Letermovir as secondary prophylaxis of cytomegalovirus infection after allogeneic hematopoietic cell transplantation: A single center experience.

Letermovir, a novel anti-cytomegalovirus (CMV) agent acts by inhibiting the viral terminase complex and is approved for primary prophylaxis in CMV seropositive patients post allogeneic hematopoietic cell transplantation (HCT). The favorable efficacy and safety profile make it an attractive option for use as secondary prophylaxis in patients at high-risk for CMV reactivation. In this study, we report the efficacy and safety of letermovir secondary prophylaxis after at least one treated episode of CMV reactivation in a cohort of 39 high-risk patients. Thirty two (82%) patients received anti-thymocyte globulin (ATG), 27 (69%) received a combination of ATG and post-transplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis. Twenty one patients (54%) received CMV seronegative grafts. In addition, 18 (46%) patients had HLA mismatched unrelated or haploidentical donors while 18 (46%) had active GVHD requiring immunosuppression at the time of commencing secondary prophylaxis. Letermovir was initiated at a median of 47 days (range, 41-56) after HCT and was administered for a median duration of 77 days (range, 46-90). A single breakthrough CMV reactivation was noted in this high-risk cohort. Four additional episodes of CMV reactivation occurred at a median of 28 days (range, 23-59 days) after discontinuation of secondary prophylaxis. The drug was well tolerated and 77% of the cohort completed the planned duration of secondary prophylaxis. None of the patients discontinued treatment due to treatment-related adverse effects. In conclusion, letermovir is effective and well tolerated and may be considered for secondary prophylaxis in patients at high risk for CMV reactivation. Prospective studies are required to validate these findings.

Genetic hypogonadal (Gnrh1hpg) mouse model uncovers influence of reproductive axis on maturation of the gut microbiome during puberty.

The gut microbiome plays a key role in human health and gut dysbiosis is linked to many sex-specific diseases including autoimmune, metabolic, and neurological disorders. Activation of the hypothalamic-pituitary-gonadal (HPG) axis during puberty leads to sexual maturation and development of sex differences through the action of gonadal sex steroids. While the gut microbiome also undergoes sex differentiation, the mechanisms involved remain poorly understood. Using a genetic hypogonadal (hpg) mouse model, we sampled the fecal microbiome of male and female wild-type and hpg mutant mice before and after puberty to determine how microbial taxonomy and function are influenced by age, sex, and the HPG axis. We showed that HPG axis activation during puberty is required for sexual maturation of the gut microbiota composition, community structure, and metabolic functions. We also demonstrated that some sex differences in taxonomic composition and amine metabolism developed independently of the HPG axis, indicating that sex chromosomes are sufficient for certain sex differences in the gut microbiome. In addition, we showed that age, independent of HPG axis activation, led to some aspects of pubertal maturation of the gut microbiota community composition and putative functions. These results have implications for microbiome-based treatments, indicating that sex, hormonal status, and age should be considered when designing microbiome-based therapeutics.

Dapagliflozin reduces systemic inflammation in patients with type 2 diabetes without known heart failure.

OBJECTIVE: Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis. RESEARCH AND DESIGN METHODS: This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Global myocardial strain was assessed by feature tracking; cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); and cardiac tissue inflammation was assessed by T2 mapping. RESULTS: Between the baseline and 12-month time point, plasma IL-1B was reduced (- 1.8 pg/mL, P = 0.003) while ketones were increased (0.26 mM, P = 0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (- 158.9 pmole/min/106 cells, P = 0.0497 vs. - 5.2 pmole/min/106 cells, P = 0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. Global myocardial strain, ECV and T2 relaxation time did not change in both study groups. GOV REGISTRATION: NCT03782259.

Impact of cytomegalovirus (CMV) seroconversion pre-allogeneic hematopoietic cell transplantation on posttransplant outcomes.

