Oligometastatic prostate cancer has classically been defined as a small volume of prostate cancer spread as defined by imaging using CT, MRI, and bone scans. With development and integration of more sensitive functional imaging including PSMA-PET imaging more oligometastatic disease will be detected than was found with conventional imaging techniques. We are currently lacking data directing the best treatment course for these oligometastatic prostate cancer cases found on PET imaging who would have been defined as localized disease prior to PET imaging. Herein, we discuss the concept of stage migration and discuss current problems and challenges with the current definition of oligometastatic disease as imaging modalities have progressed in our field.Oligometastatic prostate cancer has traditionally been defined in the literature as a limited number of metastatic lesions (either to soft tissue or bone), typically based on findings seen on CT, MRI, and skeletal scintigraphy. Although definitions have varied among research studies, many important clinical trials have documented effective treatments and prognostication in patients with oligometastatic prostate cancer. In current clinical practice, prostate-specific membrane antigen (PSMA)-PET/CT is increasingly utilized for the initial staging of high-risk patients and, in many cases, detecting metastases that would have otherwise been undetected with conventional staging imaging. Thus, patients with presumed localized and/or oligometastatic prostate cancer undergo stage migration based on more novel molecular imaging. As a result, it is challenging to apply the data from the era before widespread PET utilization to current clinical practice and to relate current trials using PSMA-PET/CT for disease detection to older studies using conventional staging imaging alone. This manuscript aims to review the definition of oligometastatic prostate cancer, summarize important studies utilizing both PSMA-PET/CT and conventional anatomic imaging, discuss the concept of stage migration, and discuss current problems and challenges with the current definition of oligometastatic disease. Prostate cancer is the most common non-cutaneous malignancy in American men, with an estimated 268,490 new cases in the United States in 2022 . There iGiven that low-volume metastatic disease is often limited to the pelvis and suitable for regional treatment and/or limited bone metastases amenable to targeted therapy if a focus extends beyond the pelvic region, the approach to the treatment of these entities differs significantly from those with systemically widespread metastases. Additionally, historical studies have found outcomes of patients with oligometastatic disease to be between those of non-metastatic and widely metastatic disease.Newer molecular imaging agents, including prostate-specific membrane antigen (PSMA)-PET/CT and fluciclovine-PET/CT, have substantially improved the detection of metastatic disease that otherwise would have gone undetected on conventional imaging . This phGenerally speaking, the term oligometastatic disease is defined as either a limited number and/or volume of metastatic lesions and applies to a number of different malignancies ,7,8. Typ99mTc-methyl diphosphonate (MDP) skeletal scintigraphy. Through these trials , many important conclusions were made regarding the prognosis and treatment of patients with oligometastatic prostate cancer at the time, often utilizing a combination of systemic therapy, targeted radiotherapy, and/or surgical resection with varying definitions of oligometastatic disease [As with many critical clinical trials that have taken place before the widespread use of emerging PET radiotracers for prostate cancer staging, these definitions rely primarily on findings as seen on CT, MRI, and  disease ,20,21,2218F-fluorodeoxyglucose (FDG) is not routinely used for imaging prostate cancer, as lower-grade prostatic adenocarcinoma typically does not demonstrate significant uptake [18F-fluciclovine, and 11C-choline are only approved for use in biochemically recurrent prostate cancer and not initial staging due to challenges in differentiating benign prostatic hyperplasia nodules from prostate cancer foci in an intact, untreated prostate gland [18F-sodium fluoride (NaF) is a radiotracer that physiologically functions similarly to 99mTc-MDP and demonstrates accumulation at sites of increased bone turnover (such as sclerotic osseous metastases) [18F-NaF can be used in lieu of skeletal scintigraphy for bone-specific imaging, but at a higher cost and still necessitates additional imaging for staging of non-osseous metastatic disease.t uptake . 18F-flute gland ,25. Howete gland ,27,28,29astases) . At stag111In-capromab pendetide gamma camera imaging and now PSMA-targeted PET radiotracers. Several PSMA PET radiotracers are currently FDA-approved for use in the initial staging of high-risk patients, and these tracers can be radiolabeled with both 68Ga and 18F. PSMA PET radiotracers allow for whole-body staging in a single imaging session. The current National Comprehensive Cancer Network guidelines suggest that PSMA PET can be the initial imaging modality used for prostate cancer staging [PSMA is a transmembrane glycoprotein that is overexpressed on the cell surface of prostate cancer cells . The PSM staging . Althoug staging ,34,35,3611C-choline PET/CT demonstrated that this approach could produce a useful single diagnostic exam in the evaluation of patients with moderate to high-risk prostate cancer with the potential of metastatic spread and can reliably rule out lymph node and distant metastases and establish eligibility for pelvic radiotherapy [11C-choline PET/CT offered acceptable local tumor control rates and may allow for a delay of ADT initiation [Given the increasing data on improved sensitivity and specificity of PET radiotracers for improving staging of prostate cancer when compared to conventional imaging, modern-day clinical practice and clinical trials have begun to utilize PET/CT for staging imaging over CT, MRI, and skeletal scintigraphy, adding a recognized stage migration with earlier detection of regional or metastatic prostate cancer spread ,37. In potherapy . Anotheritiation .18F-DCFPyL PET/CT in a phase II randomized trial of observation versus stereotactic ablation radiation in oligometastatic prostate cancer [The most recent work has utilized various PSMA radiotracers for guiding staging and treatments in the setting of oligometastatic prostate cancer. The proPSMA trial was a prospective, multicenter trial in patients with newly diagnosed high-risk prostate cancer, found that PSMA PET/CT demonstrated 27% greater accuracy than conventional imaging and was a suitable replacement to current conventional imaging methods . The ORIe cancer . All tree cancer . Additioe cancer ,45,46.It is without question that PSMA-PET/CT has significantly improved the staging and restaging of patients with prostate cancer when compared to conventional anatomic imaging. Given this improved diagnostic performance, significant uncertainties exist in clinical and research settings on what constitutes oligometastatic disease ,48. As aThe primary question in regard to this stage migration to a higher stage classification for some oligometastatic prostate cancer patients is how to apply data from the era of conventional imaging to an era where molecular imaging improves detection of disease which is otherwise occult on conventional staging techniques. Some proportion of men with oligometastatic disease on conventional imaging who were included in early trials (such as LATITUDE and CHAARTED) would likely have been upstaged to a more widespread metastatic disease definition if PET imaging had been utilized at the time.Conversely, it is challenging to relate emerging data utilizing PET imaging to historical data on the overall survival of patients with oligometastatic prostate cancer . UltimatWhile we recognize the optimized sensitivity of extraprostatic prostate cancer foci detection with PSMA PET imaging resulting in a stage migration in the initial diagnosis and staging of oligometastatic prostate cancer, we also know that the management of these patients is as uncertain as ever before. As such, more work is needed to truly establish the clinical impact of improved disease detection through PSMA-PET/CT.


