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Haemophilus influenzae is a gram-negative bacterium that encompasses a diverse group of strains with varying pathogenic potentials. Classified into six serotypes (a-f), it has been historically associated with a range of infections, including respiratory tract infections, bacteremia, meningitis, and others. Of particular significance is H. influenzae type b (Hib), which was a leading cause of invasive diseases in children prior to the introduction of the Hib vaccine. The Hib vaccine has revolutionized the prevention of severe bacterial infections and has drastically reduced the incidence of Hib. Haemophilus influenzae serotype a (Hia) has now emerged as a significant contributor to bacterial meningitis leading to morbidity and mortality. It remains a notable concern among elderly patients, despite its historical association with children. This shift in demographic susceptibility is accompanied by distinct clinical characteristics and challenges in diagnosis. Here we report a case of Hia meningitis and bacteremia in a previously healthy elderly patient, who responded to ceftriaxone treatment. Efforts to address the global burden of Hia meningitis include robust surveillance and potential vaccine development, aiming to mitigate its impact on vulnerable populations.

Adoptive immunotherapy based on chimeric antigen receptor (CAR)-engineered T cells has exhibited impressive clinical efficacy in treating B-cell malignancies. However, the potency of CAR-T cells carriethe potential for significant on-target/off-tumor toxicities when target antigens are shared with healthy cells, necessitating the development of complementary safety measures. In this context, there is a need to selectively eliminate therapeutically administered CAR-T cells, especially to revert long-term CAR-T cell-related side effects. To address this, we have developed an effective cellular-based safety mechanism to specifically target and eliminate the transferred CAR-T cells. As proof-of-principle, we have designed a secondary CAR (anti-CAR CAR) capable of recognizing a short peptide sequence (Strep-tag II) incorporated into the hinge domain of an anti-CD19 CAR. In in vitro experiments, these anti-CAR CAR-T cells have demonstrated antigen-specific cytokine release and cytotoxicity when co-cultured with anti-CD19 CAR-T cells. Moreover, in both immunocompromised and immunocompetent mice, we observed the successful depletion of anti-CD19 CAR-T cells when administered concurrently with anti-CAR CAR-T cells. We have also demonstrated the efficacy of this safeguard mechanism in a clinically relevant animal model of B-cell aplasia induced by CD19 CAR treatment, where this side effect was reversed upon anti-CAR CAR-T cells infusion. Notably, efficient B-cell recovery occurred even in the absence of any pre-conditioning regimens prior anti-CAR CAR-T cells transfer, thus enhancing its practical applicability. In summary, we developed a robust cellular safeguard system for selective in vivo elimination of engineered T cells, offering a promising solution to address CAR-T cell-related on-target/off-tumor toxicities.

Hypervirulent Klebsiella pneumoniae remains a significant global public health concern, characterized by a unique syndrome involving monomicrobial primary pyogenic liver abscesses, often leading to metastatic complications such as endophthalmitis, meningitis, and other infections. These infections are frequently observed in immunocompetent hosts or diabetic patients, particularly those of Asian ethnicity. In this report, we present the case of a 66-year-old Burmese female, currently residing in the United States, who presented with severe swelling, pain, discharge, and vision loss in her left eye, along with abdominal pain. Subsequent investigation revealed monomicrobial Klebsiella pneumoniae acute cholecystitis with an adjacent liver abscess, complicated by bacteremia, endogenous endophthalmitis, and portal vein thrombosis. Treatment with ceftriaxone proved successful in addressing her intra-abdominal infections, while anticoagulation therapy was initiated following multidisciplinary discussions among all involved subspecialties. Early diagnosis and the timely administration of appropriate treatment are crucial in reducing mortality and preventing further complications.

