Ibrutinib as part of risk-stratified treatment for post-transplant lymphoproliferative disorder: The phase 2 TIDaL trial.

Post-transplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation, and cytotoxic chemotherapy is associated with treatment-related morbidity and mortality. Current treatment takes a sequential, risk-stratified approach, patients with low-risk disease following initial immunotherapy can avoid escalation to immunochemotherapy. TIDaL is a prospective, single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of PTLD. Eligible patients were adults with newly-diagnosed CD20-positive B-cell PTLD after solid organ transplant and performance status 0 to 2. Initial treatment comprised 49 days of ibrutinib 560mg once daily, with 4 doses of weekly rituximab. Treatment response on interim scan and baseline international prognostic index were used to allocate patients to either a low-risk arm (who continued ibrutinib, alongside 4 further doses of 3-weekly rituximab) or high-risk (escalation to R-CHOP immunochemotherapy, ibrutinib continuing in patients aged <65 years). The primary outcome was complete response on interim scan, achieved by 11/38 patients (29%, 95% confidence interval (CI) 15% - 46%). This did not reach the pre-specified threshold for clinically significant activity. Secondary outcomes included allocation to the low-risk arm (41% of patients), 2-year progression-free survival (58%, 95% CI 44% - 76%), and 2-year overall survival (76%, 95% CI 63% - 91%). Adverse events were mostly haematological, gastrointestinal and infective. Whilst TIDaL does not support adding ibrutinib into first-line treatment of PTLD, increasing the proportion of patients who can be treated without cytotoxic chemotherapy remains an important aim of future research. This trial was registered as ISRCTN32667607.

Fractionated vs single-dose gemtuzumab ozogamicin with determinants of benefit in older patients with AML: the UK NCRI AML18 trial.

Addition of gemtuzumab ozogamicin (GO) to induction chemotherapy improves outcomes in older patients with acute myeloid leukemia (AML), but it is uncertain whether a fractionated schedule provides additional benefit to a single dose. We randomized 852 older adults (median age, 68-years) with AML/high-risk myelodysplasia to GO on day 1 (GO1) or on days 1 and 4 (GO2) of course 1 induction. The median follow-up period was 50.2 months. Although complete remission (CR) rates after course 1 did not significantly differ between arms (GO2, 63%; GO1, 57%; odds ratio [OR], 0.78; P = .08), there were significantly more patients who achieved CR with a measurable residual disease (MRD)<0.1% (50% vs 41%; OR, 0.72; P = .027). This differential MRD reduction with GO2 varied across molecular subtypes, being greatest for IDH mutations. The 5-year overall survival (OS) was 29% for patients in the GO2 arm and 24% for those in the GO1 arm (hazard ratio [HR], 0.89; P = .14). In a sensitivity analysis excluding patients found to have adverse cytogenetics or TP53 mutations, the 5-year OS was 33% for GO2 and 26% for GO1 (HR, 0.83; P = .045). In total, 228 (27%) patients received an allogeneic transplantation in first remission. Posttransplant OS was superior in the GO2 arm (HR, 0.67; P = .033); furthermore, the survival advantage from GO2 in the sensitivity analysis was lost when data of patients were censored at transplantation. In conclusion, GO2 was associated with a greater reduction in MRD and improved survival in older adults with nonadverse risk genetics. This benefit from GO2 was dependent on allogeneic transplantation to translate the better leukemia clearance into improved survival. This trial was registered at www.isrctn.com as #ISRCTN 31682779.

Parent-Reported Use of Pediatric Primary Care Telemedicine: Survey Study.