Streptococcus pyogenes, also known as beta-hemolytic group A Streptococcus, invades a normally sterile site in the body. This article provides guidelines for establishing surveillance for invasive Strep A infections. The primary objective of invasive Strep A surveillance is to monitor trends in rates of infection and determine the demographic and clinical characteristics of patients with laboratory-confirmed invasive Strep A infection, the age- and sex-specific incidence in the population of a defined geographic area, trends in risk factors, and the mortality rates and rates of nonfatal sequelae caused by invasive Strep A infections.Invasive group A streptococcal (Strep A) infections occur when This article includes clinical descriptions followed by case definitions, based on clinical and laboratory evidence, and case classifications  for invasive Strep A infections and for 3 Strep A syndromes: streptococcal toxic shock syndrome, necrotizing fasciitis, and pregnancy-associated Strep A infection.Considerations of the type of surveillance are also presented, noting that most people who have invasive Strep A infections will present to hospital and that invasive Strep A is a notifiable disease in some countries. Minimal surveillance necessary for invasive Strep A infection is facility-based, passive surveillance. A resource-intensive but more informative approach is active case finding of laboratory-confirmed Strep A invasive infections among a large  and well defined population.International Classification of Disease diagnosis codes, follow-up, period of surveillance, seasonality, and sample size are discussed. Finally, the core data elements to be collected on case report forms are presented.Participant eligibility, surveillance population, and additional surveillance components such as the use of  Streptococcus pyogenes infections occur when the organism invades a normally sterile site in the body. Invasive Strep A infections can manifest as any of several clinical syndromes, including empyema, bacteremic pneumonia, primary bacteremia (Strep A isolated from the blood without another apparent focus of infection), bacteremia in association with skin and soft tissue infection , deep soft-tissue infection , meningitis, peritonitis, osteomyelitis, and septic arthritis. The release of toxins can lead to further complications such as streptococcal toxic shock syndrome (STSS), a syndrome manifesting as hypotension in combination with evidence of multiple organ failure.Invasive group A streptococcal (Strep A) or The incidence of invasive Strep A infections is highest among the very young and the elderly. Persons at increased risk for invasive Strep A infections include persons with underlying chronic medical  or immunocompromising conditions, indigenous populations , and persons who experience homelessness or with drug or alcohol addiction . InvasivDiagnosis of invasive Strep A infections is established via microbiological confirmation of Strep A collected from a normally sterile site. A normally sterile site contains no microorganisms in a healthy individual and includes, but is not limited to, the following: blood, cerebrospinal fluid, pleural fluid, peritoneal fluid, pericardial fluid, bone, muscle, joint fluid, and internal organs such as brain, heart, liver, spleen, or lymph node. Confirmatory microbiological tests include bacterial culture or detection of Strep A by nucleic acid testing. Prognosis varies depending on the type of invasive Strep A infection, and accurate diagnosis and prompt treatment is critical to improve outcomes. Even with aggressive antimicrobial treatment, case fatality remains high globally (∼20%) for invasive Strep A infections, particularly in neonates and older adults and patients with concomitant necrotizing fasciitis or STSS , 4.An effective surveillance system for invasive Strep A serves to monitor trends in the following (1) numbers or incidence rates of laboratory-confirmed invasive Strep A infection for a defined population; (2) demographic and clinical characteristics of patients; (3) age- and sex-specific incidence of invasive infections; and (4) incidence rates of death and nonfatal sequelae due to invasive Strep A infections.Through monitoring trends in these factors, changes warranting initiation of rapid or longer term public health measures can be implemented, including in response to outbreaks.emm types, virulence factors, presence of vaccine antigens, and antimicrobial susceptibility) of Strep A strains to (1) measure strain-specific disease burden and facilitate outbreak detection; (2) monitor trends in Strep A strains causing invasive disease to detect shifts in predominant or virulent strains over time, including shifts due to strain-specific vaccination; (3) track antimicrobial resistance over time; and (4) predict and evaluate the effectiveness of future or existing strain-specific vaccines.Enhanced surveillance systems may also aim to determine and monitor the distribution of select genotypic or phenotypic features  may include the following: (1) monitor the impact of interventions and public health policies on rates of invasive Strep A infections, including efforts to reduce secondary spread in households; (2) identify potentially modifiable risk factors for community-acquired invasive Strep A infections; and (3) identify and monitor potentially preventable invasive Strep A infections, such as healthcare-associated infections  or invasive infections associated with facilities such as homeless shelters.Standardized case definitions are important for obtaining accurate surveillance data, comparing burden estimates and case fatality rates across surveillance sites, and monitoring the impact of vaccines and other interventions. The case definitions for invasive Strep A infections in The inclusion of probable cases with Strep A cultured from nonsterile sites requires an accurate clinical diagnosis. Not all sites will have this capacity, nor will all studies include cases from nonsterile sites; thus, the numbers or incidence rates of confirmed and probable invasive Strep A infections should be presented separately. This will identify a core set of confirmed cases and allow for comparisons between studies.A list of normally sterile sites is provided in Streptococcal toxic shock syndrome (STSS) is a severe illness associated with Strep A infection, manifesting with shock and multisystem organ failure, and most often occurs in association with skin and soft-tissue infections but can occur in association with any Strep A infection , 7.Criteria for diagnosing confirmed and probable STSS have been defined by The Working Group on Severe Streptococcal Infections and Council of State and Territorial Epidemiologists , 8. The Necrotizing fasciitis is a rapidly progressive infection that destroys deep soft tissues, including muscle fascia and overlying subcutaneous fat. Multiple species of bacteria can cause necrotizing fasciitis; however, Strep A is a common cause of this syndrome. Imaging  can reveal the presence of swelling, inflammation, and gas in soft tissue; however, it cannot be relied on, or should not be used alone, for diagnosis without evidence of necrotizing fasciitis by visual examination of tissue during surgery or by histopathologic examination. Diagnostic tests should not delay definitive surgical management, because delays can lead to increased morbidity and mortality. Case definitions and classification are summarized in Invasive Strep A infections associated with pregnancy are an important cause of maternal and infant mortality. Also called “maternal infections”, pregnancy-associated invasive Strep A infections are those associated with pregnancy, delivery, and the postpartum period (or “puerperium”), although most infections occur in the postpartum period . The posnd-day postpartum and for which Strep A is the etiology of the infection  based on sequence determination of a core set of housekeeping genes) and, more commonly, WGS of individual strains. More importantly, each of the classic typing schemes  and lincosamides . Clindamycin, used as an adjunctive therapy with penicillin, is recommended for severe invasive Strep A infections, such as necrotizing fasciitis and STSS .Staphylococcus aureus (methicillin-resistant S aureus), an important bacterial cause of skin infections and toxic shock syndrome.At this time, Strep A is universally sensitive to penicillin and other β-lactam antibiotics such as cephalosporins. However, mutations in penicillin-binding protein genes that confer reduced susceptibility to β-lactam antibiotics have been reported , 26. ResAntimicrobial susceptibility testing is usually determined phenotypically by measuring minimum inhibitory concentrations for individual antibiotics. Methods to determine this include disk diffusion, Etest, and broth