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Abstract Background Treatment for first recurrent Clostridioides difficile infection (frCDI) or multiply recurrent CDI (mrCDI) is complex and may include antibiotics, monoclonal antibodies, or fecal transplantation. Improved understanding of rCDI pathogenesis can help guide treatment. We report microbiome findings of patients (pts) with frCDI and mrCDI from a post hoc analysis of two phase 3 trials with fecal microbiota spores, live-brpk (FMS; formerly SER-109), an FDA-approved, microbiota-based therapeutic comprised of Firmicutes spores. Methods Stool samples were collected from pts with mrCDI in ECOSPOR III (n=158) and with frCDI or mrCDI in ECOSPOR IV (n=218) at baseline (pre-dose) and Week 1 post treatment. Shannon diversity was calculated from species profiles from analysis of whole metagenomic sequencing data using MetaPhlAn2. Primary (1°BA) and secondary bile acid (2°BA) concentrations were measured via targeted liquid chromatography–mass spectrometry panel. Subgroup differences were analyzed with linear mixed models. Results At baseline, Shannon diversity was not significantly different between mrCDI and frCDI groups (P>0.05). At Week 1, Shannon diversity (Fig 1) was greater vs baseline (P< 0.001); gains were not significantly different between subgroups (P>0.05). For pts receiving FMS vs placebo in ECOSPOR III, greater reductions in 1°BA and increases in 2°BA from baseline–Week 1 were observed, similar to FMS-treated pts in ECOSPOR IV. At Week 1, 2°BA concentrations were greater vs baseline (P< 0.001); similar gains were seen between subgroups (P>0.05) (Fig 2). Consistent with these microbiome findings, in an integrated analysis, rCDI rates with FMS at Week 8 were low in both subgroups (frCDI, 6.5% [5/77] vs mrCDI, 10.3% [28/271]). Conclusion After antibiotics, pts with frCDI or mrCDI had low Shannon diversity and 2°BA concentrations that were no different between subgroups, highlighting a need for microbiome restoration. Both subgroups showed rapid, significant improvement in Shannon diversity and 2°BA concentrations and reductions in 1°BA after FMS, with comparable clinical outcomes. These data suggest that regardless of number of prior CDI episodes, FMS therapy following antibiotics may be an optimal treatment. Disclosures Colleen R. Kelly, MD, Openbiome: Advisor/Consultant|Sebela Pharmaceuticald: Advisor/Consultant Tim Straub, MS, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Kevin Litcofsky, PhD, Seres Therapeutics: inventor on patents assigned to Seres Therapeutics|Seres Therapeutics: Employment|Seres Therapeutics: Stocks/Bonds Jennifer R. Wortman, MS, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Barbara McGovern, MD, Seres Therapeutics: Stocks/Bonds Brooke Hasson, PhD, Sage Therapeutics: Stocks/Bonds|Seres Therapeutics: Stocks/Bonds Dina Hot, PhD, Aimmune Therapeutics: Employee Darrell Pardi, MD, Abbvie: Advisor/Consultant|AMT: Grant/Research Support|BI: Advisor/Consultant|Immunic: Advisor/Consultant|Rise: Advisor/Consultant|Seres Therapeutics: Advisor/Consultant|Seres Therapeutics: Grant/Research Support|Summit: Advisor/Consultant|Takeda: Grant/Research Support|Vedanta: Advisor/Consultant|Vedanta: Grant/Research Support Christopher Ford, PhD, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Matthew Henn, PhD, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds

Study Design. Prospective multicenter study data were used for model derivation and externally validated using retrospective cohort data. Objective. Derive and validate a prognostic model of benefit from bracing for adolescent idiopathic scoliosis (AIS). Summary of Background Data. The Bracing in Adolescent Idiopathic Scoliosis Trial (BrAIST) demonstrated the superiority of bracing over observation to prevent curve progression to the surgical threshold; 42% of untreated subjects had a good outcome, and 28% progressed to the surgical threshold despite bracing, likely due to poor adherence. To avoid over-treatment and to promote patient goal setting and adherence, bracing decisions (who and how much) should be based on physician and patient discussions informed by individual-level data from high-quality predictive models. Materials and Methods. Logistic regression was used to predict curve progression to <45° at skeletal maturity (good prognosis) in 269 BrAIST subjects who were observed or braced. Predictors included age, sex, body mass index, Risser stage, Cobb angle, curve pattern, and treatment characteristics (hours of brace wear and in-brace correction). Internal and external validity were evaluated using jackknifed samples of the BrAIST data set and an independent cohort (n=299) through estimates of discrimination and calibration. Results. The final model included age, sex, body mass index, Risser stage, Cobb angle, and hours of brace wear per day. The model demonstrated strong discrimination ( c -statistics 0.83–0.87) and calibration in all data sets. Classifying patients as low risk (high probability of a good prognosis) at the probability cut point of 70% resulted in a specificity of 92% and a positive predictive value of 89%. Conclusion. This externally validated model can be used by clinicians and families to make informed, individualized decisions about when and how much to brace to avoid progression to surgery. If widely adopted, this model could decrease overbracing of AIS, improve adherence, and, most importantly, decrease the likelihood of spinal fusion in this population.

