Persistent Low Levels Research Articles

The substantial role of sleep, stress and physical activity in persistent high levels of fatigue in patients with inflammatory bowel disease: A longitudinal trajectory study.

Fatigue is a common and burdensome problem for patients with inflammatory bowel disease (IBD). Previous studies lack insight into the individual variability in fatigue severity and course over time, and the characteristics of patients at risk of severe and persistent fatigue. This study aimed to identify distinct groups of IBD patients based on their level and course of fatigue over five years. Subsequently, we examined the relationship between these trajectories, patient characteristics and trajectories of perceived stress, sleep and physical activity. This longitudinal cohort study used prospectively collected data from the myIBDcoach telemedicine monitoring tool, including 320 IBD patients who completed three or more online consultations between 2016 and 2021. Latent class growth analyses were performed to identify distinct trajectories. We found five subgroups with distinct trajectories of fatigue, differing in level and course over time, with 33% of patients experiencing chronic stable and high levels of fatigue. Few differences in patient characteristics were found between trajectories, yet the chronic high fatigue subgroup was more likely to report persistent stable sleep problems, perceived stress, and little physical activity over time compared to the other groups. Distinct subgroups of IBD patients can be identified based on longitudinal fatigue trajectories. The relatively stable levels of fatigue, stress, sleep, and physical activity suggest that a one-time screening of patients on these topics may be sufficient to identify those at risk. Interventions aiming to reduce fatigue should target persistent stress, sleep problems, and low levels of physical activity.

A conserved two-component system senses intracellular iron levels and regulates redox balance in Mycobacterium spp.

For bacteria, an intricate coordination between sensing and regulating iron levels and managing oxidative stress is required as their levels are tightly interlinked. While various oxidative stress and heme-based redox sensors have been reported for both pathogenic and non-pathogenic bacteria, the mechanisms governing the modulation of intracellular iron levels in response to changes in redox status remain unclear. In this study, a gene-inactivated strain of mycobacterial sensor kinase PdtaS showed dysregulated expression of genes associated with iron metabolism, including Fe-S clusters, NADH dehydrogenases, and iron uptake. The strain showed poor growth in nutrient-limiting conditions, a defect rescuable by heme but not by Fe3+ supplementation. This observation was associated with the PAS domain of the PdtaS sensor kinase. Biochemical and biophysical experiments established heme-binding to the PAS domain and its inhibitory effect on PdtaS auto-kinase activity, suggesting that the absence of heme induces activation of this sensor kinase. Interestingly, despite having an endogenous heme biosynthetic pathway or even external heme supplementation, the ∆pdtaS mutant exhibited persistent low intracellular iron levels concomitant with elevated oxidative stress. Antioxidant supplementation mitigated growth defects, emphasizing the link between oxidative stress, intracellular iron levels, and PdtaS activity. RNA-IP identified key targets associated with redox homeostasis and iron metabolism as targets of the PdtaR response regulator. The study proposes a novel role for the PdtaS-PdtaR TCS in sensing heme, regulation of intracellular iron levels, and redox balance.IMPORTANCEThe research article investigates the intricate interplay between bacteria's ability to take and utilize iron without inducing excess iron's toxic effects, including oxidative stress. The study shows that bacteria achieve this by sensing intracellular iron available as heme through a sensory protein PdtaS, which turns off when heme is in excess and prevents iron uptake and iron efflux. The process shields bacteria from generating Fe-dependent free radicals and allows it to maintain viability. The absence of sensor kinase abrogates all these processes, increasing bacteria susceptibility to ROS and thereby slowing growth. This feature of the sensor kinase PdtaS makes it an attractive co-therapeutic target for tuberculosis therapy, where its inhibition will prevent iron uptake, even in the presence of low iron, thereby halting bacterial proliferation.

Locally Adaptive Shrinkage Priors for Trends and Breaks in Count Time Series

Non-stationary count time series characterized by features such as abrupt changes and fluctuations about the trend arise in many scientific domains including biophysics, ecology, energy, epidemiology, and social science domains. Current approaches for integer-valued time series lack the flexibility to capture local transient features while more flexible models for continuous data types are inadequate for universal applications to integer-valued responses such as settings with small counts. We present a modeling framework, the negative binomial Bayesian trend filter (NB-BTF), that offers an adaptive model-based solution to capturing multiscale features with valid integer-valued inference for trend filtering. The framework is a hierarchical Bayesian model with a dynamic global-local shrinkage process. The flexibility of the global-local process allows for the necessary local regularization while the temporal dependence induces a locally smooth trend. In simulation, the NB-BTF outperforms a number of alternative trend filtering methods. Then, we demonstrate the method on weekly power outage frequency in Massachusetts townships. Power outage frequency is characterized by a persistent low level trend with occasional spikes. These illustrations show the estimation of a smooth, non-stationary trend with adequate uncertainty quantification.

