Cold Spring Harbor perspectives in medicine最新文献

{"title":"What's New Is Old: \"Cultural Lag\" and Governance of Risk in the Life Sciences.","authors":"Jasmine C Arunachalam, David A Relman","doi":"10.1101/cshperspect.a041953","DOIUrl":"https://doi.org/10.1101/cshperspect.a041953","url":null,"abstract":"<p><p>As advancement in the life sciences quickens, management of risks remains reactive, creating problematic delays in risk mitigation and difficulties for development of a holistic risk governance strategy. A reactive posture for addressing risk undermines biosecurity and contributes to public distrust in science. This problem is not new. A temporal offset between scientific advancement and oversight of associated risks was described more than a century ago. In 1922, the American sociologist, William Ogburn, coined the term, \"cultural lag.\" Cultural lag was premised on the interconnectedness of technology and society and referred to a period of maladjustment between the introduction of a new technology and societal responses to mitigate its downsides. We examine the consequences of cultural lag for risk governance in the life sciences by looking at three recently introduced technologies, CRISPR-Cas9 gene editing, the proposed creation of mirror life, and microbiome engineering. Our observations lead to three recommendations for addressing cultural lag. The first recommendation is structural, namely, consolidation of governmental oversight on emerging technologies; the second is goal-oriented, that is, a call for a holistic form of horizon scanning; and the third concerns process and calls for implementation of deliberative democratic principles and practices. By pursuing an anticipatory governance regime, with policymaking closely aligned to and coordinated with technology breakthroughs, we enhance research safety and security while promoting innovation, and as a secondary benefit, help to restore public trust in science.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Host-Directed Therapies for Tuberculosis.","authors":"Stefan H Oehlers, Sakshi Agarwal, Amit Singhal","doi":"10.1101/cshperspect.a041823","DOIUrl":"10.1101/cshperspect.a041823","url":null,"abstract":"<p><p>Host-directed therapies (HDTs) to increase host control of <i>Mycobacterium tuberculosis</i> and limit the pathology caused by tuberculosis (TB) have advanced from the laboratory to the clinic. Several of these HDTs are repurposed drugs, which provide significant advantages over lengthy and costly traditional drug discovery approaches. This review covers the preclinical, retrospective clinical, and randomized controlled trial (RCT) evidence supporting the rapid repurposing of drugs for use as TB HDTs. We explore classes of potential HDTs by preclinical mechanism of action to identify cases where the concept of the therapy is sound, but the current availability of therapeutic agent is lacking. Apart from the drugs that have progressed through to RCTs, we highlight drugs with strong preclinical and retrospective portfolios that may form the next wave of trial candidates. Overall, HDTs are poised to contribute to a reduction in the global burden of TB and posttreatment lung disease.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147389528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tuberculosis and HIV Coinfection: Advances and Remaining Concerns.","authors":"Judith Bruchfeld, Marianne Jansson, Gunilla Källenius","doi":"10.1101/cshperspect.a041807","DOIUrl":"10.1101/cshperspect.a041807","url":null,"abstract":"<p><p>Tuberculosis (TB) and acquired immunodeficiency syndrome (AIDS) are the leading causes of death from single infectious agents in low- and middle-income countries. Moreover, in the individual host, the two pathogens, <i>Mycobacterium tuberculosis</i> and human immunodeficiency virus (HIV), potentiate one another, accelerating the deterioration of immunological functions. In high-burden settings, HIV coinfection is the most important risk factor for TB disease, due to reactivation. Susceptibility to primary TB infection, or reinfection, is also elevated in people living with HIV (PLWH). TB disease also has a negative impact in PLWH not receiving antiretroviral therapy (ART), accelerating the progression to AIDS. The clinical management of HIV-associated TB includes the integration of effective TB treatment, use of concurrent ART, prevention of HIV-related comorbidities, management of drug cytotoxicity, and prevention/treatment of immune reconstitution inflammatory syndrome. ⁵.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147580739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Parasite to Pill: Harnessing Biology for Breakthroughs in Antimalarial Drug Discovery.","authors":"John G Woodland, Mariana Laureano De Souza, Ferdinand W Ndubi, Christabel N Hikaambo, Kathryn J Wicht","doi":"10.1101/cshperspect.a041858","DOIUrl":"10.1101/cshperspect.a041858","url":null,"abstract":"<p><p>The global imperative for malaria eradication demands innovative strategies for antimalarial drug discovery, particularly in the face of growing drug resistance. This article describes how biological insights into <i>Plasmodium</i> parasites and their interactions with the human host are transforming the antimalarial drug discovery landscape. We examine the parasite's complex life cycle and its unique metabolic pathways and organelles as potential sources of drug targets. We demonstrate how advances in omics technologies and gene-editing tools are revolutionizing our understanding of parasite biology and accelerating target identification. Novel approaches to overcoming existing resistance mechanisms, with improved methods for predicting and preventing drug resistance, are presented, while promising new drug targets are discussed, as well as emerging approaches to target dormant forms of the parasite. The potential of host-directed therapies is explored together with notable case studies that highlight recent successes in biologically driven drug discovery efforts. The future of the field must embrace artificial intelligence, pharmacogenomics, and collaborative innovation anchored in ethical and equitable frameworks, to maximize global health impact.