6-Thioguanine nucleotide levels are associated with infliximab but not adalimumab levels in inflammatory bowel disease patients on combination therapy.

BACKGROUND: Thiopurine co-therapy with anti-tumour necrosis factor-alpha (anti-TNFα) agents is associated with higher anti-TNFα drug levels and reduced immunogenicity in inflammatory bowel disease (IBD). AIMS: We aimed to evaluate the association between 6-thioguanine nucleotide (6-TGN) and anti-TNFα levels and the optimal 6-TGN threshold level associated with higher anti-TNFα levels in combination therapy. METHODS: We performed a retrospective cross-sectional multicentre study of patients with IBD on combination anti-TNFα and thiopurine maintenance therapy between January 2015 and August 2021. Primary outcomes were infliximab and adalimumab levels. Secondary outcomes were antibodies to infliximab (ATI) or adalimumab (ATA). Univariable and multivariable linear regression were performed to identify variables associated with anti-TNFα levels. Receiver operator characteristic curves were used to define the optimal 6-TGN cut-off levels associated with therapeutic anti-TNFα levels. RESULTS: The study included 743 paired 6-TGN and anti-TNFα levels (640 infliximab and 103 adalimumab). 6-TGN levels were associated with infliximab levels, but not adalimumab levels, on univariable and multivariable regression. The optimal 6-TGN cut-off associated with therapeutic infliximab levels (≥5 mcg/mL) was 261 pmol/8 × 108 red blood cell (RBC) (area under the curve (AUC) = 0.57) for standard infliximab dosing and 227.5 pmol/8 × 108 RBC (AUC = 0.58) for escalated dosing. For therapeutic adalimumab levels (≥7.5 mcg/mL), the 6-TGN cut-off was 218.5 pmol/8 × 108 RBC (AUC = 0.59) for standard adalimumab dosing and 237.5 pmol/8 × 108 RBC (AUC = 0.63) for escalated dosing. CONCLUSION: 6-TGN levels were weakly associated with infliximab but not adalimumab levels in combination therapy. 6-TGN levels in the lower end of the therapeutic range (230-260 pmol/8 × 108 RBC) may be adequate to maintain higher infliximab levels, particularly with escalated infliximab dosing.

The Oral Cholate Challenge Test Quantifies Risk for Liver-Related Clinical Outcomes in Primary Sclerosing Cholangitis.

Background and Aims: We quantified hepatic functional impairment using quantitative function tests and linked severity of functional impairment to liver-related complications and outcome in primary sclerosing cholangitis. Methods: Forty-seven patients had baseline testing, and 40 were retested after 1 year. For each test, cholates labeled with cold, nonradioactive isotopes were administered orally (DuO, SHUNT tests) and intravenously (SHUNT test), and blood was analyzed at 20 and 60 minutes (DuO), or 0, 5, 20, 45, 60, and 90 minutes (SHUNT). Disease severity index (DSI), hepatic reserve (HR%), and portal-systemic shunting (SHUNT%) were calculated. Results: Three subgroups with low, moderate, and high disease severity were defined from the age-adjusted results for DSI, HR%, and SHUNT%. Standard laboratory tests, clinical scores, cytokine levels, and clinical outcome correlated with these subgroups. In univariate analysis of baseline tests, SHUNT% was a strong predictor of clinical outcome (n = 13 of 47; areas under the receiver operating characteristic curve, 0.84DuO, 0.90SHUNT). A model combining SHUNT%, DSI (or HR%), platelet count, and changes from baseline was most predictive of outcome (n = 10 of 40; areas under the receiver operating characteristic curve, 0.95DuO, 0.96SHUNT). Conclusion: DSI, HR%, and SHUNT% identified subgroups of primary sclerosing cholangitis based on the age-related severity of hepatic impairment that predicted risk for liver-related clinical outcome. Further study is warranted to confirm and validate these intriguing findings both in studies of natural progression of primary sclerosing cholangitis and in clinical trials. DuO enhances the utility of quantitative liver function testing.

