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ImportanceThe optimal radiotherapy technique for unresectable locally advanced non–small cell lung cancer (NSCLC) is controversial, so evaluating long-term prospective outcomes of intensity-modulated radiotherapy (IMRT) is important.ObjectiveTo compare long-term prospective outcomes of patients receiving IMRT and 3-dimensional conformal radiotherapy (3D-CRT) with concurrent carboplatin/paclitaxel for locally advanced NSCLC.Design, Setting, and ParticipantsA secondary analysis of a prospective phase 3 randomized clinical trial NRG Oncology–RTOG 0617 assessed 483 patients receiving chemoradiotherapy (3D-CRT vs IMRT) for locally advanced NSCLC based on stratification.Main Outcomes and MeasuresLong-term outcomes were analyzed, including overall survival (OS), progression-free survival (PFS), time to local failure, development of second cancers, and severe grade 3 or higher adverse events (AEs) per Common Terminology Criteria for Adverse Events, version 3. The percentage of an organ volume (V) receiving a specified amount of radiation in units of Gy is reported as V(radiation dose).ResultsOf 483 patients (median [IQR] age, 64 [57-70] years; 194 [40.2%] female), 228 (47.2%) received IMRT, and 255 (52.8%) received 3D-CRT (median [IQR] follow-up, 5.2 [4.8-6.0] years). IMRT was associated with a 2-fold reduction in grade 3 or higher pneumonitis AEs compared with 3D-CRT (8 [3.5%] vs 21 [8.2%]; P = .03). On univariate analysis, heart V20, V40, and V60 were associated with worse OS (hazard ratios, 1.06 [95% CI, 1.04-1.09]; 1.09 [95% CI, 1.05-1.13]; 1.16 [95% CI, 1.09-1.24], respectively; all P < .001). IMRT significantly reduced heart V40 compared to 3D-CRT (16.5% vs 20.5%; P < .001). Heart V40 (<20%) had better OS than V40 (≥20%) (median [IQR], 2.5 [2.1-3.1] years vs 1.7 [1.5-2.0] years; P < .001). On multivariable analysis, heart V40 (≥20%), was associated with worse OS (hazard ratio, 1.34 [95% CI, 1.06-1.70]; P = .01), whereas lung V5 and age had no association with OS. Patients receiving IMRT and 3D-CRT had similar rates of developing secondary cancers (15 [6.6%] vs 14 [5.5%]) with long-term follow-up.Conclusions and RelevanceThese findings support the standard use of IMRT for locally advanced NSCLC. IMRT should aim to minimize lung V20 and heart V20 to V60, rather than constraining low-dose radiation bath. Lung V5 and age were not associated with survival and should not be considered a contraindication for chemoradiotherapy.Trial RegistrationClinicalTrials.gov Identifier: NCT00533949

Abstract Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objectives By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate genome-wide association study and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n = 1,278) and adults from the UKBiobank (n = 369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP (hedgehog interacting protein), DSP, and NPNT as potential molecular targets based on colocalization of their expression. A higher dysanapsis genetic risk score was associated with obstructive spirometry among 5-year-old children and among adults in the fifth, sixth, and seventh decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development, and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endophenotype link between the genetic variations associated with lung function and COPD.

Abstract To investigate the cellular and molecular mechanisms associated with targeting CD30-expressing Hodgkin lymphoma (HL) and immune checkpoint modulation induced by combination therapies of CTLA4 and PD1, we leveraged Phase 1/2 multicenter open-label trial NCT01896999 that enrolled patients with refractory or relapsed HL (R/R HL). Using peripheral blood, we assessed soluble proteins, cell composition, T-cell clonality, and tumor antigen-specific antibodies in 54 patients enrolled in the phase 1 component of the trial. NCT01896999 reported high (>75%) overall objective response rates with brentuximab vedotin (BV) in combination with ipilimumab (I) and/or nivolumab (N) in patients with R/R HL. We observed a durable increase in soluble PD1 and plasmacytoid dendritic cells as well as decreases in plasma CCL17, ANGPT2, MMP12, IL13, and CXCL13 in N-containing regimens (BV + N and BV + I + N) compared with BV + I (P < 0.05). Nonresponders and patients with short progression-free survival showed elevated CXCL9, CXCL13, CD5, CCL17, adenosine–deaminase, and MUC16 at baseline or after one treatment cycle and a higher prevalence of NY-ESO-1-specific autoantibodies (P < 0.05). The results suggest a circulating tumor-immune-derived signature of BV ± I ± N treatment resistance that may be useful for patient stratification in combination checkpoint therapy. Significance: Identification of multi-omic immune markers from peripheral blood may help elucidate resistance mechanisms to checkpoint inhibitor and antibody–drug conjugate combinations with potential implications for treatment decisions in relapsed HL.

