Models were adjusted for economic assistance use, race, and ethnicity. RESULTS: No outcomes were significantly different between 2019 (with mostly biweekly service) and 2021 (with weekly service). Length of mobile market shopping (e.g., >2 years, 1-2 years, etc.) was positively associated with affordable, quality food access (ß = 0.20, SE = 0.10, p = .03) and fruit/vegetable intake (ß = 0.28, SE = 0.08, p < .001) as well as lower odds of food insecurity in the last 12 months (aOR = 0.79, 95% CI = 0.64, 0.99). CONCLUSIONS: Despite COVID-19 interrupting scheduled market service, the length of time that a survey respondent identified as a full-service mobile market customer was associated with higher food access and fruit/vegetable intake and reduced food insecurity odds. These findings suggest promise and encourage further evaluation.

Implementing a fluid volume management program to decrease intra-dialytic hypotensive events in a paediatric in-centre haemodialysis unit: a quality improvement project.

BACKGROUND: Intra-dialytic hypotension (IDH) is the most common serious adverse event in paediatric haemodialysis (HD). Repeated IDH results in chronic multi-organ damage and increased mortality. At the Hospital for Sick Children, Toronto, retrospective data from all in-centre HD sessions revealed frequently occurring IDH events (16.5 ± 5.6% of HD sessions per week). Based on literature review and clinical expertise, fluid volume management was selected as a potential modifiable risk factor to decrease IDH. Root causes identified as contributing to IDH were incorporated into a Paediatric haemodialysis fluid volume management (PedHDfluid) program using the Model for Improvement methodology including rapid cycles of change. METHODS: Multiple measures were evaluated including (i) Outcome: IDH events per number of HD sessions per week; (ii) Process: number of changes to estimated dry weight per number of HD sessions per week; (iii) Balancing: time spent on dry weight meeting per week. Data was analysed using statistical process control charts. We aimed to decrease IDH in our dialysis unit to < 10% of HD sessions per week over a 6-month period by implementing a PedHDfluid program, including a multifaceted dry weight assessment protocol, multidisciplinary meetings and electronic health records "Dry Weight Evaluation flow sheet/synopsis". RESULTS: The project resulted in a decline in IDH events from 16.5 ± 5.6% to 8.8 ± 3.3% of HD sessions per week. More frequent dry weight changes and increased awareness of fluid removal goals were noted. CONCLUSIONS: A multidisciplinary approach including regular assessment, guidelines and systematic discussion, with an embedded electronic health record assessment and data gathering tool may sustainably reduce IDH events. A higher resolution version of the Graphical abstract is available as Supplementary information.

Social vulnerability and COVID-19: A call to action for paediatric clinicians.

The COVID-19 pandemic has had dramatic effects on the lives of children globally. However, socially vulnerable children have been particularly impacted. Certain populations have increased vulnerabilities, including children and youth experiencing homelessness. Increased infection risk due to congregant living and challenges with physical distancing are contributing factors. An urgent need exists for a wholistic approach to care with unique cross-sectoral partnerships across disciplines. A recognition of the unintended consequence of the COVID-19 pandemic on this population is urgently required by all those supporting children. Families should receive direct support in clinical settings to identify their social needs. Partnership with community agencies and advocacy for appropriate isolation facilities for patients experiencing homelessness are critical.

A randomized phase 2 network trial of tivantinib plus cetuximab versus cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma.