microdilution, following standardized protocols published by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)  and the Invasive Strep A infections are typically acute and severe; many are life-threatening. In contrast to less severe manifestations of Strep A infections such as pharyngitis and impetigo, most people with an invasive Strep A infection will seek medical care. Therefore, the surveillance approach to identifying cases among people who present for medical care may be either passive or active .In some countries, invasive Strep A infections are notifiable, meaning probable or confirmed cases are required by law to be immediately reported to local or state health authorities. If invasive Strep A infections are notifiable within the surveillance jurisdiction, healthcare providers should be engaged with, and regularly reminded of, their responsibility to report suspected cases.Consideration needs to be given to establishing surveillance across sites to capture the full array of patients. Because isolation or detection of Strep A from a normally sterile site is essential to the definition of a confirmed case of invasive disease, the microbiology laboratories in acute care hospitals and reference laboratories processing specimens for residents of the surveillance area are efficient sites for case identification. Where possible, laboratory data should be further augmented through review or data linkage to medical records such as admission and discharge registers, medical charts, and operating room records or death certificates for clinical syndromes typical of invasive Strep A . Medical records providing clinical diagnosis are essential sources of information if the surveillance protocol includes probable cases with Strep A isolates from nonsterile sites. Note that relying solely on medical records can be unreliable to estimate the incidence of invasive Strep A infections because cases can be misdiagnosed and the clinical information or causative pathogen needed to confirm a case of invasive Strep A infection may not be recorded. Considerations for using administrative health databases to identify cases are provided in International Classification of Disease (ICD) diagnosis code for STSS.Surveillance for STSS can be conducted by requiring that the illness meets the criteria defined in For each data source, surveillance staff should (1) know the purpose of the data source , (2) identify any legal mandates governing the operations of the data source that may impact the accessibility or quality of the data from that source, and (3) describe the representative population for the data.The selection of surveillance strategies depends on specific epidemiologic and clinical characteristics of the disease outcome of interest, the overall surveillance objectives, surveillance location, services accessibility, and the resources available . The objectives of these surveillance systems can include estimating strain-specific disease burden, evaluating the effectiveness of prospective or existing strain-specific vaccines, detecting shifts in predominant or virulent strains over time, and tracking antimicrobial resistance [Some invasive Strep A surveillance includes monitoring and describing the distribution of select genotypic or phenotypic features of Strep A isolates  to allow for additional characterization and for potential strain comparisons in outbreak investigations . AcquisiAntimicrobial resistance among invasive Strep A isolates is typically expressed as the proportion or prevalence of isolates demonstrating resistance to the antibiotic. Monitoring local antimicrobial resistance and trends over time is important for local healthcare providers making treatment plans for patients and public health agencies. When calculating the prevalence of antimicrobial resistance, it is important to avoid double-counting results from testing more than 1 isolate per patient per infection. In addition, the percentage of isolates used for antimicrobial testing should be calculated and included in any descriptions of antimicrobial resistance.The specific protocol will determine the extent of follow-up of patient illness outcomes. Data collected on invasive Strep A infections should include in-hospital mortality or mortality within 30 days of illness onset and a range of other severe outcomes such as renal failure and major and minor amputation, where possible. Data on clinical outcomes can be obtained via follow-up surveys conducted several months post discharge, with the patient’s consent.Hospitals that obtain bacterial cultures as part of routine practice should ensure that appropriate cultures are obtained prior or close to initiation of antibiotic treatment of patients with the following syndromes: sepsis and septic shock, necrotizing fasciitis, puerperal sepsis, arthritis or septic joint, meningitis, erysipelas, lymphangitis, and osteomyelitis. Any protocol that results in changes to clinical practice would need to occur before starting a prospective study because such changes will likely alter case detection.International Classification of Diseases diagnosis codes available in the country of surveillance can be used to identify several invasive Strep A infections. However, for many invasive Strep A infections, ICD diagnosis codes are unreliable. For some syndromes, a specific code for the infection does not exist  or is not specific for Strep A as the cause of the syndrome  (see tis) see . In addiCase ascertainment can be improved if the surveillance team makes regular visits to the surveillance sites to review clinical and laboratory records for missed cases and inform healthcare workers of the goals and methods of Strep A surveillance.The duration of surveillance depends on the availability of resources to support the surveillance system and the time needed to achieve the surveillance objectives. Multiple years of surveillance are generally required to detect outbreaks, to evaluate temporal trends  or the impact of an intervention such as the introduction of a vaccine program.Investigators should consider conducting surveillance through a full year to include all months or seasons. In temperate climates, invasive Strep A infections often exhibit seasonal peaks  and troughs . This is not the case in all climates; however, completion of surveillance over a 12-month period enables capture of other nonseasonal cyclic variations. Several years of surveillance is necessary to describe seasonality.To derive meaningful estimates of disease burden, the size of the population under surveillance should be considered, given the relatively low incidence of invasive Strep A disease compared with other acute Strep A infections.It is important to record each case of invasive Strep A infection, but not to record any case more than once during a single hospitalization or illness episode, defined as within 30 days of the first positive culture result. For example, if a patient has an illness during which Strep A grows from multiple body sites  correlating with 2 diagnoses (eg pericarditis and bacteremia) or a patient is diagnosed with both necrotizing fasciitis and STSS due to Strep A, his/her illness should be counted as a single case of invasive Strep A infection.Given the frequency of invasive Strep A infections, incidence is typically expressed as cases per 100 000 population per year. Incidence rates for confirmed and probable episodes should be reported separately. It is also helpful for regional comparison if reported incidence rates are stratified by the body site from which Strep A was cultured , because many healthcare facilities do not routinely culture some body sites  for which Strep A infection is suspected. Decisions on enumerating these episodes should be made at the analytical level.Case report forms should be based on collecting only the information required to achieve the surveillance objectives. See “General surveillance variables” include unique identifier, date and time of first enrollment or specimen collection, and site where participant is seen, such as setting, location, postcode, state/province/region, country. Each encounter should also record a surveillance visit number/episode number if repeated episodes from the same person are included.“Key demographic variables” include date of birth or age (in days or months if <12 months and otherwise in years), sex, ethnic origin/race, residential postcode, state, and country, and residential setting at the time of infection .“Clinical and epidemiologic variables” include site of Strep A infection, clinical risk factors, severity of illness and disease outcome, potential portal of Strep A entry, epidemiologic risk factors, treatment details, and microbiological variables.Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.ofac281_Supplementary_DataClick here for additional data file.


