Biomanufacturing of value-added chemicals from lignin.

Lignin valorization faces persistent biomanufacturing challenges due to the heterogeneous and toxic carbon substrates derived from lignin depolymerization. To address the heterogeneous nature of aromatic feedstocks, plant cell wall engineering and 'lignin first' pretreatment methods have recently emerged. Next, to convert the resulting aromatic substrates into value-added chemicals, diverse microbial host systems also continue to be developed. This includes microbes that (1) lack aromatic metabolism, (2) metabolize aromatics but not sugars, and (3) co-metabolize both aromatics and sugars, each system presenting unique pros and cons. Considering the intrinsic complexity of lignin-derived substrate mixtures, emerging and non-model microbes with native metabolism for aromatics appear poised to provide the greatest impacts on lignin valorization via biomanufacturing.

Use of cigarettes and e-cigarettes, impulsivity and anxiety: Influences on suicidal ideation among youth and young adults in Texas.

INTRODUCTION: Cigarette use and smoking intensity increase risk of suicidal ideation. Less is known about e-cigarette use. Here we examine direct influences of cigarette versus e-cigarette use on suicidal ideation among 16-to-23-year-olds in Texas. METHODS: Since 2019 the Texas Adolescent Tobacco and Marketing Surveillance study collected data on suicidal ideation every six months covering the previous two-weeks. Youths answering that they had "thoughts that you would be better off dead, or of hurting yourself" on more than two of 14 days were categorized as having suicidal ideation. Generalized linear mixed-effects logistic regressions examined the influence of ever and past 30-day (P30D) use of cigarettes, e-cigarettes, impulsivity and anxiety on suicidal ideation, controlling for gender, race/ethnicity, SES, and grade in school. Interactions between ever and P30D use of both products and a) impulsivity and b) gender were examined. RESULTS: Of the 2,329 participants, 29.1% reported ever and 6.5% reported P30D cigarette use, 48.2% reported ever and 11.6% reported P30D e-cigarette use, and 18.5% reported suicidal ideation. Ever cigarette use among females (aOR=1.83; 95% CI: 1.36-2.46), P30D e-cigarette use (aOR=1.30; 95% CI: 1.00-1.68), and P30D cigarette use (aOR=1.47; 95% CI: 1.06-2.05) were independently associated with higher risk for suicidal ideation, after adjusting for covariates. Impulsivity and anxiety directly increased risk for suicidal ideation regardless of product type used. Hispanic youth had higher risk of suicidal ideation than white youth, while higher levels of SES were protective. CONCLUSION: Cigarette/e-cigarette use, as well as impulsivity and anxiety, directly increase the risk of suicidal ideation. IMPLICATIONS: Clinicians should ask young adults with a history of tobacco use, anxiety or impulsive behavior, about suicidal ideationNicotine prevention and cessation programs might be more effective if they simultaneously target substance use and mental healthCulturally appropriate support is needed for ethnic and racial minority youth and young adults in school, college and at workWhen evaluating and understanding risk, the role of multiple social identities (such as minority status, gender, and SES) is important.

Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals.

Synergistic co-utilization of biomass-derived sugars enhances aromatic amino acid production by engineered Escherichia coli.

Efficient co-utilization of mixed sugar feedstocks remains a biomanufacturing challenge, thus motivating ongoing efforts to engineer microbes for improved conversion of glucose-xylose mixtures. This study focuses on enhancing phenylalanine production by engineering Escherichia coli to efficiently co-utilize glucose and xylose. Flux balance analysis identified E4P flux as a bottleneck which could be alleviated by increasing the xylose-to-glucose flux ratio. A mutant copy of the xylose-specific activator (XylR) was then introduced into the phenylalanine-overproducing E. coli NST74, which relieved carbon catabolite repression and enabled efficient glucose-xylose co-utilization. Carbon contribution analysis through 13 C-fingerprinting showed a higher preference for xylose in the engineered strain (NST74X), suggesting superior catabolism of xylose relative to glucose. As a result, NST74X produced 1.76 g/L phenylalanine from a model glucose-xylose mixture; a threefold increase over NST74. Then, using biomass-derived sugars, NST74X produced 1.2 g/L phenylalanine, representing a 1.9-fold increase over NST74. Notably, and consistent with the carbon contribution analysis, the xylR* mutation resulted in a fourfold greater maximum rate of xylose consumption without significantly impeding the maximum rate of total sugar consumption (0.87 vs. 0.70 g/L-h). This study presents a novel strategy for enhancing phenylalanine production through the co-utilization of glucose and xylose in aerobic E. coli cultures, and highlights the potential synergistic benefits associated with using substrate mixtures over single substrates when targeting specific products.

Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort.

Importance: Many psychiatric outcomes share a common etiologic pathway reflecting behavioral disinhibition, generally referred to as externalizing (EXT) disorders. Recent genome-wide association studies (GWASs) have demonstrated the overlap between EXT disorders and important aspects of veterans' health, such as suicide-related behaviors and substance use disorders (SUDs). Objective: To explore correlates of risk for EXT disorders within the Veterans Health Administration (VA) Million Veteran Program (MVP). Design, Setting, and Participants: A series of phenome-wide association studies (PheWASs) of polygenic risk scores (PGSs) for EXT disorders was conducted using electronic health records. First, ancestry-specific PheWASs of EXT PGSs were conducted in the African, European, and Hispanic or Latin American ancestries. Next, a conditional PheWAS, covarying for PGSs of comorbid psychiatric problems (depression, schizophrenia, and suicide attempt; European ancestries only), was performed. Lastly, to adjust for unmeasured confounders, a within-family analysis of significant associations from the main PheWAS was performed in full siblings (European ancestries only). This study included the electronic health record data from US veterans from VA health care centers enrolled in MVP. Analyses took place from February 2022 to August 2023 covering a period from October 1999 to January 2020. Exposures: PGSs for EXT, depression, schizophrenia, and suicide attempt. Main Outcomes and Measures: Phecodes for diagnoses derived from the International Statistical Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification, codes from electronic health records. Results: Within the MVP (560 824 patients; mean [SD] age, 67.9 [14.3] years; 512 593 male [91.4%]), the EXT PGS was associated with 619 outcomes, of which 188 were independent of risk for comorbid problems or PGSs (from odds ratio [OR], 1.02; 95% CI, 1.01-1.03 for overweight/obesity to OR, 1.44; 95% CI, 1.42-1.47 for viral hepatitis C). Of the significant outcomes, 73 (11.9%) were significant in the African results and 26 (4.5%) were significant in the Hispanic or Latin American results. Within-family analyses uncovered robust associations between EXT PGS and consequences of SUDs, including liver disease, chronic airway obstruction, and viral hepatitis C. Conclusions and Relevance: Results of this cohort study suggest a shared polygenic basis of EXT disorders, independent of risk for other psychiatric problems. In addition, this study found associations between EXT PGS and diagnoses related to SUDs and their sequelae. Overall, this study highlighted the potential negative consequences of EXT disorders for health and functioning in the US veteran population.

'Dark' CO2 fixation in succinate fermentations enabled by direct CO2 delivery via hollow fiber membrane carbonation.

Anaerobic succinate fermentations can achieve high-titer, high-yield performance while fixing CO2 through the reductive branch of the tricarboxylic acid cycle. To provide the needed CO2, conventional media is supplemented with significant (up to 60 g/L) bicarbonate (HCO3-), and/or carbonate (CO32-) salts. However, producing these salts from CO2 and natural ores is thermodynamically unfavorable and, thus, energetically costly, which reduces the overall sustainability of the process. Here, a series of composite hollow fiber membranes (HFMs) were first fabricated, after which comprehensive CO2 mass transfer measurements were performed under cell-free conditions using a novel, constant-pH method. Lumen pressure and total HFM surface area were found to be linearly correlated with the flux and volumetric rate of CO2 delivery, respectively. Novel HFM bioreactors were then constructed and used to comprehensively investigate the effects of modulating the CO2 delivery rate on succinate fermentations by engineered Escherichia coli. Through appropriate tuning of the design and operating conditions, it was ultimately possible to produce up to 64.5 g/L succinate at a glucose yield of 0.68 g/g; performance approaching that of control fermentations with directly added HCO3-/CO32- salts and on par with prior studies. HFMs were further found to demonstrate a high potential for repeated reuse. Overall, HFM-based CO2 delivery represents a viable alternative to the addition of HCO3-/CO32- salts to succinate fermentations, and likely other 'dark' CO2-fixing fermentations.

