Treatment of clinically uninfected diabetic foot ulcers, with and without antibiotics.

OBJECTIVE: Current guidelines do not recommend the use of antibiotics to treat clinically uninfected ulcers. However, physicians continue to prescribe antibiotics for clinically uninfected ulcers with the rationale 'better to be safe than sorry'. Yet, antibiotic resistance is increasing, side-effects are common and treatment costs are rising. Evidence is needed to identify whether antibiotic treatment for clinically uninfected ulcers can be justified or we should stop prescribing them. The aim of this study was to evaluate whether antibiotic treatment in cases of clinically uninfected ulcers improved ulcer healing compared to treatment without antibiotics. METHOD: Consecutive patients treated in the outpatient clinic for clinically uninfected diabetic foot ulcer both in 2015 and in 2017 were retrospectively analysed. Primary outcome was ulcer healing at one year. Secondary outcomes were limb salvage, freedom from any amputation, amputation-free survival (AFS) and survival. RESULTS: A total of 102 ulcers of 91 patients were included for final analyses. The non-antibiotics and antibiotics groups both consisted of 51 ulcers. Ulcer healing at one year was 77.3% in the non-antibiotics group and 74.7% in the antibiotics group (p=0.158). No difference was found for limb salvage (93.8% versus 95.9%, respectively; p=0.661), freedom from any amputation (85.6% versus 85.6%, respectively; p=1.000), AFS (85.4% versus 79.1%, respectively; p=0.460) or survival (89.6% versus 83.7%, respectively; p=0.426). CONCLUSION: In this study, no benefits of antibiotic treatment over non-antibiotic treatment for clinically uninfected ulcers were identified. The findings of this study emphasise the recommendation of current guidelines to not treat clinically uninfected ulcer with antibiotics.

Time is a terrible thing to waste: optimising use of intraoperative monitoring practitioner time towards maximising in-house IOM service provision and reducing spend on external provision.

Intraoperative monitoring (IOM) during orthopaedic and neurosurgical operations informs surgeons about the integrity of patients' central and peripheral nervous systems. It is provided by IOM practitioners (IOMPs), who are usually neurophysiology healthcare scientists. Increasing awareness of the benefits for patient safety and surgical outcomes, along with post-COVID-19 service recovery, has resulted in a material increase in demand for IOM provision nationally, and particularly at Salford Royal Hospital (SRH), which is a regional specialist neurosciences centre.There is a shortage of IOMPs in the UK National Health Service (NHS). At SRH, this is exacerbated by staff capacity shortage, requiring £202 800 of supplementary private provision in 2022.At SRH, IOMPs work in pairs. Our productive time is wasted by delays to surgical starts beyond our control and by paired working for much of a surgery session. This quality improvement (QI) project set out to release productive time by: calling the second IOMP to theatre only shortly before start time, the other IOMP returning to the office during significant delays, releasing an IOMP from theatre when appropriate and providing a laptop in theatre for other work.We tested and refined these change ideas over two plan-do-study-act improvement cycles. Compared with complete paired working, we increased the time available for additional productive work and breaks from an average of 102 to 314 min per operating day, not quite achieving our project target of 360 min.The new ways of working we developed are a step towards ability (when staff capacity increases) to test supporting two (simultaneous) operations with three IOMPs (rather than two pairs of IOMPs). Having significantly improved the use of staff time, we then also used our QI project data to make a successful business case for investment in two further IOMP posts with a predicted net saving of £20 000 per year along with other associated benefits.

Drug-Drug Interaction Studies of Esmethadone (REL-1017) Involving CYP3A4- and CYP2D6-Mediated Metabolism.