Using mHealth Technology to Evaluate Daily Symptom Burden among Adult Survivors of Childhood Cancer: A Feasibility Study.

BACKGROUND: Cancer therapies predispose survivors to a high symptom burden. This study utilized mobile health (mHealth) technology to assess the feasibility of collecting daily symptoms from adult survivors of childhood cancer to evaluate symptom fluctuation and associations with future health-related quality-of-life (HRQOL). METHODS: This prospective study used an mHealth platform to distribute a 20-item cancer-related symptom survey (5 consecutive days each month) and an HRQOL survey (the day after the symptom survey) over 3 consecutive months to participants from the Childhood Cancer Survivor Study. These surveys comprised a PROMIS-29 Profile and Neuro-QOL assessed HRQOL. Daily symptom burden was calculated by summing the severity (mild, moderate, or severe) of 20 symptoms. Univariate linear mixed-effects models were used to analyze total, person-to-person, day-to-day, and month-to-month variability for the burden of 20 individual symptoms. Multivariable linear regression was used to analyze the association between daily symptom burden in the first month and HRQOL in the third month, adjusted for covariates. RESULTS: Out of the 60 survivors invited, 41 participated in this study (68% enrollment rate); 83% reported their symptoms ≥3 times and 95% reported HRQOL in each study week across 3 months. Variability of daily symptom burden differed from person-to-person (74%), day-to-day (18%), and month-to-month (8%). Higher first-month symptom burden was associated with poorer HRQOL related to anxiety (regression coefficient: 6.56; 95% CI: 4.10-9.02), depression (6.32; 95% CI: 3.18-9.47), fatigue (7.93; 95% CI: 5.11-10.80), sleep (6.07; 95% CI: 3.43-8.70), pain (5.16; 95% CI: 2.11-8.22), and cognitive function (-6.89; 95% CI: -10.00 to -3.79) in the third month. CONCLUSIONS: Daily assessment revealed fluctuations in symptomology, and higher symptom burden was associated with poorer HRQOL in the future. Utilizing mHealth technology for daily symptom assessment improves our understanding of symptom dynamics and sources of variability.

Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis.

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis. Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. Here, we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models, including mice exhibiting advanced pulmonary disease, can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

Optimal performance objectives in the highly conserved bone morphogenetic protein signaling pathway.

Throughout development, complex networks of cell signaling pathways drive cellular decision-making across different tissues and contexts. The transforming growth factor ß (TGF-ß) pathways, including the BMP/Smad pathway, play crucial roles in determining cellular responses. However, as the Smad pathway is used reiteratively throughout the life cycle of all animals, its systems-level behavior varies from one context to another, despite the pathway connectivity remaining nearly constant. For instance, some cellular systems require a rapid response, while others require high noise filtering. In this paper, we examine how the BMP-Smad pathway balances trade-offs among three such systems-level behaviors, or "Performance Objectives (POs)": response speed, noise amplification, and the sensitivity of pathway output to receptor input. Using a Smad pathway model fit to human cell data, we show that varying non-conserved parameters (NCPs) such as protein concentrations, the Smad pathway can be tuned to emphasize any of the three POs and that the concentration of nuclear phosphatase has the greatest effect on tuning the POs. However, due to competition among the POs, the pathway cannot simultaneously optimize all three, but at best must balance trade-offs among the POs. We applied the multi-objective optimization concept of the Pareto Front, a widely used concept in economics to identify optimal trade-offs among various requirements. We show that the BMP pathway efficiently balances competing POs across species and is largely Pareto optimal. Our findings reveal that varying the concentration of NCPs allows the Smad signaling pathway to generate a diverse range of POs. This insight identifies how signaling pathways can be optimally tuned for each context.

Neighborhood Vulnerability and Associations with Poor Health-Related Quality-of-Life Among Adult Survivors of Childhood Cancer.