Fundamentals of Mechanobiology and Potential Applications in Spinal Fusion.

BACKGROUND: Mechanobiology can help optimize spinal fusion by providing insights into the mechanical environment required for bone healing and fusion. This includes understanding the optimal loading conditions, the mechanical properties of implanted materials, and the effects of mechanical stimuli on the cells involved in bone formation. The present article reviews the evidence for surface technologies and implant modification of spinal cages in enhancing spinal fusion. METHODS: Databases used included Embase, MEDLINE, Springer, and Cochrane Library. Relevant articles were identified using specific keywords and search fields. Only systematic reviews, meta-analyses, review articles, and original research articles in English were included. Two researchers independently performed the search and selection process. A flowchart of the search strategy and study selection method is provided in the article. RESULTS: The studies indicate that surface modification can significantly enhance osseointegration and interbody fusion by promoting cellular adhesion, proliferation, differentiation, and mineralization. Various surface modification techniques such as coating, etching, nanotopography, and functionalization achieve this. Similarly, implant material modification can improve implant stability, biocompatibility, and bioactivity, leading to better fusion outcomes. Mechanobiology plays a vital role in this process by influencing the cellular response to mechanical cues and promoting bone formation. CONCLUSIONS: The studies reviewed indicate that surface technologies and implant material modification are promising approaches for improving the success of spinal cage fusion. Mechanobiology is critical in this process by influencing the cellular response to mechanical signals and promoting bone growth.

miR-124-3p target genes identify globus pallidus role in suicide ideation recovery in borderline personality disorder.

Borderline personality disorder (BPD) is characterized by patterns of unstable affect, unstable interpersonal relationships, and chronic suicidal tendencies. Research on the genetics, epigenetics, and brain function of BPD is lacking. MicroRNA-124-3p (miR-124-3p) was recently identified in a Genome-Wide Association Study as likely associated with BPD. Here, we identified the anatomical brain expression of genes likely modulated by miR-124-3p and compared morphometry in those brain regions in BPD inpatients vs. controls matched for psychiatric comorbidities. We isolated lists of targets likely modulated by miR-124-3p from TargetScan (v 8.0) by their preferentially conserved targeting (Aggregate PCT > 0.99, see Supplementary Table 1). We applied Process Genes List (PGL) to identify regions of interest associated with the co-expression of miR-124-3p target genes. We compared the gray matter volume of the top region of interest co-expressing those genes between BPD inpatients (n = 111, 46% female) and psychiatric controls (n = 111, 54% female) at The Menninger Clinic in Houston, Texas. We then correlated personality measures, suicidal ideation intensity, and recovery from suicidal ideation with volumetrics. Gene targets of miR-124-3p were significantly co-expressed in the left Globus Pallidus (GP), which was smaller in BPD than in psychiatric controls. Smaller GP volume was negatively correlated with agreeableness and with recovery from suicidal ideation post-treatment. In BPD, GP volume may be reduced through miR-124-3p regulation and suppression of its target genes. Importantly, we identified that a reduction of the GP in BPD could serve as a potential biomarker for recovery from suicidal ideation.

Promoter region variant C-824T in the TH gene modulates the subjective effects of cocaine.

BACKGROUND AND OBJECTIVES: This study examined how a promoter variant of TH (rs10770141) affects subjective effects of cocaine in 65 nontreatment-seeking individuals with cocaine dependence. METHODS: Participants received cocaine/saline intravenously, and TH genotypes were evaluated. RESULTS: Homozygous individuals for the minor T allele reported greater "good" and "bad" subjective effects to cocaine than those with the major C allele. DISCUSSION AND CONCLUSIONS: TH rs10770141 modulates subjective effects of cocaine in participants with cocaine dependence. SCIENTIFIC SIGNIFICANCE: These results are among the first to indicate that homozygosity of the T allele of rs10770141 modulates greater sensitivity to cocaine.