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

ABSTRACT Over 2.5 million prosthetic joint implantation surgeries occur annually in the United States. Periprosthetic joint infections (PJIs), though occurring in only 1–2% of patients receiving replacement joints, are challenging to diagnose and treat and are associated with significant morbidity. The Gram-positive bacterium Enterococcus faecalis , which can be highly antibiotic-resistant and is a robust biofilm producer on indwelling medical devices, accounts for 2–11% of PJIs. E. faecalis PJIs are understudied compared to those caused by other pathogens, such as Staphylococcus aureus . This motivates the need to generate a comprehensive understanding of E. faecalis PJIs to guide future treatments for these infections. To address this, we describe a panel of E. faecalis strains isolated from the surface of prosthetic joints in a cohort of individuals treated at the Mayo Clinic in Rochester, MN. Here, we present the first complete genome assemblage of E. faecalis PJI isolates. Comparative genomics shows differences in genome size, virulence factors, antimicrobial resistance genes, plasmids, and prophages, underscoring the genetic diversity of these strains. These isolates have strain-specific differences in in vitro biofilm biomass, biofilm burden, and biofilm morphology. We measured robust changes in biofilm architecture and aggregation for all isolates when grown in simulated synovial fluid (SSF). Finally, we evaluated the antibiotic efficacy of these isolates and found strain-specific changes across all strains when grown in SSF. Results of this study highlight the existence of genetic and phenotypic heterogeneity among E. faecalis PJI isolates which will provide valuable insight and resources for future E. faecalis PJI research. IMPORTANCE Periprosthetic joint infections (PJIs) affect ~1–2% of those who undergo joint replacement surgery. Enterococcus faecalis is a Gram-positive opportunistic pathogen that causes ~10% of PJIs in the United States each year, but our understanding of how and why E. faecalis causes PJIs is limited. E. faecalis infections are typically biofilm-associated and can be difficult to clear with antibiotic therapy. Here, we provide complete genomes for four E. faecalis PJI isolates from the Mayo Clinic. These isolates have strain-specific differences in biofilm formation, aggregation, and antibiotic susceptibility in simulated synovial fluid. These results provide important insight into the genomic and phenotypic features of E. faecalis isolates from PJI.

The use of single-stranded oligodeoxynucleotide (ssODN) along with CRISPR–Cas9-mediated double-strand breaks (DSB) is one of the most commonly deployed methods for introducing genetic alterations, but this approach has notable limitations. Recognizing this, we have developed a protocol article that provides a step-by-step process of donorguide, a covalent fusion of trans-activating CRISPR RNA (tracrRNA) and ssODN. Donorguide has the potential to enhance the introduction of specific genetic alterations (insertion, deletion, and substitution) at a DSB, improving homology-directed repair methods from zebrafish in vivo to human cells in vitro . We also explored and discuss the impact of increasing the length of donorguide homology arms in zebrafish.

Abstract Background Polygenic risk scores (PRS) aggregate the contribution of many risk variants to provide a personalized genetic susceptibility profile. Since sample sizes of glioma genome-wide association studies (GWAS) remain modest, there is a need to efficiently capture genetic risk using available data. Methods We applied a method based on continuous shrinkage priors (PRS-CS) to model the joint effects of over 1 million common variants on disease risk and compared this to an approach (PRS-CT) that only selects a limited set of independent variants that reach genome-wide significance (P < 5 × 10–8). PRS models were trained using GWAS stratified by histological (10 346 cases and 14 687 controls) and molecular subtype (2632 cases and 2445 controls), and validated in 2 independent cohorts. Results PRS-CS was generally more predictive than PRS-CT with a median increase in explained variance (R2) of 24% (interquartile range = 11–30%) across glioma subtypes. Improvements were pronounced for glioblastoma (GBM), with PRS-CS yielding larger odds ratios (OR) per standard deviation (SD) (OR = 1.93, P = 2.0 × 10–54 vs. OR = 1.83, P = 9.4 × 10–50) and higher explained variance (R2 = 2.82% vs. R2 = 2.56%). Individuals in the 80th percentile of the PRS-CS distribution had a significantly higher risk of GBM (0.107%) at age 60 compared to those with average PRS (0.046%, P = 2.4 × 10–12). Lifetime absolute risk reached 1.18% for glioma and 0.76% for IDH wildtype tumors for individuals in the 95th PRS percentile. PRS-CS augmented the classification of IDH mutation status in cases when added to demographic factors (AUC = 0.839 vs. AUC = 0.895, PΔAUC = 6.8 × 10–9). Conclusions Genome-wide PRS has the potential to enhance the detection of high-risk individuals and help distinguish between prognostic glioma subtypes.