BACKGROUND: MET signaling is a well described mechanism of resistance to anti-EGFR therapy, and MET overexpression is common in head and neck squamous cell carcinomas (HNSCCs). In the current trial, the authors compared the oral MET inhibitor tivantinib (ARQ197) in combination with cetuximab (the TC arm) versus a control arm that received cetuximab monotherapy (C) in patients with recurrent/metastatic HNSCC. METHODS: In total, 78 evaluable patients with cetuximab-naive, platinum-refractory HNSCC were enrolled, including 40 on the TC arm and 38 on the C arm (stratified by human papillomavirus [HPV] status). Patients received oral tivantinib 360 mg twice daily and intravenous cetuximab 500 mg/m2 once every 2 weeks. The primary outcome was the response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), and secondary outcomes included progression-free and overall survival. After patients progressed on the C arm, tivantinib monotherapy was optional. RESULTS: The response rate was 7.5% in the TC arm (N = 3; 1 complete response) and 7.9% in the C arm (N = 3; not significantly different [NS]). The median progression-free survival in both arms was 4 months (NS), and the median overall survival was 8 months (NS). Both treatments were well tolerated, with a trend toward increased hematologic toxicities in the TC arm (12.5% had grade 3 leukopenia). The response rate in 31 HPV-positive/p16-positive patients was 0% in both arms, whereas the response rate in HPV-negative patients was 12.7% (12.5% in the TC arm and 13% in the C arm). Fifteen patients received tivantinib monotherapy, and no responses were observed. CONCLUSIONS: Combined tivantinib plus cetuximab does not significantly improve the response rate or survival compared with cetuximab alone but does increase toxicity in an unselected HNSCC population. Cetuximab responses appear to be limited to patients who have HPV-negative HNSCC. MET-aberration-focused trials for HNSCC and the use of higher potency, selective MET inhibitors remain of interest.

Local-scale biotic interactions embedded in macroscale climate drivers suggest Eltonian noise hypothesis distribution patterns for an invasive grass.

A hierarchical view of niche relations reconciles the scale-dependent effects of abiotic and biotic processes on species distribution patterns and underlies most current approaches to distribution modeling. A key prediction of this framework is that the effects of biotic interactions will be averaged out at macroscales - an idea termed the Eltonian noise hypothesis (ENH). We test this prediction by quantifying regional variation in local abiotic and biotic niche relations and assess the role of macroclimate in structuring biotic interactions, using a non-native invasive grass, Microstegium vimineum, in its introduced range. Consistent with hierarchical niche relations and the ENH, macroclimate structures local biotic interactions, while local abiotic relations are regionally conserved. Biotic interactions suppress M. vimineum in drier climates but have little effect in wetter climates. A similar approach could be used to identify the macroclimatic conditions under which biotic interactions affect the accuracy of local predictions of species distributions.

Potential negative ecological effects of corridors.

Despite many studies showing that landscape corridors increase dispersal and species richness for disparate taxa, concerns persist that corridors can have unintended negative effects. In particular, some of the same mechanisms that underlie positive effects of corridors on species of conservation interest may also increase the spread and impact of antagonistic species (e.g., predators and pathogens), foster negative effects of edges, increase invasion by exotic species, increase the spread of unwanted disturbances such as fire, or increase population synchrony and thus reduce persistence. We conducted a literature review and meta-analysis to evaluate the prevalence of each of these negative effects. We found no evidence that corridors increase unwanted disturbance or non-native species invasion; however, these have not been well-studied concerns (1 and 6 studies, respectively). Other effects of corridors were more often studied and yielded inconsistent results; mean effect sizes were indistinguishable from zero. The effect of edges on abundances of target species was as likely to be positive as negative. Corridors were as likely to have no effect on antagonists or population synchrony as they were to increase those negative effects. We found 3 deficiencies in the literature. First, despite studies on how corridors affect predators, there are few studies of related consequences for prey population size and persistence. Second, properly designed studies of negative corridor effects are needed in natural corridors at scales larger than those achievable in experimental systems. Third, studies are needed to test more targeted hypotheses about when corridor-mediated effects on invasive species or disturbance may be negative for species of management concern. Overall, we found no overarching support for concerns that construction and maintenance of habitat corridors may result in unintended negative consequences. Negative edge effects may be mitigated by widening corridors or softening edges between corridors and the matrix. Other negative effects are relatively small and manageable compared with the large positive effects of facilitating dispersal and increasing diversity of native species.

BNC210, a negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor, demonstrates anxiolytic- and antidepressant-like effects in rodents.

