Comparison of sleep improvement in patients undergoing lumbar spine decompression.

OBJECTIVE: Degenerative spine conditions affect many people each year. These conditions have been shown to negatively impact pain, function, and patient quality of life (QOL), which often require surgical intervention. It is understood that sleep plays an important role in all of these factors. However, the relationship between sleep disruption and lumbar surgery is not well understood. The objective of this study was to use a large database to understand the relationship between sleep quality and lumbar spine surgery outcomes. METHODS: The surgical database of the authors' institute was used to identify all patients undergoing lumbar spine surgery for degenerative spine disease from January 1, 2012, through December 31, 2021. Patient-Reported Outcomes Measurement Information System (PROMIS) sleep disturbance scores were collected, and only patients with both pre- and postoperative scores were included. Additional measures related to disability, pain, and depression were also obtained. Chart review was performed to collect patient demographics, health risk factors, and information related to sleep disturbances such as sleep medication usage and prior sleep condition diagnosis. RESULTS: The study had 674 patients who met the criteria. At 3, 6, and 12 months postoperatively, there was a significant decrease in sleep disruption scores (i.e., sleep improvement), although these decreases were not greater than the minimal clinically important difference (MCID). When stratified based on preoperative sleep quality, patients with poor preoperative scores (PROMIS sleep disruption > 63.04) showed a significant decrease in sleep disruption by 8.17 at 3 months, 7.99 at 6 months, and 7.21 at 12 months. All of these decreases were greater than the sleep disruption MCID of 6.5. Multivariate analysis showed high preoperative sleep disruption and improvement in PROMIS physical health were most associated with decreased postoperative sleep disruption at all postoperative time points. CONCLUSIONS: In patients with degenerative spine conditions, lumbar spine surgery offers improvement in sleep disruption for all patients. Those with poor preoperative sleep quality are more likely to see clinical improvement in their sleep disruption.

Senescence marker p16INK4a expression in patients with multiple sclerosis.

OBJECTIVES: Telomere attrition is associated with disability accumulation and brain atrophy in multiple sclerosis (MS). Downstream of telomere attrition is cellular senescence. We sought to determine differences in the cellular senescence marker p16INK4a expression between MS and healthy control participants and the association of p16INK4a expression with MS disability and treatment exposure. METHODS: Patients meeting diagnostic criteria for MS and healthy controls were recruited for a cross-sectional pilot study. RNA was extracted from peripheral blood mononuclear cells (PBMCs) and p16INK4a expression levels were measured using qRT PCR. Spearman correlation coefficients and regression models were applied to compare expression levels to chronological age, assess case control differences, and determine associations with clinical outcome measures. RESULTS: Fifty-two participants with MS (67 % female, ages 25-70) and 38 healthy controls (66 % female, ages 23-65) were included. p16INK4a levels were not linearly correlated with chronological age in MS (rhos = -0.01, p = 0.94) or control participants (rhos = 0.02, p = 0.92). Higher median p16INK4a levels were observed in the >50-year age group for MS (0.25, IQR 0.14-0.35) vs. controls (0.12, IQR 0.05-0.15) and in this age group B cell depletion therapy was associated with lower expression levels. p16INK4a expression was not associated with any of the measured MS disability outcomes. DISCUSSION: Caution is needed with using p16INK4a expression level from PBMCs as an aging biomarker in MS participants, given lack of correlation with chronological age or large associations with clinical outcomes.

A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer.

