Bacteroidota inhibit microglia clearance of amyloid-beta and promote plaque deposition in Alzheimer's disease mouse models.

The gut microbiota and microglia play critical roles in Alzheimer's disease (AD), and elevated Bacteroides is correlated with cerebrospinal fluid amyloid-ß (Aß) and tau levels in AD. We hypothesize that Bacteroides contributes to AD by modulating microglia. Here we show that administering Bacteroides fragilis to APP/PS1-21 mice increases Aß plaques in females, modulates cortical amyloid processing gene expression, and down regulates phagocytosis and protein degradation microglial gene expression. We further show that administering Bacteroides fragilis to aged wild-type male and female mice suppresses microglial uptake of Aß1-42 injected into the hippocampus. Depleting murine Bacteroidota with metronidazole decreases amyloid load in aged 5xFAD mice, and activates microglial pathways related to phagocytosis, cytokine signaling, and lysosomal degradation. Taken together, our study demonstrates that members of the Bacteroidota phylum contribute to AD pathogenesis by suppressing microglia phagocytic function, which leads to impaired Aß clearance and accumulation of amyloid plaques.

Novel Surgical Approaches in Childhood Epilepsy: Laser, Brain Stimulation, and Focused Ultrasound.

Pediatric epilepsy has a worldwide prevalence of approximately 1% (Berg et al., Handb Clin Neurol 111:391-398, 2013) and is associated with not only lower quality of life but also long-term deficits in executive function, significant psychosocial stressors, poor cognitive outcomes, and developmental delays (Schraegle and Titus, Epilepsy Behav 62:20-26, 2016; Puka and Smith, Epilepsia 56:873-881, 2015). With approximately one-third of patients resistant to medical control, surgical intervention can offer a cure or palliation to decrease the disease burden and improve neurological development. Despite its potential, epilepsy surgery is drastically underutilized. Even today only 1% of the millions of epilepsy patients are referred annually for neurosurgical evaluation, and the average delay between diagnosis of Drug Resistant Epilepsy (DRE) and surgical intervention is approximately 20 years in adults and 5 years in children (Solli et al., Epilepsia 61:1352-1364, 2020). It is still estimated that only one-third of surgical candidates undergo operative intervention (Pestana Knight et al., Epilepsia 56:375, 2015). In contrast to the stable to declining rates of adult epilepsy surgery (Englot et al., Neurology 78:1200-1206, 2012; Neligan et al., Epilepsia 54:e62-e65, 2013), rates of pediatric surgery are rising (Pestana Knight et al., Epilepsia 56:375, 2015). Innovations in surgical approaches to epilepsy not only minimize potential complications but also expand the definition of a surgical candidate. In this chapter, three alternatives to classical resection are presented. First, laser ablation provides a minimally invasive approach to focal lesions. Next, both central and peripheral nervous system stimulation can interrupt seizure networks without creating permanent lesions. Lastly, focused ultrasound is discussed as a potential new avenue not only for ablation but also modulation of small, deep foci within seizure networks. A better understanding of the potential surgical options can guide patients and providers to explore all treatment avenues.

Common variation in a long non-coding RNA gene modulates variation of circulating TGF-ß2 levels in metastatic colorectal cancer patients (Alliance).

BACKGROUND: Herein, we report results from a genome-wide study conducted to identify protein quantitative trait loci (pQTL) for circulating angiogenic and inflammatory protein markers in patients with metastatic colorectal cancer (mCRC). The study was conducted using genotype, protein marker, and baseline clinical and demographic data from CALGB/SWOG 80405 (Alliance), a randomized phase III study designed to assess outcomes of adding VEGF or EGFR inhibitors to systemic chemotherapy in mCRC patients. Germline DNA derived from blood was genotyped on whole-genome array platforms. The abundance of protein markers was quantified using a multiplex enzyme-linked immunosorbent assay from plasma derived from peripheral venous blood collected at baseline. A robust rank-based method was used to assess the statistical significance of each variant and protein pair against a strict genome-wide level. A given pQTL was tested for validation in two external datasets of prostate (CALGB 90401) and pancreatic cancer (CALGB 80303) patients. Bioinformatics analyses were conducted to further establish biological bases for these findings. RESULTS: The final analysis was carried out based on data from 540,021 common typed genetic variants and 23 protein markers from 869 genetically estimated European patients with mCRC. Correcting for multiple testing, the analysis discovered a novel cis-pQTL in LINC02869, a long non-coding RNA gene, for circulating TGF-ß2 levels (rs11118119; AAF = 0.11; P-value < 1.4e-14). This finding was validated in a cohort of 538 prostate cancer patients from CALGB 90401 (AAF = 0.10, P-value < 3.3e-25). The analysis also validated a cis-pQTL we had previously reported for VEGF-A in advanced pancreatic cancer, and additionally identified trans-pQTLs for VEGF-R3, and cis-pQTLs for CD73. CONCLUSIONS: This study has provided evidence of a novel cis germline genetic variant that regulates circulating TGF-ß2 levels in plasma of patients with advanced mCRC and prostate cancer. Moreover, the validation of previously identified pQTLs for VEGF-A, CD73, and VEGF-R3, potentiates the validity of these associations.