BACKGROUND: Telemedicine delivered from primary care practices became widely available for children during the COVID-19 pandemic. OBJECTIVE: Focusing on children with a usual source of care, we aimed to examine factors associated with use of primary care telemedicine. METHODS: In February 2022, we surveyed parents of children aged ≤17 years on the AmeriSpeak panel, a probability-based panel of representative US households, about their children's telemedicine use. We first compared sociodemographic factors among respondents who did and did not report a usual source of care for their children. Among those reporting a usual source of care, we used Rao-Scott F tests to examine factors associated with parent-reported use versus nonuse of primary care telemedicine for their children. RESULTS: Of 1206 respondents, 1054 reported a usual source of care for their children. Of these respondents, 301 of 1054 (weighted percentage 28%) reported primary care telemedicine visits for their children. Factors associated with primary care telemedicine use versus nonuse included having a child with a chronic medical condition (87/301, weighted percentage 27% vs 113/753, 15%, respectively; P=.002), metropolitan residence (262/301, weighted percentage 88% vs 598/753, 78%, respectively; P=.004), greater internet connectivity concerns (60/301, weighted percentage 24% vs 116/753, 16%, respectively; P=.05), and greater health literacy (285/301, weighted percentage 96% vs 693/753, 91%, respectively; P=.005). CONCLUSIONS: In a national sample of respondents with a usual source of care for their children, approximately one-quarter reported use of primary care telemedicine for their children as of 2022. Equitable access to primary care telemedicine may be enhanced by promoting access to primary care, sustaining payment for primary care telemedicine, addressing barriers in nonmetropolitan practices, and designing for lower health-literacy populations.

Accessing surgical care for esophageal cancer: patient travel patterns to reach higher volume center.

While better outcomes at high-volume surgical centers have driven the regionalization of complex surgical care, access to high-volume centers often requires travel over longer distances. We sought to evaluate the travel patterns among patients undergoing esophagectomy to assess willingness of patients to travel for surgical care. The California Office of Statewide Health Planning database was used to identify patients who underwent esophagectomy between 2005 and 2016. Total distance traveled, as well as whether a patient bypassed the nearest hospital that performed esophagectomy to get to a higher volume center, was assessed. Overall 3,269 individuals underwent an esophagectomy for cancer in 154 hospitals; only five hospitals were high volume according to Leapfrog standards. Median travel time to a hospital that performed esophagectomy was 26 minutes (IQR: 13.1-50.7). The overwhelming majority of patients (85%) bypassed the nearest providing hospital to seek care at a destination hospital. Among patients who bypassed a closer hospital, only 36% went to a high-volume hospital. Of the 2,248 patients who underwent esophagectomy at a low-volume center, 1,491 patients had bypassed a high-volume hospital. Of the remaining 757 patients who did not bypass a high-volume hospital, half of the individuals would have needed to travel less than an additional hour to reach a high-volume center. Nearly two-thirds of patients undergoing an esophagectomy for cancer received care at a low-volume center; 85% of patients either bypassed a high-volume hospital or would have needed to travel less than an additional hour to reach a high-volume center.

Accessing surgical care for pancreaticoduodenectomy: Patient variation in travel distance and choice to bypass hospitals to reach higher volume centers.

BACKGROUND: While better outcomes at high-volume surgical centers have driven regionalization of complex surgical care, access to high-volume centers often requires travel over longer distances. We sought to evaluate travel patterns of patients undergoing pancreaticoduodenectomy (PD) for pancreatic cancer to assess willingness of patients to travel for surgical care. METHODS: The California Office of Statewide Health Planning database was used to identify patients who underwent PD between 2005 and 2016. Total distance traveled, as well as whether a patient bypassed the nearest hospital that performed PD to get to a higher-volume center was assessed. Multivariate analyses were used to identify factors associated with bypassing a local hospital for a higher-volume center. RESULTS: Among 23 014 patients who underwent PD, individuals traveled a median distance of 18.0 miles to get to a hospital that performed PD. The overwhelming majority (84%) of patients bypassed the nearest providing hospital and traveled a median additional 16.6 miles to their destination hospital. Among patients who bypassed the nearest hospital, 13,269 (68.6%) did so for a high-volume destination hospital. Specifically, average annual PD volume at the nearest "bypassed" vs final destination hospital was 29.6 vs 56 cases, respectively. Outcomes at bypassed vs destination hospitals varied (incidence of complications: 39.2% vs 32.4%; failure-to-rescue: 14.5% vs 9.1%). PD at a high-volume center was associated with lower mortality (OR = 0.46 95% CI, 0.22-0.95). High-volume PD ( > 20 cases) was predictive of hospital bypass (OR = 3.8 95% CI, 3.3-4.4). Among patients who had surgery at a low-volume center, nearly 20% bypassed a high-volume hospital in route. Furthermore, among patients who did not bypass a high-volume hospital, one-third would have needed to travel only an additional 30 miles or less to reach the nearest high-volume hospital. CONCLUSION: Most patients undergoing PD bypassed the nearest providing hospital to seek care at a higher-volume hospital. While these data reflect increased regionalization of complex surgical care, nearly 1 in 5 patients still underwent PD at a low-volume center.