This work describes the characterization of BNC210 (6-[(2,3-dihydro-1H-inden-2-yl)amino]-1-ethyl-3-(4-morpholinylcarbonyl)-1,8-naphthyridin-4(1H)-one), a selective, small molecule, negative allosteric modulator (NAM) of α7 nicotinic acetylcholine receptors (α7 nAChR). With the aim to discover a non-sedating, anxiolytic compound, BNC210 was identified during phenotypic screening of a focused medicinal chemistry library using the mouse Light Dark (LD) box to evaluate anxiolytic-like activity and the mouse Open Field (OF) (dark) test to detect sedative and/or motor effects. BNC210 exhibited anxiolytic-like activity with no measurable sedative or motor effects. Electrophysiology showed that BNC210 did not induce α7 nAChR currents by itself but inhibited EC80 agonist-evoked currents in recombinant GH4C1 cell lines stably expressing the rat or human α7 nAChR. BNC210 was not active when tested on cell lines expressing other members of the cys-loop ligand-gated ion channel family. Screening over 400 other targets did not reveal any activity for BNC210 confirming its selectivity for α7 nAChR. Oral administration of BNC210 to male mice and rats in several tests of behavior related to anxiety- and stress- related disorders, demonstrated significant reduction of these behaviors over a broad therapeutic range up to 500 times the minimum effective dose. Further testing for potential adverse effects in suitable rat and mouse tests showed that BNC210 did not produce sedation, memory and motor impairment or physical dependence, symptoms associated with current anxiolytic therapeutics. These data suggest that allosteric inhibition of α7 nAChR function may represent a differentiated approach to treating anxiety- and stress- related disorders with an improved safety profile compared to current treatments.

Predictors of willingness to participate in window-of-opportunity breast trials.

OBJECTIVE: We conducted a pilot survey to evaluate breast cancer patients' willingness to participate in a preoperative chemoprevention (ie, window-of-opportunity) study. Design A 27-question written survey was developed and administered to participants. Setting A breast cancer specialty clinic at the University of Wisconsin Hospital and Clinics. Participants 30 adult patients with newly diagnosed operable breast cancer participated after signing informed consent. METHODS: A convenience sample of 30 participants was recruited from July 2005 through January 2006. Participants were administered the survey in clinic. Univariate ordinal logistic regression models were used to identify predictors of willingness to participate in window-of-opportunity trials. RESULTS: Overall, 26.7% of respondents were willing to participate in a research trial between the time of breast cancer diagnosis and surgery. Univariate ordinal logistic regression models identified that women with a prior history of breast cancer (P=0.060), prior research participation (P=0.006), more education (P=0.034), and self-reported breast cancer knowledge (P=0.043) were more willing to participate. On average, women preferred to have surgery 7 days (range 1-14) after their diagnosis, but the actual average wait time between diagnostic biopsy and surgery was 37.5 days (standard deviation = 23.4 days). CONCLUSION: There is ample time before breast surgery to conduct preoperative window-of-opportunity trials. Interventions aimed at expanding patients' breast cancer knowledge may improve accrual to window-of-opportunity studies.

Use of in situ solid-phase adsorption in microbial natural product fermentation development.

It has been half a century since investigators first began experimenting with adding ion exchange resins during the fermentation of microbial natural products. With the development of nonionic polymeric adsorbents in the 1970s, the application of in situ product adsorption in bioprocessing has grown slowly, but steadily. To date, in situ product adsorption strategies have been used in biotransformations, plant cell culture, the production of biofuels, and selected bulk chemicals, such as butanol and lactic acid, as well as in more traditional natural product fermentation within the pharmaceutical industry. Apart from the operational gains in efficiency from the integration of fermentation and primary recovery, the addition of adsorbents during fermentation has repeatedly demonstrated the capacity to significantly increase titers by sequestering the product and preventing or mitigating degradation, feedback inhibition and/or cytotoxic effects. Adoption of in situ product adsorption has been particularly valuable in the early stages of natural product-based drug discovery programs, where quickly and cost-effectively generating multigram quantities of a lead compound can be challenging when using a wild-type strain and fermentation conditions that have not been optimized. While much of the literature involving in situ adsorption describes its application early in the drug development process, this does not imply that the potential for scale-up is limited. To date, commercial-scale processes utilizing in situ product adsorption have reached batch sizes of at least 30,000 l. Here we present examples where in situ product adsorption has been used to improve product titers or alter the ratios among biosynthetically related natural products, examine some of the relevant variables to consider, and discuss the mechanisms by which in situ adsorption may impact the biosynthesis of microbial natural products.