PTH may predict early mortality in incident patients on hemodialysis: results from a large cohort.

Parathyroid hormone (PTH) is merit as a risk factor for mortality in patients with chronic kidney disease in prevalent hemodialysis patients in a U shape. Most studies, however, do not focus on incident patients and those who died within the first 90days of therapy. We evaluated PTH as a risk factor for mortality in a large cohort population in Brazil. This is an observational cohort study that included 4317 adult patients who initiated hemodialysis between July 1st, 2012 and June 30, 2017. The main outcome was all-cause mortality. Fine-gray sub-distribution hazard models were used to evaluate survival in the presence of a competing event (kidney transplant). Median PTH levels of 252 (118, 479) pg/mL. There were 331 deaths during the first 90days of therapy (6.7%), 430 in a 1-year follow-up (10.7%) and 1282 (32%) during the 5-year study period. Deaths according to PTH < 150, 150-600 and > 600pg/mL corresponded to 38.1%, 33.0% and 28.5%, respectively (p < 0.001). In an adjusted model, patients who started dialysis with PTH < 150pg/mL had a higher mortality risk within the first 90days, but not in 1year and 5years after starting dialysis. Analyses in a subset of patients with a repeated PTH in 1year (N = 1954) showed that although persistent PTH low levels (< 150pg/mL) at 1year were significantly associated with all-cause mortality, this result was not sustained after multiple adjustments. PTH < 150pg/mL confers a high mortality risk in the first 90days of dialysis. If this result reflects poor nutritional conditions, it deserves further investigations.

Cross-sectional and longitudinal associations of PAHs exposure with serum uric acid and hyperuricemia among Chinese urban residents: The potential role of oxidative damage

A few studies found polycyclic aromatic hydrocarbons (PAHs) were associated with serum uric acid (SUA) or hyperuricemia (HUA). However, the longitudinal study is vacant, and the underlying mechanisms remain unclear. We aimed to assess the cross-sectional and longitudinal associations of urinary PAHs metabolites with SUA levels and HUA risk, and explore the mediating effects of oxidative stress and inflammation. 10 urinary mono-hydroxylated PAHs metabolites and SUA levels were measured among 4047 Chinese urban residents at baseline and 1496 individuals at 6-year follow-up. Biomarkers of oxidative damage and inflammation in urine/plasma were determined at baseline. We adopted generalized linear mixed models and logistic regression to assess the associations of PAHs metabolites with SUA and HUA, weighted quantile sum regression and adaptive elastic net regression to evaluate the overall effects of multi-PAHs mixture, and mediation analysis to estimate the mediating roles of the biomarkers. In the cross-sectional study, each 1-unit increase in the ln-transformed values of 2-OHNa, 2-OHFlu, 4-OHPh, 9-OHPh, 3-OHPh, 2-OHPh, ΣOHNa, ΣOHPh, and ΣOHPAHs was associated with a 4.10-, 3.90-, 6.42-, 7.33-, 4.85-, 5.43-, 4.47-, 7.67-, and 5.22-μmol/L increase in SUA, respectively. Meanwhile, each 1-unit increase in the ln-transformed values of 1-OHNa, 2-OHNa, 4-OHPh, 9-OHPh, 3-OHPh, 2-OHPh, ΣOHNa, ΣOHPh, and ΣOHPAHs was associated with a 17, 14, 15, 22, 14, 19, 18, 27, and 21% increment in HUA risk, respectively. After 6 years, individuals with persistent high level of 9-OHPh had a 12.5 μmol/L increase in SUA compared with those with persistent low level. The overall effects of multi-PAHs mixture on SUA and HUA remain positive. 8-hydroxy-deoxyguanosine mediated the associations of PAHs metabolites with SUA and HUA, and the mediated proportion ranged from 5.39% to 15.34%. PAHs exposure was associated with the elevated SUA levels and increased HUA risk, and oxidative DNA damage may be one of the underlying mechanisms.

Administration of bicarbonates through percutaneous gastrostomy with continuous nocturnal infusion in a patient with Kearns-Sayre disease: a life changing therapeutical paradigm

BackgroundMitochondrial diseases (MDs) are systemic disorders that can affect multiple organs. Renal manifestations, including renal tubular acidosis, are common because kidneys are particularly vulnerable to energy deprivation. Treatment of MDs is often complex and electrolyte replacement can be difficult especially in pediatric patients, because large and repeated amounts of oral supplements are needed but are not well tolerated.Case presentationWe describe the case of a girl affected by Kearns-Sayre disease with severe renal tubular acidosis. The management of her metabolic acidosis was challenging because she showed persistent low levels of serum bicarbonates despite a progressive incrementation of oral bicarbonates. Furthermore, as a result to the ingestion of large amounts of alkali, the girl developed an aversion to oral supplementation. After positioning a percutaneous gastrostomy (PEG) and starting enteral administration of bicarbonates (with daily boluses and continuous nocturnal infusion), she finally obtained an adequate electrolyte control, with a significant increase in her quality of life.ConclusionsIn MDs, the combination of nocturnal continuous enteral administration of alkali plus diurnal boluses may represent a valid solution to correct metabolic acidosis. It can also result in an improved patients’ quality of life, particularly in pediatric settings, where compliance to oral therapy is often lacking due to the large and repeated amounts of unpalatable bicarbonates solutions required.