Human regulatory memory B cells defined by expression of TIM-1 and TIGIT are dysfunctional in multiple sclerosis.

Background: Regulatory B cells (Bregs) play a pivotal role in suppressing immune responses, yet there is still a lack of cell surface markers that can rigorously identify them. In mouse models for multiple sclerosis (MS), TIM-1 or TIGIT expression on B cells is required for maintaining self-tolerance and regulating autoimmunity to the central nervous system. Here we investigated the activities of human memory B cells that differentially express TIM-1 and TIGIT to determine their potential regulatory function in healthy donors and patients with relapsing-remitting (RR) MS. Methods: FACS-sorted TIM-1+/-TIGIT+/- memory B (memB) cells co-cultured with allogenic CD4+ T cells were analyzed for proliferation and induction of inflammatory markers using flow cytometry and cytokine quantification, to determine Th1/Th17 cell differentiation. Transcriptional differences were assessed by SMARTSeq2 RNA sequencing analysis. Results: TIM-1-TIGIT- double negative (DN) memB cells strongly induce T cell proliferation and pro-inflammatory cytokine expression. The TIM-1+ memB cells enabled low levels of CD4+ T cell activation and gave rise to T cells that co-express IL-10 with IFNγ and IL-17A or FoxP3. T cells cultured with the TIM-1+TIGIT+ double positive (DP) memB cells exhibited reduced proliferation and IFNγ, IL-17A, TNFα, and GM-CSF expression, and exhibited strong regulation in Breg suppression assays. The functional activity suggests the DP memB cells are a bonafide Breg population. However, MS DP memB cells were less inhibitory than HC DP memB cells. A retrospective longitudinal study of anti-CD20 treated patients found that post-treatment DP memB cell frequency and absolute number were associated with response to therapy. Transcriptomic analyses indicated that the dysfunctional MS-derived DP memB/Breg population exhibited increased expression of genes associated with T cell activation and survival (CD80, ZNF10, PIK3CA), and had distinct gene expression compared to the TIGIT+ or TIM-1+ memB cells. Conclusion: These findings demonstrate that TIM-1/TIGIT expressing memory B cell subsets have distinct functionalities. Co-expression of TIM-1 and TIGIT defines a regulatory memory B cell subset that is functionally impaired in MS.

The prognostic value of the Merkel cell polyomavirus serum antibody test: A dual institutional observational study.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive cancer with often poor outcomes. Limited biomarkers exist for predicting clinical outcomes. The Merkel cell polyomavirus (MCPyV) serum antibody test (AMERK) has shown potential for indicating better recurrence-free survival in a single-institution study. The study aimed to evaluate the link between initial AMERK serostatus and survival. Secondary objectives included examining the relationship between initial AMERK titer levels and tumor burden. METHODS: A retrospective cohort study across two institutions analyzed patients tested with AMERK within 90 days of MCC diagnosis. Regression models assessed the association of survival outcomes with serostatus, considering various factors. The relationship between AMERK titer and tumor burden indicators was evaluated using ANOVA. Significance testing was exploratory, without a fixed significance level. RESULTS: Of 261 MCC patients tested, 49.4% were initially seropositive (titer ≥75). Multivariable analysis showed that seropositivity improved recurrence, event-free, overall, and MCC-specific survival rates. Strong associations were found between initial AMERK titer and clinical, tumor, and nodal stages, tumor size, and disease extent. Notably, improved survival with seropositivity was observed only in patients with localized disease at initial presentation. CONCLUSION: Circulating antibodies to MCPyV oncoproteins, as indicated by the AMERK test, are linked with better survival in MCC patients with localized disease at presentation. This could enhance patient risk profiling and treatment personalization. The study's retrospective nature and exploratory analysis are key limitations. PLAIN LANGUAGE SUMMARY: Merkel cell carcinoma (MCC) is a potentially aggressive skin cancer, and tools to predict patient outcomes are limited. A blood test called anti-Merkel cell panel (AMERK), which checks for specific antibodies related to this cancer, might give us some clues. In this study, we looked at 261 MCC patients who took the AMERK test within 90 days of diagnosis. We found that patients with an initial positive AMERK result tended to have better outcomes, especially if their cancer was in the early stages. However, it is important to note that this study has limitations, including using retrospective data and exploratory analyses.