De novo testicular tissue generation in this manner will require a focus on both cellular and environmental aspects of tissue engineering. Put together, these studies highlight the future potential for expanded clinical, reproductive, and endocrine management options for individuals who are currently excluded from aspects of biologic reproduction most consistent with their gender identity and reproductive preferences.In recent decades, reproductive science has revolutionized the options for biological parenthood for the 20–50% of infertility cases affected by male factors. However, current solutions exclude those who are infertile due to absent testicular tissue. This includes anorchic 46, XY individuals due to trauma or congenital factors and transgender men with a 46, XX genotype. There is a clinical need for methods to restore testicular function independent of pre-existing testicular tissue. This mini-review analyzes studies that have applied non-testicular cell lines to generate germline and non-germline testicular parenchymal components. While only 46, XY cell lines have been evaluated in this context to date, the potential for future application of cell lines from 46, XX individuals is also included. Additionally, the role of varied culture methods, media supplementation, and biologic and synthetic scaffolds to further support testicular parenchyma generation are critiqued.  Infertility impacts nearly 50 million couples globally. Male factor infertility is identified as the primary cause in 20–30% and as a contributing factor in 50% of total heterosexual infertile couples . Assistein vitro spermatogenesis for more than a century. One of the earliest described methods  and testosterone to maintain androgenic homeostasis.The testis serves two primary roles: reproductive and endocrine. In the reproductive context, spermatogenesis occurs in the seminiferous tubules and represents a continuum from SSC through spermatocytes, spermatids, and spermatozoa. Sertoli cells provide structural and metabolic support to the differentiating spermatogenic cells and are responsive to follicle stimulating hormone (FSH) secreted by the pituitary gland. In the endocrine context, the hypothalamic-pituitary-testicular axis includes Leydig cells and operates In this section, the most successful studies in the derivation of testicular cell lines from non-testicular progenitors and the varied microenvironments and culture conditions applied to accomplish this task are described. Study details are included in iPSC cell lines are derived from adult tissues that, after genetic manipulation with a core set of genes, can be expanded and differentiated into organ-specific cell lines . Given tvia embryoid bodies followed by transplantation of cells with testicular tissue into host mice, seminiferous tubule-like structures were likewise observed  co-culture conditions, human iPSC and ESC cell lines were cultured in SSC conditions with GDNF . Differentiation was demonstrated by presence of germ cell markers followed by a subset differentiated to round spermatids . Small aobserved .Two more recent iPSC applications have advanced further toward the ultimate objective of deriving an effective testicular environment. In one of these studies, various testicular cell types including spermatogonia, Leydig, peritubular myoid, and endothelial cells were derived from human iPSCs using cell-line specific 2D culture media conditions. Resulting cells were then co-cultured as organoids, leading to formation of tubular structures, mature somatic cell, and post-meiotic gametes . UltimatThe above-mentioned studies affirm the differentiation potential of iPSCs to generate haploid gametes as well as somatic cells. Future studies that confirm the genetic stability, safety of implantation, and efficacy of gametes in producing progeny are needed to improve understanding of iPSC translational potential.Another potential cell line for clinical translation are VSELs, a relatively rare cell population in the gonads. VSELs are regarded as a pluripotent and quiescent (during steady state) subpopulation among SSCs, comprising ∼0.03% of testicular cells and sharing numerous PGCLC markers . In addivia injection of the alkylating agent busulphan, the VSEL population persists within the testes. However, VSELs did not spontaneously differentiate until allogeneic Sertoli cells were transplanted, suggesting that paracrine signaling between Sertoli cells and the VSEL population may be key for resumption of spermatogenesis. These findings emphasize that supporting cell lines are critical components of a microenvironment in which VSELs can differentiate into germ cell lines capable of in vitro fertilization (IVF) (After induction of azoospermia in mice on (IVF) . VSELs aIn vitro, cell differentiation to small round cell morphology expressing a range of pre, meitoic, and post-meiotic markers has been observed. When injected into the rete testis of azoospermic mice, transplanted cells migrated to intratubular spaces and differentiated to germline cells. , and Eif2s3x (eukaryotic initiation factor), homologs for SRY on the X chromosome resulted in mice with evidence of spermatogenesis despite absence of the Y chromosome. One of the modifications yielded spermatids that enabled production of live offspring  construct consisting of either a biologic or synthetic scaffold with select cell lines. In the first section the outcomes of recellularization of biologic scaffolds with stem cells will be discussed; the subsequent section will discuss advancements in synthetic scaffold engineering. Study details are included in in vitro, human and porcine SSCs cultured on decellularized human ECM indeed provided a microenvironment that successfully maintained human germline progenitor cells . Constructs implanted into liver and mesentery remained intact with demonstrated biocompatibility. Additionally, vascularized constructs contained multiple classes of non-germline testicular cells. This supports the potential to use in vivo models as functional bioreactors to achieve cellular differentiation of non-germline testicular cells  coated polyglycolic acid (PGA) polymer with chondrocytes to support cartilage development. Following an initial culture period, the scaffold was loaded with testosterone enanthate. The scaffold sustained hormonal elution in vitro and in vivo, thereby demonstrating the potential to apply scaffolds to retain physiologic levels of intratesticular testosterone. Such hormonal-structural microenvironments will be critical to increase functionality and efficiency of spermatogenesis. , media selection and steps in its use, and the role that cell-cell interactions and the secretome of each cell in culture may have had in co-culture studies. Additionally, the epigenome of cells impacts the yield of their differentiation to higher levels and using pharmaco-epigenetic agents, the differentiation yield can be significantly influenced . Finallyin vitro generation of fully differentiated haploid gametes from a non-testicular progenitor cell line derived from 46, XX or 46, XY individuals. To achieve this, seeding in a 3D environment using a scaffold that emulates key components of the healthy testis microenvironment and structure will be invaluable, including promotion of cell-cell interactions. The resulting structure can be adapted for auto-transplantation, thereby supporting gametogenesis and endocrine functions of a healthy testis in an autologous, biocompatible manner. While this prospect is currently out of reach, several key independent functions of the ultimate structure have been demonstrated, including maintenance of testosterone physiological concentration, cell differentiation of progenitor cells into both germline and non-germline cells using a biological scaffold, and testis-like structural support generation for progenitor cells transplanted into host animals. As this work proceeds, it will be key to evaluate each step for its potential short- and long-term effects on epigenetic and genetic stability and transmission for effective and safe biologic reproduction for all individuals, regardless of gonadal presence or gender identity.As demonstrated in