Abstract SS02-02: Hormone Replacement and Alternatives for Relief of Vasomotor Symptoms in Women at Increased Risk for Breast Cancer

Abstract 70% of women will experience vasomotor symptoms sufficient to impact their quality of life during menopause transition and the early menopause. These symptoms are thought result from neurotransmitter imbalances resulting from ovarian hormone reductions and hypersecretion of gonadotropins. Increases in gonadotropins result in neurotransmitter triggered stimulation of the neurokinin 3 (NK3) receptor and thermoregulatory imbalance. Estrogen deficiency also reduces serotonin which can also trigger increases in hot flashes, and sleep disturbances. Vasomotor symptoms last on the average for 7 years until acclimation to persistent low estrogen levels occurs. Estrogen +/- progestin replacement therapy is associated with the greatest likelihood of vasomotor symptom relief as it reduces gonadotropin and NK3 receptor signaling and increases serotonin. Progestins also increase the neuroinhibitory transmitter gamma-aminobutyric acid (GABA) which improves sleep quality. There continues to be confusion on the part of providers and patients regarding the excess risk of breast cancer and thromboembolic events as these risks are affected by type of agent, route of delivery, age, duration of treatment, and presence of obesity. The majority of placebo controlled randomized clinical trial data on hormone replacement with estrogen or estrogen + a progestin comes from the Women’s Health Initiative (WHI) for women 50-79 in which oral conjugated estrogen (CE) 0.625 mg was used as the estrogen for women without a uterus and medroxyprogesterone acetate (MPA) was added to CE for women with a uterus to protect against endometrial hyperplasia and cancer. The median age at entry to WHI that trial was 63 and a substantial proportion had previously taken hormones. Large longitudinal cohort studies have been helpful in assessing risks in women starting hormones at a more clinically relevant age (45-55) and with hormonal preparations other than oral CE and MPA. Five to seven years of estrogen alone results in minimal if any increased risk for breast cancer. However, combined estrogen+ progestin replacement for women over 50, necessary for women with a uterus, results in an ~ 30 % relative increased risk for breast cancer if taken for up to 5 years and a doubling of risk with 10 years of treatment. So called bioidentical hormones often compounded as oral troches of estradiol, progesterone, and testosterone, are also associated with increased breast cancer risk. Vaginal hormones have not been found to increase risk for breast cancer. Increased risk of thromboembolism is predominately observed in women over 50 using oral as opposed to transdermal preparations. Increased risk for stroke and dementia was observed in the WHI again with oral hormones in women over 65. In the WHI there was no increase in cancer related, cardiovascular or overall mortality with estrogen or estrogen and progestin. For high-risk peri and post-menopausal women with who would like to reduce/alleviate their vasomotor symptoms with no increase in risk for breast cancer there are several options: 1) the tissue selective estrogen complex bazedoxifene (BZA) combined with conjugated estrogen (CE) 2) the non-hormonal option of NK3 receptor antagonists such as fezolinetant ( 3) non-hormonal options of gabapentin, selective serotonin reuptake inhibitors (SSRI) and serotonin and norepinephrine uptake inhibitors (SNRI). BZA and CE and fezolinetant are reported to reduce hot flashes in 70% or more of individuals with paroxetine effectiveness reported as 50%. All three are FDA approved for reduction of vasomotor symptoms. The combination of BZA and CE is also being investigated for breast cancer risk reduction. These agents differ with respect to side effects with increased risk of blood clots for bazedoxifene and conjugated estrogen, increased risk of nausea, diarrhea, and liver dysfunction for fezolinetant and drowsiness and dry mouth for SSRIs. Drug costs may also dramatically affect insurance coverage and patient uptake of a particular strategy. A recent online perusal of a popular site for finding the lowest drug price suggested substantial differences in the cost of drugs for relief of vasomotor symptoms. The approximate cost for a 30- day supply of oral estradiol was $30, estradiol transdermal patches $35, oral progesterone $15, combined estradiol and levonorgestrel transdermal patches $240, oral CE $200, oral CE + medoxyprogesterone acetate $240, and for BZA+ CE $200. For non-hormonal therapies the cost of 30 days of gabapentin was $11, paroxetine $30 and fezolinetant $550. Crandall, Mehta, and Manson JAMA 2023 329:405-420 Collaborative Group on Hormonal Factors in Breast Cancer Lancet 2019 394: 1159-1168 Fabian et al Ca Prev Res 2019 10:711-720 Modi and Dhillo Neuroendocrinology 2019 109:242–248 Citation Format: C. Fabian. Hormone Replacement and Alternatives for Relief of Vasomotor Symptoms in Women at Increased Risk for Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr SS02-02.