Here we characterize a novel pan-RAS inhibitor, ADT-007, that potently and selectively inhibited the growth of histologically diverse cancer cell lines with mutant or activated RAS irrespective of the RAS mutation or isozyme. Growth inhibition was dependent on activated RAS and associated with reduced GTP-RAS levels and MAPK/AKT signaling. ADT-007 bound RAS in lysates from sensitive cells with sub-nanomolar EC 50 values but did not bind RAS in lysates from insensitive cells with low activated RAS. Insensitivity to ADT-007 was attributed to metabolic deactivation by UGT-mediated glucuronidation, providing a detoxification mechanism to protect normal cells from pan-RAS inhibition. Molecular modeling and experiments using recombinant RAS revealed that ADT-007 binds RAS in a nucleotide-free conformation to block GTP activation. Local injection of ADT-007 strongly inhibited tumor growth in syngeneic immune competent and xenogeneic immune deficient mouse models of colorectal and pancreatic cancer and activated innate and adaptive immunity in the tumor microenvironment. SIGNIFICANCE: ADT-007 is a novel pan-RAS inhibitor with a unique mechanism of action having potential to circumvent resistance to mutant-specific KRAS inhibitors and activate antitumor immunity. The findings support further development of ADT-007 analogs and/or prodrugs with oral bioavailability as a generalizable monotherapy or combined with immunotherapy for RAS mutant cancers. BACKGROUND: It is projected that colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDA) will cause 52,580 and 49,830 deaths in the US in 2023, respectively (1). The 5-year survival rates for CRC and PDA are 65% and 12%, respectively (1). Over 50% of CRC and 90% of PDA patients harbor mutations in KRAS genes that are associated with poor prognosis, making the development of novel KRAS inhibitors an urgent unmet medical need (2).

The Influence of a Therapeutic Drug Monitoring Service on Vancomycin-Associated Nephrotoxicity.

Vancomycin's widespread use as the mainstay antibiotic against methicillin-resistant Staphylococcus aureus infections is complicated by its narrow therapeutic index. Therapeutic drug monitoring using area under the concentration-time curve (AUC)-guided dosing is recommended to optimize therapy and prevent vancomycin-associated nephrotoxicity (VAN). In 2018, a consultative therapeutic drug monitoring Advisory Service (the Service) was piloted at an Australian hospital to enable AUC-guided vancomycin dosing. This study sought to compare the incidence of VAN pre- and post-Service implementation. A 4-year retrospective observational study of intravenous vancomycin therapy (greater than 48 hours) in adults (aged 18 years or older), spanning 3 years before and 1-year after implementation of the Service was undertaken. Nephrotoxicity was defined as an increase in serum creatinine concentrations of 26.5 µmol/L or greater or 50% or more from baseline, on 2 or more consecutive days. Univariate analysis was performed to compare patients before and after implementation, and with and without VAN. Independent factors associated with VAN were identified using a multivariate model. In total, 971 courses of vancomycin therapy, administered to 781 patients, were included: 764 courses (603 patients) before implementation and 207 courses (163 patients) after implementation. The incidence of VAN decreased by 5% after Service implementation (15% before implementation vs 10% after implementation; P = .075). Independent factors associated with VAN were sepsis, heart failure, solid-organ transplant, concomitant piperacillin-tazobactam, and average vancomycin AUC during therapy. In conclusion, there was a nonsignificant trend toward a reduced incidence of VAN after the Service. Larger prospective studies are needed to confirm the efficacy of the Service.

Lack of Routine Postoperative Labs Not Associated With Complications in Pediatric Perforated Appendicitis.

INTRODUCTION: Postoperative (postop) management of pediatric perforated appendicitis varies significantly, and postop intra-abdominal abscesses (IAA) remain a significant issue. Between 2019 and 2020, our standardized protocol included routine postop labs after an appendectomy for perforated appendicitis. However, given the lack of predictive utility of these routine labs, we discontinued this practice in 2021. We hypothesize that discontinuing routine postop labs will not be associated with an increase in complication rates after an appendectomy for pediatric perforated appendicitis. METHODS: A single-institution, retrospective review of all pediatric appendectomies for perforated appendicitis from January 2019 to December 2021 was conducted at University Hospitals Rainbow Babies and Children's Hospital in Cleveland, Ohio. Data were collected on rate of complications (IAA development, re-admissions, bowel obstructions, superficial surgical site infections, intensive care unit transfers, Clostridium difficile infections, allergic reactions, and transfusions), postop imaging, postop interventions, and length of stay. Statistical analysis was completed using Fisher's exact test and Mann-Whitney U-test. RESULTS: A total of 109 patients (2019-2020 n = 61, 2021 n = 48) were included in the study. All 61 patients from 2019 to 2020 had postop labs compared to only eight patients in 2021. There was no statistically significant difference between the two groups in overall complication rates, but there was a decrease in IAAs reported in 2021 (P = 0.03). There were no statistically significant differences in other complications, postop imaging usage, or postop interventions. The median length of stay was 4.5 d in 2021 compared to 6.0 d in 2019-2020 (P = 0.009). CONCLUSIONS: Discontinuing routine postop labs is not associated with an increase in overall complications rates. Further studies are needed to determine whether routine postop labs can be safely removed in pediatric patients with perforated appendicitis, which would reduce patient discomfort and care costs.