Climate change poses an existential global risk, and mitigation requires population-level behavioral change. Due to their shortened time horizon, older adults may not perceive climate change as a personal risk within their lifetime and may be less likely to take action to combat climate change. Socioemotional selectivity theory  posits that, as people age and perceive a shorter time horizon ahead, they become more focused on maintaining emotional wellbeing. This study, rooted in SST, manipulated the emotional framing of climate-change information in a sample of U.S. older adults. Participants were given EPA climate-change information localized to their state of residence and were instructed that, by taking action, the impact of climate change could be reduced (instilling hope) or that, by not taking action, the impact of climate change could be exacerbated (instilling fear). Afterward, they completed measures assessing their willingness to engage in pro-environmental behaviors and support of macro-level legislation to combat climate change. Compared to older adults who received the "hope" frame, older adults who received the "fear" frame reported greater willingness to engage in pro-environmental behaviors (p = 0.007) and greater support of legislation to combat climate change (p = 0.038), perhaps an effect of older adults' motivation to reduce the negative affective state induced by the "fear" frame. Implications of these results for catalyzing older adults toward climate action are discussed.


Neurodegenerative diseases (NDs) involve complex cellular mechanisms that are incompletely understood. Emerging findings have revealed that disruption of nuclear processes play key roles in ND pathogenesis. The nucleus is a nexus for gene regulation and cellular processes that together, may underlie pathomechanisms of NDs. Furthermore, many genetic risk factors for NDs encode proteins that are either present in the nucleus or are involved in nuclear processes . While recent advances in nuclear transcriptomics have been significant, studies of the nuclear proteome in brain have been relatively limited. We propose that a comprehensive analysis of nuclear proteomic alterations of various brain cell types in NDs may provide novel biological and therapeutic insights. This may be feasible because emerging technical advances allow isolation and investigation of intact nuclei from post-mortem frozen human brain tissue with cell type-specific and single-cell resolution. Accordingly, nuclei of various brain cell types harbor unique protein markers which can be used to isolate cell-type specific nuclei followed by down-stream proteomics by mass spectrometry. Here we review the literature providing a rationale for investigating proteomic changes occurring in nuclei in NDs and then highlight the potential for brain cell type-specific nuclear proteomics to enhance our understanding of distinct cellular mechanisms that drive ND pathogenesis. Neurodegenerative diseases (NDs), including Alzheimer's Disease (AD), afflict more than 50 million people worldwide, resulting in lower quality of life for both the afflicted individuals and their caretakers  including neurons, microglia, astrocytes, oligodendrocytes and endothelial cells are affected by (and may in turn contribute to) ND pathology in a cell-type specific manner. To highlight this, De Strooper and Karran describe a “cellular phase” of AD, which follows a “biochemical phase” characterized by amyloid beta accumulation and tau hyperphosphorylation  and Serine/Arginine-rich (SR) proteins Fu, . Many otIn conclusion, the nucleus has functionally distinct compartments which are spatially organized rather than organized by membranes . These dThe relevance of the nucleus in NDs is indicated by the results of genomic studies, which have found that nuclear-expressed gene products are risk factors for disease. Findings from genome-wide association studies (GWAS) have helped define the genetic risk architecture underlying NDs including late onset AD (LOAD) , Huntington's Disease (HD), Spinocerebellar Ataxia type 1 (SCA1), and Dentatorubral-Pallidoluysian Atrophy (DRPLA)  with assignment to “nucleus” GO category and performed pathway analyses   of GWAS studies of over 100,000 subjects have used SNP association data to nominate 1,822 genes with potential causal links to LOAD  proteinopathies because both of these proteins are normally enriched in the nucleus, although in ALS/FTD spectrum disorders, they are mislocalized in the cytoplasm  and aging-related neuronal deterioration. CIN mediates neuronal loss and acts as a key feature of the pathogenic cascade in NDs  in AD  , and symptomatic AD , was discovered in Japanese populations and recently replicated in a European ancestry cohort  of proteins contribute to the functional diversity of the human proteome by covalently attaching functional groups to amino acids, impacting a protein's localization, functionality, (re)folding and stability. These PTMs include phosphorylation, ubiquitination, and methylation, among many others. Maintenance of homeostatic PTMs is critical to retaining a cell's function and health.Phosphorylation is one of the most widespread PTMs, and homeostatic regulation of phosphorylation by protein kinases and protein phosphatases can drastically alter the functionality of target proteins. Aberrant hyper-phosphorylation is seen in many NDs, including tauopathies (in which tau becomes hyperphosphorylated and forms NFTs) and TDP-43 proteinopathies . Hyperphosphorylation of specific amino acid residues on tau is seen to directly incite conformational changes in the protein. Tau hyperphosphorylation is further implicated in neuronal toxicity because hyperphosphorylation of tau precedes NFT aggregation and is also seen to contribute to neuronal toxicity independent of the aggregation of NFTs  hypo-acetylation of histone proteins can decrease the expression of specific proteins or cause widespread transcriptional deficits at several loci . While FTLD and ALS afflict ~1/1,000 individuals, LATE afflicts ~1/3 persons above the age of 80  gene  and by mutations of the MAPT gene on the ability of tau to stabilize chromatin, further implicating nuclear tau in chromosomal stability  may be significant mediators of ND pathogenesis, but are very difficult to detect and distinguish cell-type-specific changes using bulk proteome analysis. By conducting more focused (including cell-type or