Characterizing the antigenic evolution of pandemic influenza A (H1N1) pdm09 from 2009 to 2023.

The H1N1pdm09 virus has been a persistent threat to public health since the 2009 pandemic. Particularly, since the relaxation of COVID-19 pandemic mitigation measures, the influenza virus and SARS-CoV-2 have been concurrently prevalent worldwide. To determine the antigenic evolution pattern of H1N1pdm09 and develop preventive countermeasures, we collected influenza sequence data and immunological data to establish a new antigenic evolution analysis framework. A machine learning model (XGBoost, accuracy = 0.86, area under the receiver operating characteristic curve = 0.89) was constructed using epitopes, physicochemical properties, receptor binding sites, and glycosylation sites as features to predict the antigenic similarity relationships between influenza strains. An antigenic correlation network was constructed, and the Markov clustering algorithm was used to identify antigenic clusters. Subsequently, the antigenic evolution pattern of H1N1pdm09 was analyzed at the global and regional scales across three continents. We found that H1N1pdm09 evolved into around five antigenic clusters between 2009 and 2023 and that their antigenic evolution trajectories were characterized by cocirculation of multiple clusters, low-level persistence of former dominant clusters, and local heterogeneity of cluster circulations. Furthermore, compared with the seasonal H1N1 virus, the potential cluster-transition determining sites of H1N1pdm09 were restricted to epitopes Sa and Sb. This study demonstrated the effectiveness of machine learning methods for characterizing antigenic evolution of viruses, developed a specific model to rapidly identify H1N1pdm09 antigenic variants, and elucidated their evolutionary patterns. Our findings may provide valuable support for the implementation of effective surveillance strategies and targeted prevention efforts to mitigate the impact of H1N1pdm09.

Computation and analysis of optimal disturbances of stationary solutions of the hepatitis B dynamics model

Abstract Optimal disturbances of a number of typical stationary solutions of the hepatitis B virus infection dynamics model have been found. Specifically optimal disturbances have been found for stationary solutions corresponding to various forms of the chronic course of the disease, including those corresponding to the regime of low-level virus persistence. The influence of small optimal disturbances of individual groups of variables on the stationary solution is studied. The possibility of transition from stable stationary solutions corresponding to chronic forms of hepatitis B to stable stationary solutions corresponding to the state of functional recovery or a healthy organism using optimal disturbances is studied. Optimal disturbances in this study were constructed on the basis of generalized therapeutic drugs characterized by one-compartment and two-compartment pharmacokinetics.

N-Substituted Bicyclic Carbamoyl Pyridones: Integrase Strand Transfer Inhibitors that Potently Inhibit Drug-Resistant HIV-1 Integrase Mutants.

HIV-1 integrase (IN) is an important molecular target for the development of anti-AIDS drugs. A recently FDA-approved second-generation integrase strand transfer inhibitor (INSTI) cabotegravir (CAB, 2021) is being marketed for use in long-duration antiviral formulations. However, missed doses during extended therapy can potentially result in persistent low levels of CAB that could select for resistant mutant forms of IN, leading to virological failure. We report a series of N-substituted bicyclic carbamoyl pyridones (BiCAPs) that are simplified analogs of CAB. Several of these potently inhibit wild-type HIV-1 in single-round infection assays in cultured cells and retain high inhibitory potencies against a panel of viral constructs carrying resistant mutant forms of IN. Our lead compound, 7c, proved to be more potent than CAB against the therapeutically important resistant double mutants E138K/Q148K (>12-fold relative to CAB) and G140S/Q148R (>36-fold relative to CAB). A significant number of the BiCAPs also potently inhibit the drug-resistant IN mutant R263K, which has proven to be problematic for the FDA-approved second-generation INSTIs.

Not every elevating enzyme tells the same story: unpacking creatine kinase and anti-Jo-1 positivity beyond inflammatory myositis

Gitelman syndrome (GS) is an autosomal recessive familial disorder characterized by hypokalemia and metabolic alkalosis. Rhabdomyolysis due to hypokalemia is extremely rare. The presentation of GS leading to rhabdomyolysis is extremely rare as well. This case report describes a situation in which GS mimicked inflammatory myositis. A 30-year-old woman presented to the rheumatology outpatient clinic with an inability to walk and severe muscle weakness. Her creatine kinase level was elevated at 9900 U/L and her potassium level was low at 2.6 mmol/L. A myositis panel was ordered on suspicion of inflammatory myositis, and the results showed a positive anti-Jo-1. A muscle biopsy, performed with a presumptive diagnosis of inflammatory myositis, yielded pathology results inconsistent with myositis. Despite persistent low potassium levels during follow-up, potassium replacement was administered. The patient’s clinical condition improved significantly with potassium replacement, leading to a reduction in muscle weakness.