BACKGROUND AND OBJECTIVE: Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is the opioid inactive dextro-isomer of racemic methadone. Esmethadone is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker with higher affinity for GluN2D subtypes. Esmethadone showed robust, rapid, and sustained antidepressant effects in patients with major depressive disorder (MDD) with inadequate response to ongoing serotonergic antidepressant treatment. METHODS: Here we described the results of in vitro and phase 1 clinical trials aimed at investigating the esmethadone metabolism and possible drug-drug interactions. RESULTS: Esmethadone is primarily metabolized to EDDP (2-ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine) by multiple enzymes, including CYP3A4/5 and CYP2B6. In vitro studies showed that esmethadone inhibits CYP2D6 with IC50 of 9.6 µM and is an inducer of CYP3A4/5. The clinical relevance of the inhibition of CYP2D6 and the induction of CYP3A4 were investigated by co-administering esmethadone and dextromethorphan (a substrate for CYP2D6) or midazolam (a substrate for CYP3A4) in healthy volunteers. The administration of esmethadone at the dosage of 75 mg (which is the loading dose administered to patients in MDD clinical trials) significantly increased the exposure (AUC) of both dextromethorphan and its metabolite dextrorphan by 2.71 and 3.11-fold, respectively. Esmethadone did not modify the pharmacokinetic profile of midazolam, while it increased Cmax and AUC of its metabolite 1'-hydroxymidazolam by 2.4- and 3.8-fold, respectively. A second study evaluated the effect of the CYP3A4 inhibitor cobicistat on the pharmacokinetics of esmethadone. Cobicistat slightly increase (+32%) the total exposure (AUC0-inf) of esmethadone. CONCLUSIONS: In summary, esmethadone demonstrated a negligible effect on CYP3A4 induction and its metabolism was not meaningfully affected by strong CYP3A4 inhibitors while it increased exposure of CYP2D6-metabolized drugs.

Construction of a high-density genetic linkage map and QTL mapping for bioenergy-related traits in sweet sorghum [Sorghum bicolor (L.) Moench].

Sorghum is an important but arguably undervalued cereal crop, grown in large areas in Asia and Africa due to its natural resilience to drought and heat. There is growing demand for sweet sorghum as a source of bioethanol as well as food and feed. The improvement of bioenergy-related traits directly affects bioethanol production from sweet sorghum; therefore, understanding the genetic basis of these traits would enable new cultivars to be developed for bioenergy production. In order to reveal the genetic architecture behind bioenergy-related traits, we generated an F2 population from a cross between sweet sorghum cv. 'Erdurmus' and grain sorghum cv. 'Ogretmenoglu'. This was used to construct a genetic map from SNPs discovered by double-digest restriction-site associated DNA sequencing (ddRAD-seq). F3 lines derived from each F2 individual were phenotyped for bioenergy-related traits in two different locations and their genotypes were analyzed with the SNPs to identify QTL regions. On chromosomes 1, 7, and 9, three major plant height (PH) QTLs (qPH1.1, qPH7.1, and qPH9.1) were identified, with phenotypic variation explained (PVE) ranging from 10.8 to 34.8%. One major QTL (qPJ6.1) on chromosome 6 was associated with the plant juice trait (PJ) and explained 35.2% of its phenotypic variation. For fresh biomass weight (FBW), four major QTLs (qFBW1.1, qFBW6.1, qFBW7.1, and qFBW9.1) were determined on chromosomes 1, 6, 7, and 9, which explained 12.3, 14.5, 10.6, and 11.9% of the phenotypic variation, respectively. Moreover, two minor QTLs (qBX3.1 and qBX7.1) of Brix (BX) were mapped on chromosomes 3 and 7, explaining 8.6 and 9.7% of the phenotypic variation, respectively. The QTLs in two clusters (qPH7.1/qBX7.1 and qPH7.1/qFBW7.1) overlapped for PH, FBW and BX. The QTL, qFBW6.1, has not been previously reported. In addition, eight SNPs were converted into cleaved amplified polymorphic sequences (CAPS) markers, which can be easily detected by agarose gel electrophoresis. These QTLs and molecular markers can be used for pyramiding and marker-assisted selection studies in sorghum, to develop advanced lines that include desirable bioenergy-related traits.

Functional impact and molecular binding modes of drugs that target the PI3K isoform p110δ.