Snail coordinately regulates downstream pathways to control multiple aspects of mammalian neural precursor development.

The Snail transcription factor plays a key role in regulating diverse developmental processes but is not thought to play a role in mammalian neural precursors. Here, we have examined radial glial precursor cells of the embryonic murine cortex and demonstrate that Snail regulates their survival, self-renewal, and differentiation into intermediate progenitors and neurons via two distinct and separable target pathways. First, Snail promotes cell survival by antagonizing a p53-dependent death pathway because coincident p53 knockdown rescues survival deficits caused by Snail knockdown. Second, we show that the cell cycle phosphatase Cdc25b is regulated by Snail in radial precursors and that Cdc25b coexpression is sufficient to rescue the decreased radial precursor proliferation and differentiation observed upon Snail knockdown. Thus, Snail acts via p53 and Cdc25b to coordinately regulate multiple aspects of mammalian embryonic neural precursor biology.

Selective targeting of bioengineered platelets to prostate cancer vasculature: new paradigm for therapeutic modalities.

Androgen deprivation therapy (ADT) provides palliation for most patients with advanced prostate cancer (CaP); however, greater than 80% subsequently fail ADT. ADT has been indicated to induce an acute but transient destabilization of the prostate vasculature in animal models and humans. Human re-hydrated lyophilized platelets (hRL-P) were investigated as a prototype for therapeutic agents designed to target selectively the tumour-associated vasculature in CaP. The ability of hRL-P to bind the perturbed endothelial cells was tested using thrombin- and ADP-activated human umbilical vein endothelial cells (HUVEC), as well as primary xenografts of human prostate tissue undergoing acute vascular involution in response to ADT. hRL-P adhered to activated HUVEC in a dose-responsive manner. Systemically administered hRL-P, and hRL-P loaded with super-paramagnetic iron oxide (SPIO) nanoparticles, selectively targeted the ADT-damaged human microvasculature in primary xenografts of human prostate tissue. This study demonstrated that hRL-P pre-loaded with chemo-therapeutics or nanoparticles could provide a new paradigm for therapeutic modalities to prevent the rebound/increase in prostate vasculature after ADT, inhibiting the transition to castration-recurrent growth.

Genetic variants at chromosomes 2q35, 5p12, 6q25.1, 10q26.13, and 16q12.1 influence the risk of breast cancer in men.

Male breast cancer accounts for approximately 1% of all breast cancer. To date, risk factors for male breast cancer are poorly defined, but certain risk factors and genetic features appear common to both male and female breast cancer. Genome-wide association studies (GWAS) have recently identified common single nucleotide polymorphisms (SNPs) that influence female breast cancer risk; 12 of these have been independently replicated. To examine if these variants contribute to male breast cancer risk, we genotyped 433 male breast cancer cases and 1,569 controls. Five SNPs showed a statistically significant association with male breast cancer: rs13387042 (2q35) (odds ratio (OR)  = 1.30, p = 7.98×10⁻4), rs10941679 (5p12) (OR = 1.26, p = 0.007), rs9383938 (6q25.1) (OR = 1.39, p = 0.004), rs2981579 (FGFR2) (OR = 1.18, p = 0.03), and rs3803662 (TOX3) (OR = 1.48, p = 4.04×10⁻6). Comparing the ORs for male breast cancer with the published ORs for female breast cancer, three SNPs--rs13387042 (2q35), rs3803662 (TOX3), and rs6504950 (COX11)--showed significant differences in ORs (p<0.05) between sexes. Breast cancer is a heterogeneous disease; the relative risks associated with loci identified to date show subtype and, based on these data, gender specificity. Additional studies of well-defined patient subgroups could provide further insight into the biological basis of breast cancer development.