FLT3 Ligand Kinetic Profile Predicts Response to Treatment and Event-Free Survival (EFS) in Adults with High-Risk MDS/CMML Receiving CPX-351: A GFM Study

Background: Our group recently reported, in a prospective multicentre phase 2 study of 31 patients with higher-risk (HR)-MDS or CMML receiving CPX-351 as first-line induction treatment 87% of overall responses (including 64.5% of CR/ CR according to ELN2017 criteria), and 93.5% of the patients could be bridged to transplant (GFM-CPX MDS trial, Peterlin et al. Lancet Haematol 2023). We had also previously reported, in AML, that the soluble forms of FLT3 ligand (FL) and IL6 could be prognostic factors of refractoriness to chemotherapy and overall survival (OS) (Peterlin et al. Cancer Medicine, 2021). A secondary objective of the GFM-CPX MDS trial was to assess the prognostic value of these two cytokines in HR-MDS/CMML receiving CPX-351. Methods: All patients included in the GFM-CPX MDS trial (clinicaltrials.gov#NCT04273802), induction chemotherapy with CPX-351 (44 mg Daunorubicin/100 mg Aracytine/m 2 on days 1, 3, and 5) also consented for the present biological FLAM-MDS sub-study. Using a new cytokine multiplex assay from Milliplex (MILLIPLEX®), FL levels (expressed in pg/mL) were evaluated on Day (D) 1, D8, D15 and D22 of the first cycle of induction; IL-6 (expressed in pg/mL) and CRP (known to be correlated with IL6, expressed in mg/L, normal value 0-5) levels were evaluated on D1 and D22 only. Patients who failed to achieve response (CR or CRi or MLFS, ELN2017 criteria) after the first induction cycle could receive a second one. The impact on CR/CRi rate after one cycle of CPX-351, OS and EFS of FL, IL-6 and CRP dosages and their kinetic profile during this first cycle were studied. Results: Dosages could be performed in 28 of the 31 patients included ( Table 1). Overall response (CR+CRi+MLFS) after cycle 1 was achieved in 24 (87%, MLFS n=7, CR+CRi n=17) patients; 3/4 non-responders received a second induction (1 achieved CR). Allograft was performed in 26/28 (93%). With a median follow-up of 18 months for surviving patients, 1y and 18-month OS were 79% and 75%, respectively. 1y and 18-month EFS were both 76%, respectively. Achieving CR/CRi versus MLFS/non-response was associated with better 1-y EFS (71% (52-96) vs 27% (10-72), p=0.009) but not 1-y OS (82% (66-100) vs 73% (51-100), p=0.8). Median (range) FL levels were 4.5 [0- 33.5] on D1, 74.1 [4.1-296.6] at D8, 326.6 [47.4-678] at D15 and 381.3 [4.4-800.1] at D22. As in AML (Peterlin et al, 2021), patients could be categorized according to three FLc kinetic profiles: i) sustained increase from D 1 to 22 (FLI group n=17, 61% of the cohort), ii) increase from D 1 to 15, then decrease on D 22 (FLD group, n=9, 32% of the cohort) and iii) persistent low levels (&amp;lt;100 pg/mL from D 1 to 22, FLL group, n=2, 7% of the cohort). Median (range) IL6 levels were 11 (0-587.8) on D1 and 179.8 (0-531) on D22. Increase of IL6 levels between D1 and D22 was observed in 19 patients (68%) and decrease in 7, while 2 patients had no IL6 detectable at either times. Finally, median (range) CRP levels were 2.3 (0-108) on D1 and 40.5 (7.2-323) on D22. Increase of CRP level was observed in most patients between D1 and D22 (n=25, 96%). There was no correlation between IL6 and CRP levels on D1 (p=0.64) or D22 (p=0.48). CR/CR rates, 1-y OS and EFS were not correlated with FL levels (&amp;lt; vs &amp;gt; median) at the 4 time points considered. However, a FLD kinetic profile was significantly associated with higher CR/CRi rates (100% vs FLI 47% vs FLL 50%, p=0.002) and 1-y EFS (78% (55-100) vs FLI 47% (28-78) vs FLL: 0%, p=0.003), Figure 1). 1-y OS was similar between the 3 FL kinetic profile groups (FLD: 89% (71-100) vs FLI 76% (59-100) vs FLL 50% (13-100), p=0.7)). In multivariate analysis, taking into account age, gender, R-IPSS and the FL kinetic profile during cycle 1 of CPX-351, a FLD kinetic profile was the only factor associated with higher CR/CRi rate (OR: 24.2, 95%CI: 2.4-3278, p=0.004) and better EFS (OR: 21.91; 95%CI: 2.47-194.77, p=0.006). Levels and kinetic profiles of IL6 and CRP had no impact on CR/CRi rates, OS and EFS. Conclusion: As in AML, FL kinetic profile predicts response and survival in HR-MDS/CMML. A FLD kinetic profile was the only factor independently associated with higher CR/CRi rates and better EFS. These results have to be confirmed on larger cohorts. Other treatment approaches may be of interest in patient with a non FLD profile.