Targeting the PI3K isoform p110δ against B cell malignancies is at the mainstay of PI3K inhibitor (PI3Ki) development. Therefore, we generated isogenic cell lines, which express wild type or mutant p110δ, for assessing the potency, isoform-selectivity and molecular interactions of various PI3Ki chemotypes. The affinity pocket mutation I777M maintains p110δ activity in the presence of idelalisib, as indicated by intracellular AKT phosphorylation, and rescues cell functions such as p110δ-dependent cell viability. Resistance owing to this substitution consistently affects the potency of p110δ-selective in contrast to most multi-targeted PI3Ki, thus distinguishing usually propeller-shaped and typically flat molecules. Accordingly, molecular dynamics simulations indicate that the I777M substitution disturbs conformational flexibility in the specificity or affinity pockets of p110δ that is necessary for binding idelalisib or ZSTK474, but not copanlisib. In summary, cell-based and molecular exploration provide comparative characterization of currently developed PI3Ki and structural insights for future PI3Ki design.

The proto-oncogene TCL1A deregulates cell cycle and genomic stability in CLL.

Upregulation of the proto-oncogene T-cell leukemia/lymphoma 1A (TCL1A) is causally implicated in various B-cell and T-cell malignancies. High-level TCL1A correlates with aggressive disease features and inferior clinical outcomes. However, the molecular and cell biological consequences of, particularly nuclear, TCL1A are not fully elucidated. We observed here in mouse models of subcellular site-specific TCL1A-induced lymphomagenesis that TCL1A exerts a strong transforming impact via nuclear topography. In proteomic screens of TCL1A-bound molecules in chronic lymphocytic leukemia (CLL) cells and B-cell lymphoma lines, we identified regulators of cell cycle and DNA repair pathways as novel TCL1A interactors, particularly enriched under induced DNA damage and mitosis. By functional mapping and in silico modeling, we specifically identified the mitotic checkpoint protein, cell division cycle 20 (CDC20), as a direct TCL1A interactor. According to the regulatory impact of TCL1A on the activity of the CDC20-containing mitotic checkpoint and anaphase-promoting complexes during mitotic progression, TCL1A overexpression accelerated cell cycle transition in B-cell lymphoma lines, impaired apoptotic damage responses in association with pronounced chromosome missegregation, and caused cellular aneuploidy in Eµ-TCL1A mice. Among hematopoietic cancers, CDC20 levels seem particularly low in CLL. CDC20 expression negatively correlated with TCL1A and lower expression marked more aggressive and genomically instable disease and cellular phenotypes. Knockdown of Cdc20 in TCL1A-initiated murine CLL promoted aneuploidy and leukemic acceleration. Taken together, we discovered a novel cell cycle-associated effect of TCL1A abrogating controlled cell cycle transition. This adds to our concept of oncogenic TCL1A by targeting genome stability. Overall, we propose that TCL1A acts as a pleiotropic adapter molecule with a synergistic net effect of multiple hijacked pathways.

Meningococcal disease in North America: Updates from the Global Meningococcal Initiative.

This review summarizes the recent Global Meningococcal Initiative (GMI) regional meeting, which explored meningococcal disease in North America. Invasive meningococcal disease (IMD) cases are documented through both passive and active surveillance networks. IMD appears to be decreasing in many areas, such as the Dominican Republic (2016: 18 cases; 2021: 2 cases) and Panama (2008: 1 case/100,000; 2021: <0.1 cases/100,000); however, there is notable regional and temporal variation. Outbreaks persist in at-risk subpopulations, such as people experiencing homelessness in the US and migrants in Mexico. The recent emergence of ß-lactamase-positive and ciprofloxacin-resistant meningococci in the US is a major concern. While vaccination practices vary across North America, vaccine uptake remains relatively high. Monovalent and multivalent conjugate vaccines (which many countries in North America primarily use) can provide herd protection. However, there is no evidence that group B vaccines reduce meningococcal carriage. The coronavirus pandemic illustrates that following public health crises, enhanced surveillance of disease epidemiology and catch-up vaccine schedules is key. Whole genome sequencing is a key epidemiological tool for identifying IMD strain emergence and the evaluation of vaccine strain coverage. The Global Roadmap on Defeating Meningitis by 2030 remains a focus of the GMI.