A systematic review of anterior lumbar interbody fusion (ALIF) versus posterior lumbar interbody fusion (PLIF), transforaminal lumbar interbody fusion (TLIF), posterolateral lumbar fusion (PLF).

PURPOSE: The rate of elective lumbar fusion has continued to increase over the past two decades. However, there remains to be a consensus on the optimal fusion technique. This study aims to compare stand-alone anterior lumbar interbody fusion (ALIF) with posterior fusion techniques in patients with spondylolisthesis and degenerative disc disease through a systematic review and meta-analysis of the available literature. METHODS: A systematic review was performed by searching the Cochrane Register of Trials, MEDLINE, and EMBASE from inception to 2022. In the two-stage screening process, three reviewers independently reviewed titles and abstracts. The full-text reports of the remaining studies were then inspected for eligibility. Conflicts were resolved through consensus discussion. Two reviewers then extracted study data, assessed it for quality, and analysed it. RESULTS: After the initial search and removal of duplicate records, 16,435 studies were screened. Twenty-one eligible studies (3686 patients) were ultimately included, which compared stand-alone ALIF with posterior approaches such as posterior lumbar interbody fusion (PLIF), transforaminal lumbar interbody fusion (TLIF), and posterolateral lumbar fusion (PLF). A meta-analysis showed surgical time and blood loss was significantly lower in ALIF than in TLIF/PLIF, but not in those who underwent PLF (p = 0.08). The length of hospital stay was significantly shorter in ALIF than in TLIF, but not in PLIF or PLF. Fusion rates were similar between the ALIF and posterior approaches. The Visual Analogue Scale (VAS) scores for back and leg pain were not significantly different between the ALIF and PLIF/TLIF groups. However, VAS back pain favoured ALIF over PLF at one year (n = 21, MD - 1.00, CI - 1.47, - 0.53), and at two years (2 studies, n = 67, MD - 1.39, CI - 1.67, - 1.11). The VAS leg pain scores (n = 46, MD 0.50, CI 0.12 to 0.88) at two years significantly favoured PLF. The Oswestry Disability Index (ODI) scores at one year were not significantly different between ALIF and the posterior approaches. At two years, ODI scores were also similar between the ALIF and the TLIF/PLIF. However, the ODI scores at two years (2 studies, n = 67, MD - 7.59, CI - 13.33, - 1.85) significantly favoured ALIF over PLF (I2 = 70%). The Japanese Orthopaedic Association Score (JOAS) for low back pain at one year (n = 21, MD - 0.50, CI - 0.78) and two years (two studies, n = 67, MD - 0.36, CI - 0.65, - 0.07) significantly favoured ALIF over PLF. No significant differences were found in leg pain at the 2-year follow-up. Adverse events displayed no significant differences between the ALIF and posterior approaches. CONCLUSIONS: Stand-alone-ALIF demonstrated a shorter operative time and less blood loss than the PLIF/TLIF approach. Hospitalisation time is reduced with ALIF compared with TLIF. Patient-reported outcome measures were equivocal with PLIF or TLIF. VAS and JOAS, back pain, and ODI scores mainly favoured ALIF over PLF. Adverse events were equivocal between the ALIF and posterior fusion approaches.

Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort.