Parent Perceptions of Telemedicine for Acute Pediatric Respiratory Tract Infections: Sequential Mixed Methods Study.

BACKGROUND: Since 2020, parents have had increasing opportunities to use telemedicine for their children, but how parents decide whether to use telemedicine for acute pediatric care relative to alternative sites of care is not clear. One of the most common reasons parents seek acute care for their children is for acute respiratory tract infections (ARTIs). OBJECTIVE: This study aims to examine parental expectations of care via telemedicine for pediatric ARTIs, contrasting expectations of care delivered via primary care telemedicine and direct-to-consumer (DTC) telemedicine. METHODS: We performed a sequential mixed methods analysis to examine how parents assess telemedicine for their children's acute care. We used ARTIs as a case study for examining parent perceptions of telemedicine. First, we analyzed semistructured interviews focused on parent responses about the use of telemedicine. Each factor discussed by parents was coded to reflect whether parents indicated it incentivized or disincentivized their preferences for telemedicine versus in-person care. Results were organized by a 7-dimension framework of parental health care seeking that was generated previously, which included dimensions related to care sites (expected access, affordability, clinical quality, and site quality) and dimensions related to child or family factors (perceived illness severity, perceived child susceptibility, and parent self-efficacy). Second, we analyzed responses to a national survey, which inquired about parental expectations of primary care telemedicine, commercial DTC telemedicine, and 3 in-person sites of care (primary care, urgent care, and emergency department) across 21 factors identified through prior qualitative work. To assess whether parents had different expectations of different telemedicine models, we compared survey responses for primary care telemedicine and commercial DTC telemedicine using weighted logistic regression. RESULTS: Interview participants (n=40) described factors affecting their perceptions of telemedicine as a care modality for pediatric ARTIs. Generally, factors aligned with access and affordability (eg, decreased wait time and lower out-of-pocket cost) were discussed as potential incentives for telemedicine use, while factors aligned with perceived illness severity, child susceptibility, and clinician quality (eg, trustworthiness) were discussed as potential disincentives for telemedicine use. In survey responses (n=1206), primary care and commercial DTC telemedicine were rated similarly on items related to expected accessibility and affordability. In contrast, on items related to expected quality of care, primary care telemedicine was viewed similarly to in-person primary care, while commercial DTC telemedicine was rated lower. For example, 69.7% (weighted; 842/1197) of respondents anticipated their children would be comfortable and cooperative with primary care telemedicine versus 49.7% (weighted; 584/1193) with commercial DTC telemedicine (P<.001). CONCLUSIONS: In a mixed methods analysis focused on telemedicine for ARTIs, parents expressed more concerns about telemedicine quality in commercial DTC models compared with primary care-based telemedicine. These results could help health systems better design telemedicine initiatives to support family-centered care.

Parent Care-Seeking Decisions for Pediatric Acute Respiratory Tract Infections in the United States: A Mental Models Approach.

OBJECTIVE: To understand US parent health care-seeking decisions in the context of multiple in-person and telehealth care options. As the health care landscape evolves, new research is needed to explain how parents now decide when and where to seek acute pediatric health care. METHODS: We applied a mental models approach, focusing on the archetypal example of care-seeking for pediatric acute respiratory tract infections (ARTIs), by first reviewing pediatric ARTI guidelines with 16 health care professionals to inform 40 subsequent semi-structured interviews with parents of young children in 2021. Interviews were qualitatively coded using thematic analysis, with code frequency and co-occurrence informing the final influence model of parent health care-seeking decisions. RESULTS: Parent interviewees identified 33 decisional factors which were synthesized into seven dimensions influencing care-seeking decisions: perceived illness severity, perceived child susceptibility, parental self-efficacy, expected accessibility of care, expected affordability of care, expected quality of clinician, and expected quality of site. The first three dimensions (perceived severity, perceived susceptibility, parental self-efficacy) influenced an initial decision about whether to seek care, while all seven factors influenced a subsequent decision about where to seek care (eg, in-person primary care, primary care-based telehealth, urgent care, direct-to-consumer telehealth). Uncertainty was present within many dimensions (eg, severity, access, quality) indicating potential targets to support parent decision-making processes and optimize care-seeking behaviors. CONCLUSIONS: A mental models approach identified dimensions influencing parent choice to seek care and choice of care site for children with ARTIs, suggesting targets to advance family-centered practice and policy.