Refractory Status Epilepticus Associated With a Pathogenic Variant in TNFRSF13B.

Febrile infection-related epilepsy syndrome (FIRES) is a rare epileptic syndrome characterized by new-onset refractory status epilepticus preceded by a febrile illness. Limited literature exists regarding the relationship between primary immunodeficiencies and immune-mediated epilepsy, and the relationship between new-onset refractory status epilepticus and common variable immunodeficiency (CVID) is not well-understood. We present a case of a 21-year-old female with a history of recurrent sinus infections, asthma, thrombocytopenia, atrioventricular nodal reentrant tachycardia, and neonatal seizures who presented with fever and new-onset status epilepticus. She was ultimately diagnosed with a heterozygous variant in TNFRSF13B c.311G>A (p.Cys104Tyr), which encodes for a tumor necrosis factor receptor implicated in CVID.

Dysregulation of humoral immunity, iron homeostasis, and lipid metabolism is associated with multiple sclerosis progression.

BACKGROUND: Though most patients with multiple sclerosis (MS) presented earlier on as a relapsing-remitting (RR) disease, disability progression eventually occurred. Uncovering the mechanisms underlying progression may facilitate the unmet need for developing therapies to prevent progression. Benign MS (BMS), a rare form of MS, is the opposite from secondary progressive MS (SPMS) in that it lacks disease progression defined as Expanded Disability Status Scale (EDSS) ≤3 after at least 15 years of disease onset. BMS is characterized by rare and mild relapses with complete remission of clinical symptoms (lower activity of the disease) and lack of progression. Our study aims to identify transcriptomic and immunological differences between BMS and SPMS to unravel the pathogenesis of disease progression. METHODS: We took multi-modal approaches with microarrays, flow cytometry, and lipidomics by three-way comparisons of patients with BMS vs. RRMS (low disease activity vs. moderate or severe activity), RRMS vs. SPMS (continued activity vs. complete transformation into progressive phase) as well as BMS vs. SPMS, matched for age and disease-duration (low disease activity and no progression vs. progression with or without activity). RESULTS: We found that patients with RRMS and SPMS have a significantly higher percentage of B cells than those with BMS. BMS shows a different transcriptomic profile than SPMS. Many of the differentially expressed genes (DEGs) are involved in B cell-mediated immune responses. Additionally, long-chain fatty acids (LCFA), which can act as inflammatory mediators, are also altered in SPMS. Overall, our data suggest a role for the dysregulation of B cell differentiation and function, humoral immunity, and iron and lipid homeostasis in the pathogenesis of MS disease progression. CONCLUSION: BMS has a unique transcriptomic and immunological profile compared to RRMS and SPMS. These differences will allow for personalized precision medicine and may ultimately lead to the discovery of new therapeutic targets for disease progression.

Immunosenescence and multiple sclerosis: inflammaging for prognosis and therapeutic consideration.

Aging is associated with a progressive decline of innate and adaptive immune responses, called immunosenescence. This phenomenon links to different multiple sclerosis (MS) disease courses among different age groups. While clinical relapse and active demyelination are mainly related to the altered adaptive immunity, including invasion of T- and B-lymphocytes, impairment of innate immune cell (e.g., microglia, astrocyte) function is the main contributor to disability progression and neurodegeneration. Most patients with MS manifest the relapsing-remitting phenotype at a younger age, while progressive phenotypes are mainly seen in older patients. Current disease-modifying therapies (DMTs) primarily targeting adaptive immunity are less efficacious in older patients, suggesting that immunosenescence plays a role in treatment response. This review summarizes the recent immune mechanistic studies regarding immunosenescence in patients with MS and discusses the clinical implications of these findings.