BACKGROUND: Few studies investigate the relationship between neighborhood vulnerability and health-related quality-of-life (HRQOL) in the childhood cancer population. This study evaluated the impact of neighborhood vulnerability on HRQOL among adult survivors of childhood cancer. METHODS: This cross-sectional study included 4,393 adult survivors of childhood cancer from the St Jude Lifetime Cohort Study. At the baseline (2007-2020), HRQOL was assessed using the SF36v2's physical/mental components summaries (PCS/MCS). Neighborhood vulnerability was assessed using the overall, domain, and indicator-specific scores of the Social Vulnerability Index (SVI) and Minority Health SVI (MHSVI). Multivariable logistic regression was used to evaluate associations of neighborhood vulnerability (quartiles: Q1-Q4) with impaired HRQOL (1SD below the norm), adjusting for diagnosis, demographics, personal socioeconomic status (SES), lifestyle, and chronic health condition burden. Interactions of SVI/MHSVI with personal SES on impaired HRQOL were analyzed. RESULTS: Among survivors, 51.9% were male, averaging 30.3 years of age at evaluation and 21.5 years since diagnosis. Comparing neighborhoods with higher vs lower vulnerability (Q4 vs Q1), overall (OR = 1.60, 95%CI = 1.19-2.16) and domain-specific vulnerability (socioeconomic: OR = 1.59, 95%CI = 1.18-2.15; household composition: OR = 1.54, 95%CI = 1.16-2.06; housing/transportation: OR = 1.33, 95%CI = 1.00-1.76; medical vulnerability: OR = 1.60, 95%CI = 1.22-2.09) were significantly associated with impaired PCS, but not MCS. Residing in neighborhoods lacking urgent care clinics was significantly associated with impaired PCS (OR = 1.39, 95%CI = 1.08-1.78). Having lower vs higher personal education and living in higher vulnerability neighborhoods were associated with more impaired PCS (P  interaction=0.021). CONCLUSIONS: Specific aspects of neighborhood vulnerability increase the risk for impaired physical HRQOL. Addressing these neighborhood factors is essential to enhance the HRQOL of survivors.

Frequent CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression.

We analyzed genomic data from the prostate cancer of African- and European American men to identify differences contributing to racial disparity of outcome. We also performed FISH-based studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate cancer tissue microarrays. We created CHD1-deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. Subclonal deletion of CHD1 was nearly three times as frequent in prostate tumors of African American than in European American men and it associates with rapid disease progression. CHD1 deletion was not associated with HR deficiency associated mutational signatures or HR deficiency as detected by RAD51 foci formation. This was consistent with the moderate increase of olaparib and talazoparib sensitivity with several CHD1 deficient cell lines showing talazoparib sensitivity in the clinically relevant concentration range. CHD1 loss may contribute to worse disease outcome in African American men.

Outcomes of synthetic and biologic mesh in abdominal wall reconstruction: A propensity-matched analysis in Centers for Disease Control and Prevention class 1 and 2 wounds.