Increasing Incidence of Streptococcus anginosus Group Intracranial Infections Associated With Sinusitis, Otitis Media, and Mastoiditis in Children.

BACKGROUND: The Streptococcus anginosus group (SAG) pathogens have the potential to cause head and neck space infections, including intracranial abscesses. Several centers noted an increase in intracranial abscesses in children during the SARS-CoV-2 pandemic, prompting a Centers for Disease Control and Prevention health alert in May 2022. We examined the epidemiology of pediatric intracranial abscesses at a tertiary care center with a focus on SAG pre- and post-pandemic. METHODS: Cases of intracranial abscesses of any microbiologic etiology admitted from January 2011 to December 2022 were identified using International Classification of Diseases 10 codes. Subjects were cross-referenced with culture results from the microbiology laboratory at Texas Children's Hospital. Cases included were those associated with either otitis media, mastoiditis or sinusitis and medical records were reviewed. RESULTS: A total of 157 cases were identified and 59.9% (n = 94) were caused by SAG. The incidence of all sinogenic/otogenic intracranial infections (P = 0.002), and SAG-specific infections (P = 0.004), increased from 2011 to 2022. SAG infection was more often associated with multiple surgeries, and these subjects were more likely to require craniotomy or craniectomy. Among sinogenic abscesses, S. intermedius was the most common pathogen, while among otogenic cases, S. pyogenes predominated. From March 2020 to Dec 2022, 9/49 cases tested positive for SARS-CoV-2 (18.4%); characteristics of infection were not significantly different among cases with and without SARS-CoV-2. CONCLUSIONS: Over the last decade, intracranial complications of sinusitis/otitis have been increasing, specifically those caused by SAG; this trend, however, predated the SARS-CoV-2 pandemic. SAG was associated with a greater need for surgical intervention, specifically neurosurgery. Further work is necessary to determine the cause for these rising infections.

Glial Activity Load on PET Reveals Persistent "Smoldering" Inflammation in MS Despite Disease-Modifying Treatment: 18 F-PBR06 Study.

PURPOSE OF THE REPORT: 18 F-PBR06-PET targeting 18-kDa translocator protein can detect abnormal microglial activation (MA) in multiple sclerosis (MS). The objectives of this study are to develop individualized mapping of MA using 18 F-PBR06, to determine the effect of disease-modifying treatment (DMT) efficacy on reducing MA, and to determine its clinical, radiological, and serological correlates in MS patients. PATIENTS AND METHODS: Thirty 18 F-PBR06-PET scans were performed in 22 MS patients (mean age, 46 ± 13 years; 16 females) and 8 healthy controls (HCs). Logarithmically transformed "glial activity load on PET" scores (calculated as the sum of voxel-by-voxel z -scores ≥4), "lnGALP," were compared between MS and HC and between MS subjects on high-efficacy DMTs (H-DMT, n = 13) and those on no or lower-efficacy treatment, and correlated with clinical measures, serum biomarkers, and cortical thickness. RESULTS: Cortical gray matter (CoGM) and white matter (WM) lnGALP scores were higher in MS versus HC (+33% and +48%, P < 0.001). In H-DMT group, CoGM and WM lnGALP scores were significantly lower than lower-efficacy treatment ( P < 0.01) but remained abnormally higher than in HC group ( P = 0.006). Within H-DMT patients, CoGM lnGALP scores correlated positively with physical disability, fatigue and serum glial fibrillary acid protein levels ( r = 0.65-0.79, all P 's < 0.05), and inversely with cortical thickness ( r = -0.66, P < 0.05). CONCLUSIONS: High-efficacy DMTs decrease, but do not normalize, CoGM and WM MA in MS patients. Such "residual" MA in CoGM is associated with clinical disability, serum biomarkers, and cortical degeneration. Individualized mapping of translocator protein PET using 18 F-PBR06 is clinically feasible and can potentially serve as an imaging biomarker for evaluating "smoldering" inflammation in MS patients.

Oncolytic herpes simplex virus expressing IL-2 controls glioblastoma growth and improves survival.