Colloidal Systems in Concentrated Electrolyte Solutions Exhibit Re-entrant Long-Range Electrostatic Interactions due to Underscreening.

Surface force measurements have revealed that at very high electrolyte concentrations as well as in neat and diluted ionic liquids and deep eutectic solvents, the range of electrostatic interactions is far greater than the Debye length. Here, we explore the consequences of this underscreening for soft-matter and colloidal systems by investigating the stability of nanoparticle dispersions, the self-assembly of ionic surfactants, and the thickness of soap films. In each case, we find clear evidence of re-entrant properties due to underscreening at high salt concentrations. Our results show that underscreening in concentrated electrolytes is a general phenomenon and is not dependent on confinement by macroscopic surfaces. The stability of systems at very high salinity due to underscreening may be beneficially applied to processes that currently use low-salinity water.

The Effect of Varying Interval Definitions on the Prevalence of SARS-CoV-2 Reinfections: A Retrospective Cross-Sectional Cohort Study.

BACKGROUND: We assessed the SARS-CoV-2 reinfection rate in a large patient cohort, and evaluated the effect of varying time intervals between two positive tests on assumed reinfection rates using viral load data. METHODS: All positive SARS-CoV-2 samples collected between 1 March 2020 and 1 August 2021 from a laboratory in the region Kennemerland, the Netherlands, were included. The reinfection rate was analyzed using different time intervals between two positive tests varying between 2 and 16 weeks. SARS-CoV-2 PCR crossing point (Cp) values were used to estimate viral loads. RESULTS: In total, 679,513 samples were analyzed, of which 53,366 tests (7.9%) were SARS-CoV-2 positive. The number of reinfections varied between 260 (0.52%) for an interval of 2 weeks, 89 (0.19%) for 4 weeks, 52 (0.11%) for 8 weeks, and 37 (0.09%) for a minimum interval of 16 weeks between positive tests. The median Cp-value (IQR) in the second positive samples decreased when a longer interval was chosen, but stabilized from week 8 onwards. CONCLUSIONS: Although the calculated reinfection prevalence was relatively low (0.11% for the 8-week time interval), choosing a different minimum interval between two positive tests resulted in major differences in reinfection rates. As reinfection Cp-values stabilized after 8 weeks, we hypothesize this interval to best reflect novel infection rather than persistent shedding.

SARS-CoV-2 viral-load distribution reveals that viral loads increase with age: a retrospective cross-sectional cohort study.

BACKGROUND: Describing the SARS-CoV-2 viral-load distribution in different patient groups and age categories. METHODS: All results from first nasopharyngeal (NP) and oropharyngeal (OP) swabs from unique patients tested via SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) collected between 1 January and 1 December 2020 predominantly in the Public Health Services regions Kennemerland and Hollands Noorden, province of North Holland, the Netherlands, were included in this study. SARS-CoV-2 PCR crossing-point (Cp)-values were used to estimate viral loads. RESULTS: In total, 278 455 unique patients were tested, of whom 9.1% (n = 25.374) were SARS-CoV-2-positive. PCRs performed by Public Health Services (n = 211 914), in which sampling and inclusion were uniform, revealed a clear relation between age and SARS-CoV-2 viral load, with especially children aged <12 years showing lower viral loads than adults (ß: -0.03, 95% confidence interval: -0.03 to -0.02, p < 0.001), independently of sex and/or symptom duration. Interestingly, the median Cp-values between the >79- and <12-year-old populations differed by more than four PCR cycles, suggesting an ∼16-fold difference in viral load. In addition, the proportion of children aged <12 years with a low load (Cp-value >30) was higher compared with other patients (31.1% vs 17.2%, p-value < 0.001). CONCLUSIONS: In patients tested by Public Health Services, SARS-CoV-2 viral load increases with age. Further studies should elucidate whether the lower viral load in children is indeed related to their suggested limited role in SARS-CoV-2 transmission. Moreover, as rapid antigen tests are less sensitive than PCR, these results suggest that SARS-CoV-2 antigen tests have lower sensitivity in children than in adults.