CAR-T Cell Therapy in Patients with Refractory Systemic Autoimmune Diseases Exhibits Less Inflammation, Toxicities and Different Cellular Dynamics Compared to Patients with B Cell Lymphoma

Chimeric antigen receptor (CAR) T-cell therapies have shown high efficacy in the treatment of B cell non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL) and are established as a standard treatment for patients with hematological malignancies. Aside from malignant B cells, autoreactive B cells can also cause great harm in patients with autoimmune diseases (AID), resulting in chronic inflammation, organ damage, and increased mortality. We have recently demonstrated that CD19-directed CAR-T cell therapy is feasible and effective in patients with refractory systemic lupus erythematosus (Mougiakakos et al, 2021; Mackensen et al., 2022), antisynthetase syndrome (Müller et al., 2023) and systemic sclerosis (Bergmann et al., 2023). Despite these promising data, there are many uncertainties in the treatment of AID patients with cellular therapies, which were primarily developed for the treatment of cancer patients. Here, we analyzed the occurrence and severity of toxicities, inflammatory markers, and the cellular dynamics of 15 AID patients and 40 NHL patients undergoing CAR-T cell therapy. All patients were treated in our center with either commercial CAR-T cell products (Axicabtagenee ciloleucel, Tisagenlecleucel, Lisocabtagen maraleucel) or with the investigational medicinal product MB-CART19.1 (in-house manufactured 2 nd generation anti-CD19 CAR-T cells with a 4.1BB co-stimulatory domain; Kretschmann et al., 2023). Average peak expansion was reached at day 7 in both patient groups. Despite comparable average peak levels, patients with AID showed lower incidence and severity of cytokine-release syndrome (CRS) and immune-effector cell associated neurotoxicity syndrome (ICANS) compared to the NHL cohort. Consistent with reduced toxicity, AID patients received less tocilizumab and glucocorticoid treatment. Bone marrow toxicity with severe and/or prolonged cytopenia is a frequent long-term CAR-T cell related adverse event. Of interest, AID patients demonstrated a less profound decrease of neutrophils, platelet counts, and hemoglobin after CAR-T cell therapy compared to NHL patients and a faster recovery to normal values. Occurrence and duration of severe neutropenia (&amp;lt;500 neutrophils/µl) also differed between both patient cohorts. There was no late bone marrow toxicity in AID patients, whereas 19 of 40 patients with NHL showed at least one &amp;gt; grade 3 blood count reduction. In line with the Hematotox-Score predicting bone marrow toxicity, baseline inflammation (e.g. C-reactive protein, ferritin) prior to CAR-T cell treatment was higher in lymphoma patients than in AID patients. While AID patients quickly returned to normal ferritin values, elevated ferritin levels often persisted in the NHL cohort after CAR-T cell therapy. Given that AID patients showed fewer late toxicity and lower long-term inflammation, we speculated that persistence of CAR-T cells was lower. In line, longitudinal monitoring of the patient's immune cells including CAR-T cell kinetics demonstrated a typical contraction of CAR-T cell numbers with low-level persistence in both cohorts. We did not observe a difference in absolute CAR-T cell numbers or dynamics within the first three months after treatment. In contrast to NHL patients in remission, AID patients did not develop long-term persistence of CAR-T cells as most patients lost CAR-T cells within 1 year after cell infusion. Consistent with this observation, all AID patients showed B-cell reconstitution after loss of CAR-T cell persistence. Taken together, we observed less toxicities and severe adverse events in AID patients than in NHL patients despite similar CAR-T cell expansion and dynamics. The lack of CAR-T cell persistence and the early recurrence of B cells in AID patients is so far not explained and could provide novel insights in the biological processes controlling long-term CAR-T cell persistence.

Chance Favors the Prepared Genomes: Horizontal Transfer Shapes the Emergence of Antibiotic Resistance Mutations in Core Genes.

