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The article discusses a study conducted by Mrimi et al., published in the journal "New England Journal of Medicine." The study explores the effectiveness of a new antiparasitic drug called emodepside against whipworm and other soil-transmitted helminths. Emodepside shows promise as an effective treatment for two out of the three main helminths, targeting unique processes or structures in the parasite and demonstrating potential for use in animals.

The article discusses shortening tuberculosis treatment which includes TRUNCATE-TB trial, a treatment strategy for tuberculosis that could reduce the treatment duration from six to four months or even shorter. The study enrolled 675 participants who received either a standard tuberculosis treatment regimen or an intensified regimen with high-dose rifampin plus linezolid or bedaquiline plus linezolid. The treatment strategy aimed to reduce the logistic burden of the treatment regimen.

The article shares insight on the targeting of cytotoxic T cells in metastatic pancreatic cancer. It explains how cytotoxic cells work in dealing with viral infections, how chimeric antigen receptor (CAR) T cells target tumors and how cytotoxic T cells target virally infected cells. It discusses how the gene KRAS is targeted and the difficulty of this approach since a peptide-specific T-cell receptor (TCR) needs to be generated and the correct human leukocyte antigen (HLA) class I molecule.

The article focuses on acknowledging and expressing gratitude to the reviewers who contributed their expertise to peer review for the Journal between July and December 2023.

The article focuses on acknowledging and addressing historical injustices perpetuated by the New England Journal of Medicine (NEJM) over its long history. It recognize biases related to race, ethnicity, religion, gender, and health conditions that have been justified or advocated in the Journal. It emphasize the importance of confronting these biases, learning from past mistakes, and initiating conversations for positive change in medicine.

The article acknowledges and expresses gratitude to the reviewers who contributed their expertise to the peer review process of the journal between January and June 2023.

Diverse chemical modifications fine-tune the function and metabolism of tRNA. Although tRNA modification is universal in all kingdoms of life, profiles of modifications, their functions, and physiological roles have not been elucidated in most organisms including the human pathogen, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. To identify physiologically important modifications, we surveyed the tRNA of Mtb, using tRNA sequencing (tRNA-seq) and genome-mining. Homology searches identified 23 candidate tRNA modifying enzymes that are predicted to create 16 tRNA modifications across all tRNA species. Reverse transcription-derived error signatures in tRNA-seq predicted the sites and presence of nine modifications. Several chemical treatments prior to tRNA-seq expanded the number of predictable modifications. Deletion of Mtb genes encoding two modifying enzymes, TruB and MnmA, eliminated their respective tRNA modifications, validating the presence of modified sites in tRNA species. Furthermore, the absence of mnmA attenuated Mtb growth in macrophages, suggesting that MnmA-dependent tRNA uridine sulfation contributes to Mtb intracellular growth. Our results lay the foundation for unveiling the roles of tRNA modifications in Mtb pathogenesis and developing new therapeutics against tuberculosis. [ABSTRACT FROM AUTHOR]

The authors reflect on the potential of intentional drug development by citing the results of a phase three randomized controlled trial on the effectiveness of ritonavir and nirmatrelvir as treatment against SARS-CoV-2 infection in COVID-19 unvaccinated patients. Based on the results, the combination drug was linked with mild dysgeusia and diarrhea, but it is effective against COVID-19.

The article presents the discussion on communicating the most important information in medicine and health care. Topics include communication medium with instructional videos such as Videos in Clinical Medicine and discussions such as Perspective Roundtables; and curating and presenting important information in health care.

An introduction is presented in which the authors discuss articles within the issue on topics such as the duration of detection of Ebola virus by polymerase-chain-reaction assay and the randomized controlled trial of standard of care for Ebola infection.

An editorial is presented on shortening the course of Tuberculosis treatment. Topics include prediction derived from preclinical studies in animals having higher doses of rifamycins increasing the rate of clearance of infecting bacteria in tuberculosis; and widespread use of the antibiotic for the treatment of tuberculosis promoting resistance to fluoroquinolones in other bacteria.