A High-Density SNP Genetic Map Construction Using ddRAD-Seq and Mapping of Capsule Shattering Trait in Sesame.

The seed-bearing capsule of sesame shatters at harvest. This wildish trait makes the crop unsuitable for mechanized harvesting and also restricts its commercial potential by limiting the cultivation for countries that have no access to low-cost labor. Therefore, the underlying genetic basis of the capsule shattering trait is highly important in order to develop mechanization-ready varieties for sustainable sesame farming. In the present study, we generated a sesame F2 population derived from a cross between a capsule shattering cultivar (Muganli-57) and a non-shattering mutant (PI 599446), which was used to construct a genetic map based on double-digest restriction-site-associated DNA sequencing. The resulting high-density genetic map contained 782 single-nucleotide polymorphisms (SNPs) and spanned a length of 697.3 cM, with an average marker interval of 0.89 cM. Based on the reference genome, the capsule shattering trait was mapped onto SNP marker S8_5062843 (78.9 cM) near the distal end of LG8 (chromosome 8). In order to reveal genes potentially controlling the shattering trait, the marker region (S8_5062843) was examined, and a candidate gene including six CDSs was identified. Annotation showed that the gene encodes a protein with 440 amino acids, sharing ∼99% homology with transcription repressor KAN1. Compared with the capsule shattering allele, the SNP change and altered splicing in the flanking region of S8_5062843 caused a frameshift mutation in the mRNA, resulting in the loss of function of this gene in the mutant parent and thus in non-shattering capsules and leaf curling. With the use of genomic data, InDel and CAPS markers were developed to differentiate shattering and non-shattering capsule genotypes in marker-assisted selection studies. The obtained results in the study can be beneficial in breeding programs to improve the shattering trait and enhance sesame productivity.

Whole-genome assembly of Corylus avellana cv "Tonda Gentile delle Langhe" using linked-reads (10X Genomics).

The European hazelnut (Corylus avellana L.; 2n = 2x = 22) is a worldwide economically important tree nut that is cross-pollinated due to sporophytic incompatibility. Therefore, any individual plant is highly heterozygous. Cultivars are clonally propagated using mound layering, rooted suckers, and micropropagation. In recent years, the interest in this crop has increased, due to a growing demand related to the recognized health benefits of nut consumption. C. avellana cv "Tonda Gentile delle Langhe" ("TGdL") is well-known for its high kernel quality, and the premium price paid for this cultivar is an economic benefit for producers in northern Italy. Assembly of a high-quality genome is a difficult task in many plant species because of the high level of heterozygosity. We assembled a chromosome-level genome sequence of "TGdL" with a two-step approach. First, 10X Genomics Chromium Technology was used to create a high-quality sequence, which was then assembled into scaffolds with cv "Tombul" genome as the reference. Eleven pseudomolecules were obtained, corresponding to 11 chromosomes. A total of 11,046 scaffolds remained unplaced, representing 11% of the genome (46,504,161 bp). Gene prediction, performed with Maker-P software, identified 27,791 genes (AED ≤0.4 and 92% of BUSCO completeness), whose function was analyzed with BlastP and InterProScan software. To characterize "TGdL" specific genetic mechanisms, Orthofinder was used to detect orthologs between hazelnut and closely related species. The "TGdL" genome sequence is expected to be a powerful tool to understand hazelnut genetics and allow detection of markers/genes for important traits to be used in targeted breeding programs.

Derivation and validation of a two-variable index to predict 30-day outcomes following heart failure hospitalization.