compartment-specific) proteomic analyses, we may overcome these barriers, and prove more detailed, targeted, and ultimately valuable insights into local changes during ND pathogenesis  and NeuN-negative  nuclei were isolated from frozen post-mortem human brain by wide-clearance dounce homogenization, centrifugation, and then flow cytometry based sorting of nuclei, followed by mass spectrometry proteomic analyses. Using this approach, termed Fluorescence Activated Nuclear Sorting (FANS), Dammer et al. identified 487 nuclear proteins that were highly enriched in NeuN+ve nuclei and 420 which were highly enriched in NeuN-ve nuclei. Using these differentially expressed nuclear proteins, we cross referenced these lists against known genetic risk factors for AD, PD and ALS  Nalls e, and ideThe study of the nuclear proteome offers intriguing possibilities, not only because of its enabling of cell-type specific proteomics, but additionally because of the ability to investigate nuclear alterations that occur during ND pathogenesis that may be missed by whole cell or bulk tissue proteomics. Alterations in protein can be linked to additional omic data obtained from additional samples of the same purified nuclei. As previously mentioned, numerous studies implicate nuclear pathways in NDs, including but not limited to: NCT, chromosomal stability, RBPs, and nuclear inclusion bodies. Thus, investigating cell-type specific nuclear proteomes would provide us with a better understanding of how these biological pathways, and specific cell phenotypes are altered in a cell type specific manner over the course of NDs.Recently, Nott and colleagues designed a protocol aimed at isolating cell type specific nuclei for the purpose of genomic and epigenomic investigation. The authors of this new protocol asserted that nuclei isolated using their protocol can be used to identify chromatin features including chromatin architecture and to identify the binding sites of transcription factors using chromatin immunoprecipitation-sequencing (ChIP-seq)  to sort the nuclei. Dammer et al. found that FANS not only allowed cell-type specific nuclear sorting but additionally reduced non-nuclear protein contamination  are also promising approaches that may be capable of obtaining deep proteomes from single cells or nuclei or pools of small numbers of nuclei (10–100) from brain , R01 AG075820 , and R01AG061800 (NS).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cannabis and its major cannabinoids (−)-trans-Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are gaining momentum for various medical purposes as their therapeutic qualities are becoming better established. However, studies regarding their efficacy are oftentimes inconclusive. This is chiefly because Cannabis is a versatile plant rather than a single drug and its effects do not depend only on the amount of THC and CBD. Hundreds of Cannabis cultivars and hybrids exist worldwide, each with a unique and distinct chemical profile. Most studies focus on THC and CBD, but these are just two of over 140 phytocannabinoids found in the plant in addition to a milieu of terpenoids, flavonoids and other compounds with potential therapeutic activities. Different plants contain a very different array of these metabolites in varying relative ratios, and it is the interplay between these molecules from the plant and the endocannabinoid system in the body that determines the ultimate therapeutic response and associated adverse effects. Here, we discuss how phytocannabinoid profiles differ between plants depending on the chemovar types, review the major factors that affect secondary metabolite accumulation in the plant including the genotype, growth conditions, processing, storage and the delivery route; and highlight how these factors make Cannabis treatment highly complex.Medical  Cannabis as its therapeutic virtues are becoming better known and accepted (trans-Δ9-tetrahydrocannabinol (THC), which was first isolated and structurally elucidated by Mechoulam and colleagues in 1964  in vertebrates , with cannabigerolic acid (CBGA) as the first cannabinoid compound, made by the prenylation of olivetolic acid with the isoprenoid geranyl pyrophosphate (GPP) (trans-Δ9-tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) and cannabichromenic acid (CBCA) are derived from CBGA-type phytocannabinoids via specific enzymatic reactions (trans-Δ9-tetrahydrocannabivarinic acid (THCVA) and cannabidivarinic acid (CBDVA), or the seven-carbon (-)-trans-Δ9-tetrahydrocannabiphorol (THCP) and cannabidiphorol (CBDP)  . Other peactions . Thus, oeactions  such as l (CBDP)  and othel (CBDP) . Though r nigrum .Cannabis are terpenes and terpenoids . Terpenes are naturally occurring volatile unsaturated hydrocarbon biomolecules built up by branched 5-carbon isoprene units, sharing the same isoprenoid precursor as phytocannabinoids. Terpenoids are modified terpenes that contain additional functional groups, usually varying oxygen arrangements or oxidation states. Monoterpenoids are built by two isoprene units (10 carbons) and sesquiterpenoids are built up by three isoprene units (15 carbons)  . Monotercarbons) . Terpenocarbons) . Terpeno effects , and wer effects . Terpeno effects .Cannabis and may give the plant some of its exclusive medicinal benefits , either coupled to a flame ionization detector or a mass-spectrometer (MS). However, there are a few limitations to this method, as some analytes may not be sufficiently separated and decomposition is required for accurate quantification. Therefore, an alternative method using ultra-high-performance liquid chromatography with an ultraviolet detector (UHPLC/UV) and electrospray ionization-liquid chromatography/mass spectrometry (ESI-LC/MS)   allows fI-LC/MS) . TerpenoI-LC/MS) . SimilarI-LC/MS) .Cannabis is one genus with one species, sativa L.  or ingestion of edibles , but still induce heat and expose to a variety of undesirable chemicals (Cannabis are susceptible to degradation processes such as decarboxylation when Cannabis is heated above 120°C by smoking or vaping, as well as by cooking (Inhalation provides a rapid and efficient method of drug delivery. Symptom relief is immediate and effective, the dosage can be more controlled than via the alternative routes, and a lower dose can be used to get the desired effect . Howeverhemicals . All the cooking .Cannabis metabolites. For example, when THC is ingested rather than inhaled, it is metabolized by the liver before entering the bloodstream and hydroxylated to 11-hydroxy-THC, which is equally potent (Cannabis delivery system vital for its effective administration and treatment (The pharmacokinetics of the current consumption options modulates and limits the therapeutic bioavailability of y potent  or mighty potent , and thereatment .Cannabis metabolites both in the plant itself and in the tissues they affect, allowing to better investigate their disposition over time by the body of the organism (Cannabis (New analytical approaches now allow for more accurate profiling of organism . Many ofCannabis .Cannabis is ever increasing in the treatment of numerous conditions as it has been proven to be both effective and safe, but the Cannabis plant contains more than 500 different components, each with potential therapeutic qualities. The components of Cannabis