The current regimens used to treat tuberculosis are largely comprised of serendipitously discovered drugs that are combined based on clinical experience. Despite curing millions, these drug regimens are limited by the long course of therapy, the emergence of resistance, and the persistent tissue damage that remains after treatment. The last two decades have produced only a single new drug but have represented a renaissance in our understanding of the physiology of tuberculosis infection. The advent of mycobacterial genetics, sophisticated immunological methods, and imaging technologies have transformed our understanding of bacterial physiology as well as the contribution of the host response to disease outcome. Specific alterations in bacterial metabolism, heterogeneity in bacterial state, and drug penetration all limit the effectiveness of antimicrobial therapy. This review summarizes these new biological insights and discusses strategies to exploit them for the rational development of more effective therapeutics. Three general strategies are discussed. First, our emerging insight into bacterial physiology suggests new pathways that might be targeted to accelerate therapy. Second, we explore whether the concept of genetic synergy can be used to design effective combination therapies. Finally, we outline possible approaches to modulate the host response to accentuate antibiotic efficacy. These biology-driven strategies promise to produce more effective therapies. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis, which is the aetiological agent of tuberculosis, owes much of its success as a pathogen to its unique cell wall and unusual mechanism of growth, which facilitate its adaptation to the human host and could have a role in clinical latency. Asymmetric growth and division increase population heterogeneity, which may promote antibiotic tolerance and the fitness of single cells. In this Review, we describe the unusual mechanisms of mycobacterial growth, cell wall biogenesis and division, and discuss how these processes might affect the survival of M. tuberculosis in vivo and contribute to the persistence of infection. [ABSTRACT FROM AUTHOR]

The article presents information on revival of drug for treatment of tuberculosis and prodrugs that are activated using bacterial enzymes of Mycobacterium tuberculosis. Topics discussed include generation of toxic radicals, inhibition of carrier protein reductase, and use of genomewide transcriptional analysis.

para-Aminosalicylic acid (PAS) is one of the antimycobacterial drugs currently used for multidrug-resistant tuberculosis. Although it has been in clinical use for over 60 years, its mechanism(s) of action remains elusive. Here we report that PAS is a prodrug targeting dihydrofolate reductase (DHFR) through an unusual and novel mechanism of action. We provide evidences that PAS is incorporated into the folate pathway by dihydropteroate synthase (DHPS) and dihydrofolate synthase (DHFS) to generate a hydroxyl dihydrofolate antimetabolite, which in turn inhibits DHFR enzymatic activity. Interestingly, PAS is recognized by DHPS as efficiently as its natural substrate para-amino benzoic acid. Chemical inhibition of DHPS or mutation in DHFS prevents the formation of the antimetabolite, thereby conferring resistance to PAS. In addition, we identified a bifunctional enzyme (riboflavin biosynthesis protein (RibD)), a putative functional analog of DHFR in a knock-out strain. This finding is further supported by the identification of PAS-resistant clinical isolates encoding a RibD overexpression mutation displaying cross-resistance to genuine DHFR inhibitors. Our findings reveal that a metabolite of PAS inhibits DHFR in the folate pathway. RibD was shown to act as a functional analog of DHFR, and as for DHFS, both were shown to be associated in PAS resistance in laboratory strains and clinical isolates. [ABSTRACT FROM AUTHOR]

An editorial is presented on SARS-CoV-2 Vaccination with strong public health measures as well as , strategies to increase the speed of vaccine development. Topics include version of the SARS-CoV-2 spike protein containing mutations that lock the protein into a conformation that can induce neutralizing antibody responses; and primary outcomes were safety and the incidence of symptomatic Covid-19 with onset occurring at second dose of vaccine or placebo.

Intracellular bacterial pathogens often rely on their hosts for essential nutrients. Host cells, in turn, attempt to limit nutrient availability, using starvation as a mechanism of innate immunity. Here we discuss both host mechanisms of amino acid starvation and the diverse adaptations of pathogens to their nutrient-deprived environments. These processes provide both key insights into immune subversion and new targets for drug development. [ABSTRACT FROM AUTHOR]

The article focuses on the incidence and management of latent tuberculosis infection in the U.S. The case of a healthy 43-year-old woman from Ghana requiring a pre-employment physical examination that included a tuberculosis test is described. Information on two new diagnostic tests for latent tuberculosis infection available on the market is presented. Factors to consider in selecting a latent tuberculosis test are also discussed.

Mycobacterium tuberculosis, which causes tuberculosis, remains a major human public health threat. This is largely due to a sizeable reservoir of latently infected individuals, who may relapse into active disease decades after first acquiring the infection. Furthermore, patients have a very slow response to treatment of active disease. Latency and antibiotic tolerance are commonly taken as a proxy for dormancy, a stable nonreplicative state. However, latency is a clinical term that is solely defined by a lack of disease indicators. The actual state of the bacterium in human latency is not well understood. Here we evaluate the results of several in vitro models of dormancy and consider the applicability of various animal models for studying aspects of human latency and resistance to killing by antibiotics. Furthermore, we propose a model for the initiation of dormancy and resuscitation during infection. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) claims a life every 10 seconds and global mortality rates are increasing despite the use of chemotherapy. But why have we not progressed towards the eradication of the disease? There is no simple answer, although apathy, politics, poverty and our inability to fight the chronic infection have all contributed. Drug resistance and HIV-1 are also greatly influencing the current TB battle plans, as our understanding of their complicity grows. In this Review, recent efforts to fight TB will be described, specifically focusing on how drug discovery could combat the resistance and persistence that make TB worthy of the moniker 'The Great White Plague'. [ABSTRACT FROM AUTHOR]

The article offers information on the public health challenges faced by the Covid-19 pandemic. It examines the association between hydroxychloroquine use and outcomes in patients hospitalized with Covid-19 pandemic. It mentions the guidelines for the use of hydroxychloroquine for patients who had a resting oxygen saturation of less than a certain level.