BACKGROUND: Glioblastoma (GBM), a highly immunosuppressive and often fatal primary brain tumor, lacks effective treatment options. GBMs contain a subpopulation of GBM stem-like cells (GSCs) that play a central role in tumor initiation, progression, and treatment resistance. Oncolytic viruses, especially oncolytic herpes simplex virus (oHSV), replicate selectively in cancer cells and trigger antitumor immunity-a phenomenon termed the "in situ vaccine" effect. Although talimogene laherparepvec (T-VEC), an oHSV armed with granulocyte macrophage-colony stimulating factor (GM-CSF), is Food and Drug Administration (FDA)-approved for melanoma, its use in patients with GBM has not been reported. Interleukin 2 (IL-2) is another established immunotherapy that stimulates T cell growth and orchestrates antitumor responses. IL-2 is FDA-approved for melanoma and renal cell carcinoma but has not been widely evaluated in GBM, and IL-2 treatment is limited by its short half-life, minimal tumor accumulation, and significant systemic toxicity. We hypothesize that local intratumoral expression of IL-2 by an oHSV would avoid the systemic IL-2-related therapeutic drawbacks while simultaneously producing beneficial antitumor immunity. METHODS: We developed G47Δ-mIL2 (an oHSV expressing IL-2) using the flip-flop HSV BAC system to deliver IL-2 locally within the tumor microenvironment (TME). We then tested its efficacy in orthotopic mouse GBM models (005 GSC, CT-2A, and GL261) and evaluated immune profiles in the treated tumors and spleens by flow cytometry and immunohistochemistry. RESULTS: G47Δ-mIL2 significantly prolonged median survival without any observable systemic IL-2-related toxicity in the 005 and CT-2A models but not in the GL261 model due to the non-permissive nature of GL261 cells to HSV infection. The therapeutic activity of G47Δ-mIL2 in the 005 GBM model was associated with increased intratumoral infiltration of CD8+ T cells, critically dependent on the release of IL-2 within the TME, and CD4+ T cells as their depletion completely abrogated therapeutic efficacy. The use of anti-PD-1 immune checkpoint blockade did not improve the therapeutic outcome of G47Δ-mIL2. CONCLUSIONS: Our findings illustrate that G47Δ-mIL2 is efficacious, stimulates antitumor immunity against orthotopic GBM, and may also target GSC. OHSV expressing IL-2 may represent an agent that merits further exploration in patients with GBM.

Safety and immunogenicity of the Euvichol-S oral cholera vaccine for prevention of Vibrio cholerae O1 infection in Nepal: an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial.

BACKGROUND: In October, 2017, WHO launched a strategy to eliminate cholera by 2030. A primary challenge in meeting this goal is the limited global supply capacity of oral cholera vaccine and the worsening of cholera outbreaks since 2021. To help address the current shortage of oral cholera vaccine, a WHO prequalified oral cholera vaccine, Euvichol-Plus was reformulated by reducing the number of components and inactivation methods. We aimed to evaluate the immunogenicity and safety of Euvichol-S (EuBiologics, Seoul, South Korea) compared with an active control vaccine, Shanchol (Sanofi Healthcare India, Telangana, India) in participants of various ages in Nepal. METHODS: We did an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial at four hospitals in Nepal. Eligible participants were healthy individuals aged 1-40 years without a history of cholera vaccination. Individuals with a history of hypersensitivity reactions to other preventive vaccines, severe chronic disease, previous cholera vaccination, receipt of blood or blood-derived products in the past 3 months or other vaccine within 4 weeks before enrolment, and pregnant or lactating women were excluded. Participants were randomly assigned (1:1:1:1) by block randomisation (block sizes of two, four, six, or eight) to one of four groups (groups A-D); groups C and D were stratified by age (1-5, 6-17, and 18-40 years). Participants in groups A-C were assigned to receive two 1·5 mL doses of Euvichol-S (three different lots) and participants in group D were assigned to receive the active control vaccine, Shanchol. All participants and site staff (with the exception of those who prepared and administered the study vaccines) were masked to group assignment. The primary immunogenicity endpoint was non-inferiority of immunogenicity of Euvichol-S (group C) versus Shanchol (group D) at 2 weeks after the second vaccine dose, measured by the seroconversion rate, defined as the proportion of participants who had achieved seroconversion (defined as ≥four-fold increase in V cholerae O1 Inaba and Ogawa titres compared with baseline). The primary immunogenicity endpoint was assessed in the per-protocol analysis set, which included all participants who received all their planned vaccine administrations, had no important protocol deviations, and who provided blood samples for all immunogenicity assessments. The primary safety endpoint was the number of solicited adverse events, unsolicited adverse events, and serious adverse events after each vaccine dose in all ages and each age stratum, assessed in all participants who received at least one dose of the Euvichol-S or Shanchol. Non-inferiority of Euvichol-S compared with Shanchol was shown if the lower limit of the 95% CI for the difference between the seroconversion rates in Euvichol-S group C versus Shanchol group D was above the predefined non-inferiority margin of -10%. The trial was registered at ClinicalTrials.gov, NCT04760236. FINDINGS: Between Oct 6, 2021, and Jan 19, 2022, 2529 healthy participants (1261 [49·9%] males; 1268 [50·1%] females), were randomly assigned to group A (n=330; Euvichol-S lot number ES-2002), group B (n=331; Euvichol-S ES-2003), group C (n=934; Euvichol-S ES-2004]), or group D (n=934; Shanchol). Non-inferiority of Euvichol-S versus Shanchol in seroconversion rate for both serotypes at 2 weeks after the second dose was confirmed in all ages (difference in seroconversion rate for V cholerae O1 Inaba -0·00 [95% CI -1·86 to 1·86]; for V cholerae O1 Ogawa -1·62 [-4·80 to 1·56]). Treatment-emergent adverse events were reported in 244 (9·7%) of 2529 participants in the safety analysis set, with a total of 403 events; 247 events were reported among 151 (9·5%) of 1595 Euvichol-S recipients and 156 events among 93 (10·0%) of 934 Shanchol recipients. Pyrexia was the most common adverse event in both groups (57 events among 56 [3·5%] of 1595 Euvichol-S recipients and 37 events among 35 [3·7%] of 934 Shanchol recipients). No serious adverse events were deemed to be vaccine-related. INTERPRETATION: A two-dose regimen of Euvichol-S vaccine was non-inferior to the active control vaccine, Shanchol, in terms of seroconversion rates 2 weeks after the second dose. The simplified formulation and production requirements of the Euvichol-S vaccine have the potential to increase the supply of oral cholera vaccine and reduce the gap between the current oral cholera vaccine supply and demand. FUNDING: The Bill & Melinda Gates Foundation. TRANSLATION: For the Nepali translation of the abstract see Supplementary Materials section.