Background Inconsistent nomenclature and anatomical descriptions of regional anesthetic techniques hinder scientific communication and engender confusion; this in turn has implications for research, education and clinical implementation of regional anesthesia. Having produced standardized nomenclature for abdominal wall, paraspinal and chest wall regional anesthetic techniques, we aimed to similarly do so for upper and lower limb peripheral nerve blocks. Methods We performed a three-round Delphi international consensus study to generate standardized names and anatomical descriptions of upper and lower limb regional anesthetic techniques. A long list of names and anatomical description of blocks of upper and lower extremities was produced by the members of the steering committee. Subsequently, two rounds of anonymized voting and commenting were followed by a third virtual round table to secure consensus for items that remained outstanding after the first and second rounds. As with previous methodology, strong consensus was defined as ≥75% agreement and weak consensus as 50%–74% agreement. Results A total of 94, 91 and 65 collaborators participated in the first, second and third rounds, respectively. We achieved strong consensus for 38 names and 33 anatomical descriptions, and weak consensus for five anatomical descriptions. We agreed on a template for naming peripheral nerve blocks based on the name of the nerve and the anatomical location of the blockade and identified several areas for future research. Conclusions We achieved consensus on nomenclature and anatomical descriptions of regional anesthetic techniques for upper and lower limb nerve blocks, and recommend using this framework in clinical and academic practice. This should improve research, teaching and learning of regional anesthesia to eventually improve patient care.

Background: Severe adolescent idiopathic scoliosis (AIS) can be treated with instrumented fusion, but the number of anchors needed for optimal correction is controversial. Methods: We conducted a multicenter, randomized study that included patients undergoing spinal fusion for single thoracic curves between 45° and 65°, the most common form of operatively treated AIS. Of the 211 patients randomized, 108 were assigned to a high-density screw pattern and 103, to a low-density screw pattern. Surgeons were instructed to use ≥1.8 implants per spinal level fused for patients in the high-implant-density group or ≤1.4 implants per spinal level fused for patients in the low-implant-density group. The primary outcome measure was the percent correction of the coronal curve at the 2-year follow-up. The power analysis for this trial required 174 patients to show equivalence, defined as a 95% confidence interval (CI) within a ±10% correction margin with a probability of 90%. Results: In the intention-to-treat analysis, the mean percent correction of the coronal curve was equivalent between the high-density and low-density groups at the 2-year follow-up (67.6% versus 65.7%; difference, −1.9% [95% CI: −6.1%, 2.2%]). In the per-protocol cohorts, the mean percent correction of the coronal curve was also equivalent between the 2 groups at the 2-year follow-up (65.0% versus 66.1%; difference, 1.1% [95% CI: −3.0%, 5.2%]). A total of 6 patients in the low-density group and 5 patients in the high-density group required reoperation (p = 1.0). Conclusions: In the setting of spinal fusion for primary thoracic AIS curves between 45° and 65°, the percent coronal curve correction obtained with use of a low-implant-density construct and that obtained with use of a high-implant-density construct were equivalent. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Abstract BACKGROUND Preclinical studies have demonstrated that IDH1-mutant (IDHmt) gliomas harbor a BRCAness phenotype with a defect in homologous recombination that confers PARP inhibitor sensitivity. METHODS The phase II component of ABTC 1801 examined the efficacy of the combination of pamiparib (BeiGene BGB-290) with low dose metronomic temozolomide in recurrent IDHmt grade 2 and 3 gliomas. In this two-stage design, Arm A enrolled patients who had failed two lines and Arm B a single line of alkylator therapy. Pamiparib and temozolomide doses based on phase I results was 60 mg BID and 20 mg daily. Primary endpoint was objective response rate (ORR). RESULTS 39 patients (Arm A 15, Arm B 24) enrolled in the phase II. Median age was 45 (range: 25-69), 56% male, and median KPS 90. 72% of tumors were MGMT methylated. There were no confirmed responses in Arm A and one in Arm B; neither arm met the threshold for additional accrual. One-third of subjects discontinued treatment for reasons other than progressive disease. Estimated median PFS was 5.8 months in Arm A and 11.3 months in Arm B. Seven subjects (Arm A 3, Arm B 4) developed DLT during treatment. Grade 3+ toxicity was principally hematologic; 9 patients had grade 3 anemia, 7 grade 3 and 3 grade 4 neutropenia, and 3 grade 3 thrombocytopenia. In enhancing and non-enhancing tumors from 8 surgical arm patients, median unbound drug tumor/plasma ratios were 0.98 and 0.92, respectively; and median unbound pamiparib tumor concentrations were 209 and 188 nmol/L (or nmol/kg), respectively, which were &gt;20-fold the in vitro IC50 for PARP inhibition. CONCLUSIONS While pamiparib appeared to achieve sufficient pharmacologically active concentrations in both enhancing and non-enhancing tumors, combination with temozolomide did not produce a meaningful ORR in IDHmt recurrent gliomas. Cumulative hematologic toxicity was substantial.