Obesity-induced inflammation exacerbates clonal hematopoiesis.

Characterized by the accumulation of somatic mutations in blood cell lineages, clonal hematopoiesis of indeterminate potential (CHIP) is frequent in aging and involves the expansion of mutated hematopoietic stem and progenitor cells (HSC/Ps) that leads to an increased risk of hematologic malignancy. However, the risk factors that contribute to CHIP-associated clonal hematopoiesis (CH) are poorly understood. Obesity induces a proinflammatory state and fatty bone marrow (FBM), which may influence CHIP-associated pathologies. We analyzed exome sequencing and clinical data for 47,466 individuals with validated CHIP in the UK Biobank. CHIP was present in 5.8% of the study population and was associated with a significant increase in the waist-to-hip ratio (WHR). Mouse models of obesity and CHIP driven by heterozygosity of Tet2, Dnmt3a, Asxl1, and Jak2 resulted in exacerbated expansion of mutant HSC/Ps due in part to excessive inflammation. Our results show that obesity is highly associated with CHIP and that a proinflammatory state could potentiate the progression of CHIP to more significant hematologic neoplasia. The calcium channel blockers nifedipine and SKF-96365, either alone or in combination with metformin, MCC950, or anakinra (IL-1 receptor antagonist), suppressed the growth of mutant CHIP cells and partially restored normal hematopoiesis. Targeting CHIP-mutant cells with these drugs could be a potential therapeutic approach to treat CH and its associated abnormalities in individuals with obesity.

Turning the clock forward: Inflammation accelerates the aging of hematopoietic stem cells.

In the current issue of Cell Stem Cell, Bogeska et al. demonstrate that repeated exposures to inflammation cause indelible and specific functional compromise and accelerated aging of long-term hematopoietic stem cells (LT-HSCs). This study proposes the notion that the cumulative inflammatory events over the course of an organism's lifespan may irreversibly damage LT-HSCs.

Targeting SHP2 phosphatase in hematological malignancies.

INTRODUCTION: Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a ubiquitously expressed, non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene. Gain-of-function (GOF) mutations in PTPN11 are associated with the development of various hematological malignancies and Noonan syndrome with multiple lentigines (NS-ML). Preclinical studies performed with allosteric SHP2 inhibitors and combination treatments of SHP2 inhibitors with inhibitors of downstream regulators (such as MEK, ERK, and PD-1/PD-L1) demonstrate improved antitumor benefits. However, the development of novel SHP2 inhibitors is necessary to improve the therapeutic strategies for hematological malignancies and tackle drug resistance and disease relapse. AREAS COVERED: This review examines the structure of SHP2, its function in various signaling cascades, the consequences of constitutive activation of SHP2 and potential therapeutic strategies to treat SHP2-driven hematological malignancies. EXPERT OPINION: While SHP2 inhibitors have exhibited promise in preclinical trials, numerous challenges remain in translation to the clinic, including drug resistance. Although PROTAC-based SHP2 degraders show better efficacy than SHP2 inhibitors, novel strategies need to be designed to improve SHP2-specific therapies in hematologic malignancies. Genome-wide CRISPR screening should also be used to identify molecules that confer resistance to SHP2 inhibitors. Targeting these molecules together with SHP2 can increase the target specificity and reduce drug resistance.

Size-exclusive nanosensor for quantitative analysis of fullerene C60.

