Annual review of medicine最新文献

The human microbiome is a sensor and modulator of physiology and homeostasis. Remarkable tractability underpins the promise of therapeutic manipulation of the microbiome. However, the definition of a normal or healthy microbiome has been elusive. This is in part due to the underrepresentation of minority groups and major global regions in microbiome studies to date. We review studies of the microbiome in different populations and highlight a commonality among health-associated microbiome signatures along with major drivers of variation. We also provide an overview of microbiome-associated therapeutic interventions for some widespread, widely studied diseases. We discuss sources of bias and the challenges associated with defining population-specific microbiome reference bases. We propose a roadmap for defining normal microbiome references that can be used for population-customized microbiome therapeutics and diagnostics.

Pathogenic variants in BRCA1 and BRCA2 are associated with significantly elevated lifetime risks of breast, ovarian, pancreatic, and prostate cancer. These genes are critical in double-strand break repair through homologous recombination. An understanding of the biology of BRCA1 and BRCA2 led to the development of targeted therapeutics, specifically poly(ADP-ribose) polymerase (PARP) inhibitors, which are approved by the US Food and Drug Administration for multiple BRCA1/2-associated cancers. Here, we discuss the development of PARP inhibitors, mechanisms of resistance, and the potential utility of these drugs beyond canonical BRCA1/2 tumors, and we describe novel agents under study.

Monoclonal antibodies (mAbs) targeting the SARS-CoV-2 Spike protein were deployed during the COVID-19 pandemic. While all of the clinically authorized mAbs were eventually defeated by SARS-CoV-2 variants, they were highly effective in preventing disease progression when given early in the course of the disease. The experience with mAbs to SARS-CoV-2 offers important lessons for the use of mAbs in future infectious disease emergencies, such as choosing mAbs that target conserved epitopes and designing cocktails to reduce the emergence of escape variants. Planning for future use must include the creation of infusion centers and the development of strategies to minimize the emergence of escape variants.

Oral selective estrogen receptor degraders (SERDs) are pure estrogen receptor antagonists that have the potential to overcome common resistance mechanisms to endocrine therapy in estrogen receptor-positive breast cancer. There are currently five oral SERDs in published and ongoing clinical trials-elacestrant, camizestrant, giredestrant, imlunestrant, and amcenestrant-with more in development. They offer a reasonably well-tolerated oral therapy option with low discontinuation rates in studies. This review summarizes the currently available literature on this new class of drugs.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by the formation of nodules, abscesses, and fistulae at intertriginous sites. Pain, pruritus, malodor, and suppuration have a significant impact on quality of life for HS patients. Prevalence figures vary greatly in the literature from 0.05% to 4.1%, and HS is more common in females. The current understanding of the etiology and pathogenesis of HS is incomplete; numerous hypotheses concern the interplay of lifestyle factors, skin microbiota, genetics, and a dysregulated immune system. Due to its phenotypic heterogeneity and multifactorial pathogenesis, HS is a complex disease that can prove challenging to manage. Two approved biologic therapies for the management of HS have led to clinical response in approximately 50% of treated patients. New therapies targeting the interleukin (IL)-1, IL-17, IL-36, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways are in ongoing clinical trials, and preliminary data offer hope for greater clinical efficacy in HS in the future.

Immune checkpoint blockade targeting the novel targets of the lymphocyte activation gene 3 (LAG3) and the T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) has marked a significant advancement in oncology, offering new therapeutic opportunities to fight diverse malignancies. This review covers the biological basis and clinical application of LAG3 and TIGIT inhibitors, highlighting pivotal trials and therapeutic outcomes. We underscore the use of dual therapy immune checkpoint blockade in enhancing antitumor immunity, particularly in settings where monotherapy has shown limited efficacy. Additionally, we address the emerging challenges such as treatment resistance and adverse effects. We explore the strategic integration of LAG3 and TIGIT blockade within the broader immunotherapy landscape, emphasizing innovative combinations and the quest for predictive biomarkers to optimize patient selection and treatment efficacy.

Over the past decade, new modalities have emerged to treat acute pulmonary embolism (PE). However, PE remains a leading cause of morbidity and mortality worldwide. In the absence of robust clinical trial data and definitive guidelines and recommendations for a variety of clinical situations, individual patient treatment decisions have become paradoxically more challenging as innovation in the space has grown. In this review, we discuss a practical and current approach to patients diagnosed with PE, focusing on their risk stratification and treatment selection.

Depressive disorders present an enormous global public health burden. A notable treatment gap exists between the prevalence of depression and our ability to provide rapid-acting, effective treatment that achieves remission. Brexanolone and zuranolone, the first US Food and Drug Administration-approved drugs for postpartum depression, signify a critical advancement in addressing the unmet needs of a vulnerable patient population. Psilocybin shows promise for treatment-resistant depression and for those who have struggled to find relief with existing treatments. This review discusses transformative therapies that represent significant advancements in postpartum depression, major depressive disorder, and treatment-resistant depression.

The population of cancer survivors is on the rise due to an increase in cancer incidence and a decline in cancer mortality. This growing survivor population creates a number of challenges. Although there have been improvements in care planning for cancer survivors, our healthcare system still lacks the delivery of coordinated care between primary care physicians and specialists. Understanding the needs of cancer survivors can help improve the current care models. In this review we describe existing survivorship care models. We also describe emerging models using some programs at the Cleveland Clinic to highlight various potential approaches.

Consumption of probiotic products continues to increase, perhaps driven by an interest in gut health. However, the field is filled with controversy, inconsistencies, misuse of terminology, and poor communication. While the probiotic concept is biologically plausible and in some cases mechanistically well established, extrapolation of preclinical results to humans has seldom been proven in well-conducted clinical trials. With noteworthy exceptions, clinical guidance has often been derived not from large, adequately powered clinical trials but rather from comparisons of disparate, small studies with insufficient power to identify the optimal strain. The separation of probiotics from live biotherapeutic products has brought some clarity from a regulatory perspective, but in both cases, consumers should expect scientific rigor and strong supporting evidence for health claims.