As the population in many industrial countries is aging, the risk, incidence, and prevalence of CKD increases. In the kidney, advancing age results in a progressive decrease in nephron number and an increase in glomerulosclerosis. In this review, we focus on the effect of aging on glomerular podocytes, the post-mitotic epithelial cells critical for the normal integrity and function of the glomerular filtration barrier. The podocytes undergo senescence and transition to a senescence-associated secretory phenotype typified by the production and secretion of inflammatory cytokines that can influence neighboring glomerular cells by paracrine signaling. In addition to senescence, the aging podocyte phenotype is characterized by ultrastructural and functional changes; hypertrophy; cellular, oxidative, and endoplasmic reticulum stress; reduced autophagy; and increased expression of aging genes. This results in a reduced podocyte health span and a shortened life span. Importantly, these changes in the pathways/processes characteristic of healthy podocyte aging are also often similar to pathways in the disease-induced injured podocyte. Finally, the better understanding of podocyte aging and senescence opens therapeutic options to slow the rate of podocyte aging and promote kidney health.

Background: Little is known about the specific risk of knee injuries due to trampoline accidents in adults compared with children. Purpose: To investigate the differences in trampoline-related knee injuries between children and adults and identify risk factors and protective strategies to reduce injury incidence. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Data on 229 consecutive patients treated for trampoline-related knee injuries in a single institution were prospectively collected, analyzed, and included. Risk factors, injury patterns, and clinical treatments were compared between skeletally immature and skeletally mature patients. Logistic regression was used to determine the odds ratios for specific risk factors for trampoline-related injuries—including body mass index (BMI), trauma mechanism, patient age, and accident location. Results: A total of 229 patients met the inclusion criteria; 118 (52%) patients (women, 54.2%; mean age, 8.5 ± 4.1 years) were skeletally immature at the time of injury, and 111 (48%) patients (women, 72%; mean age, 31.9 ± 13.1 years) had closed physes on initial presentation and were classified as skeletally mature. A total of 63 patients (28%) required surgical treatment for their knee injury. Overall, 50 anterior cruciate ligament (ACL) tears, 46 fractures, 39 meniscal tears, 31 ligamentous tears other than ACL, 22 patellar dislocations, and 38 soft tissue injuries, such as lacerations, were recorded. Skeletally mature patients had 7.8 times higher odds (95% CI, 1.6-46.8; P < .05) and 19.1 increased odds (95% CI, 5.5-74.9; P < .05) of an ACL tear or another ligamentous tear, respectively, compared with skeletally immature patients. Patients who described instability and giving way of the knee as relevant trauma mechanisms had odds of 3.11 (95% CI, 0.9-14.8; P < .05) of an ACL tear compared with other trauma mechanisms. Meniscal tears were observed more frequently in the skeletally mature cohort ( P < .05). An elevated BMI was associated with a significantly higher relative risk of an ACL tear, a ligamentous tear other than the ACL, and an injury requiring surgery. A third of surgically treated patients were subject to a delayed diagnosis. Conclusion: Adults had a significantly increased risk of ligamentous and meniscal tears and required operative intervention more often than skeletally immature individuals. Elevated BMI, age, and instability events in terms of trauma mechanism conveyed an increased risk of structural damage to the knee.

Abstract Objectives To determine the impact of residual platelets on dilute Russell’s viper venom time (DRVVT) assay in frozen-thawed plasma submitted for lupus anticoagulant (LAC) testing. Methods We measured platelet counts in frozen-thawed samples submitted for LAC testing and evaluated the association between platelet count and the DRVVT screening time and ratios. We also spiked platelets into a LAC-positive sample to observe the effect on the DRVVT. Results Progressive increase in platelet count resulted in a statistically significant shortening of the DRVVT assay results on plasma after 1 freeze-thaw cycle. A similar effect was noted on the LAC-positive sample. Conclusions Residual platelets in plasma samples result in shortening of DRVVT assay after 1 freeze-thaw cycle. This may result in a false-negative LAC test result.