Cytomegalovirus (CMV) reactivation post-allogeneic hematopoietic cell transplantation (post-alloHCT) increases morbidity and mortality. We sought to determine the frequency of CMV seroconversion in patients pre-alloHCT and to investigate the impact on posttransplant outcomes. We retrospectively investigated 752 adult patients who underwent alloHCT at our center from January 2015 to February 2020 before the adoption of letermovir prophylaxis. CMV serology was assessed at consult and pretransplant. The cohort was divided into four groups based on pretransplant CMV seroconversion: negative to positive (Group 1), positive to negative (Group 2), consistently negative (Group 3), and consistently positive (Group 4). Eighty-nine patients (12%) had seroconverted from negative to positive, 17 (2%) from positive to negative, 151 (20%) were consistently seronegative, and 495 (66%) were consistently seropositive pretransplant. For the four CMV serostatus groups, cumulative incidence of CMV reactivation at 6 months posttransplant was 4.5%, 47.1%, 6.6%, and 76.6% for Groups 1, 2, 3, and 4, respectively (p < .0001). No differences between groups were seen regarding Grade III-IV acute graft-versus-host disease (GVHD) (p = .91), moderate/severe chronic GVHD (p = .41), or graft failure (p = .28). On multivariable analysis, there was no impact of CMV serostatus group on overall survival (p = .67), cumulative incidence of relapse (p = .83) or non-relapse mortality. alloHCT patients who demonstrate CMV seroconversion pretransplant from negative to positive have a very low risk of CMV reactivation posttransplant. The observed seroconversion may be due to passive CMV immunity acquired through blood products. Quantitative CMV immunoglobulin G/immunoglobulin M pretransplant may help differentiate between true seroconversion and passively transmitted CMV immunoglobulin.

Combined neuromodulation and resection for functional cortex epilepsy: a case series.

OBJECTIVE: Medically refractory epilepsy (MRE) often requires resection of the seizure onset zone (SOZ) for effective treatment. However, when the SOZ is in functional cortex (FC), achieving complete and safe resection becomes difficult, due to the seizure network overlap with function. The authors aimed to assess the safety and outcomes of a combined approach involving partial resection combined with focal neuromodulation for FC refractory epilepsy. METHODS: The authors performed a retrospective analysis of individuals diagnosed with MRE who underwent surgical intervention from January 2015 to December 2022. Patients whose SOZ was located in FC and were treated with resection combined with simultaneous implantation of a focal neuromodulation device (responsive neurostimulation [RNS] device) with more than 12 months of follow-up data were included. All patients underwent a standard epilepsy preoperative assessment including intracranial electroencephalography and extraoperative stimulation mapping. Resections were performed under general anesthesia, followed by the concurrent implantation of an RNS device. RESULTS: Seven patients (4 males, median age 32.3 years, all right-handed) were included. The median interval from seizure onset to surgery was 17.4 years. The epileptogenic network included sensorimotor areas (cases 2, 3, and 6), visual cortex (case 1), language areas (cases 4 and 7), and the insula (case 5). The median follow-up was 3 years (range 1-5.8 years). No significant changes in neuropsychological tests were reported. One permanent nondisabling planned neurological deficit (left inferior quadrantanopia) was observed. Six patients had stimulation activated at a median of 4.7 months after resection. All patients achieved good seizure outcomes (5 with Engel class I and 2 with Engel class II outcomes). CONCLUSIONS: Maximal safe resection combined with focal neuromodulation presents a promising alternative to stand-alone resections for MRE epileptogenic zones overlapping with functional brain. This combined approach prioritizes the preservation of function while improving seizure outcomes.

Regulation of THI and PDC genes by Pdc2 in Nakaseomyces glabratus (Candida glabrata) is complex.