Survival Analysis of Immunotherapy Effects on Relapse Rate in Pediatric and Adult Autoimmune Encephalitis.

BACKGROUND AND OBJECTIVES: Prior observational studies for autoimmune encephalitis (AE) have mostly focused on outcomes after acute immunotherapies with better outcomes associated with earlier immunotherapy use. However, the impact of long-term immunotherapy and its association with clinical relapse is not well known. METHODS: We conducted a retrospective study of consecutive patients meeting published clinical criteria for AE evaluated at UC San Diego and Rady Children's Hospital from January 2007 to November 2021. Survival analysis and Cox multivariable regression models were used to evaluate relapse risk using rituximab exposure as a time-dependent variable. Pooled and age-stratified analyses were performed. RESULTS: A total of 204 pediatric and 380 adult participants were screened of which 30 pediatric and 75 adult participants were included. The most common antibody subtype in both cohorts was anti-NMDA receptor (76% in pediatric, 34% in adult). Relapses occurred in 31% of pediatric antibody-positive, 40% of adult antibody-positive, and 20% of adult antibody-negative cases. Times to first relapse (TTFR) were 10.6 ± 7.4 months (pediatric antibody-positive), 13.1 ± 24.5 months (adult antibody-positive), and 6.9 ± 3.8 months (adult antibody-negative). Rituximab was the most common second-line immunotherapy used. Combining pediatric and adult data, rituximab use was associated with a 71% lower hazard for time to first relapse (hazard ratio [HR] 0.29, 95% CI 0.09-0.85) and 51% lower hazard for recurring relapses (HR 0.49, 95% CI 0.9-1.26). The HR for TTFR with rituximab use in children was 0.30 (95% CI 0.05-1.69), 0.29 (95% CI 0.07-1.29) in adults, 0.32 in non-NMDA antibody-positive encephalitis (95% CI 0.07-1.39), and 0.42 (95% CI 0.07-2.67) for anti-NMDAR. DISCUSSION: Relapses are common in pediatric and adult patients with AE, although less frequently in anti-NMDARE. Using a rigorous survival model, we demonstrate a substantial benefit of rituximab use for reducing relapse rates in AE, especially for the adult population. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that rituximab is associated with a lower hazard to relapse in patients with AE.

Identification of commensal gut microbiota signatures as predictors of clinical severity and disease progression in multiple sclerosis.

Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown. Methods: In a longitudinal study, disability status and associated clinical features in 60 MS patients were tracked over 4.2 ± 0.97 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression. Results: We found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 45 bacterial species were associated with worsening disease, including a marked depletion in Akkermansia , Lachnospiraceae, and Oscillospiraceae , with an expansion of Alloprevotella , Prevotella-9 , and Rhodospirillales . Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed a significant enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K 2 production (linked to Akkermansia ), and a depletion in SCFA metabolism (linked to Lachnospiraceae and Oscillospiraceae ). Further, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to robustly predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status. Conclusions: These results demonstrate the utility of the gut microbiome for predicting disease progression in MS. Further, analysis of the inferred metagenome revealed that oxidative stress, vitamin K 2 and SCFAs are associated with progression.

Longitudinal analysis and treatment of neuropsychiatric symptoms in post-acute sequelae of COVID-19.