INTRODUCTION: The choice of biologic compared with synthetic mesh in abdominal wall reconstruction remains controversial, especially in Centers for Disease Control and Prevention class 1 and 2 wounds. This study evaluated wound complications and hernia recurrence with a 2:1 propensity-matched sample and extended follow-up. METHODS AND PROCEDURES: A prospectively maintained abdominal wall reconstruction database was queried for patients undergoing open abdominal wall reconstruction using biologic or synthetic mesh in Centers for Disease Control and Prevention class 1 and 2 wounds. Patients receiving synthetic or biologic mesh were propensity score matched in a 2:1 fashion. Univariate, bivariate, and inferential analyses were conducted. Unless stated, data are reported as biologic compared with synthetic. RESULTS: In total, 519 patients were compared, 173 with biologic and 346 with synthetic mesh. Defect size (215.2 ± 153.6 cm2 vs 251.5 ± 284.3 cm2), body mass index (33.6 ± 9 kg/m2 vs 34 ±17.7 kg/m2), and comorbidities were well matched (all P > .05). Although Centers for Disease Control and Prevention wound class was used in the match, it was significantly different between groups (Centers for Disease Control and Prevention 1:43.4% vs 81.2%, Centers for Disease Control and Prevention 2:56.6% vs 18.8%; P < .001). The rate of component separation (40.1% vs 44.2%; P = .397), fascial closure (97.7% vs 98.3%; P = .738), and panniculectomy (33.5% vs 29.2%; P = .315) were similar. Mesh size was also similar (816.4 ± 555.5 vs 892.2 ± 487.8 cm2; P = .112). Wound complications were equal, including wound breakdown (10.5% vs 7.5%; P = .315), wound cellulitis (5.2% vs 5.8%; P = .843), wound infection (7.5% vs 4.6%; P = .223), seroma requiring intervention (6.4% vs 7.8%; P = .597), and mesh infection (1.2% vs 0.9%; P > .999). The biologic group had an increased length of stay (6.8 ± 5.5 days vs 5.4 ± 2.3 days; P < .001) and greater hospital charges ($82,181 ± 50,356 vs $62,221 ± 26,817 USD; P < .001). Mean follow-up after biologic repair was longer (33.9 ± 36.6 months vs 23.3 ± 32.3 months; P < .001). Hernia recurrence between the biologic and synthetic groups was not significantly different (2.9% vs 1.4%; P = .313). On multivariable regression, wound complications were predictive of recurrence, and panniculectomy was predictive of wound complications. CONCLUSION: In a 2:1 matched analysis of Centers for Disease Control and Prevention 1 and 2 wounds with nearly 3-years of follow-up, biologic and synthetic mesh had similar rates of wound complications and recurrence in abdominal wall reconstruction.

Implementation of a penicillin allergy protocol in open abdominal wall reconstruction: Preoperative optimization program.

INTRODUCTION: Beta-lactam prophylaxis is the first-line preoperative antibiotic in open abdominal wall reconstruction. However, of the 11% patients reporting a penicillin allergy (PA), most receive second-line, non-ß-lactam prophylaxis. Previously, abdominal wall reconstruction research from our institution demonstrated increased wound complications, readmissions, and reoperations with non-ß-lactam prophylaxis. Therefore, a collaborative quality improvement initiative was developed with the infectious disease service, and a penicillin allergy protocol was instituted that stratified patients' risk of allergic reaction with a goal to increase ß-lactam prophylaxis use. The effect of the penicillin allergy protocol on open abdominal wall reconstruction outcomes was prospectively evaluated. METHODS: Patients with penicillin allergy undergoing open abdominal wall reconstruction were identified and grouped according to penicillin allergy protocol implementation. Pre-penicillin allergy protocol underwent open abdominal wall reconstruction before January 1, 2020, predominantly receiving non-ß-lactam prophylaxis; post-penicillin allergy protocol underwent open abdominal wall reconstruction between January 1, 2020-November 1, 2023, predominantly receiving ß-lactam prophylaxis. Incidence of surgical site infection was the primary outcome. Standard and inferential statistical analyses were performed. RESULTS: Of 315 patients with penicillin allergy, 250 underwent open abdominal wall reconstruction pre-penicillin allergy protocol and 65 post-penicillin allergy protocol. Pre- and post-penicillin allergy protocol were similar in allergic reaction severity history, sex, race, age, diabetes, American Society of Anesthesiologists score, hernia defect size, and mesh type (P > .05). Post-penicillin allergy protocol had lower body mass index (33.4 ± 7.9 vs 29.8 ± 5.3 kg/m2; P = .002) and fewer active smokers (12.4% vs 1.5%; P = .019). Expectedly, post-penicillin allergy protocol received more ß-lactam prophylaxis (22.8% vs 83.1%; P < .001) and no antibiotic-induced allergic reactions. Post-penicillin allergy protocol had significantly fewer surgical site infections (24.4% vs 3.1%; P < .001), wound breakdown (16.0% vs 3.1%; P = .004), reoperations (19.2% vs 0.0%; P < .001), and readmissions (25.3% vs 9.2%; P = .006) but no statistically significant reduction in recurrence (8.4% vs 1.5%; P = .057). CONCLUSIONS: The penicillin allergy protocol safely increased the number of patients with penicillin allergy undergoing open abdominal wall reconstruction receiving ß-lactam prophylaxis and decreased the rate of surgical site infections, wound complications, reoperations, and readmissions. These data supported the systemwide implementation of the penicillin allergy protocol for both general and orthopedic surgery, which has been incorporated into the electronic medical record of 13 hospitals within the system.