Thiamine (vitamin B1) is essential for glucose catabolism. In the yeast species Nakaseomyces glabratus (formerly Candida glabrata) and Saccharomyces cerevisiae, the transcription factor Pdc2 (with Thi3 and Thi2) upregulates pyruvate decarboxylase (PDC) genes and thiamine biosynthetic and acquisition (THI) genes during starvation. There have not been genome-wide analyses of Pdc2 binding. Previously, we identified small regions of Pdc2 regulated genes sufficient to confer thiamine regulation. Here, we performed deletion analyses on these regions. We observed that when the S. cerevisiae PDC5 promoter is introduced into N. glabratus, it is thiamine starvation inducible but does not require the Thi3 coregulator. The ScPDC5 promoter contains a 22 bp duplication with an AT-rich spacer between the two repeats, which are important for regulation. Loss of the first 22 bp element does not eliminate regulation, but the promoter becomes Thi3-dependent, suggesting cis architecture can generate a Thi3-independent, thiamine starvation inducible response. Whereas many THI promoters only have one copy of this element, addition of the first 22 bp element to a Thi3-dependent promoter confers Thi3-independence. Finally, we performed fluorescence anisotropy and ChIP-seq. Pdc2 and Thi3 bind to regions that share similarity to the 22 bp element in the ScPDC5 promoter and previously identified cis elements in N. glabratus promoters. Also, while Pdc2 binds to THI and PDC promoters, neither Pdc2 nor Thi3 appear to bind the evolutionarily new NgPMU3 promoter that is regulated by Pdc2. Further study is warranted because PMU3 is required for cells to acquire thiamine from environments where thiamine is phosphorylated, such as in the human bloodstream.

Motive and Opportunity: MYC rearrangements in high-grade B-cell lymphoma with MYC and BCL2 rearrangements-an LLMPP study.

Rearrangements that place the oncogenes MYC, BCL2, or BCL6 adjacent to superenhancers are common in mature B-cell lymphomas. Lymphomas with diffuse large B-cell lymphoma (DLBCL) or high-grade morphology with both MYC and BCL2 rearrangements are classified as high-grade B-cell lymphoma with MYC and BCL2 rearrangements ("double hit": HGBCL-DH-BCL2) and are associated with aggressive disease and poor outcomes. Although it is established that MYC rearrangements involving immunoglobulin (IG) loci are associated with inferior outcomes relative to those involving other non-IG superenhancers, the frequency of, and mechanisms driving, IG vs non-IG MYC rearrangements have not been elucidated. Here we used custom targeted capture and/or whole genome sequencing to characterize oncogene rearrangements across 883 mature B-cell lymphomas including Burkitt lymphoma, follicular lymphoma, DLBCL, and HGBCL-DH-BCL2 tumors. We demonstrate that, while BCL2 rearrangement topology is consistent across entities, HGBCL-DH-BCL2 have distinct MYC rearrangement architecture relative to tumors with single MYC rearrangements or with both MYC and BCL6 rearrangements (HGBCL-DH-BCL6), including both a higher frequency of non-IG rearrangements and different architecture of MYC::IGH rearrangements. The distinct MYC rearrangement patterns in HGBCL-DH-BCL2 occur on the background of high levels of somatic hypermutation across MYC partner loci in HGBCL-DH-BCL2, creating more opportunity to form these rearrangements. Furthermore, because one IGH allele is already disrupted by the existing BCL2 rearrangement, the MYC rearrangement architecture in HGBCL-DH-BCL2 likely reflects selective pressure to preserve both BCL2 and B cell receptor expression. These data provide new mechanistic explanations for the distinct patterns of MYC rearrangements observed across different lymphoma entities.

Review of the Association Between Long-Term and Current Systemic Steroid Use With Electromechanical Complications and Inpatient Mortality After ST-Elevation Myocardial Infarction.

Background The impact of long-term systemic steroid use on electrical and mechanical complications following ST-segment elevation myocardial infarction (STEMI) has not been extensively studied. Methods In a retrospective cohort study of the National Inpatient Sample (NIS) from 2018 to 2020, adults admitted with STEMI were dichotomized based on the presence of long-term (current) systemic steroid (LTCSS) use. The primary outcome was all-cause mortality. Secondary outcomes included a composite of mechanical complications, electrical, hemodynamic, and thrombotic complications, as well as revascularization complexity, length of stay (LOS), and total charge. Multivariate linear and logistic regressions were used to adjust for confounders. Results Out of 608,210 admissions for STEMI, 5,310 (0.9%) had LTCSS use. There was no significant difference in the odds of all-cause mortality (aOR: 0.89, 95%CI: 0.74-1.08, p-value: 0.245) and the composite of mechanical complications (aOR: 0.74, 95%CI: 0.25-2.30, p-value: 0.599). LTCSS use was associated with lower odds of ventricular tachycardia, atrioventricular blocks, new permanent-pacemaker insertion, cardiogenic shock, the need for mechanical circulatory support, mechanical ventilation, cardioversion, a reduced LOS by 1 day, and a reduced total charge by 34,512 USD (all p-values: <0.05). There were no significant differences in the revascularization strategy (coronary artery bypass graft (CABG) vs. percutaneous coronary interventions (PCI)) or in the incidence of composite thrombotic events. Conclusion LTCSS use among patients admitted with STEMI was associated with lower odds of electrical dysfunction and hemodynamic instability but no difference in the odds of mechanical complications, CABG rate, all-cause mortality, cardiac arrest, or thrombotic complications. Further prospective studies are needed to evaluate these findings further.