Recommendations for pharmacogenetic testing in clinical practice guidelines in the US.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Pharmacogenetic testing can identify patients who may benefit from personalized drug treatment. However, clinical uptake of pharmacogenetic testing has been limited. Clinical practice guidelines recommend biomarker tests that the guideline authors deem to have demonstrated clinical utility, meaning that testing improves treatment outcomes. The objective of this narrative review is to describe the current status of pharmacogenetic testing recommendations within clinical practice guidelines in the US. SUMMARY: Guidelines were reviewed for pharmacogenetic testing recommendations for 21 gene-drug pairs that have well-established drug response associations and all of which are categorized as clinically actionable by the Clinical Pharmacogenetics Implementation Consortium. The degree of consistency within and between organizations in pharmacogenetic testing recommendations was assessed. Relatively few clinical practice guidelines that provide a pharmacogenetic testing recommendation were identified. Testing recommendations for HLA-B*57:01 before initiation of abacavir and G6PD before initiation of rasburicase, both of which are included in drug labeling, were mostly consistent across guidelines. Gene-drug pairs with at least one clinical practice guideline recommending testing or stating that testing could be considered included CYP2C19-clopidogrel, CYP2D6-codeine, CYP2D6-tramadol, CYP2B6-efavirenz, TPMT-thiopurines, and NUDT15-thiopurines. Testing recommendations for the same gene-drug pair were often inconsistent between organizations and sometimes inconsistent between different guidelines from the same organization. CONCLUSION: A standardized approach to evaluating the evidence of clinical utility for pharmacogenetic testing may increase the inclusion and consistency of pharmacogenetic testing recommendations in clinical practice guidelines, which could benefit patients and society by increasing clinical use of pharmacogenetic testing.

LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology progression.

BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). These mutations elevate the LRRK2 kinase activity, making LRRK2 kinase inhibitors an attractive therapeutic. LRRK2 kinase activity has been consistently linked to specific cell signaling pathways, mostly related to organelle trafficking and homeostasis, but its relationship to PD pathogenesis has been more difficult to define. LRRK2-PD patients consistently present with loss of dopaminergic neurons in the substantia nigra but show variable development of Lewy body or tau tangle pathology. Animal models carrying LRRK2 mutations do not develop robust PD-related phenotypes spontaneously, hampering the assessment of the efficacy of LRRK2 inhibitors against disease processes. We hypothesized that mutations in LRRK2 may not be directly related to a single disease pathway, but instead may elevate the susceptibility to multiple disease processes, depending on the disease trigger. To test this hypothesis, we have previously evaluated progression of α-synuclein and tau pathologies following injection of proteopathic seeds. We demonstrated that transgenic mice overexpressing mutant LRRK2 show alterations in the brain-wide progression of pathology, especially at older ages. METHODS: Here, we assess tau pathology progression in relation to long-term LRRK2 kinase inhibition. Wild-type or LRRK2G2019S knock-in mice were injected with tau fibrils and treated with control diet or diet containing LRRK2 kinase inhibitor MLi-2 targeting the IC50 or IC90 of LRRK2 for 3-6 months. Mice were evaluated for tau pathology by brain-wide quantitative pathology in 844 brain regions and subsequent linear diffusion modeling of progression. RESULTS: Consistent with our previous work, we found systemic alterations in the progression of tau pathology in LRRK2G2019S mice, which were most pronounced at 6 months. Importantly, LRRK2 kinase inhibition reversed these effects in LRRK2G2019S mice, but had minimal effect in wild-type mice, suggesting that LRRK2 kinase inhibition is likely to reverse specific disease processes in G2019S mutation carriers. Additional work may be necessary to determine the potential effect in non-carriers. CONCLUSIONS: This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a rational workflow for systematic evaluation of brain-wide phenotypes in therapeutic development.

Pharmacogenetic and clinical risk factors for bevacizumab-related gastrointestinal hemorrhage in prostate cancer patients treated on CALGB 90401 (Alliance).

The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage. In 1008 patients, grade 2 or higher gastrointestinal hemorrhage occurred in 9.5% and 3.8% of bevacizumab (n = 503) and placebo (n = 505) treated patients, respectively. Bevacizumab (P < 0.001) and age (P = 0.002) were associated with gastrointestinal hemorrhage. In 616 genetically estimated Europeans (n = 314 bevacizumab and n = 302 placebo treated patients), grade 2 or higher gastrointestinal hemorrhage occurred in 9.6% and 2.0% of patients, respectively. One SNP (rs1478947; HR 6.26; 95% CI 3.19-12.28; P = 9.40 × 10-8) surpassed Bonferroni-corrected significance. Grade 2 or higher gastrointestinal hemorrhage rate was 33.3% and 6.2% in bevacizumab-treated patients with the AA/AG and GG genotypes, versus 2.9% and 1.9% in the placebo arm, respectively. Prospective validation of these findings and functional analyses are needed to better understand the genetic contribution to treatment-related gastrointestinal hemorrhage.

Efficacy and safety of tildrakizumab for the treatment of moderate-to-severe plaque psoriasis of the scalp: A multicenter, randomized, double-blind, placebo-controlled, Phase 3b study.

BACKGROUND: Scalp psoriasis is common and difficult to treat. OBJECTIVE: To evaluate efficacy and safety of tildrakizumab for the treatment of scalp psoriasis. METHODS: In this Phase 3b, randomized, double-blind, placebo (PBO)-controlled study (NCT03897088), patients with moderate-to-severe plaque psoriasis affecting the scalp (Investigator Global Assessment modified [IGA mod] 2011 [scalp] ≥3, Psoriasis Scalp Severity Index [PSSI] ≥12, ≥30% scalp surface area affected) received tildrakizumab 100 mg or PBO at W0 and W4. The primary endpoint was IGA mod 2011 (scalp) score of "clear" or "almost clear" with ≥2-point reduction from baseline at W16 (IGA mod 2011 [scalp] response). Key secondary endpoints were PSSI 90 response at W12 and W16 and IGA mod 2011 (scalp) response at W12. Safety was assessed from adverse events. RESULTS: Of patients treated with tildrakizumab (n = 89) vs PBO (n = 82), 49.4% vs 7.3% achieved IGA mod 2011 (scalp) response at W16 (primary endpoint) and 46.1% vs 4.9% at W12; 60.7% vs 4.9% achieved PSSI 90 response at W16 and 48.3% vs 2.4% at W12 (all P < .00001). No serious treatment-related adverse events occurred. LIMITATIONS: Only short-term data are presented. CONCLUSION: Tildrakizumab was efficacious for the treatment of scalp psoriasis with no new safety signals.

Impact of trainees involvement on surgical outcomes of abdominal and laparoscopic myomectomy.