BACKGROUND: Persistent neuropsychiatric symptoms following acute COVID-19 infection are frequently reported. These include anxiety, depression, difficulty concentrating, fatigue, and insomnia. The longitudinal evolution of this neuropsychiatric burden is poorly understood and clinical guidelines concerning treatment are lacking. OBJECTIVE: We sought to describe the longitudinal evolution of neuropsychiatric symptoms in the post-acute sequelae of COVID-19 (PASC) syndrome and examine symptom treatment at a single center. METHODS: Consecutive participants experiencing persistent neurologic symptoms after acute COVID-19 infection were recruited from October 2020 to July 2022. Data collected included COVID-19 infection history, neurological exam and review of systems, Montreal Cognitive Assessment (MoCA), and self-reported surveys concerning neuropsychiatric symptoms and treatment. Data were collected at baseline and at 1-year follow-up. RESULTS: A total of 106 participants (mean age 48.6, females 67%) were included in the study. At 1-year follow-up, 72.5% of participants reported at least one neuropsychiatric symptom. Over half (52.5%) of participants reported persistent fatigue. At baseline, 38.8% of all participants had met the established MoCA cut-off score of < 26 for mild cognitive impairment; this decreased to 20.0% at 1 year. COVID-19 infection severity was associated with neuro-PASC symptoms (including fatigue and anxiety) at 1 year. Overall, 29% of participants started at least one new medication for COVID-19-associated neuropsychiatric symptoms. Of the participants who started new medications, fatigue was the most common indication (44.8%) followed by insomnia (27.6%). CONCLUSIONS: Neuropsychiatric symptoms related to neuro-PASC improve over time but can persist for over a year post-recovery. Most treatment modalities targeted neuro-PASC fatigue.

The NHANES Biological Age Index demonstrates accelerated aging in MS patients.

BACKGROUND: Chronological age is associated with disability accumulation in multiple sclerosis (MS). Biological age may give more precise estimates of aging pathways associations with MS severity. Both normal aging and accelerated aging from MS may negatively impact disease course. Multi-marker indices of aging, such as the NHANES biological age index (BAI), may be more robust than single biomarkers in capturing biological age and are strongly associated with mortality risk and aging-related diseases. OBJECTIVE: We sought to investigate whether the NHANES BAI, utilizing readily available measures in the clinic, captures accelerating aging and correlates with disability in MS participants. METHODS: We conducted a prospective, cross-sectional case-control pilot study. Consecutive patients who met the 2017 McDonald's Criteria for MS were recruited from May 2020 to May 2022 along with age-similar healthy controls. BAI components included blood pressure, FEV1, serum creatinine, C-reactive protein, blood-urea nitrogen, albumin, alkaline phosphatase, cholesterol, CMV IgG, and hemoglobin A1c. The index was calculated using the Klemara and Doubal method. Spearman correlation and multivariable linear regression models were used to assess the association between BAI and MS clinical outcomes. RESULTS: A total of 51 MS (68.6% female) and 38 control (68.4% female) participants were recruited. BAI correlated with chronological age (CA) in MS (r2=0.90,p<0.0001) and control participants (r2 =0.87,p<0.0001). The mean BAI was 1.4 years older than CA in MS participants (range +15 to -10.5 years) and 2.2 years younger in control participants (range +11.2 to -14.1 years). In unadjusted Spearman analyses, BAI correlated with the timed 25-foot walk (T25FW, rhos=0.31, p = 0.045) and symbol digit modalities test (SDMT rhos = 0.35, p = 0.018). In a multivariable regression model, a 5-year older BAI was associated with a 1.2-point lower score on SDMT (95%CI -2.2 to -0.25, p = 0.014). CONCLUSIONS: MS participants were biologically older than their own chronological age and age-similar controls. In this modest-sized pilot sample, there was strongest correlation for MS outcome measures between BAI and the SDMT. These results support further study of the BAI as a marker of biological age variability in MS.

Obstetric cholestasis: A case report on rapid bile acid elevation.

Obstetric cholestasis is a pregnancy-specific liver disorder which most commonly develops in the second or third trimester. It typically presents with generalised pruritus, often worst on the hands and feet, and no rash. Diagnosis is made on the basis of clinical presentation and elevated bile acid levels. Whilst obstetric cholestasis usually has no significant maternal adverse outcomes, aside from decreased quality of life from pruritus, it can lead to significant foetal complications, including stillbirth. There are no treatments for obstetric cholestasis, which resolves only following delivery. Thus, depending on the severity of obstetric cholestasis, early induction of labour may be recommended. As symptoms may precede bile acid elevation, repeat testing after a week is usually recommended when initial levels are normal. This report describes a case where a 35-year-old pregnant woman presented with pruritus but a normal bile acid level of 3 µmol/L. On repeat testing the following day the level had risen to 62, diagnosing obstetric cholestasis, and resulting in an urgent induction of labour at 38 weeks and 2 days of gestation. The patient gave birth to a healthy girl. This highlights the importance of close monitoring and consideration of early repeated blood tests where clinical suspicion is high, and/or a diagnosis of obstetric cholestasis would have significant management implications, to prevent adverse foetal outcomes.