Assessing the Impact of Comorbid Hypercalcemia on Inpatient Outcomes of Patients With Diffuse Large B-cell Lymphoma During Admission for Chemotherapy.

Introduction Diffuse large B-cell lymphoma (DLBCL) may be complicated by hypercalcemia at various stages of treatment. The impact of hypercalcemia on chemotherapy admission outcomes in DLBCL is not well described.  Methods In a retrospective analysis, using the National Inpatient Sample database (2018 - 2020), patients with DLBCL admitted for chemotherapy were dichotomized based on the presence of hypercalcemia. Our primary outcome was all-cause mortality. Secondary outcomes included length of stay (LOS), total charge, rate of acute kidney injury (AKI), tumor lysis syndrome (TLS), hyperkalemia, metabolic acidosis, acute encephalopathy, septic shock, Clostridiodes difficile infection, acute respiratory failure, and venous thromboembolic events (VTE). Results We identified 78,955 patients, among whom 1,375 (1.74%) had hypercalcemia. Hypercalcemia was associated with higher odds of all-cause mortality (aOR:3.05, p-value:0.020), TLS (aOR:8.81, p-value<0.001), acute metabolic encephalopathy (aOR:4.89, p-value<0.001), AKI (aOR:5.29, p-value<0.001), hyperkalemia (aOR:2.84, p-value:0.002), metabolic acidosis (aOR:3.94, p-value<0.001) and respiratory failure (aOR:2.29, p-value:0.007) and increased LOS by 1 day and total charge by 12, 501 USD. Conclusions In patients with DLBCL admitted for inpatient chemotherapy, those with hypercalcemia compared to a cohort without had higher odds of; all-cause mortality, TLS, AKI, acute encephalopathy, acute metabolic acidosis, hyperkalemia, and acute respiratory failure as well as higher LOS and total charge.

MYC overexpression in natural killer cell lymphoma: prognostic and therapeutic implications.

The current clinical management of Extranodal NK/T-cell lymphoma (ENKTL) primarily depends on conventional chemotherapy and radiotherapy, underscoring the need for innovative therapeutic strategies. This study explores the clinical significance and therapeutic implication of c-MYC (MYC) in ENKTL. Initially, we identified MYC protein overexpression in approximately 75% of cases within a large cohort of 111 patients. MYC overexpression was strongly correlated with lymphoma cell proliferation and poor clinical outcomes. Intriguingly, integrating MYC expression into the PINK-E prognostic model significantly enhanced its predictive power. Subsequently, we implemented MYC knockdown (KD) in NK malignancy cell lines with MYC overexpression, resulting in significant viability reduction. RNA-sequencing (RNA-seq) used to determine MYC function revealed a high overlap with canonical MYC-regulated genes and enrichment in metabolism and cell cycle regulation. Integrative analysis of the RNA-seq data upon MYC KD with gene expression profiles of primary ENKTL cases identified a subset of genes closely associated with MYC overexpression. Among these, CDK4 emerged as a potential therapeutic target, and its inhibition not only abrogated MYC function but also decreased MYC expression in NK malignancy cells. Furthermore, the clinical-grade CDK4/6 inhibitor palbociclib exhibited a potent anti-tumor effect in xenograft mouse models, especially when combined with gemcitabine. In summary, our study firmly establishes MYC as an oncogene with prognostic significance in ENKTL and highlights CDK4 inhibition as a promising therapeutic strategy for treating ENKTL with MYC overexpression.

Optimized Multilayer Perceptron for Sensorimotor Functional Mapping Based on a Few Minutes of Intracranial Electroencephalogram Data.