BACKGROUND: The LACE index-length of stay (L), acuity (A), Charlson co-morbidities (C), and emergent visits (E)-predicts 30-day outcomes following heart failure (HF) hospitalization but is complex to score. A simpler LE index (length of stay and emergent visits) could offer a practical advantage in point-of-care risk prediction. METHODS AND RESULTS: This was a sub-study of the patient-centred care transitions in HF (PACT-HF) multicentre trial. The derivation cohort comprised patients hospitalized for HF, enrolled in the trial, and followed prospectively. External validation was performed retrospectively in a cohort of patients hospitalized for HF. We used log-binomial regression models with LACE or LE as the predictor and either 30-day composite all-cause readmission or death or 30-day all-cause readmission as the outcomes, adjusting only for post-discharge services. There were 1985 patients (mean [SD] age 78.1 [12.1] years) in the derivation cohort and 378 (mean [SD] age 73.1 [13.2] years) in the validation cohort. Increments in the LACE and LE indices were associated with 17% (RR 1.17; 95% CI 1.12, 1.21; C-statistic 0.64) and 21% (RR 1.21; 95% CI 1.15, 1.26; C-statistic 0.63) increases, respectively, in 30-day composite all-cause readmission or death; and 16% (RR 1.16; 95% CI 1.11, 1.20; C-statistic 0.64) and 18% (RR 1.18; 95% CI 1.13, 1.24; C-statistic 0.62) increases, respectively, in 30-day all-cause readmission. The LE index provided better risk discrimination for the 30-day outcomes than did the LACE index in the external validation cohort. CONCLUSIONS: The LE index predicts 30-day outcomes following HF hospitalization with similar or better performance than the more complex LACE index.

Direct observation of hyperpolarization breaking through the spin diffusion barrier.

Dynamic nuclear polarization (DNP) is a widely used tool for overcoming the low intrinsic sensitivity of nuclear magnetic resonance spectroscopy and imaging. Its practical applicability is typically bounded, however, by the so-called "spin diffusion barrier," which relates to the poor efficiency of polarization transfer from highly polarized nuclei close to paramagnetic centers to bulk nuclei. A quantitative assessment of this barrier has been hindered so far by the lack of general methods for studying nuclear polarization flow in the vicinity of paramagnetic centers. Here, we fill this gap and introduce a general set of experiments based on microwave gating that are readily implemented. We demonstrate the versatility of our approach in experiments conducted between 1.2 and 4.2 K in static mode and at 100 K under magic angle spinning (MAS)-conditions typical for dissolution DNP and MAS-DNP-and directly observe the marked dependence of polarization flow on temperature.

Editorial for the Special Issue: Bacterial Meningitis-Epidemiology and Vaccination.

Bacterial meningitis has serious health, economic, and social consequences with a high risk of death and lifelong disability [...].

Using Machine Learning Imputed Outcomes to Assess Drug-Dependent Risk of Self-Harm in Patients with Bipolar Disorder: A Comparative Effectiveness Study.