BACKGROUND: To determine the association of trainees involvement with surgical outcomes of abdominal and laparoscopic myomectomy including operative time, rate of transfusion, and complications. METHODS: A retrospective cohort study of 1145 patients who underwent an abdominal or laparoscopic myomectomy from 2008-2012 using the American College of Surgeons National Surgical Quality Improvement Program database (Canadian Task Force Classification II-2). RESULTS: Overall, 64% of myomectomies involved trainees. Trainees involvement was associated with a longer operative time for abdominal myomectomies (mean difference 20.17 minutes, 95% Confidence Interval (CI) [11.37,28.97], p < 0.01) overall and when stratified by fibroid burden. For laparoscopic myomectomy, there was no difference in operative time between trainees vs no trainees involvement (mean difference 4.64 minutes, 95% CI [-18.07,27.35], p = 0.67). There was a higher rate of transfusion with trainees involvement for abdominal myomectomies (10% vs 2%, p < 0.01; Odds Ratio (OR) 5.62, 95% CI [2.53,12.51], p < 0.01). Trainees involvement was not found to be associated with rate of transfusion for laparoscopic myomectomy (4% vs 5%, p = 0.86; OR 0.82, 95% CI [0.16,4.14], p = 0.81). For abdominal myomectomy, there was a higher rate of overall complications (15% vs 5%, p < 0.01; OR 2.96, 95% CI [1.77,4.93], p < 0.01) and minor complications (14% vs 4%, p < 0.01; OR 3.71, 95% CI [2.09,6.57], p < 0.01) with no difference in major complications (3% vs 2%, p = 0.23). For laparoscopic myomectomy, there was no difference in overall (6% vs 10% p = 0.41; OR 0.59, 95% CI [0.18,2.01], p = 0.40), major (2% vs 0%, p = 0.38), or minor (5% vs 10%, p = 0.32; OR 0.52, 95% CI [0.15,1.79], p = 0.30) complications. CONCLUSION: Trainees involvement was associated with increased operative time, rate of transfusion, and complications for abdominal myomectomy, however, did not impact surgical outcomes for laparoscopic myomectomy.

TITLE: Trainees Involvement in MyomectomyThe goal of our study was to determine the association of trainees involvement with surgical outcomes of fibroid excision surgery or myomectomy. We conducted a study of abdominal and laparoscopic myomectomies using an international surgical database. We found that trainees involvement in myomectomy was associated with increased operative time, rate of transfusion, and complications for abdominal myomectomy. However, trainees involvement did not impact surgical outcomes for laparoscopic myomectomy.

Adaptive, behavioral, and emotional outcomes following postoperative pediatric cerebellar mutism syndrome in survivors treated for medulloblastoma.

OBJECTIVE: Patients who experience postoperative pediatric cerebellar mutism syndrome (CMS) during treatment for medulloblastoma have long-term deficits in neurocognitive functioning; however, the consequences on functional or adaptive outcomes are unknown. The purpose of the present study was to compare adaptive, behavioral, and emotional functioning between survivors with and those without a history of CMS. METHODS: The authors examined outcomes in 45 survivors (15 with CMS and 30 without CMS). Comprehensive neuropsychological evaluations, which included parent-report measures of adaptive, behavioral, and emotional functioning, were completed at a median of 2.90 years following craniospinal irradiation. RESULTS: Adaptive functioning was significantly worse in the CMS group for practical and general adaptive skills compared with the group without CMS. Rates of impairment in practical, conceptual, and general adaptive skills in the CMS group exceeded expected rates in the general population. Despite having lower overall intellectual functioning, working memory, and processing speed, IQ and related cognitive processes were uncorrelated with adaptive outcomes in the CMS group. No significant group differences or increased rates of impairment were observed for behavioral and emotional outcomes. CONCLUSIONS: Survivors with CMS, compared with those without CMS, are rated as having significant deficits in overall or general adaptive functioning, with specific weakness in practical skills several years posttreatment. Findings from this study demonstrate the high risk for ongoing functional deficits despite acute recovery from symptoms of CMS, highlighting the need for intervention to mitigate such risk.

Targeting the Cell Cycle, RRM2 and NF-κB for the Treatment of Breast Cancers.

A hallmark of cancer is the dysregulation of the cell cycle. The CDK4/6 inhibitor palbociclib is approved for treating advanced estrogen-receptor-positive breast cancer, but its success is limited by the development of acquired resistance owing to long-term therapy despite promising clinical outcomes. This situation necessitates the development of potential combination strategies. Here, we report that didox, an inhibitor of ribonucleotide reductase in combination with palbociclib, can overcome palbociclib resistance in ER-positive and ER-negative breast cancers. This study shows didox downregulates an element of the cell cycle checkpoint, cyclin D1, accompanied by a reduction in NF-κB activity in vitro and tumor growth inhibition of palbociclib-resistant ER positive breast cancer tumor growth in vivo. Furthermore, didox induces cell cycle arrest at G1 as well as reduces ROS generated by on-target effects of palbociclib on the cell cycle. Our current study also reports that the CCND1 and RRM2 upregulation associated with palbociclib-resistant breast cancers decreases upon ribonucleotide reductase inhibition. Our data present a novel and promising biomarker-driven combination therapeutic approach for the treatment of ER-positive and ER-negative breast cancers that involves the inhibition of the CDK4/6-cyclinD1/pRb cell cycle axis that merits further clinical investigation in human models.