Bacterial lineages acquire novel traits at diverse rates in part because the genetic background impacts the successful acquisition of novel genes by horizontal transfer. Yet, how horizontal transfer affects the subsequent evolution of core genes remains poorly understood. Here, we studied the evolution of resistance to quinolones in Escherichia coli accounting for population structure. We found 60 groups of genes whose gain or loss induced an increase in the probability of subsequently becoming resistant to quinolones by point mutations in the gyrase and topoisomerase genes. These groups include functions known to be associated with direct mitigation of the effect of quinolones, with metal uptake, cell growth inhibition, biofilm formation, and sugar metabolism. Many of them are encoded in phages or plasmids. Although some of the chronologies may reflect epidemiological trends, many of these groups encoded functions providing latent phenotypes of antibiotic low-level resistance, tolerance, or persistence under quinolone treatment. The mutations providing resistance were frequent and accumulated very quickly. Their emergence was found to increase the rate of acquisition of other antibiotic resistances setting the path for multidrug resistance. Hence, our findings show that horizontal gene transfer shapes the subsequent emergence of adaptive mutations in core genes. In turn, these mutations further affect the subsequent evolution of resistance by horizontal gene transfer. Given the substantial gene flow within bacterial genomes, interactions between horizontal transfer and point mutations in core genes may be a key to the success of adaptation processes.

Trajectories of perinatal suicidal ideation from early pregnancy to six weeks postpartum and their influencing factors: A prospective longitudinal study

Few studies focused on the trajectory of perinatal suicidal ideation from early pregnancy and covered whole routine perinatal periods. This study aimed to investigate the prevalence of suicidal ideation from early pregnancy to six weeks postpartum, and further explore the trajectories of perinatal suicidal ideation and their risk factors. A prospective longitudinal study was conducted in a comprehensive tertiary hospital in Hunan province, China among 1089 participants. Perinatal suicidal ideation and depression were assessed by item 9 of Patient Health Questionnaire 9 and the remaining eight items. Sociodemographic and psychological factors were collected by self-reported comprehensive questionnaires. Latent Growth Curve and Growth Mixture Modeling were used to identify the trajectories of suicidal ideation and logistic regression was used to explore risk factors of trajectories. A total of 629 participants were included. The prevalence of suicidal ideation was 16.4% from early pregnancy to six weeks postpartum, with 12.1% in pregnancy and 7.8% in postpartum. Two trajectories were identified: “persistent low levels of suicidal ideation” (92.9%) and “persistent high levels of suicidal ideation” (7.1%). 40.63% of women who screened positive for suicidal ideation during early pregnancy were in the “persistent high level of suicidal ideation” trajectory. A low level of neuroticism and anxiety symptoms during early pregnancy was associated with “persistent high levels of suicidal ideation”. In conclusion, suicidal ideation of women during the perinatal period was dynamic, Suicidal ideation screening and identification in early pregnancy should be addressed for perinatal women to facilitate timely early interventions.

Alleviating Medical Debt in the United States.

Alleviating Medical Debt in the United States.

Social avoidance and testosterone enhanced exposure efficacy in women with social anxiety disorder: A pilot investigation

Social avoidance has been associated with more persistent social anxiety disorder (SAD) symptoms and low testosterone levels in individuals with SAD. We tested whether pre-treatment avoidance tendencies moderate the efficacy of testosterone-augmented exposure therapy. Fifty-five females with SAD received two exposure sessions during which fear levels were assessed. Session 1 was augmented with testosterone (0.50 mg) or placebo. Avoidance tendencies and symptom severity were assessed pre- and post-exposure. Participants showed stronger avoidance for social versus non-social stimuli and this tendency remained stable over time. Stronger pretreatment avoidance tendencies were associated with larger fear reduction in the testosterone but not the placebo condition. This effect did not transfer to the second non-enhanced session or symptom severity. The findings support the hypothesis that individuals suffering from SAD with relatively stronger pretreatment avoidance tendencies benefit more from testosterone-augmentation, pointing to a potential behavioral marker for testosterone enhancement of exposure therapy.

Assessment of antigenemia among children in four hotspots of filarial endemic districts of Nepal during post-MDA surveillance

BackgroundSixty-three out of 77 districts reported lymphatic filariasis (LF) endemic in Nepal. Mass drug administration (MDA) with diethylcarbamazine (DEC) and albendazole (ALB) treatment program was continued for 6 to 11 rounds in these districts. Nepal government has stopped the MDA program based on the transmission assessment survey (TAS) report of 2014 and 2018 indicating Wuchereria bancrofti antigenemia prevalence < 2%. But the persistence of low levels of the circulating filarial antigen (CFA) in some foci of four endemic districts of Central Nepal, i.e., 0.4% in Dhading, 0.7% in Mahottari, 0.21% in Lalitpur and 1.2% in Bara district could responsible for enhancing the risk of infection resurgence. Hence the present study was designed to assess antigenic prevalence using Filariasis Test Strip (Alere, Scarborough ME) in children born after MDA in hotspot areas of four endemic districts of Central Nepal.ResultsThe present study covers 70% children of the eligible population. The result revealed significantly high CFA prevalence in hotspots of Mahottari district belonging to the Terai region and Dhading district belonging to the hilly region, i.e., 13% and 10%, respectively, compared to baseline prevalence and TAS report. While in Lalitpur district and Bara district CFA prevalence was still found to be less than 2%. A higher number of MDA rounds covered in hotspots were found significantly associated with the low antigenic prevalence of W. bancrofti. Whereas median treatment coverage and inter-quartile range (IQR) in study districts were not found significantly associated with CFA prevalence. Although the clinical manifestation of hydrocele (1%) was found in all four study districts, it was not due to the W. bancrofti infection.ConclusionsTwo hotspot regions, one each from the Terai (Mahottari) and hilly (Dhading) districts were found highly prevalent with CFA and significantly associated with the number of MDA rounds but were not associated with treatment coverage and IQR. Higher CFA prevalence was observed in hotspots where baseline prevalence was high together indicating that rounds of MDA program need to be extended further in these hotspot regions of endemic districts.