Teriflunomide modulates both innate and adaptive immune capacities in multiple sclerosis.

BACKGROUND: Teriflunomide (TER) (Aubagio™) is an FDA-approved disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS). The mechanism of action of TER is thought to be related to the inhibition of dihydroorotate dehydrogenase (DHODH), a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway required by rapidly dividing lymphocytes. Several large pivotal studies have established the efficacy and safety of TER in patients with RRMS. Despite this, little is known about how the adaptive and innate immune cell subsets are affected by the treatment in patients with MS. METHODS: We recruited 20 patients with RRMS who were newly started on TER and performed multicolor flow cytometry and functional assays on peripheral blood samples. A paired t-test was used for the statistical analysis and comparison. RESULTS: Our data showed that TER promoted a tolerogenic environment by shifting the balance between activated pathogenic and naïve or immunosuppressive immune cell subsets. In our cohort, TER increased the expression of the immunosuppressive marker CD39 on regulatory T cells (Tregs) while it decreased the expression of the activation marker CXCR3 on CD4+ T helper cells. TER treatment also reduced switched memory (sm) B cells while it increased naïve B cells and downregulated the expression of co-stimulatory molecules CD80 and CD86. Additionally, TER reduced the percentage and absolute numbers of natural killer T (NKT) cells, as well as the percentage of natural killer (NK) cells and showed a trend toward reducing the CD56dim NK pathogenic subset. CONCLUSION: TER promotes the tolerogenic immune response and suppresses the pathogenic immune response in patients with RRMS.

A Novel Autologous CAR-T Therapy, YTB323, with Preserved T-cell Stemness Shows Enhanced CAR T-cell Efficacy in Preclinical and Early Clinical Development.

CAR T-cell product quality and stemness (Tstem) are major determinants of in vivo expansion, efficacy, and clinical response. Prolonged ex vivo culturing is known to deplete Tstem, affecting clinical outcome. YTB323, a novel autologous CD19-directed CAR T-cell therapy expressing the same validated CAR as tisagenlecleucel, is manufactured using a next-generation platform in <2 days. Here, we report the preclinical development and preliminary clinical data of YTB323 in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL; NCT03960840). In preclinical mouse models, YTB323 exhibited enhanced in vivo expansion and antitumor activity at lower doses than traditionally manufactured CAR T cells. Clinically, at doses 25-fold lower than tisagenlecleucel, YTB323 showed (i) promising overall safety [cytokine release syndrome (any grade, 35%; grade ≥3, 6%), neurotoxicity (any grade, 25%; grade ≥3, 6%)]; (ii) overall response rates of 75% and 80% for DL1 and DL2, respectively; (iii) comparable CAR T-cell expansion; and (iv) preservation of T-cell phenotype. Current data support the continued development of YTB323 for r/r DLBCL. SIGNIFICANCE: Traditional CAR T-cell manufacturing requires extended ex vivo cell culture, reducing naive and stem cell memory T-cell populations and diminishing antitumor activity. YTB323, which expresses the same validated CAR as tisagenlecleucel, can be manufactured in <2 days while retaining T-cell stemness and enhancing clinical activity at a 25-fold lower dose. See related commentary by Wang, p. 1961. This article is featured in Selected Articles from This Issue, p. 1949.

MRI Features and Their Association With Outcomes in Children With Anti-NMDA Receptor Encephalitis.