Emergence of antibiotic-specific Mycobacterium tuberculosis phenotypes during prolonged treatment of mice.

A major challenge in tuberculosis (TB) therapeutics is that antibiotic exposure leads to changes in the physiologic state of M. tuberculosis (Mtb) which may enable the pathogen to withstand treatment. While antibiotic-treated Mtb have been evaluated in short-term in vitro experiments, it is unclear if and how long-term in vivo treatment with diverse antibiotics with varying treatment-shortening activity (sterilizing activity) affect Mtb physiologic states differently. Here, we used SEARCH-TB, a pathogen-targeted RNA-sequencing platform, to characterize the Mtb transcriptome in the BALB/c high-dose aerosol infection mouse model following 4-week treatment with three sterilizing and three non-sterilizing antibiotics. Certain transcriptional changes were concordant among most antibiotics, including decreased expression of genes associated with protein synthesis and metabolism, and the induction of certain genes associated with stress responses. However, the magnitude of this concordant response differed between antibiotics. Sterilizing antibiotics rifampin, pyrazinamide, and bedaquiline generated a more quiescent Mtb state than did non-sterilizing antibiotics isoniazid, ethambutol, and streptomycin, as indicated by decreased expression of genes associated with translation, transcription, secretion of immunogenic proteins, metabolism, and cell wall synthesis. Additionally, we identified distinguishing transcriptional effects specific to each antibiotic, indicating that different mechanisms of action induce distinct patterns of cellular injury. In addition to elucidating Mtb physiologic changes associated with antibiotic stress, this study demonstrates the value of SEARCH-TB as a highly granular pharmacodynamic assay that reveals antibiotic effects that are not apparent based on culture alone.

Single-cell analysis of chromatin and expression reveals age- and sex-associated alterations in the human heart.

Sex differences and age-related changes in the human heart at the tissue, cell, and molecular level have been well-documented and many may be relevant for cardiovascular disease. However, how molecular programs within individual cell types vary across individuals by age and sex remains poorly characterized. To better understand this variation, we performed single-nucleus combinatorial indexing (sci) ATAC- and RNA-Seq in human heart samples from nine donors. We identify hundreds of differentially expressed genes by age and sex and find epigenetic signatures of variation in ATAC-Seq data in this discovery cohort. We then scale up our single-cell RNA-Seq analysis by combining our data with five recently published single nucleus RNA-Seq datasets of healthy adult hearts. We find variation such as metabolic alterations by sex and immune changes by age in differential expression tests, as well as alterations in abundance of cardiomyocytes by sex and neurons with age. In addition, we compare our adult-derived ATAC-Seq profiles to analogous fetal cell types to identify putative developmental-stage-specific regulatory factors. Finally, we train predictive models of cell-type-specific RNA expression levels utilizing ATAC-Seq profiles to link distal regulatory sequences to promoters, quantifying the predictive value of a simple TF-to-expression regulatory grammar and identifying cell-type-specific TFs. Our analysis represents the largest single-cell analysis of cardiac variation by age and sex to date and provides a resource for further study of healthy cardiac variation and transcriptional regulation at single-cell resolution.

Associations between perceived cancer impact and measures of health behavior in survivors of childhood cancer.