Overcoming Barriers to Discovery and Implementation of Equitable Pharmacogenomic Testing in Oncology.

Pharmacogenomics (PGx), the study of inherited genomic variation and drug response or safety, is a vital tool in precision medicine. In oncology, testing to identify PGx variants offers patients the opportunity for customized treatments that can minimize adverse effects and maximize the therapeutic benefits of drugs used for cancer treatment and supportive care. Because individuals of shared ancestry share specific genetic variants, PGx factors may contribute to outcome disparities across racial and ethnic categories when genetic ancestry is not taken into account or mischaracterized in PGx research, discovery, and application. Here, we examine how the current scientific understanding of the role of PGx in differential oncology safety and outcomes may be biased toward a greater understanding and more complete clinical implementation of PGx for individuals of European descent compared with other genetic ancestry groups. We discuss the implications of this bias for PGx discovery, access to care, drug labeling, and patient and provider understanding and use of PGx approaches. Testing for somatic genetic variants is now the standard of care in treatment of many solid tumors, but the integration of PGx into oncology care is still lacking despite demonstrated actionable findings from PGx testing, reduction in avoidable toxicity and death, and return on investment from testing. As the field of oncology is poised to expand and integrate germline genetic variant testing, it is vital that PGx discovery and application are equitable for all populations. Recommendations are introduced to address barriers to facilitate effective and equitable PGx application in cancer care.

Laparoscopic Trocars: Marketed Versus True Dimensions-A Descriptive Study.

STUDY OBJECTIVE: To establish true dimensions of single-use laparoscopic trocars compared with marketed dimensions, calculate corresponding incision sizes, examine what trocar size categories are based on, and outline accessibility of information regarding true dimensions. DESIGN: Descriptive study. SETTING: Laparoscopic disposable trocars available in North America and Europe are marketed in several distinct categories. In practice, trocars in the same-size category exhibit different functionality (ability to introduce instruments/needles and retrieve specimens) and warrant different incision lengths. PATIENTS: Not applicable. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: True dimensions for 125 trocars (bladeless, optical, and balloon) were obtained from 9 vendors covering 8 marketed size categories (3-, 3.5-, 5-, 8-, 10-, 11-, 12-, and 15-mm trocars). On average, true inner cannula diameter was 0.92 mm wider (SD, 0.41 mm; range, 0-2.4 mm) than the marketed size category, with the widest range in the 5 mm category. For 5-mm trocars, mean true inner diameter was 6.1 mm (SD, 0.45; range, 5.5-7.4) and true outer diameter 8.3 mm (SD, 0.71; range, 8.0-10.7). For 12-mm trocars, mean true inner diameter was 13.0 mm (SD, 0.21; range, 12-13.3) and outer diameter 15.3 mm (SD, 0.48; range, 14.4-16.8). Five-mm trocars necessitate a mean incision size of 13.0 mm (SD, 1.1; range, 12.1-16.8) and 12-mm trocars a mean incision of 24.0 mm (SD, 0.75; range, 22.6-26.4). No vendors stated actual diameters on company website or catalog. In one instance the Instructions For Use document contained the true inner diameter. CONCLUSION: Trocar size categories give a false sense of standardization when in actuality there are considerable within-category differences in both inner and outer diameters, corresponding to differences in functionality and required incision sizes. There is no universally applied definition for trocar size categories. Accessibility of information on true dimensions is limited.

Gamma-delta T cells suppress microbial metabolites that activate striatal neurons and induce repetitive/compulsive behavior in mice.

Intestinal γδ T cells play an important role in shaping the gut microbiota, which is critical not only for maintaining intestinal homeostasis but also for controlling brain function and behavior. Here, we found that mice deficient for γδ T cells (γδ-/-) developed an abnormal pattern of repetitive/compulsive (R/C) behavior, which was dependent on the gut microbiota. Colonization of WT mice with γδ-/- microbiota induced R/C behavior whereas colonization of γδ-/- mice with WT microbiota abolished the R/C behavior. Moreover, γδ-/- mice had elevated levels of the microbial metabolite 3-phenylpropanoic acid in their cecum, which is a precursor to hippurate (HIP), a metabolite we found to be elevated in the CSF. HIP reaches the striatum and activates dopamine type 1 (D1R)-expressing neurons, leading to R/C behavior. Altogether, these data suggest that intestinal γδ T cells shape the gut microbiota and their metabolites and prevent dysfunctions of the striatum associated with behavior modulation.