This paper presents the first development of a mass-sensitive nanosensor for the isolation and quantitative analyses of engineered fullerene (C60) nanoparticles, while excluding mixtures of structurally similar fullerenes. Amino-modified beta-cyclodextrin (ß-CD-NH2) was synthesized and confirmed by ¹HNMR as the host molecule to isolate the desired fullerene C60. This was subsequently assembled onto the surfaces of gold-coated quartz crystal microbalance (QCM) electrodes using N-dicyclohexylcarbodiimide/N-hydroxysuccinimide (DCC/NHS) surface immobilization chemistry to create a selective molecular configuration described as (Au)-S-(CH2)²-CONH-beta-CD sensor. The mass change on the sensor configuration on the QCM was monitored for selective quantitative analysis of fullerene C60 from a C60/C70 mixture and soil samples. About ~10¹4-10¹6 C60 particles/cm² were successfully quantified by QCM measurements. Continuous spike of 200 µL of 0.14 mg C60 /mL produced changes in frequency (-Δf) that varied exponentially with concentration. FESEM and time-of-flight secondary-ion mass spectrometry confirmed the validity of sensor surface chemistry before and after exposure to fullerene C60. The utility of this sensor for spiked real-world soil samples has been demonstrated. Comparable sensitivity was obtained using both the soil and purified toluene samples. This work demonstrates that the sensor has potential application in complex environmental matrices.

The DEAD-box helicase DDX56 is a conserved stemness regulator in normal and cancer stem cells.

Across the animal kingdom, adult tissue homeostasis is regulated by adult stem cell activity, which is commonly dysregulated in human cancers. However, identifying key regulators of stem cells in the milieu of thousands of genes dysregulated in a given cancer is challenging. Here, using a comparative genomics approach between planarian adult stem cells and patient-derived glioblastoma stem cells (GSCs), we identify and demonstrate the role of DEAD-box helicase DDX56 in regulating aspects of stemness in four stem cell systems: planarians, mouse neural stem cells, human GSCs, and a fly model of glioblastoma. In a human GSC line, DDX56 localizes to the nucleolus, and using planarians, when DDX56 is lost, stem cells dysregulate expression of ribosomal RNAs and lose nucleolar integrity prior to stem cell death. Together, a comparative genomic approach can be used to uncover conserved stemness regulators that are functional in both normal and cancer stem cells.

Early phase clinical studies of AR-42, a histone deacetylase inhibitor, for neurofibromatosis type 2-associated vestibular schwannomas and meningiomas.

OBJECTIVES: Two pilot studies of AR-42, a pan-histone deacetylase inhibitor, in human neurofibromatosis type 2 (NF2), vestibular schwannomas (VS), and meningiomas are presented. Primary endpoints included safety, and intra-tumoral pharmacokinetics (PK) and pharmacodynamics (PD). METHODS: Pilot 1 is a subset analysis of a phase 1 study of AR-42 in solid tumors, which included NF2 or sporadic meningiomas. Tumor volumes and treatment-related adverse events (TRAEs) are reported (NCT01129193).Pilot 2 is a phase 0 surgical study of AR-42 assessing intra-tumoral PK and PD. AR-42 was administered for 3 weeks pre-operatively. Plasma and tumor drug concentrations and p-AKT expression were measured (NCT02282917). RESULTS: Pilot 1: Five patients with NF2 and two with sporadic meningiomas experienced a similar incidence of TRAEs to the overall phase I trial. The six evaluable patients had 15 tumors (8 VS, 7 meningiomas). On AR-42, tumor volume increased in six, remained stable in eight, and decreased in one tumor. The annual percent growth rate decreased in eight, remained stable in three, and increased in four tumors. Pilot 2: Four patients with sporadic VS and one patient with meningioma experienced no grade 3/4 toxicities. Expression of p-AKT decreased in three of four VS. All tumors had higher AR-42 concentrations than plasma. CONCLUSIONS: AR-42 is safe. Tumor volumes showed a mixed response, but most slowed growth. On a 40-mg regimen, drug concentrated in tumors and growth pathways were suppressed in most tumors, suggesting this may be a well-tolerated and effective dose. A phase 2 study of AR-42 for NF2-associated tumors appears warranted. LEVEL OF EVIDENCE: 1b, 4.

Development and evaluation of a nanopore 16S rRNA gene sequencing service for same day targeted treatment of bacterial respiratory infection in the intensive care unit.