Background: Many psychiatric outcomes are thought to share a common etiological pathway reflecting behavioral disinhibition, generally referred to as externalizing disorders (EXT). Recent genome-wide association studies (GWAS) have demonstrated the overlap between EXT and important aspects of veterans' health, such as suicide-related behaviors, substance use disorders, and other medical conditions. Methods: We conducted a series of phenome-wide association studies (PheWAS) of polygenic scores (PGS) for EXT, and comorbid psychiatric problems (depression, schizophrenia, and suicide attempt) in an ancestrally diverse cohort of U.S. veterans (N = 560,824), using diagnostic codes from electronic health records. We conducted ancestry-specific PheWASs of EXT PGS in the European, African, and Hispanic/Latin American ancestries. To determine if associations were driven by risk for other comorbid problems, we performed a conditional PheWAS, covarying for comorbid psychiatric problems (European ancestries only). Lastly, to adjust for unmeasured confounders we performed a within-family analysis of significant associations from the main PheWAS in full-siblings (N = 12,127, European ancestries only). Results: The EXT PGS was associated with 619 outcomes across all bodily systems, of which, 188 were independent of risk for comorbid problems of PGS. Effect sizes ranged from OR = 1.02 (95% CI = 1.01, 1.03) for overweight/obesity to OR = 1.44 (95% CI = 1.42, 1.47) for viral hepatitis C. Of the significant outcomes 73 (11.9%) and 26 (4.5%) were significant in the African and Hispanic/Latin American results, respectively. Within-family analyses uncovered robust associations between EXT and consequences of substance use disorders, including liver disease, chronic airway obstruction, and viral hepatitis C. Conclusion: Our results demonstrate a shared polygenic basis of EXT across populations of diverse ancestries and independent of risk for other psychiatric problems. The strongest associations with EXT were for diagnoses related to substance use disorders and their sequelae. Overall, we highlight the potential negative consequences of EXT for health and functioning in the US veteran population.

Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Objective: Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed mental and physical health problems, prior pharmacological treatments, and aggregate genetic factors has potential to inform risk stratification and mitigation strategies. Methods: In this study of 3,942 SCZ and 5,414 BPI patients receiving VA care, self-reported SB and ideation were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS). These cross-sectional data were integrated with electronic health records (EHR), and compared by lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. Polygenic scores (PGS) for traits related to psychiatric disorders, substance use, and cognition were constructed using available genomic data, and exploratory genome-wide association studies were performed to identify and prioritize specific loci. Results: Only 20% of veterans who self-reported SB had a corroborating ICD-9/10 code in their EHR; and among those who denied prior behaviors, more than 20% reported new-onset SB at follow-up. SB were associated with a range of psychiatric and non-psychiatric diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking, suicide attempt, and major depressive disorder were also associated with attempt and ideation. Conclusions: Among individuals with a diagnosed mental illness, a GWAS for SB did not yield any significant loci. Self-reported SB were strongly associated with clinical variables across several EHR domains. Overall, clinical and polygenic analyses point to sequelae of substance-use related behaviors and other psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in clinical settings, underscoring the value of regular screening based on direct, in-person assessments, especially among high-risk individuals.

A Clinical Trial of Entolimod a TLR-5 Adjuvant for Vaccines Using Diphtheria or Tetanus as Carrier Proteins.

Anti-drug vaccines previously failed clinical trials because they did not provide a sufficient titer or duration of antibodies (AB), but new adjuvants enhance both AB titers and efficacy duration. This clinical trial assessed AB titers after a single booster of commercial tetanus-diphtheria (Td) vaccine in 40 males randomized as 15 to Td alone and 25 to Td combined with the TLR5 adjuvant, Entolimod (Ent). Ent significantly increased ABs against diphtheria (DPT) (0.46 vs. 0.29 IU/mL increase; n = 40, p < 0.05), but against tetanus (TT) only if baseline TT AB was below 3 IU/mL (3.1 vs. 2.1 IU/mL; n = 20; p < 0.05). These 20 participants also showed a two-fold increase in anti-TT AB titer more often when given Ent than non-Ent (33% vs. 82%) (p < 0.03). Anti-Ent AB was low and appeared unlikely to reduce Ent efficacy after repeated Ent administration. Medical safety was excellent, and a TLR5 missense polymorphism reduced anti-DPT AB production, but Ent increased anti-DPT AB titers to levels induced in subjects with genetically "normal" TRL5 functioning. Further clinical testing of TLR5 adjuvants like Ent seems warranted for anti-drug vaccines.

Paternal alcohol exposure has task- and sex-dependent behavioral effect in offspring.