act together, hitting several targets at once and mutually enhancing each other’s activity so that the overall outcome is greater than that of their additive effect. The concentrations and combinations of the various secondary metabolites, including the way they complement each other, determine both the final medicinal response and adverse effects.The use of medical Cannabis can treat a multitude of very different conditions as it exerts its effects via the ECS, which is involved in many physiological processes. Cannabis treatment can be personalized to both the condition and the person to improve treatment outcomes while also reducing the drug load and minimizing the adverse effects. Most patients do not receive Cannabis-based medication but rather whole plants or extracts that contain many active bio-compounds in different proportions. Each has a different profile of components, undergoing different drug interactions. It is still unknown which molecules in the whole extract are responsible for its overall effect and via which ECS receptors, effectors and metabolic pathways. Further research is needed to find which whole extracts or specific molecules are best suited to treat a given condition.Cannabis and improve human health.Physicians and patients require more information to guide them in choosing the most appropriate cultivar or molecules, in the correct dose and via the optimal delivery route. The number of studies that tested different cannabinoids or tried to recognize the specific bioactive molecules from whole extracts is low and should be addressed to fulfill the full potential of


Among malignant tumors, lung cancer has the highest morbidity and mortality worldwide. Surgery is the first-line treatment for early-stage lung cancers, and has gradually advanced from conventional open-chest surgery to video-assisted thoracic surgery (VATS). Additionally, increasingly smaller surgical incisions and less surgical trauma have resulted in reduced pulmonary function damage. Previous studies have found that the level of pulmonary function loss and recovery is significantly correlated with postoperative complications and the quality of life. Thus, an accurate assessment of the preoperative pulmonary function and effective rehabilitation of postoperative pulmonary function are highly important for patients undergoing lung surgery. In addition, pulmonary function assessment after pulmonary rehabilitation serves as an objective indicator of the postoperative pulmonary rehabilitation status and is crucial to facilitating pulmonary function recovery. Furthermore, a complete preoperative assessment and effective rehabilitation are especially critical in elderly patients with pulmonary tumors, poor basic physiological functions, comorbid lung diseases, and other underlying diseases. In this review, we summarize the clinical significance of pulmonary function assessment in patients undergoing lung cancer surgery, postoperative changes in pulmonary function, effective pulmonary function rehabilitation, and the influencing factors of pulmonary function rehabilitation. Among malignant tumors, lung cancer has the highest morbidity and mortality in China and throughout the world . SurgeryAmong pulmonary function indices, the forced expiratory volume in the 1st second (FEV1) and the diffusing capacity of the lung for carbon monoxide (DLCO) show the best correlations with postoperative morbidity and mortality rates . The prePneumonectomy: ppoFEV1 = preoperative FEV1 × Lobectomy: ppoFEV1 = preoperative FEV1 × The same equations can be used to estimate the ppoDLCO. Both a ppoFEV1 and ppoDLCO >60% indicate a low risk for anatomic pneumonectomy  . Hence, Lung surgery exerts notable short-term and long-term impacts on the postoperative pulmonary function of patients with lung cancer. There are various causes of pulmonary function impairment after pneumonectomy, including the resection of lung tissues and changes in the mechanical structure of the chest wall induced by surgical incisions . ConventIn brief, a long-term postoperative decline in pulmonary function is inevitable, regardless of whether the surgery is open-chest or VATS. Although pulmonary function gradually improves after surgery, the overall level is still lower than the preoperative level, which affects the postoperative quality of life to varying degrees.Pulmonary function recovery after lung cancer surgery is affected by various factors. The choice of surgical method and the range of lung tissue excision are major factors of pulmonary function decline . SmokingGeneral pre-operative condition factors, including age , BMI 2424, smokiCompared to normal weight and obesity, underweight status is associated with decreased pulmonary function . Good prLong-term smoking is a risk factor for pulmonary complications after pneumonectomy, and smoking cessation can effectively lower the incidence of pulmonary complications , 31. HowThe process of pulmonary function recovery after lung cancer surgery is accompanied by various influencing factors, including pulmonary atelectasis, pleural effusion, and postoperative chest pain. After lung cancer surgery, early postoperative rehabilitation and improvement in pulmonary function should be facilitated by the aggressive administration of expectorants, proper use of analgesics, tapping on the back in a prone position , improvement in pulmonary ventilation and gas-exchange function, and aggressive treatment of complications, including pleural effusion and pulmonary infections.Surgical trauma is an important factor influencing postoperative pulmonary function recovery. Posterolateral incisions are most widely used in conventional open-chest surgery. The incisions are relatively long and the latissimus dorsi muscle needs to be incised. Additionally, intraoperative rib spreading usually damages the ribs and intercostal nerves, which causes persistent postoperative pain and affects pulmonary function recovery. Liu et al. showed greater FVC decline and FVC% decline at 6 months and 2 years postoperatively with pneumonectomy and chest wall resection than with chest wall-sparing pneumonectomy . Harada With the development of minimally invasive techniques, most lung cancer surgeries have been performed by VATS in recent years. The range of lung tissue excision varies depending on the size, amount, and location of the lesions, which are major factors affecting postoperative pulmonary function recovery. Mori et al. demonstrated that, in patients who underwent lung wedge resection, postoperative FVC decreased temporarily, but nearly recovered to the preoperative level after 12 months, whereas the postoperative FEV1 recovered gradually over the course of 12 months, but did not recover to the preoperative level . FurtherTherefore, when choosing the surgical method, surgeons should consider retaining normal lung tissues when possible, on the premise of complete tumor resection, in order to facilitate pulmonary function recovery in the early postoperative period and improve the quality of life.Changes in pulmonary function are associated with the location, volume, and severity of emphysema . Lung vovia two mechanisms: enhancement of the diffusing capacity of the residual lung and the generation of new pulmonary gas-exchange units  can cause some damage to normal lung tissues