Abstract Objective To characterize the long‐term (56‐week) benefits of continuous onabotulinumtoxinA treatment response in individuals with chronic migraine (CM) who achieved reduction to <15 headache days/month with treatment. Background There are limited data exploring reductions in monthly headache days to levels consistent with episodic migraine among those experiencing CM. Understanding the impact of sustained preventive treatment response in CM can provide important information about the impact of successful therapy. Methods The two Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy trials of onabotulinumtoxinA in adults included a 24‐week, randomized, double‐blind, placebo‐controlled phase and a 32‐week open‐label phase. Data were pooled to determine proportions of individuals with <15 headache days/month while on treatment during several time periods in the double‐blind phase (Weeks 21–24; any 12 consecutive weeks; Weeks 13–24) and the entire study (Weeks 53–56; any 12 consecutive weeks; any 4‐week period). We assessed the long‐term impact on mean monthly headache days and changes from baseline on the six‐item Headache Impact Test (HIT‐6) and Migraine‐Specific Quality of Life questionnaire version 2.1 (MSQv2.1). Results We analyzed 1384 participants with chronic migraine (double‐blind: onabotulinumtoxinA, n = 688; placebo, n = 696; open‐label: n = 688 [onabotulinumtoxinA]). The discontinuation rates prior to the completion of the full 56‐week treatment period for onabotulinumtoxinA and placebo were 25.4% ( n = 175) and 29.3% ( n = 204), respectively. During Weeks 13–24 of the double‐blind phase, significantly more onabotulinumtoxinA‐treated (386/688 [56.1%]) than placebo‐treated (342/696 [49.1%]) individuals had <15 headache days/month ( p = 0.010), with fewer monthly headache days for onabotulinumtoxinA versus placebo responders. The proportions of participants achieving <15 monthly headache days with onabotulinumtoxinA were 60.9% (419/688) at Weeks 25–56, 81.1% (558/688) at Weeks 53–56, and 79.4% (546/688) during any consecutive 12‐week period. Mean changes from baseline on the HIT‐6 and MSQv2.1 questionnaire surpassed within‐group minimal important difference thresholds in all periods. At Week 24, onabotulinumtoxinA‐treated participants who achieved <15 monthly headache days during Weeks 21–24 had a greater mean HIT‐6 score reduction (−6.5 vs. −1.4) and greater mean MSQv2.1 Role‐Function Restrictive score improvements (21.3 vs. 6.4) than those who did not achieve <15 monthly headache days during the same period. Conclusions Participants who achieved <15 monthly headache days with onabotulinumtoxinA treatment achieved meaningful benefits in headache‐related disability and migraine‐specific quality of life compared with those who remained at or above the 15–monthly headache days threshold. Sustained benefits observed over 56 weeks support long‐term onabotulinumtoxinA use for the prevention of CM.

Background: In this systematic review, we assessed the therapeutic efficacy and safety of Clostridium histolyticum collagenase (CCH) and tissue subcision (TS) for treating cellulite, which ranges from subtle to pronounced lesions. Methods: A systematic review was performed following PRISMA guidelines for CCH and TS treatment to the thigh and gluteal regions. A proportion meta-analysis was then conducted using Stata statistical software. Results: A total of 14 studies were incorporated into the final analysis. Nine focused on TS and five on CCH injection, collectively reporting outcomes for 1254 patients. Of these, 465 received CCH injection and 789 underwent subcision. For bruising, rates were 89% [95% confidence interval (CI), 71%–96%] with CCH injection and 99% (95% CI, 85%–99%) for subcision; pain requiring analgesic was reported at 74% (95% CI, 55%–87%) for CCH and 60% (95% CI, 43%–76%) for subcision; both showed induration at 7% (95% CI, 5%–11% for CCH, 95% CI, 2%–25% for subcision), whereas skin discoloration was higher post-CCH injection at 16% (95% CI, 10%–26%) compared with 7% (95% CI, 5%–10%) postsubcision. Conclusions: Both CCH and TS seem effective treatments for cellulite. However, upon evaluating the adverse outcomes between the two modalities, subcision demonstrated a higher incidence of bruising, albeit similar rates of induration compared with CCH injection. Conversely, the CCH injection group manifested a higher propensity for pain requiring analgesia and notably exhibited increased instances of skin discoloration compared with their subcision patient group. Further standardized research is crucial for more informed cellulite treatment decisions and for comparing efficacy, safety, and cost-effectiveness between TS and CCH.