BACKGROUND: Incomplete suicidality coding in administrative claims data is a known obstacle for observational studies. With most of the negative outcomes missing from the data, it is challenging to assess the evidence on treatment strategies for the prevention of self-harm in bipolar disorder (BD), including pharmacotherapy and psychotherapy. There are conflicting data from studies on the drug-dependent risk of self-harm, and there is major uncertainty regarding the preventive effect of monotherapy and drug combinations. OBJECTIVE: The aim of this study was to compare all commonly used BD pharmacotherapies, as well as psychotherapy for the risk of self-harm, in a large population of commercially insured individuals, using self-harm imputation to overcome the known limitations of this outcome being underrecorded within US electronic health care records. METHODS: The IBM MarketScan administrative claims database was used to compare self-harm risk in patients with BD following 65 drug regimens and drug-free periods. Probable but uncoded self-harm events were imputed via machine learning, with different probability thresholds examined in a sensitivity analysis. Comparators included lithium, mood-stabilizing anticonvulsants (MSAs), second-generation antipsychotics (SGAs), first-generation antipsychotics (FGAs), and five classes of antidepressants. Cox regression models with time-varying covariates were built for individual treatment regimens and for any pharmacotherapy with or without psychosocial interventions ("psychotherapy"). RESULTS: Among 529,359 patients, 1.66% (n=8813 events) had imputed and/or coded self-harm following the exposure of interest. A higher self-harm risk was observed during adolescence. After multiple testing adjustment (P≤.012), the following six regimens had higher risk of self-harm than lithium: tri/tetracyclic antidepressants + SGA, FGA + MSA, FGA, serotonin-norepinephrine reuptake inhibitor (SNRI) + SGA, lithium + MSA, and lithium + SGA (hazard ratios [HRs] 1.44-2.29), and the following nine had lower risk: lamotrigine, valproate, risperidone, aripiprazole, SNRI, selective serotonin reuptake inhibitor (SSRI), "no drug," bupropion, and bupropion + SSRI (HRs 0.28-0.74). Psychotherapy alone (without medication) had a lower self-harm risk than no treatment (HR 0.56, 95% CI 0.52-0.60; P=8.76×10-58). The sensitivity analysis showed that the direction of drug-outcome associations did not change as a function of the self-harm probability threshold. CONCLUSIONS: Our data support evidence on the effectiveness of antidepressants, MSAs, and psychotherapy for self-harm prevention in BD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02893371; https://clinicaltrials.gov/ct2/show/NCT02893371.

The Global Burden of Meningitis in Children: Challenges with Interpreting Global Health Estimates.

The World Health Organization (WHO) has developed a global roadmap to defeat meningitis by 2030. To advocate for and track progress of the roadmap, the burden of meningitis as a syndrome and by pathogen must be accurately defined. Three major global health models estimating meningitis mortality as a syndrome and/or by causative pathogen were identified and compared for the baseline year 2015. Two models, (1) the WHO and the Johns Hopkins Bloomberg School of Public Health's Maternal and Child Epidemiology Estimation (MCEE) group's Child Mortality Estimation (WHO-MCEE) and (2) the Institute for Health Metrics and Evaluation (IHME) Global Burden of Disease Study (GBD 2017), identified meningitis, encephalitis and neonatal sepsis, collectively, to be the second and third largest infectious killers of children under five years, respectively. Global meningitis/encephalitis and neonatal sepsis mortality estimates differed more substantially between models than mortality estimates for selected infectious causes of death and all causes of death combined. Estimates at national level and by pathogen also differed markedly between models. Aligning modelled estimates with additional data sources, such as national or sentinel surveillance, could more accurately define the global burden of meningitis and help track progress against the WHO roadmap.

Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1.

Richter's transformation (RT) is an aggressive lymphoma that occurs upon progression from chronic lymphocytic leukemia (CLL). Transformation has been associated with genetic aberrations in the CLL phase involving TP53, CDKN2A, MYC, and NOTCH1; however, a significant proportion of RT cases lack CLL phase-associated events. Here, we report that high levels of AKT phosphorylation occur both in high-risk CLL patients harboring TP53 and NOTCH1 mutations as well as in patients with RT. Genetic overactivation of Akt in the murine Eµ-TCL1 CLL mouse model resulted in CLL transformation to RT with significantly reduced survival and an aggressive lymphoma phenotype. In the absence of recurrent mutations, we identified a profile of genomic aberrations intermediate between CLL and diffuse large B-cell lymphoma. Multiomics assessment by phosphoproteomic/proteomic and single-cell transcriptomic profiles of this Akt-induced murine RT revealed an S100 protein-defined subcluster of highly aggressive lymphoma cells that developed from CLL cells, through activation of Notch via Notch ligand expressed by T cells. Constitutively active Notch1 similarly induced RT of murine CLL. We identify Akt activation as an initiator of CLL transformation toward aggressive lymphoma by inducing Notch signaling between RT cells and microenvironmental T cells.