PURPOSE: Perceived cancer impact (PCI) is the degree to which one feels cancer has impacted one's life. It is unknown if PCI is associated with health behaviors. The aim of this study is to determine associations between PCI and health behaviors in childhood cancer survivors. METHODS: Participants were ≥ 5-year survivors enrolled in the St. Jude Lifetime (SJLIFE) cohort. The Brief Cancer Impact (BCIA) assessed PCI across four domains (caregiving/finances, diet/exercise, social/emotional functioning, religiosity). Responses were categorized as negative, neutral, or positive impact. Smoking, risky drinking, illicit drug use, and diet quality data were obtained via self-report. Physical activity (PA) was assessed via self-report and actigraphy. Cross-sectional and longitudinal associations between PCI and health behaviors were evaluated via multivariable logistic regression. RESULTS: A total of 3623 participants (mean age 30.4 ± 8.3 years, 49.6% female, 81.5% NH White) were included in baseline cross-sectional analysis; 1709 had a second visit 5.0 ± 1.4 years later and were included in longitudinal analysis. At baseline, the percentage of participants who endorsed cancer as having a negative impact on caregiving/finances was 37.5%, diet/exercise 30.5%, social/emotional functioning 40.6%, and religiosity 8.7%. Negative and neutral PCI across all four domains were cross-sectionally associated with all behaviors except illicit drug use. Negative and neutral PCI at the first time point across all four domains were associated with smoking, diet quality, and PA (ORs ranging from 1.35 to 2.41) in longitudinal analyses. CONCLUSIONS: Endorsing negative or neutral PCI is associated with adverse health behaviors. IMPLICATIONS FOR CANCER SURVIVORS: Promoting optimal health behavior should include addressing PCI.

Effects of access condition on substance use disorder-like phenotypes in male and female rats self-administering MDPV or cocaine.

Substance use disorder (SUD) is a heterogeneous disorder, where severity, symptoms, and patterns of use vary across individuals. Yet, when rats self-administer cocaine under short-access conditions, their behavior tends to be well-regulated, though individual differences can emerge with long- or intermittent-access. In contrast, significant individual differences emerge when rats self-administer 3,4-methylenedioxypyrovalerone (MDPV), even under short-access conditions, wherein ~30 % of rats exhibit high levels of drug-taking. This study assessed SUD-like phenotypes of male and female rats self-administering MDPV or cocaine by comparing level of drug intake, responding during periods of signaled drug unavailability, and sensitivity to footshock punishment to determine whether: (1) under short-access conditions, rats that self-administer MDPV will exhibit a more robust SUD-like phenotype than rats that self-administer cocaine; (2) female rats will have a more severe phenotype than male rats; and (3) compared to short-access, long- and intermittent-access to MDPV or cocaine self-administration will result in a more robust SUD-like phenotype. Compared to cocaine, rats that self-administered MDPV exhibited a more severe phenotype, even under short-access conditions. Long- and intermittent-access to cocaine and MDPV temporarily altered drug-taking patterns but did not systematically change SUD-like phenotypes. Behavioral and quantitative autoradiography studies suggest phenotypic differences are not due to expression of dopamine transporter, dopamine D2 or D3 receptors, or 5-HT1B, 5-HT2A, or 5-HT2C receptors. This study suggests individuals who use synthetic cathinones may be at greater risk for developing a SUD, and short-access MDPV self-administration may provide a useful method to study the transition to disordered substance use in humans.

Dynamics of BMP signaling and stable gene expression in the early Drosophila embryo.