Novel non-stimulants rescue hyperactive phenotype in an adgrl3.1 mutant zebrafish model of ADHD.

ADHD is a highly prevalent neurodevelopmental disorder. The first-line therapeutic for ADHD, methylphenidate, can cause serious side effects including weight loss, insomnia, and hypertension. Therefore, the development of non-stimulant-based therapeutics has been prioritized. However, many of these also cause other effects, most notably somnolence. Here, we have used a uniquely powerful genetic model and unbiased drug screen to identify novel ADHD non-stimulant therapeutics. We first found that adgrl3.1 null (adgrl3.1-/-) zebrafish larvae showed a robust hyperactive phenotype. Although the hyperactivity was rescued by three ADHD non-stimulant therapeutics, all interfered significantly with sleep. Second, we used wild-type zebrafish larvae to characterize a simple behavioral phenotype generated by atomoxetine and screened the 1200 compound Prestwick Chemical Library® for a matching behavioral profile resulting in 67 hits. These hits were re-assayed in the adgrl3.1-/-. Using the previously identified non-stimulants as a positive control, we identified four compounds that matched the effect of atomoxetine: aceclofenac, amlodipine, doxazosin, and moxonidine. We additionally demonstrated cognitive effects of moxonidine in mice using a T-maze spontaneous alternation task. Moxonidine, has high affinity for imidazoline 1 receptors. We, therefore, assayed a pure imidazoline 1 agonist, LNP599, which generated an effect closely matching other non-stimulant ADHD therapeutics suggesting a role for this receptor system in ADHD. In summary, we introduce a genetic model of ADHD in zebrafish and identify five putative therapeutics. The findings offer a novel tool for understanding the neural circuits of ADHD, suggest a novel mechanism for its etiology, and identify novel therapeutics.

Vertigoheel promotes rodent cognitive performance in multiple memory tests.

Introduction: Cognitive impairment associated with old age or various brain disorders may be very disabling for affected individuals, placing their carers and public health services under considerable stress. The standard-of-care drugs produce only transient improvement of cognitive impairment in older people, so the search for novel, safe and effective therapeutics that would help to reverse or delay cognitive impairment is warranted. Repurposing pharmacological therapies with well-established safety record for additional indications is a promising recent trend in drug development. Vertigoheel (VH-04), a multicomponent drug made of Ambra grisea, Anamirta cocculus L., Conium maculatum, and Petroleum rectificatum, has been successfully used for several decades in the treatment of vertigo. Here, we investigated effects of VH-04 on cognitive performance in standard behavioral tests assessing different types of memory and explored cellular and molecular underpinnings of VH-04's biological activity. Methods: In the majority of behavioral experiments, namely in the spontaneous and rewarded alternation tests, passive avoidance test, contextual/cued fear conditioning, and social transmission of food preference, we examined the ability of single and repeated intraperitoneal administrations of VH-04 to improve cognitive parameters of mice and rats disrupted by the application of the muscarinic antagonist scopolamine. In addition, we also assessed how VH-04 affected novel object recognition and influenced performance of aged animals in Morris water maze. Furthermore, we also studied the effects of VH-04 on primary hippocampal neurons in vitro and mRNA expression of synaptophysin in the hippocampus. Results: Administration of VH-04 positively influenced visual recognition memory in the novel object recognition test and alleviated the impairments in spatial working memory and olfactory memory caused by the muscarinic antagonist scopolamine in the spontaneous alternation and social transmission of food preference tests. In addition, VH-04 improved retention of the spatial orientation memory of old rats in the Morris water maze. In contrast, VH-04 did not have significant effects on scopolamine-induced impairments in tests of fear-aggravated memory or rewarded alternation. Experiments in vitro showed that VH-04 stimulated neurite growth and possibly reversed the age-dependent decrease in hippocampal synaptophysin mRNA expression, which implies that VH-04 may preserve synaptic integrity in the aging brain. Discussion: Our findings allow a cautious conclusion that in addition to its ability to alleviate manifestations of vertigo, VH-04 may be also used as a cognitive enhancer.

Genetic modulation of the HTR2A gene reduces anxiety-related behavior in mice.