BACKGROUND: Endophenotypes for alcohol use disorder are well known and may reflect paternal exposure effects passed down to offspring via epigenetic mechanisms. Previously, we showed that paternal alcohol exposure prior to conception attenuates the acquisition of operant alcohol self-administration. We now test whether paternal alcohol exposure alters their offsprings' behavioral responses to alcohol (endophenotypes) and global DNA methylation levels in reward-related brain regions. METHODS: Adult male rats were exposed to alcohol vapors or air for 6 weeks and mated with alcohol-naïve females 8 weeks later. Adult male and female offspring of the alcohol- and control-sired litters were tested on three behaviors 30 m after gavage with water or alcohol (1.5 g/kg): open field, elevated plus maze, and accelerating rotarod. Global DNA methylation levels in sperm, nucleus accumbens, and prefrontal cortex were examined in male sires and in another group of offspring. RESULTS: Alcohol-sired males showed less anxiety-like behavior in the elevated plus maze that was not affected by alcohol administration. By contrast, alcohol had anxiolytic effects in the open field in male offspring only with no paternal alcohol effect. Neither paternal alcohol exposure nor alcohol administration altered locomotor activity in either sex. Sex-specific effects of paternal alcohol exposure were seen in the rotarod test. Alcohol-sired male offspring showed blunted sensitivity to the alcohol's motor-impairing effects, whereas alcohol-sired female offspring showed enhanced sensitivity. Global DNA methylation was altered in the sperm of alcohol-exposed males, but no changes were seen in their offspring. CONCLUSIONS: Paternal alcohol exposure prior to conception has sex- and task-dependent effects on unconditioned behaviors in their offspring.

Pharmacogenetics of Addiction Therapy.

Drug addiction is a serious relapsing disease that has high costs to society and to the individual addicts. Treatment of these addictions is still in its nascency, with only a few examples of successful therapies. Therapeutic response depends upon genetic, biological, social, and environmental components. A role for genetic makeup in the response to treatment has been shown for several addiction pharmacotherapies with response to treatment based on individual genetic makeup. In this chapter, we will discuss the role of genetics in pharmacotherapies, specifically for cocaine, alcohol, and opioid dependences. The continued elucidation of the role of genetics should aid in the development of new treatments and increase the efficacy of existing treatments.

Single-Level Total Disc Replacement: Index-Level and Adjacent-Level Revision Surgery Incidence, Characteristics, and Outcomes.

BACKGROUND: The literature reports that index level (IL) revision spine surgery (RSS) and adjacent level (AL) RSS are diminished in lumbar TDR compared with fusion procedures. There is a paucity of PROMs reported after RSS. OBJECTIVE: To present the incidence of RSS at the IL and AL following single-level lumbar total disc replacement (TDR) and to document patient-related outcome measures (PROMs) associated with RSS. METHODS: PROMs and timelines were analyzed for 32 RSS patients from a prospective cohort study of 401 patients treated with TDR for single-level degenerative disc disease. The data collected prospectively are analyzed from baseline (prior to index surgery) to latest follow-up following RSS. PROMs, including visual analog scales for back and leg, Oswestry Disability Index, and Roland-Morris Disability Questionnaire, were collected preoperatively; postoperatively at 3, 6, and 12 months; and annually thereafter until RSS. The time to RSS was recorded, and PROMs for RSS (IL, AL, or both) were documented, analyzed, and compared. RESULTS: The median time to RSS in the IL cohort was 35 months (interquartile range [IQR] = 9-51 months). The median time to RSS cohort was 70 months (IQR = 41.3-105.3 months). Timepoints facilitate PROM discussion for RSS. Patients in both groups achieved thresholds for the minimum clinically important difference for pain and disability scores. The small sample size in each group contributed to the variability demonstrated by the 95% CIs, thereby cautioning definitive conclusions. CONCLUSIONS: This study reveals that statistically significant and modest clinical improvements in PROMs can be achieved in RSS for lumbar TDR at IL and AL. The surgical approach and technique are reflective of the pathology and suggest that anterior RSS for AL degeneration and posterior RSS for IL pathology yield similar results. CLINICAL RELEVANCE: Statistical and clinical improvements can be achieved in IL-RSS and AL-RSS following single level TDR. It is essential for clinicians to understand and verify the underlying IL and/or AL pathology to select an appropriate management strategy and to facilitate balanced informed discussions with patients.

Single-Level Total Disc Replacement: Mid- to Long-Term Outcomes.