In developing tissues, morphogen gradients are thought to initialize gene expression patterns. However, the relationship between the dynamics of morphogen-encoded signals and gene expression decisions is largely unknown. Here we examine the dynamics of the Bone Morphogenetic Protein (BMP) pathway in Drosophila blastoderm-stage embryos. In this tissue, the BMP pathway is highly dynamic: it begins as a broad and weak signal on the dorsal half of the embryo, then 20-30 min later refines into a narrow, intense peak centered on the dorsal midline. This dynamical progression of the BMP signal raises questions of how it stably activates target genes. Therefore, we performed live imaging of the BMP signal and found that dorsal-lateral cells experience only a short transient in BMP signaling, after which the signal is lost completely. Moreover, we measured the transcriptional response of the BMP target gene pannier in live embryos and found it to remain activated in dorsal-lateral cells, even after the BMP signal is lost. Our findings may suggest that the BMP pathway activates a memory, or 'ratchet' mechanism that may sustain gene expression.

Frequency of pathogenic germline variants in pediatric medulloblastoma survivors.

Background: Medulloblastoma is the most common malignant brain tumor in children. Most cases are sporadic, but well characterized germline alterations in APC, ELP1, GPR161, PTCH1, SUFU, and TP53 predispose to medulloblastoma. However, knowledge about pathogenic/likely pathogenic (P/LP) variants that predispose to medulloblastoma vary based on genes evaluated, patient demographics, and pathogenicity definitions. Methods: Germline exome sequencing was conducted on 160 childhood survivors of medulloblastoma. Analyses focused on rare variants in 239 known cancer susceptibility genes (CSGs). P/LP variants were identified using ClinVar and InterVar. Variants of unknown significance in known medulloblastoma predisposing genes (APC, ELP1, GPR161, PTCH1, SUFU, TP53) were further classified for loss of function variants. We compared the frequency of P/LP variants in cases to that in 1,259 cancer-free adult controls. Results: Twenty cases (12.5%) had a P/LP variant in an autosomal dominant CSG versus 5% in controls (p=1.0 x10-3), and 10 (6.3%) of these were P/LP variants in a known medulloblastoma gene, significantly greater than 0.2% observed in controls (p=1.4x10-8). The CSGs with the most P/LP variants in cases, and significantly higher than controls, were ELP1 (p=3.0x10-4) and SUFU (p=1.4x10-3). Conclusion: Approximately one in eight pediatric medulloblastoma survivors had an autosomal dominant P/LP CSG variant. We confirm several known associated genes and identify novel genes that may be important in medulloblastoma.

Enhancing the therapeutic window for Spectinamide anti-tuberculosis Agents: Synthesis, Evaluation, and activation of phosphate prodrug 3408.

Spectinamides are a novel class of narrow-spectrum antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Spectinamide 1810 has shown a good safety record following subcutaneous injection in mice or infusion in rats but exhibits transient acute toxicity following bolus administration in either species. To improve the therapeutic index of 1810, an injectable prodrug strategy was explored. The injectable phosphate prodrug 3408 has a superior maximum tolerated dose compared to 1810 or Gentamicin. Following intravenous administration in rodents, prodrug 3408 was quickly converted to 1810. The resulting 1810 exposure and pharmacokinetic profile after 3408 administration was identical to equivalent molar amounts of 1810 given directly by intravenous administration. 3408 and the parent 1810 exhibited similar overall efficacy in a BALB/c acute tuberculosis efficacy model. Delivery of 1810 in phosphate prodrug form, therefore, holds the potential to improve further the therapeutic index of an already promising tuberculosis antibiotic.

Repair of bucket handle meniscus tears improves patient outcomes versus partial meniscectomy at the time of ACL reconstruction.