The expanding field of precision gene editing using CRISPR/Cas9 has demonstrated its potential as a transformative technology in the treatment of various diseases. However, whether this genome-editing tool could be used to modify neural circuits in the central nervous system (CNS), which are implicated in complex behavioral traits, remains uncertain. In this study, we demonstrate the feasibility of noninvasive, intranasal delivery of adeno-associated virus serotype 9 (AAV9) vectors containing CRISPR/Cas9 cargo within the CNS resulting in modification of the HTR2A receptor gene. In vitro, exposure to primary mouse cortical neurons to AAV9 vectors targeting the HT2RA gene led to a concentration-dependent decrease in spontaneous electrical activity following multielectrode array (MEA) analysis. In vivo, at 5 weeks postintranasal delivery in mice, analysis of brain samples revealed single base pair deletions and nonsense mutations, leading to an 8.46-fold reduction in mRNA expression and a corresponding 68% decrease in the 5HT-2A receptor staining. Our findings also demonstrate a significant decrease in anxiety-like behavior in treated mice. This study constitutes the first successful demonstration of a noninvasive CRISPR/Cas9 delivery platform, capable of bypassing the blood-brain barrier and enabling modulation of neuronal 5HT-2A receptor pathways. The results of this study targeting the HTR2A gene provide a foundation for the development of innovative therapeutic strategies for a broad range of neurological disorders, including anxiety, depression, attentional deficits, and cognitive dysfunction.

Orthopaedic trauma residency programs: Perspectives from different countries across the world.

The ability to manage the myriad of musculoskeletal conditions successfully requires multiple years of training. Access to and completion of orthopaedic surgical training entails an often grueling, highly regulated path to certification to practice. Although the world is more connected than ever, the question is whether the local certification criteria for medical specialists leads to a generic residency program and a similar training in all countries. This report from eight nations on five continents details the distinctive features of that training, including the number of positions available, the examinations required, the gender distribution of residents, and available possibilities once the residence period is complete. This analysis shows a wide variation in the orthopaedic trauma training program worldwide, with emphasis on different skills per country.

Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial.

Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma. Design, Setting, and Participants: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. Interventions: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. Main Outcomes and Measures: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. Results: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03). Conclusions and Relevance: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone. Trial Registration: ClinicalTrials.gov Identifier: NCT00045968.

Corridors promote fire via connectivity and edge effects.

Landscape corridors, strips of habitat that connect otherwise isolated habitat patches, are commonly employed during management of fragmented landscapes. To date, most reported effects of corridors have been positive; however, there are long-standing concerns that corridors may have unintended consequences. Here, we address concerns over whether corridors promote propagation of disturbances such as fire. We collected data during prescribed fires in the world's largest and best replicated corridor experiment (Savannah River Site, South Carolina, USA), six -50-ha landscapes of open (shrubby/herbaceous) habitat within a pine plantation matrix, to test several mechanisms for how corridors might influence fire. Corridors altered patterns of fire temperature through a direct connectivity effect and an indirect edge effect. The connectivity effect was independent of fuel levels and was consistent with a hypothesized wind-driven "bellows effect." Edges, a consequence of corridor implementation, elevated leaf litter (fuel) input from matrix pine trees, which in turn increased fire temperatures. We found no evidence for corridors or edges impacting patterns of fire spread: plots across all landscape positions burned with similar probability. Impacts of edges and connectivity on fire temperature led to changes in vegetation: hotter-burning plots supported higher bunch grass cover during the field season after burning, suggesting implications for woody/herbaceous species coexistence. To our knowledge, this represents the first experimental evidence that corridors can modify landscape-scale patterns of fire intensity. Corridor impacts on fire should be carefully considered during landscape management, both in the context of how corridors connect or break distributions of fuels and the desired role of fire as a disturbance, which may range from a management tool to an agent to be suppressed. In our focal ecosystem, longleaf pine woodland, corridors might provide a previously unrecognized benefit during prescribed burning activities, by promoting fire intensity, which may assist in promoting plant biodiversity.

Underserved and Undermeasured: a Mixed-Method Analysis of Family-Centered Care and Care Coordination for Low-Income Minority Families of Children with Autism Spectrum Disorder.