OBJECTIVES: How brain MRI lesions associate with outcomes in pediatric anti-NMDA receptor encephalitis (pNMDARE) is unknown. In this study, we correlate T2-hyperintense MRI brain lesions with clinical outcomes in pNMDARE. METHODS: This was a multicenter retrospective cohort study from 11 institutions. Children younger than 18 years with pNMDARE were included. One-year outcomes were assessed by the modified Rankin Score (mRS) with good (mRS ≤2) and poor (mRS ≥3) outcomes. RESULTS: A total of 175 pNMDARE subjects were included, with 1-year mRS available in 142/175 (81%) and 60/175 (34%) had abnormal brain MRIs. The most common T2-hyperintense lesion locations were frontal, temporal, and parietal. MRI features that predicted poor 1-year outcomes included abnormal MRI, particularly T2 lesions in the frontal and occipital lobes. After adjusting for treatment within 4 weeks of onset, improvement within 4 weeks, and intensive care unit admission, MRI features were no longer associated with poor outcomes, but after multiple imputation for missing data, T2 frontal and occipital lesions associated with poor outcomes. DISCUSSION: Abnormal frontal and occipital lesions on MRI may associate with 1-year mRS in pNMDARE. MRI of the brain may be a helpful prognostication tool that should be examined in future studies.

Influence of outer membrane permeabilization on intrinsic resistance to the hydrophobic biocide triclosan in opportunistic Serratia species.

Triclosan is a hydrophobic antimicrobial agent commonly employed in health care settings. While it exhibits broad-spectrum antibacterial properties, the gram-negative nosocomial opportunists Pseudomonas aeruginosa and Serratia marcescens are atypically refractory. Intrinsic resistance to triclosan in P. aeruginosa is largely due to its outer membrane impermeability properties for hydrophobic and bulky substances. The present study was undertaken to determine the relationship between triclosan and the outer cell envelopes of thirteen strains of ten Serratia species reported to be opportunistic pathogens in humans. General intrinsic resistance to hydrophobic and other outer membrane impermeant compounds was assessed using cultural selection, disk agar diffusion, and macrobroth dilution bioassays. Uptake of the hydrophobic fluorescent probe 1-N-phenylnapthylamine was assessed in four disparate strains of S. marcescens. Batch culture kinetics in the presence of combinations of triclosan and outer membrane permeabilizer compound 48/80 allowed analysis of outer membrane involvement in intrinsic resistance. Aggregate results revealed that individual species ranged in response to hydrophobic and bulky molecules from generally refractory to extremely susceptible. Moreover, susceptivity to triclosan sensitization by chemical disruption of outer membrane exclusionary properties differed markedly among species which exhibited intrinsic resistance to triclosan. These data suggest that disparate opportunistic pathogens within the genus Serratia differ phenotypically regarding the degree to which outer membrane exclusion contributes to intrinsic resistance for impermeant molecules in general, and triclosan specifically. Ancillary resistance mechanisms appear to contribute in some species and may involve constitutive multi-drug efflux systems. Importance A paucity of knowledge exists regarding the cellular and molecular mechanisms by which opportunistically pathogenic members of the genus Serratia are able to infect immunocompromised and otherwise susceptible individuals, and then evade chemotherapy. This is especially true for species other than Serratia marcescens and Serratia liquefaciens, although much remains to be learned with regard to the nature of key virulence factors and infection mechanisms which allow for the typically nosocomial acquisition of even these species. The research described in the present study will provide a better understanding of the contribution of outer cell envelope permeability properties to the pathogenicity of these opportunistic species in an ever-increasing susceptible patient population. It is our hope that greater knowledge of the basic biology of these organisms will contribute to the mitigation of suffering they cause in patients with underlying diseases.

Delirium as a Risk Factor for Mortality in Critically Ill Patients With Cancer.