Purpose: The aim of this study was to examine demographic and surgical factors that influence patient-reported knee function in patients who undergo anterior crucial ligament reconstruction (ACLR) with concurrent bucket-handle meniscal tear (BHMT) procedures. We hypothesized that repair of BHMT in the setting of concomitant ACLR and shorter time from injury to surgery would lead to improved patient-reported outcomes. Methods: Forty-one patients (mean age: 28.0 ± 9.8 years, 72% male) with BHMT at the time of ACLR completed the International Knee Documentation Committee Subjective Knee Form (IKDC-SKF) via online survey at an average of 15.2 months postop. Patient demographics and surgical characteristics, including time from injury to surgery, were compared between repair (n = 22) and meniscectomy (n = 19) groups using one-way analysis of variances; distributions of sex, graft source, BHMT compartment and zone were compared between groups using χ 2 tests. The association between IKDC-SKF score, demographics and surgical characteristics was evaluated using multivariable linear regression. A priori alpha level was p < 0.05. Results: Meniscal repair and meniscectomy groups differed based on graft source and BHMT zone but not IKDC-SKF score (p = 0.085). Patients undergoing ACLR with autograft (p = 0.003) and with red-red zone BHMT (p < 0.001) more often underwent meniscal repair. The regression model demonstrated longer time from injury to surgery (p = 0.049), red-red tear zone (p = 0.04) and meniscectomy (p = 0.008); these were predictive of poorer IKDC-SKF scores. Conclusion: BHMT repair was more likely performed in ACL autograft and on red-red zone tears. Longer time from injury to surgery is an indicator of poorer IKDC-SKF score, as this may increase the risk of concomitant pathologies. White-white zone BHMTs are associated with better IKDC-SKF scores than red-red zone BHMTs, which may be due to the smaller volume of tissue removed during meniscectomy of white-white zone tears and the avoidance of iatrogenic complications of meniscal repair. Level of Evidence: Level III, therapeutic study.

Keratinocyte carcinomas in survivors of childhood cancer: A report from the childhood cancer survivor study.

BACKGROUND: Childhood cancer survivors (CCS) are at increased risk for keratinocyte carcinomas (KC) however, the long-term incidence of single and multiple KC is not well established. OBJECTIVE: Identify risk factors and quantify KC cumulative incidence and multiple-incidence burden in CCS. METHODS: KC were identified among Childhood Cancer Survivor Study participants, a cohort of 5-year cancer survivors diagnosed <21 years of age between 1970 and 1999 in North America. Cumulative incidence was estimated and multivariable models assessed relative rates of KC associated with survivor and treatment characteristics. RESULTS: Among 25,658 participants, 1446 developed 5363 KC (93.5% basal cell carcinoma, 6.7% squamous cell carcinoma; mean age 37.0 years (range 7.3-67.4), mean latency 25.7 years; 95.3% White and 88.4% with radiotherapy). Mean lesion count was 3.7 with 26.1% experiencing ≥4. Radiotherapy imparted a 4.5-fold increase in the rate of any KC and 9.4-fold increase in the rate of ≥4 KC. Allogeneic and autologous hematopoietic cell transplant were associated with a 3.4- and 2.3-fold increased rate of KC, respectively. LIMITATIONS: Participant self-reporting of some data including race without skin phototype and past medical history may have impacted analysis. CONCLUSIONS: The burden of KC in CCS remains high, but predictable risk factors should guide screening.

Sugar and sugar-sweetened beverages in relation to premature aging in adult survivors of childhood cancer.

BACKGROUND: Premature aging is a significant concern in adult survivors of childhood cancer as they develop aging-related conditions at a younger age than their peers with no history of childhood cancer. Although modifiable lifestyle factors, such as diet, are postulated to affect aging process, supporting evidence is sparse. METHODS: We examined if the consumption of sugar and sugar-sweetened beverages was related to premature aging in 3322 adult survivors of childhood cancer in the St. Jude Lifetime Cohort. Premature aging was assessed using the Deficit Accumulation Index (DAI) that was a ratio of the number of age-related chronic health conditions each survivor had out of 44 conditions total. Multinomial logistic regressions adjusting for confounders were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: There were 46% of childhood cancer survivors consumed SSBs once or more times per day. High intake of sugar, especially sugars added to foods during preparation or processing, and habitual consumption of sugar-sweetened beverage were associated with an increased risk of premature aging. DISCUSSION: Our findings support a need to include strategies to reduce sugar and sugar-sweetened beverages consumption in lifestyle interventions to promote healthy aging in adult survivors of childhood cancer.