This study examined how a racially and socioeconomically diverse group of caregivers of children with autism spectrum disorder (ASD) responds to national standard measures of family-centered care (FCC) and care coordination (CC) and what aspects of quality care are missing from these measures. Based on survey and interview data collected from 70 caregivers who have a child with ASD that receive services at a community-based autism clinic located in Atlanta, GA, we compared proportions of answers to FCC and CC questions to national and state representative data using chi-square analyses and contextualized our findings through a thematic analysis of qualitative interviews. Compared to national- and state-level data, the Atlanta autism clinic data had a higher percentage of participants who identified as Black, relied on public health insurance, and lived below 200% of the federal poverty line. The Atlanta autism clinic responses were significantly more positive in four measures of FCC but significantly less effective in two CC measures, including a lower reported percentage who received CC and greater reported percentage who needed extra help. Qualitative data revealed a range of positive meanings and challenges associated with FCC and identified areas of help needed beyond CC, including physical and mental health care and emotional connection, especially for low-income single Black female caregivers. Our mixed-method approach identified strengths in FCC, barriers to CC, and suggestions for developing more pragmatic questions in national surveys that address experiences of quality-of-care among low-income, racial minority families of children with ASD.

Association of glial tau pathology and LATE-NC in the ageing brain.

Ageing-related pathologies of the brain include neurofibrillary tangles, argyrophilic grains, ageing-related tau astrogliopathy (ARTAG), limbic-predominant age-related TDP-43 encephalopathy-neuropathological change (LATE-NC), vascular pathology and corpora amylacea. This study used an unbiased approach to evaluate a broad range of pathologies in an unselected European community-dwelling ageing cohort of 101 individuals (77-90 years). Pathological alterations observed included neurofibrillary tangles and corpora amylacea in all cases, ARTAG (79%), Thal amyloid-ß phase >1 (60%), cerebral amyloid angiopathy (39%), Lewy bodies (22%), LATE-NC (21%), oligodendroglial tau-positive coiled bodies (33%), and argyrophilic grains (15%). We demonstrate association of LATE-NC with the previously unappreciated age-related tau oligodendrogliopathy (ARTOG) and highlight the association of LATE-NC with various ARTAG types pointing toward common pathogenic aspects. Only neurofibrillary tangles and LATE-NC were associated with cognitive decline. This study broadens the spectrum of age-related brain pathologies and highlights a novel ageing-related tau pathology in oligodendroglia. Results from this study suggest overlapping pathogenic mechanisms between LATE-NC and glial tau pathologies in the medial temporal lobe.

Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer.

Clinical trials reporting the robust antitumor activity of immune checkpoint inhibitors (ICIs) in microsatellite instability-high (MSI-H) solid tumors have used tissue-based testing to determine the MSI-H status. This study assessed if MSI-H detected by a plasma-based circulating tumor DNA liquid biopsy test predicts robust response to ICI in patients with pancreatic ductal adenocarcinoma (PDAC). Retrospective analysis of patients with PDAC and MSI-H identified on Guardant360 from October 2018 to April 2021 was performed; clinical outcomes were submitted by treating providers. From 52 patients with PDAC +MSI-H, outcomes were available for 10 (19%) with a median age of 68 years (range: 56-82 years); the majority were male (80%) and had metastatic disease (80%). Nine of 10 patients were treated with ICI. Eight out of nine patients received single-agent pembrolizumab (8/9), while one received ipilimumab plus nivolumab. The overall response rate by Response Evaluation Criteria in Solid Tumors was 77% (7/9). The median progression-free survival and overall survival were not reached in this cohort. The median duration of treatment with ICI was 8 months (range: 1-24), and six out of seven responders continued to show response at the time of data cut-off after a median follow-up of 21 months (range: 11-33). Tissue-based MSI results were concordant with plasma-based G360 results in five of six patients (83%) who had tissue-based test results available, with G360 identifying one more patient with MSI-H than tissue testing. These results suggest that detecting MSI-H by a well-validated liquid biopsy test could predict a robust response to ICI in patients with PDAC. The use of liquid biopsy may expand the identification of PDAC patients with MSI-H tumors and enable treatment with ICI resulting in improved outcomes.