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aerobiology and Transmission of <i>Mycobacterium tuberculosis</i>.","authors":"Ben Patterson, Digby Warner, Robin Wood","doi":"10.1101/cshperspect.a041890","DOIUrl":"10.1101/cshperspect.a041890","url":null,"abstract":"<p><p>Despite vast changes in human social structures through evolution-from small hunter-gatherer bands to densely populated megacities-<i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) has persisted within human populations for millennia, underscoring the bacterium's exceptional transmissibility. This paper examines the aerobiological foundations of <i>Mtb</i> transmission, tracing the bacillus from expulsion in respiratory aerosols through environmental survival to deposition and infection in new hosts. It considers how host, mycobacterial, and environmental factors interact to influence transmission efficiency, highlighting recent advances in direct aerosol sampling that have challenged longstanding assumptions. While cough has traditionally been considered the primary dissemination route, new evidence shows that tidal breathing can generate infectious aerosols in the absence of symptoms. These findings are consistent with emerging evidence suggesting that asymptomatic individuals may contribute more substantially to transmission than previously recognized, with significant implications for understanding <i>Mtb</i> pathogenicity and host susceptibility to infection and disease.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid Alterations and Pathogenic Roles in Synucleinopathies.","authors":"Estela Area-Gómez, Saranna Fanning, Ulf Dettmer","doi":"10.1101/cshperspect.a041646","DOIUrl":"10.1101/cshperspect.a041646","url":null,"abstract":"<p><p>Mounting evidence highlights a role for lipid alterations and defects in lipid signaling in age-related neurodegenerative diseases such as Parkinson's disease (PD) and related conditions (collectively referred to as synucleinopathies). This growing interest is driven by several key findings: (1) lipid membranes are components of Lewy bodies and Lewy neurites, which are prototypical proteinaceous intraneuronal inclusions of PD and other synucleinopathies, primarily composed of α-synuclein (αS); (2) αS shares structural similarities with lipid-binding proteins and has been reported to bind to lipids; (3) glucocerebrosidase, a key enzyme in sphingolipid metabolism, is a major PD risk factor; (4) other enzymes involved in glycolipid and phospholipid regulation, such as diacylglycerol kinase-θ and fatty acid elongase-7, also contribute to PD risk; (5) αS alterations impact lipid homeostasis; (6) αS transiently binds lipid membranes, affecting its conformation. Given these findings, we review what is known about the role of lipids in normal αS biology as well as in the pathogenesis of PD and related conditions. We also highlight areas where further research is warranted.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Tuberculosis: Presentation and Diagnostic Approach.","authors":"Federico Fama, Jessica Potter, Emily Shaw, Conor Tweed, Marc Lipman","doi":"10.1101/cshperspect.a041804","DOIUrl":"https://doi.org/10.1101/cshperspect.a041804","url":null,"abstract":"<p><p>Tuberculosis (TB) in adults can present in multiple ways. The lung is the most common site of disease, with cough, hemoptysis, weight loss, and night sweats as the most frequent symptoms. Extrapulmonary involvement, which may present many years after exposure, can affect virtually any organ. Microbiological sampling is key to confirming the diagnosis, but invasive procedures may be necessary to obtain adequate samples. Molecular diagnostics have become a cornerstone of clinical practice, enabling rapid species identification and detection of drug resistance. In immunocompromising conditions, like human immunodeficiency virus (HIV) infection, TB presentation is often atypical and requires a high index of clinical suspicion and may trigger paradoxical inflammatory reactions during otherwise effective treatment. Zoonotic TB, caused predominantly by <i>Mycobacterium bovis</i>, and complications of Bacillus Calmette-Guérin (BCG) therapy are increasingly recognized clinical entities. Following successful treatment, a significant proportion of TB survivors develop post-TB disease. Early diagnosis, multidisciplinary management, and sustained clinical awareness remain essential to reducing the global burden of this disease.