Tuberculous meningitis (TBM) is a potentially life-threatening form of tuberculosis (TB) that affects the central nervous system. Its management in patients with concomitant chronic liver disease (CLD) presents unique challenges due to altered drug metabolism with potentially impaired spinal fluid drug penetration and hepatotoxicity. The standard regimen for TBM includes isoniazid (INH) and rifampin (RIF), and Pyrazinamide (PZA) which are metabolized by the liver and may cause hepatotoxicity, which can exacerbate preexisting liver disease. Thus, careful consideration is required to balance therapeutic efficacy with potential drug-induced hepatotoxicity. Regular monitoring of liver function tests and clinical response is essential to minimize adverse effects and optimize treatment outcomes. Further research is needed to establish evidence-based guidelines for the tailored management of TBM in this vulnerable patient subset. Overall, the treatment of TBM in patients with severe liver disease should be individualized and closely monitored.

An increasing number of studies are describing potential uses of circulating tumour DNA (ctDNA) in the care of patients with colorectal cancer. Owing to this rapidly developing area of research, the Colon and Rectal-Anal Task Forces of the United States National Cancer Institute convened a panel of multidisciplinary experts to summarize current data on the utility of ctDNA in the management of colorectal cancer and to provide guidance in promoting the efficient development and integration of this technology into clinical care. The panel focused on four key areas in which ctDNA has the potential to change clinical practice, including the detection of minimal residual disease, the management of patients with rectal cancer, monitoring responses to therapy, and tracking clonal dynamics in response to targeted therapies and other systemic treatments. The panel also provides general guidelines with relevance for ctDNA-related research efforts, irrespective of indication.

There is a well-established relationship between self-criticism and depression. This cross-sectional study investigated the roles that rumination, worry, and fears of compassion for self and from others play in this relationship. Undergraduate students and community participants (N = 417; 68% female; mean age 21.42 years [SD = 6.45]) completed online self-report questionnaires measuring self-criticism, depression, rumination, worry, and fears of self-compassion and receiving compassion from others. It was hypothesized that self-criticism would predict depression, partially mediated by rumination and worry, and moderated by fears of compassion for self and from others. The indirect effects of self-criticism on depression through rumination and worry were found to be conditional on levels of fears of compassion for self and from others. Fears of compassion for self and from others magnified the impact of self-criticism on rumination and rumination on depression; and fears of compassion from others magnified the impact of self-criticism on worry. These findings suggest that having high fears of compassion for self and from others potentiates the effect of self-criticism and repetitive negative thinking on depression. Fears of compassion from others and for oneself should be assessed and addressed alongside phenomena such as self-criticism and rumination when working with depression., Author(s): Lara Gama Cavalcanti [sup.1] , Stanley R. Steindl [sup.2] , Marcela Matos [sup.3] , Mark J. Boschen [sup.1] Author Affiliations: (1) grid.1022.1, 0000 0004 0437 5432, School of Applied [...]

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.

A growing body of sociological research has shown that racial identification is not only fluid, but crucially depends on other individual- and societal-level factors. When such factors are also associated with socioeconomic outcomes such as earnings, estimates of the disadvantage experienced by individuals because of how they identify racially obtained from standard regression models may be biased. We illustrate this potential bias using data from a large-scale survey conducted by the Mexican census bureau. This survey is the first by the government agency since the country's independence to include a question on black identification. We find evidence of a substantial bias in estimates of racial disadvantage. Results from our initial models treating racial self-identification as an exogenous predictor indicate that black men have higher earnings than non-black men. However, when we use an instrumental variables model that treats racial self-identification as endogenous, that is, as a function of the same unobserved characteristics as individuals' earnings, we find a significant negative effect of black identification on earnings. While previous studies have acknowledged the endogeneity of race, ours is the first to explicitly model racial self-identification as an endogenous predictor to obtain an unbiased estimate of its effect on individuals' socioeconomic conditions.