Using 6-minute free-running intracranial-electroencephalogram (icEEG) during sleep, an optimized multilayer perceptron (MLP) neural network accurately maps the sensorimotor cortex (SM) and identifies the anterior lip of the central sulcus (CS) in intractable epilepsy patients. We calculated 6 performance metrics to evaluate the MLP's efficacy: accuracy, area under the curve (AUC), recall, precision, F1-scores, and specificity. Each layer had 4 neurons with hyperbolic TanH activation function and 4 with Gaussian distribution function. Conventional 10-fold cross-validation was used. Feature extension (ε) and weighted imbalanced data (w) improved MLP performance. ANN NEUROL 2024;96:187-193.

Systematic 1 Hz direct electrical stimulation for seizure induction: A reliable method for localizing seizure onset zone and predicting seizure freedom.

OBJECTIVE: To prospectively investigate the utility of seizure induction using systematic 1 Hz stimulation by exploring its concordance with the spontaneous seizure onset zone (SOZ) and relation to surgical outcome; comparison with seizures induced by non-systematic 50 Hz stimulation was attempted as well. METHODS: Prospective cohort study from 2018 to 2021 with ≥ 1 y post-surgery follow up at Yale New Haven Hospital. With 1 Hz, all or most of the gray matter contacts were stimulated at 1, 5, and 10 mA for 30-60s. With 50 Hz, selected gray matter contacts outside of the medial temporal regions were stimulated at 1-5 mA for 0.5-3s. Stimulation was bipolar, biphasic with 0.3 ms pulse width. The Yale Brain Atlas was used for data visualization. Variables were analyzed using Fisher's exact, χ2, or Mann-Whitney test. RESULTS: Forty-one consecutive patients with refractory epilepsy undergoing intracranial EEG for localization of SOZ were included. Fifty-six percent (23/41) of patients undergoing 1 Hz stimulation had seizures induced, 83% (19/23) habitual (clinically and electrographically). Eighty two percent (23/28) of patients undergoing 50 Hz stimulation had seizures, 65% (15/23) habitual. Stimulation of medial temporal or insular regions with 1 Hz was more likely to induce seizures compared to other regions [15/32 (47%) vs. 2/41 (5%), p < 0.001]. Sixteen patients underwent resection; 11/16 were seizure free at one year and all 11 had habitual seizures induced by 1 Hz; 5/16 were not seizure free at one year and none of those 5 had seizures with 1 Hz (11/11 vs 0/5, p < 0.0001). No patients had convulsions with 1 Hz stimulation, but four did with 50 Hz (0/41 vs. 4/28, p = 0.02). SIGNIFICANCE: Induction of habitual seizures with 1 Hz stimulation can reliably identify the SOZ, correlates with excellent surgical outcome if that area is resected, and may be superior (and safer) than 50 Hz for this purpose. However, seizure induction with 1 Hz was infrequent outside of the medial temporal and insular regions in this study.

Identification of clinical disease trajectories in neurodegenerative disorders with natural language processing.

Neurodegenerative disorders exhibit considerable clinical heterogeneity and are frequently misdiagnosed. This heterogeneity is often neglected and difficult to study. Therefore, innovative data-driven approaches utilizing substantial autopsy cohorts are needed to address this complexity and improve diagnosis, prognosis and fundamental research. We present clinical disease trajectories from 3,042 Netherlands Brain Bank donors, encompassing 84 neuropsychiatric signs and symptoms identified through natural language processing. This unique resource provides valuable new insights into neurodegenerative disorder symptomatology. To illustrate, we identified signs and symptoms that differed between frequently misdiagnosed disorders. In addition, we performed predictive modeling and identified clinical subtypes of various brain disorders, indicative of neural substructures being differently affected. Finally, integrating clinical diagnosis information revealed a substantial proportion of inaccurately diagnosed donors that masquerade as another disorder. The unique datasets allow researchers to study the clinical manifestation of signs and symptoms across neurodegenerative disorders, and identify associated molecular and cellular features.

Flow cytometry-based measurable residual disease (MRD) analysis identifies AML patients who may benefit from allogeneic hematopoietic stem cell transplantation.