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological Principles in the Use and Development of Antituberculosis Drugs.","authors":"Geraint Davies","doi":"10.1101/cshperspect.a041822","DOIUrl":"https://doi.org/10.1101/cshperspect.a041822","url":null,"abstract":"<p><p>Recent advances in the development and deployment of antituberculosis drugs have been underpinned by an improved understanding of their pharmacokinetic-pharmacodynamic behavior in the complex context of tuberculosis disease in the host. New information from novel technologies has helped to clarify aspects of drug distribution and action, which contribute to the critical clinical phenomena of persistence and resistance in <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), while effective integration of these data through quantitative pharmacology tools has facilitated more rational decision-making in preclinical and clinical drug development. This new framework permits a much more extensive and efficient evaluation of the space of novel and repurposed multidrug regimens in tuberculosis with the expectation of accelerating the arrival of even shorter, safer, and more effective treatments in the clinic.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-Tuberculosis Lung Disease: Clinical Spectrum, Management Principles, and Lifelong Consequences.","authors":"Brian W Allwood, Alistair Broadhurst, Muhammad Saadiq Moolla, Anthony Carrozzi, Marieke M van der Zalm, Anthony Byrne","doi":"10.1101/cshperspect.a041887","DOIUrl":"https://doi.org/10.1101/cshperspect.a041887","url":null,"abstract":"<p><p>Post-tuberculosis lung disease (PTLD) is an increasingly recognized consequence of pulmonary tuberculosis (TB) disease, affecting millions of survivors worldwide and imposing substantial clinical, functional, and socioeconomic burdens. This narrative review synthesizes current evidence across epidemiology, definitions, clinical phenotypes, assessment, and management, with dedicated consideration of children and adolescents. PTLD is common: Studies report abnormal spirometry in ∼60% of TB survivors and persistent, activity-limiting dyspnea in a sizeable minority. Outcomes are generally worse in low- and middle-income settings. The 2019 international consensus definition-\"evidence of chronic respiratory abnormality attributable at least in part to prior TB\"-has catalyzed research and service development; a newer research definition proposes a structured, three-domain approach (symptoms, radiology, lung function) and introduces \"post-TB lung abnormality\" for single-domain findings. PTLD encompasses heterogeneous patterns, including fibrosis, cavitation with chronic pulmonary aspergillosis risk, bronchiectasis, airflow obstruction, tracheobronchial stenosis, pleural disease, vascular complications, and pulmonary hypertension. Assessment should integrate symptom review, exercise capacity, oximetry, spirometry (with Global Lung Initiative [GLI] reference standards), and context-appropriate imaging, alongside targeted microbiology and echocardiography where indicated. Evidence for disease-modifying therapy remains limited; however, pulmonary rehabilitation improves function and symptoms, and selected patients may benefit from inhaled bronchodilators or surgical interventions. A \"treatable traits\" framework-spanning pulmonary, extrapulmonary, and behavioral risk domains-offers a pragmatic, person-centered strategy while high-quality trials mature. In children, TB during critical periods of lung development confers lasting functional and growth impacts, underscoring the need for age-specific screening and follow-up. We outline key research priorities: embedding PTLD outcomes in TB trials, standardizing measurement, elucidating mechanisms, evaluating host-directed therapies, and integrating post-TB care into routine health services.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asymptomatic Tuberculosis: Prevalence, Relevance, Biology, Diagnosis, and Treatment.","authors":"Hanif Esmail, Rein M G J Houben, Anna K Coussens","doi":"10.1101/cshperspect.a041852","DOIUrl":"https://doi.org/10.1101/cshperspect.a041852","url":null,"abstract":"<p><p>Tuberculosis (TB) care and prevention have long relied on the assumption that individuals with the disease will seek care once they become aware of symptoms. However, national prevalence surveys show that nearly half of bacteriologically confirmed TB cases report no symptoms at screening, challenging this paradigm. The World Health Organization (WHO) now recognizes asymptomatic TB as part of the disease spectrum and promotes symptom-agnostic screening strategies to identify and treat these individuals. Evidence suggests that asymptomatic TB could be contributing to transmission, although further research is needed. While defining symptom status remains imprecise, individuals with asymptomatic TB present distinct diagnostic and treatment challenges. Asymptomatic pulmonary TB typically involves more limited disease, lower bacillary burden, and difficulty producing sputum, reducing the sensitivity of current sputum-based tests. Novel diagnostic approaches, including alternative sampling and molecular tools, are under development. Treatment uptake and adherence are another concern, as individuals feel well and derive no immediate symptomatic benefit, increasing the risk of poor initiation and completion. Addressing these gaps through improved diagnostics, shorter and better-tolerated regimens, and enhanced treatment support is essential. Recognizing and targeting asymptomatic TB is critical to interrupt transmission and accelerate progress toward global TB elimination.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}