PURPOSE: Although delirium is known to negatively affect critically ill patients, little data exist on delirium in critically ill patients with cancer. METHODS: We analyzed 915 critically ill patients with cancer between January and December 2018. Delirium screening was performed using the Confusion Assessment Method for the intensive care unit (ICU), performed twice daily. Confusion Assessment Method-ICU incorporates four features of delirium: acute fluctuations in mental status, inattention, disorganized thinking, and altered levels of consciousness. Multivariable analysis controlling for admitting service, pre-ICU hospital length of stay (LOS), metastatic disease, CNS involvement, Mortality Probability Model II score on ICU admission, mechanical ventilation, and others was performed to determine precipitating factors for delirium, ICU, and hospital mortality and LOS. RESULTS: Delirium occurred in 40.5% (n = 317) of patients; 43.8% (n = 401) were female; the median age was 64.9 (interquartile range, 54.6-73.2) years; 70.8% (n = 647) were White, 9.3% (n = 85) were Black, and 8.9% (n = 81) were Asian. The most common cancer types were hematologic (25.7%, n = 244) and gastrointestinal (20.9%, n = 191). Delirium was independently associated with age (OR, 1.01; 95% CI, 1.00 to 1.02; P = .038), longer pre-ICU hospital LOS (OR, 1.04; 95% CI, 1.02 to 1.06; P < .001), not resuscitating on admission (OR, 2.18; 95% CI, 1.07 to 4.44; P = .032), CNS involvement (OR, 2.25; 95% CI, 1.20 to 4.20; P = .011), higher Mortality Probability Model II score (OR, 1.02; 95% CI, 1.01 to 1.02; P < .001), mechanical ventilation (OR, 2.67; 95% CI, 1.84 to 3.87; P < .001), and sepsis diagnosis (OR, 0.65; 95% CI, 0.43 to 0.99; P = .046). Delirium was also independently associated with higher ICU mortality (OR, 10.75; 95% CI, 5.91 to 19.55; P < .001), hospital mortality (OR, 5.84; 95% CI, 4.03 to 8.46; P < .001), and ICU LOS (estimate, 1.67; 95% CI, 1.54 to 1.81; P < .001). CONCLUSION: Delirium significantly worsens outcome in critically ill patients with cancer. Delirium screening and management should be integrated into the care of this patient subgroup.

Phosphosulindac (OXT-328) prevents and reverses chemotherapy induced peripheral neuropathy in mice.

Background: Chemotherapy-induced peripheral neuropathy (CIPN), a side effect of chemotherapy, is particularly difficult to treat. We explored whether phosphosulindac (PS), a modified NSAID, could treat CIPN. Methods: CIPN was induced in male C57BL/6 J mice by paclitaxel, vincristine or oxaliplatin. Mechanical allodynia was measured with the von Frey test and cold allodynia with the acetone test. To determine the preventive effect of PS, it was administered 2 days before the induction of CIPN. Mouse Lewis lung carcinoma xenografts were used to determine if PS altered the chemotherapeutic efficacy of paclitaxel. Cultured cell lines were used to evaluate the effect of PS on neuroinflammation. Results: Treatment with each of the three chemotherapeutic agents used to induce CIPN lowered the mechanical allodynia scores by 56 to 85% depending on the specific agent. PS gel was applied topically 3x/day for 16-22 days to the hind paws of mice with CIPN. This effect was dose-dependent. Unlike vehicle, PS returned mechanical allodynia scores back to pre-CIPN levels. PS had a similar effect on paclitaxel-induced CIPN cold allodynia. Sulindac, a metabolite of PS, had no effect on CIPN. PS significantly prevented CIPN compared to vehicle. Given concomitantly with paclitaxel to mice with lung cancer xenografts, PS relieved CIPN without affecting the anticancer effect of paclitaxel. The enantiomers of PS were equally efficacious against CIPN, suggesting the therapeutic suitability of the racemate PS. There were no apparent side effects of PS. PS suppressed the levels of IL-6, IL-10, CXCL1, and CXCL2 induced by paclitaxel in a neuroblastoma cell line, and macrophage activation to the M1 proinflammatory phenotype. Conclusion: Topically applied PS demonstrated broad therapeutic and preventive efficacy against CIPN, preserved the anticancer effect of paclitaxel, and was safe. Its anti-CIPN effect appears to be mediated, in part, by suppression of neuroinflammation. These data support further evaluation of topical PS for the control of CIPN.