1161-P: Patterns of Diabetes Distress (DD) and Glycemic Outcomes in Teens with Type 1 Diabetes (T1D)

Background: DD distracts from T1D self-management, contributing to suboptimal glycemia. Yet, DD can change day-to-day and over time. We compared A1c trends in teens with increasing vs. decreasing DD over time. Methods: At baseline, 6, 12, and 18 months, participants (N=301) ages 13-17 years completed the Problem Areas in Diabetes Survey—Pediatric scale; higher scores indicate more DD with ≥41 indicating elevated DD. We identified three trajectories: participants with low baseline DD, who then reported persistent high DD; participants with high baseline DD, who then had persistent low DD levels; all others. Mean A1c levels were compared at baseline and 18 months. Results: At baseline, participants (49% male, 78% white) were 15.0±1.3 years old with T1D duration 6.5±3.7 years; 59% used insulin pumps; 12% used CGM; A1c was 8.5±1.1%. Twenty-six participants (9%) had elevated DD at baseline and then low DD at subsequent time points; A1c did not change significantly from 0 to 18 months for these participants (p=.33). Thirty-five participants (12%) had low DD at baseline and then elevated DD at subsequent time points; A1c increased significantly from 0 to 18 months for these participants (p=.01). The remaining participants (n=240) had varying levels of DD with no significant change in A1C (p=.05). Conclusion: Adolescents who initially had low DD and reported increasing DD over time may be at risk for worsening glycemic outcomes. Disclosure K.Wentzell: None. L.J.Tinsley: None. L.K.Volkening: None. D.E.Mcgill: Employee; Vertex Pharmaceuticals Incorporated. B.J.Anderson-thomas: None. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. Funding National Institutes of Health (T32DK007260); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK095273); JDRF (2-SRA-2014-253-M-B)

Lipid peroxidation mediates the association between iron overload and liver injury: cross-sectional and longitudinal analyses in general Chinese urban adults.

Iron overload has been associated with acute/chronic organ failure, but whether iron overload induces liver injury remains unclear. The objectives of this study were to assess the relationship between urinary iron and serum alanine aminotransferase (ALT, a biomarker for liver injury), and investigate the potential mediating roles of lipid peroxidation and oxidative DNA damage in such association. Levels of urinary iron, serum ALT, and urinary biomarkers of lipid peroxidation (8-iso-prostaglandin-F2α [8-iso-PGF2α]) and oxidative DNA damage (8-hydroxy-deoxyguano-sine [8-OHdG]) were measured among 5386 observations of 4220 participants from the Wuhan-Zhuhai cohort. The relationships of urinary ironwith serum ALT and risk of hyperALT were evaluated by linear mixed model and logistic regression model, respectively. The mediating roles of 8-iso-PGF2α and 8-OHdG were assessed by mediation analyses. This cross-sectional analysis found that urinary iron was positively associated with ALT (β = 0.032; 95% CI: 0.020, 0.044) and hyperALT prevalence (OR = 1.127; 95% CI: 1.065, 1.192). After 3years of follow-up, participants with persistent high iron levels had increased risk of developing hyperALT (RR = 3.800; 95% CI: 1.464, 9.972) when compared with those with persistent low iron levels. In addition, each 1% increase in urinary iron was associated with a 0.146% (95% CI: 0.128%, 0.164%) increase and a 0.192% (95% CI: 0.154%, 0.229%) increase in 8-iso-PGF2α and 8-OHdG, respectively. Urinary 8-iso-PGF2α (β = 0.056; 95% CI: 0.039, 0.074) was positively associated with ALT, while the association between 8-OHdG and ALT was insignificant. Furthermore, increased 8-iso-PGF2α significantly mediated 22.48% of the urinary iron-associated ALT increment. Our study demonstrated that iron overload was significantly associated with liver injury, which was partly mediated by lipid peroxidation. Controlling iron intake and regulating lipid peroxidation may help in preventing liver injury.