The article discusses group of researchers led by Cao B. have performed an urgent randomized clinical trial of the efficacy of lopinavir-ritonavir drugs in patients with Covid-19 in Wuhan, China. It mentions that lopinavir-ritonavir does not seem to be highly effective in patients with Covid-19; and also mentions that lopinavir is not particularly potent against Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Chemical biological approaches to understanding bacteria have largely been confined to screening for antibiotics. More complex phenotypes, such as virulence, have largely been studied using bacterial genetics. However, it has recently become clear that these two methods are complementary and that combining chemical biologic and genetic approaches to studying bacteria brings new power to old problems. [Copyright &y& Elsevier]

An editorial is presented that discussed about the concept of change as in traditional journals that are being overwhelmed by the volume of medical and scientific information. It mentions that new publishing mandates from funders and shrinking income from advertisers and subscribers threaten the ability of editorial-intensive journals. It also highlights the central principles that helps to guide including soliciting the best advice, partnering with authors, and maintaining rigor.

Although tuberculosis has been studied for more than a century, insights into the molecular mechanisms by which it causes disease remain fairly limited. The current genetic boom in this system promises to reveal new virulence mechanisms, making this an exciting time to be studying this disease. Long considered a technical ‘poor relation’, tuberculosis research has developed into a source for creative techniques and ideas. In the midst of this development, it is important to keep in mind the limitations of each new approach that is employed to study this organism. This review examines the genetic approaches that are currently being used to study tuberculosis, with an emphasis on new developments that promise to improve our understanding of the pathogenic mechanisms of Mycobacterium tuberculosis. [Copyright &y& Elsevier]

Despite the importance of tuberculosis as a public health problem, we know relatively little about the molecular mechanisms used by the causative organism, Mycobacterium tuberculosis, to persist in the host. To define these mechanisms, we have mutated virtually every nonessential gene of M. tuberculosis and determined the effect disrupting each gene on the growth rate of this pathogen during infection. A total of 194 genes that are specifically required for mycobacterial growth in vivo were identified. The behavior of these mutants provides a detailed view of the changing environment that the bacterium encounters as infection proceeds. A surprisingly large fraction of these genes are unique to mycobacteria and closely related species, indicating that many of the strategies used by this unusual group of organisms are fundamentally different from other pathogens. [ABSTRACT FROM AUTHOR]

Mobile genetic elements are often employed for constructing gene fusions or to perform mutagenesis. mariner transposons are well-suited to such applications because of their low site specificity, in vitro activity, and exceptionally broad host range. This report describes a mariner-based method for rapidly creating a large number of insertion mutants that can be converted to in-frame epitope fusions in a single step. First, a mariner-based vector is used to deliver a FLP recombinase substrate randomly into a target molecule. Expression of the FLP recombinase is then induced to catalyse the excision of sequences flanked by FLP recombinase target recognition sites, leaving behind a triple-FLAG epitope. The reversibility of the excision event provides opportunities for using genomic targeting methods easily to create transcriptional or translational fusions to genes of interest. [Copyright &y& Elsevier]

Genomic sequencing of bacterial pathogens is providing an increasing wealth of new data. It is, however, still unclear how this information can be used to develop new experimental approaches. Here, we describe recent efforts to complement existing bacterial genetics with genomic methods for the study of pathogenesis. [Copyright &y& Elsevier]

Assesses the use of transposon mutagenesis strategy in the identification of gene for Hemophilus influenzae growth. Role of genetic footprinting in detecting H. influenzae growth; Importance of proteins on cellular function mediation; Patterns of bacterial genes essentiality.

The article examines kidney transplantation from human immunodeficiency virus (HIV)-positive transplant donor to HIV-positive recipient. It mentions the challenges from the transplantation including the development of HIV-associated nephropathy, drug-drug interactions, and constant assiduous monitoring. The process is also found to be effective for HIV-infected patients requiring renal-replacement therapy.

The authors argue that the value of intensive fluid management and care is the most important take-home message from the case reports of Ebola virus disease (EVD) patients outside Africa. They say that it will be very hard to examine the contribution of a drug without comparative trials unless a new drug is profoundly effective. They add that the benefits of routine care like intravenous fluid and electrolyte support should be brought to all patients.