Measurable residual disease (MRD) monitoring independently predicts long-term outcomes in patients with acute myeloid leukemia (AML). Of the various modalities available, multiparameter flow cytometry-based MRD analysis is widely used and relevant for patients without molecular targets. In the transplant (HCT) setting, the presence of MRD pre-HCT is associated with adverse outcomes. MRD-negative remission status pre-HCT was also associated with longer overall (OS) and progression-free survival and a lower risk of relapse. We hypothesize that the combination of disease risk and MRD at the time of first complete remission (CR1) could identify patients according to the benefit gained from HCT, especially for intermediate-risk patients. We performed a retrospective analysis comparing the outcomes of HCT versus non-HCT therapies based on MRD status in AML patients who achieved CR1. Time-dependent analysis was applied considering time-to-HCT as a time-dependent covariate and compared HCT versus non-HCT outcomes according to MRD status at CR1. Among 336 patients assessed at CR1, 35.1% were MRD positive (MRDpos) post-induction. MRDpos patients benefitted from HCT with improved OS and relapse-free survival (RFS), while no benefit was observed in MRDneg patients. In adverse-risk patients, HCT improved OS (HR for OS 0.55; p = 0.05). In intermediate-risk patients, HCT benefit was not significant for OS and RFS. Intermediate-risk MRDpos patients were found to have benefit from HCT with improved OS (HR 0.45, p = 0.04), RFS (HR 0.46, p = 0.02), and CIR (HR 0.41, p = 0.02). Our data underscore the benefit of HCT in adverse risk and MRDpos intermediate-risk AML patients.

Multiple microbial guilds mediate soil methane cycling along a wetland salinity gradient.

Estuarine wetlands harbor considerable carbon stocks, but rising sea levels could affect their ability to sequester soil carbon as well as their potential to emit methane (CH4). While sulfate loading from seawater intrusion may reduce CH4 production due to the higher energy yield of microbial sulfate reduction, existing studies suggest other factors are likely at play. Our study of 11 wetland complexes spanning a natural salinity and productivity gradient across the San Francisco Bay and Delta found that while CH4 fluxes generally declined with salinity, they were highest in oligohaline wetlands (ca. 3-ppt salinity). Methanogens and methanogenesis genes were weakly correlated with CH4 fluxes but alone did not explain the highest rates observed. Taxonomic and functional gene data suggested that other microbial guilds that influence carbon and nitrogen cycling need to be accounted for to better predict CH4 fluxes at landscape scales. Higher methane production occurring near the freshwater boundary with slight salinization (and sulfate incursion) might result from increased sulfate-reducing fermenter and syntrophic populations, which can produce substrates used by methanogens. Moreover, higher salinities can solubilize ionically bound ammonium abundant in the lower salinity wetland soils examined here, which could inhibit methanotrophs and potentially contribute to greater CH4 fluxes observed in oligohaline sediments.IMPORTANCELow-level salinity intrusion could increase CH4 flux in tidal freshwater wetlands, while higher levels of salinization might instead decrease CH4 fluxes. High CH4 emissions in oligohaline sites are concerning because seawater intrusion will cause tidal freshwater wetlands to become oligohaline. Methanogenesis genes alone did not account for landscape patterns of CH4 fluxes, suggesting mechanisms altering methanogenesis, methanotrophy, nitrogen cycling, and ammonium release, and increasing decomposition and syntrophic bacterial populations could contribute to increases in net CH4 flux at oligohaline salinities. Improved understanding of these influences on net CH4 emissions could improve restoration efforts and accounting of carbon sequestration in estuarine wetlands. More pristine reference sites may have older and more abundant organic matter with higher carbon:nitrogen compared to wetlands impacted by agricultural activity and may present different interactions between salinity and CH4. This distinction might be critical for modeling efforts to scale up biogeochemical process interactions in estuarine wetlands.

Functional parcellation of the cingulate gyrus by electrical cortical stimulation: a synthetic literature review and future directions.