OBJECTIVES: Assess the feasibility and impact of nanopore-based 16S rRNA gene sequencing (Np16S) service on antibiotic treatment for acute severe pneumonia on the intensive care unit (ICU). METHODS: Speciation and sequencing accuracy of Np16S on isolates with bioinformatics pipeline optimisation, followed by technical evaluation including quality checks and clinical-reporting criteria analysing stored respiratory samples using single-sample flow cells. Pilot service comparing Np16S results with all routine respiratory tests and impact on same-day antimicrobial prescribing. RESULTS: Np16S correctly identified 140/167 (84%) isolates after 1h sequencing and passed quality control criteria including reproducibility and limit-of-detection. Sequencing of 108 stored respiratory samples showed concordance with routine culture in 80.5% of cases and established technical and clinical reporting criteria. A 10-week same-day pilot Np16S service analysed 45 samples from 37 patients with suspected community (n=15) or hospital acquired (n=30) pneumonia. Np16S showed concordance compared with all routine culture or molecular tests for 27 (82%) of 33 positive samples. It identified the causative pathogen in 32/33 (97%) samples and contributed to antimicrobial treatment changes for 30 patients (67%). CONCLUSIONS: This study demonstrates feasibility of providing a routine same-day nanopore sequencing service that makes a significant contribution to early antibiotic prescribing for bacterial pneumonia in the ICU.

Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK.

Neurofibromatosis Type 2 (NF2) is an autosomal dominant genetic syndrome caused by mutations in the NF2 tumor suppressor gene resulting in multiple schwannomas and meningiomas. There are no FDA approved therapies for these tumors and their relentless progression results in high rates of morbidity and mortality. Through a combination of high throughput screens, preclinical in vivo modeling, and evaluation of the kinome en masse, we identified actionable drug targets and efficacious experimental therapeutics for the treatment of NF2 related schwannomas and meningiomas. These efforts identified brigatinib (ALUNBRIG®), an FDA-approved inhibitor of multiple tyrosine kinases including ALK, to be a potent inhibitor of tumor growth in established NF2 deficient xenograft meningiomas and a genetically engineered murine model of spontaneous NF2 schwannomas. Surprisingly, neither meningioma nor schwannoma cells express ALK. Instead, we demonstrate that brigatinib inhibited multiple tyrosine kinases, including EphA2, Fer and focal adhesion kinase 1 (FAK1). These data demonstrate the power of the de novo unbiased approach for drug discovery and represents a major step forward in the advancement of therapeutics for the treatment of NF2 related malignancies.

Layered carbon nanotube-polyelectrolyte electrodes outperform traditional neural interface materials.

The safety, function, and longevity of implantable neuroprosthetic and cardiostimulating electrodes depend heavily on the electrical properties of the electrode-tissue interface, which in many cases requires substantial improvement. While different variations of carbon nanotube materials have been shown to be suitable for neural excitation, it is critical to evaluate them versus other materials used for bioelectrical interfacing, which have not been done in any study performed so far despite strong interest to this area. In this study, we carried out this evaluation and found that composite multiwalled carbon nanotube-polyelectrolyte (MWNT-PE) multilayer electrodes substantially outperform in one way or the other state-of-the-art neural interface materials available today, namely activated electrochemically deposited iridium oxide (IrOx) and poly(3,4-ethylenedioxythiophene) (PEDOT). Our findings provide the concrete experimental proof to the much discussed possibility that carbon nanotube composites can serve as excellent new material for neural interfacing with a strong possibility to lead to a new generation of implantable electrodes.

Clonal Hematopoiesis of Indeterminate Potential as a Novel Risk Factor for Donor-Derived Leukemia.

Hematopoietic stem cell transplantation (HSCT) is a critical treatment modality for many hematological and non-hematological diseases that is being extended to treat older individuals. However, recent studies show that clonal hematopoiesis of indeterminate potential (CHIP), a common, asymptomatic condition characterized by the expansion of age-acquired somatic mutations in blood cell lineages, may be a risk factor for the development of donor-derived leukemia (DDL), unexplained cytopenias, and chronic graft-versus-host disease. CHIP may contribute to the pathogenesis of these significant transplant complications via various cell-autonomous and non-cell-autonomous mechanisms, and the clinical presentation of DDL may be broader than anticipated. A more comprehensive understanding of the contributions of CHIP to DDL may have important implications for the screening of donors and will improve the safety of HSCT. The objective of this review is to discuss studies linking DDL and CHIP and to explore potential mechanisms by which CHIP may contribute to DDL.