BACKGROUND: Total disc replacement (TDR) has been shown to be effective for the treatment of lumbar degenerative disc disease (DDD) in carefully selected patients. Previous studies have demonstrated high rates of patient satisfaction and improvement in patient-reported outcome measures (PROMs) compared with preoperative status but most have short-term follow-up or small cohort sizes only. OBJECTIVE: The aim of this study is to report mid- to long-term PROMs from the treatment of symptomatic single-level lumbar DDD with TDR. METHODS: Data collected prospectively concerning single-level TDR performed via an anterior approach were included for analysis. A preoperative assessment was obtained followed by postoperative follow-up assessments at 3, 6, and 12 months, and yearly follow-up thereafter. PROMs included patient satisfaction, visual analog score back and leg, Oswestry Disability Index, and Roland-Morris Disability Questionnaire. RESULTS: A total of 211 patients (118 men, 93 women) operated on between June 1997 and July 2015 were included in this study. Minimum follow-up was 4 years. The average age was 42.2 (range 24-87) years and median follow-up 96 interquartile range 72-132, range 48-120) months. The operative levels were L5-S1 (160, 75.8%) and L4-L5 (61, 24.2%). Both statistically and clinically significant improvements observed postoperatively were maintained at 10 years. In addition, 92% of patients reported either good (n = 29) or excellent satisfaction (n = 155) with treatment at final review. CONCLUSIONS: This study shows that single-level lumbar TDR used appropriately in selected patient results in clinically significant improvements in pain and function, well above the minimum clinically important difference, and good to excellent satisfaction in most patients. Further study to define long-term outcomes and survivorship is required. CLINICAL RELEVANCE: Statistically significant and clinically relevant improvements can be achieved by single-level lumbar TDR, in the treatment of single-level discogenic axial low back pain, with or without radiculopathy. These outcomes are sustained in the mid- to long-term followup periods.

A Novel Approach to Link Genetics and Human MRI Identifies AKAP7-Dependent Subicular/Prefrontal Functional Connectivity as Altered in Suicidality.

Background: Brain imaging and genetics are fields acquiring data at increasing speed, but more information does not always result in a better understanding of the underlying biology. We developed the ProcessGeneLists (PGL) approach to use genetics and mRNA gene expression data to generate regions of interest for imaging studies. Methods: We applied PGL to past suicide attempt (ATT): We averaged the mRNA expression levels of genes (n = 130) possibly associated with ATT (p ≤ 10-3 in a published genome-wide association study, GWAS) in each brain region studied in the Human Allen Brain Atlas (6 ex-vivo brains, 158 to 946 regions/brain have mRNA expression data) and compared that to the averaged mRNA expression levels of all other genes in each region in each brain in the atlas. Results: PGL revealed 8 regions where "attempt-related genes" were differentially expressed (Wilcoxon test with Bonferroni correction 8.88-11 =

Multi-omic based production strain improvement (MOBpsi) for bio-manufacturing of toxic chemicals.

Robust systematic approaches for the metabolic engineering of cell factories remain elusive. The available models for predicting phenotypical responses and mechanisms are incomplete, particularly within the context of compound toxicity that can be a significant impediment to achieving high yields of a target product. This study describes a Multi-Omic Based Production Strain Improvement (MOBpsi) strategy that is distinguished by integrated time-resolved systems analyses of fed-batch fermentations. As a case study, MOBpsi was applied to improve the performance of an Escherichia coli cell factory producing the commodity chemical styrene. Styrene can be bio-manufactured from phenylalanine via an engineered pathway comprised of the enzymes phenylalanine ammonia lyase and ferulic acid decarboxylase. The toxicity, hydrophobicity, and volatility of styrene combine to make bio-production challenging. Previous attempts to create styrene tolerant E. coli strains by targeted genetic interventions have met with modest success. Application of MOBpsi identified new potential targets for improving performance, resulting in two host strains (E. coli NST74ΔaaeA and NST74ΔaaeA cpxPo) with increased styrene production. The best performing re-engineered chassis, NST74ΔaaeA cpxPo, produced ∼3 × more styrene and exhibited increased viability in fed-batch fermentations. Thus, this case study demonstrates the utility of MOBpsi as a systematic tool for improving the bio-manufacturing of toxic chemicals.