BACKGROUND: The cingulate gyrus (CG), a brain structure above the corpus callosum, is recognised as part of the limbic system and plays numerous vital roles. However, its full functional capacity is yet to be understood. In recent years, emerging evidence from imaging modalities, supported by electrical cortical stimulation (ECS) findings, has improved our understanding. To our knowledge, there is a limited number of systematic reviews of the cingulate function studied by ECS. We aim to parcellate the CG by reviewing ECS studies. DESIGN/METHODS: We searched PubMed and Embase for studies investigating CG using ECS. A total of 30 studies met the inclusion criteria. We evaluated the ECS responses across the cingulate subregions and summarised the reported findings. RESULTS: We included 30 studies (totalling 887 patients, with a mean age of 31.8±9.8 years). The total number of electrodes implanted within the cingulate was 3028 electrode contacts; positive responses were obtained in 941 (31.1%, median percentages, 32.3%, IQR 22.2%-64.3%). The responses elicited from the CG were as follows. Simple motor (8 studies, 26.7 %), complex motor (10 studies, 33.3%), gelastic with and without mirth (7 studies, 23.3%), somatosensory (9 studies, 30%), autonomic (11 studies, 36.7 %), psychic (8 studies, 26.7%) and vestibular (3 studies, 10%). Visual and speech responses were also reported. Despite some overlap, the results indicate that the anterior cingulate cortex is responsible for most emotional, laughter and autonomic responses, while the middle cingulate cortex controls most complex motor behaviours, and the posterior cingulate cortex (PCC) regulates visual, among various other responses. Consistent null responses have been observed across different regions, emphasising PCC. CONCLUSIONS: Our results provide a segmental mapping of the functional properties of CG, helping to improve precision in the surgical planning of epilepsy.

Letermovir prophylaxis for cytomegalovirus reactivation in allogeneic hematopoietic cell transplant recipients: Single center Canadian data.

BACKGROUND: Cytomegalovirus (CMV) is associated with morbidity and mortality following allogeneic hematopoietic cell transplantation (alloHCT). Letermovir is a novel antiviral agent that prevents CMV reactivation in alloHCT patients, with limited data regarding influence on post-alloHCT outcomes. METHODS: We retrospectively examined 273 alloHCT recipients, 158 in the non-letermovir cohort (NLC), and 115 in the cohort using letermovir prophylaxis (LC). Patients that received letermovir were CMV-seropositive and met criteria for high risk of CMV reactivation. RESULTS: Median start of letermovir was 21 days post-alloHCT, median duration of prophylaxis was 86 days. Letermovir prophylaxis demonstrated a statistically significant reduction in first CMV reactivation (at 200 days post 63.9% in the NLC vs. 35.7% in the LC; p < .001). On univariate analysis at 1 year, overall survival (OS) for NLC was 79.6% and 79.5% for LC (p = .54). Non relapse mortality (NRM) at 1 year for NLC was 12% and 12.3% for LC (p = .69). Cumulative incidence of relapse (CIR) at 1 year was 13.9% for NLC versus 17.1 for the LC (p = .27). On multivariable analysis, there was no significant difference between the two cohorts for OS, NRM, and CIR. CONCLUSIONS: Letermovir prophylaxis started at day +21 post-alloHCT reduced CMV reactivation, with no impact on posttransplant outcomes.

TP53-mutated acute myeloid leukemia and myelodysplastic syndrome: biology, treatment challenges, and upcoming approaches.

Improved understanding of TP53 biology and the clinicopathological features of TP53-mutated myeloid neoplasms has led to the recognition of TP53-mutated acute myeloid leukemia/myelodysplastic syndrome (TP53m AML/MDS) as a unique entity, characterized by dismal outcomes following conventional therapies. Several clinical trials have investigated combinations of emerging therapies for these patients with the poorest molecular prognosis among myeloid neoplasms. Although some emerging therapies have shown improvement in overall response rates, this has not translated into better overall survival, hence the notion that p53 remains an elusive target. New therapeutic strategies, including novel targeted therapies, immune checkpoint inhibitors, and monoclonal antibodies, represent a shift away from cytotoxic and hypomethylating-based therapies, towards approaches combining non-immune and novel immune therapeutic strategies. The triple combination of azacitidine and venetoclax with either magrolimab or eprenetapopt have demonstrated safety in early trials, with phase III trials currently underway, and promising interim clinical results. This review compiles background on TP53 biology, available and emerging therapies along with their mechanisms of action for the TP53m disease entity, current treatment challenges, and recently published data and status of ongoing clinical trials for TP53m AML/MDS.