IntroductionWhile pediatricians should receive training in the care of transgender youth, a paucity of formal educational curricula have been developed to train learners to care for this vulnerable population.MethodsWe developed a curriculum including six online modules and an in-person afternoon session observing clinic visits in a pediatric gender clinic. Learners-fourth-year medical students, interns, and nurse practitioner trainees-received protected time during an adolescent medicine rotation to complete the online modules (total duration: 77 minutes). For 20 learners, we assessed the impact of the entire curriculum-online modules and in-person observation-on self-perceived knowledge of considerations for transgender youth. For 31 learners, we assessed the effect of the online modules alone on knowledge and self-efficacy. Descriptive analyses illustrated changes in educational domains by learner group.ResultsOn evaluations of the entire curriculum (modules and observation), median self-perceived knowledge scores (1 = not at all knowledgeable/aware, 5 = extremely knowledgeable/aware) increased within learner groups: pediatric interns (from 2.3 to 4.0), nurse practitioner trainees (from 2.9 to 4.7), fourth-year medical students (from 3.3 to 4.9), and psychiatry interns (from 2.8 to 4.4). Assessment of learners completing only the online modules demonstrated increases in median knowledge and self-efficacy scores within learner groups. All learner groups highly valued the curriculum.DiscussionOur curriculum for multidisciplinary learners in the care of transgender youth was successful and well received. Increasing learner knowledge and self-efficacy is an important step towards skill development in patient care for the transgender youth population.

Plain English Summary Gender diverse is a term that includes gender identities such as (but not limited to) transgender, non-binary, and gender fluid. Eating disorders are becoming increasingly recognized among this population. In recent years there has been a better understanding of the risk factors and screening for eating disorders in the outpatient setting for gender diverse adolescents. However, the medical, anthropometric, and psychiatric characteristics of gender diverse adolescents with eating disorders requiring inpatient medical stabilization are poorly understood. This study examines these characteristics in gender diverse adolescents hospitalized for eating disorder-related medical complications from 2012 to 2020. Gender diverse adolescents presented for medical hospitalization with signs of malnutrition, including vital sign instability and laboratory abnormalities, as well as additional psychiatric diagnoses such as depression and anxiety. Understanding the medical, anthropometric, and psychiatric presentation of this population can lead to more tailored and comprehensive care with the potential to reduce the risks of adverse health outcomes.

Photoswitches capable of accessing two geometric states are highly desirable, especially if their design is modular and incorporates a pharmacophore tethering site. We describe a redox isomerization strategy for synthesizing p-formylazobenzenes from p-nitrobenzyl alcohol. The resulting azo-aldehydes can be readily converted to photoswitchable compounds with excellent photophysical properties using simple hydrazide click chemistry. As a proof of principle, we synthesized a photoswitchable surfactant enabling the photocontrol of an emulsion with exceptionally high spatiotemporal precision.

Abstract Fn14 is a cell surface receptor with key functions in tissue homeostasis and injury but is also linked to chronic diseases. Despite its physiological and medical importance, the regulation of Fn14 signaling and turnover is only partly understood. Here, we demonstrate that Fn14 is cleaved within its transmembrane domain by the protease γ‐secretase, resulting in secretion of the soluble Fn14 ectodomain (sFn14). Inhibition of γ‐secretase in tumor cells reduced sFn14 secretion, increased full‐length Fn14 at the cell surface, and enhanced TWEAK ligand‐stimulated Fn14 signaling through the NFκB pathway, which led to enhanced release of the cytokine tumor necrosis factor. γ‐Secretase‐dependent sFn14 release was also detected ex vivo in primary tumor cells from glioblastoma patients, in mouse and human plasma and was strongly reduced in blood from human cancer patients dosed with a γ‐secretase inhibitor prior to chimeric antigen receptor (CAR)‐T‐cell treatment. Taken together, our study demonstrates a novel function for γ‐secretase in attenuating TWEAK/Fn14 signaling and suggests the use of sFn14 as an easily measurable pharmacodynamic biomarker to monitor γ‐secretase activity in vivo.