while treating primary lesions, resulting in pulmonary function decline after treatment. Nomori et al. demonstrated pulmonary function decline in patients who underwent induction radiotherapy and chemotherapy; the pulmonary function decline primarily occurred on the affected side , which wPoor exercise capacity (peak oxygen consumption <15 mL/kg/min) is the major determinant of postoperative morbidity and mortality after pneumonectomy . EffectiHowever, unlike the above studies, a 20-week trial by Edvardsen et al. showed no difference in FEV1 between the rehabilitation group (who underwent high-intensity endurance and strength training) and the control group; only DLCO was higher in the rehabilitation group . StudiesClinical experience suggests that postoperative patients should perform proper breathing and aerobic exercises in the early postoperative phase, including deep breathing, pursed-lip breathing, jogging, swimming, stair climbing, etc. In addition, pulmonary function tests should be regularly performed; the exercise intensity can be gradually increased and maintained for 3-6 months, based on the pulmonary function recovery and improvement in respiratory symptoms. These measures can be instrumental in accelerating the postoperative pulmonary function recovery.via effective pulmonary rehabilitation exercise. However, some studies suggest that pulmonary rehabilitation does not induce a significant improvement in postoperative cardiopulmonary function. Current studies are mostly limited to the assessment of pulmonary function recovery in the early postoperative phase; there are few reports on the recovery of pulmonary functions after long-term pulmonary rehabilitation exercise.With continued progress in minimally invasive concepts and techniques, VATS exerts an increasingly smaller impact on postoperative pulmonary function. Thus, there exists some controversy regarding the pulmonary function changes in patients undergoing lung cancer surgery; it was previously believed that lung cancer surgery can cause an absolute decline in postoperative pulmonary function, affecting postoperative complications and the quality of life. However, in recent years, some researchers have suggested that postoperative pulmonary function in patients with lung cancer can basically recover within 6-12 months after surgery despite a transient decline, without affecting the postoperative quality of life. Such studies mainly focused on patients receiving lung segmental and lung wedge resections, who experience a mild decline in postoperative pulmonary function. After prolonged recovery and compensation for pulmonary function loss, their pulmonary function basically recovers to the preoperative level, with little impact on the postoperative quality of life. In terms of postoperative pulmonary rehabilitation, most studies suggest that cardiopulmonary function and the quality of life can be improved to a certain extent after lung cancer surgery Our research team is conducting a prospective study on long-term postoperative pulmonary rehabilitation based on telemedicine platforms in 500 patients, including a pulmonary rehabilitation remote monitoring group, in which patients are followed up and managed using wearable devices with remote monitoring functions and rehabilitation management systems; and a pulmonary rehabilitation conventional management group, in which patients are followed up and managed using common means of social communication, including phone calls, text messages, and WeChat. In this ongoing study, we are applying digital technologies and multidisciplinary individualized comprehensive interventions to improve respiratory function, relieve postoperative symptoms, improve daily activity endurance, and promote wound healing after thoracic surgery. Remote wearable devices are used for the collection of physiological parameters and data analysis. We also plan to integrate internet technologies into postoperative monitoring and rehabilitation after thoracic surgery, in order to alleviate or control the complications of minimally invasive lung cancer surgery, and eliminate surgery-induced dysfunctions and psychological issues. In addition, we educate patients on how to improve exercise and activity endurance, improve self-care ability, and reduce the risk of hospitalization. The study is currently mid-stage, and preliminary data have confirmed the feasibility of telemedicine-based post-thoracic surgery rehabilitation. We believe that the results of this study can provide evidence to verify the necessity of postoperative rehabilitation in patients with lung cancer, promote the application of telemedicine techniques in the field of post-tumor surgery rehabilitation, facilitate the introduction and promotion of post-lung cancer surgery telerehabilitation programs in China, and inspire standardized procedures for post-lung cancer surgery telerehabilitation.SX and GW provided the initial idea for this review. YF, MN and FW were in charge of data acquisition and drafting of the article. TD, WY and WJ revised the article. All authors read and approved the final manuscript.National Key Research and Development Program (2019YFE0105600).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cardiac imaging is central to the diagnosis and risk stratification of coronary artery disease, beyond symptoms and clinical risk factors, by providing objective evidence of myocardial ischaemia and characterisation of coronary artery plaque. CT coronary angiography can detect coronary plaque with high resolution, estimate the degree of functional stenosis and characterise plaque features. However, coronary artery disease risk is also driven by biological processes, such as inflammation, that are not fully reflected by severity of stenosis, myocardial ischaemia or by coronary plaque features. New cardiac CT techniques can assess coronary artery inflammation by imaging perivascular fat, and this may represent an important step forward in identifying the ‘residual risk’ that is not detected by plaque or ischaemia imaging. Coronary artery disease risk assessment that incorporates clinical factors, plaque characteristics and perivascular inflammation offers a more comprehensive individualised approach to quantify and stratify coronary artery disease risk, with potential healthcare benefits for prevention, diagnosis and treatment recommendations. Furthermore, identifying new biomarkers of cardiovascular risk has the potential to refine early-life prevention strategies, before atherosclerosis becomes established. Cardiac CT (CCT) imaging has transformed the detection, characterisation and stratification of coronary artery disease (CAD) risk in individuals. Historically, evaluation of CAD was guided by symptoms, and crude measures of myocardial ischaemia with limited sensitivity and specificity from exercise ECG (ExECG) and other stress tests. These provided poor diagnostic and prognostic value. Consequently, invasive coronary angiography (ICA) became the gold standard for diagnosis of CAD. However, ICA has major limitations. First, two-dimensional imaging cannot assess haemodynamic consequences of stenoses, in terms of myocardial ischaemia. Second, the ICA ‘lumenogram’ does not image disease in the vessel wall. Intravascular imaging, using ultrasound (IVUS) or optical coherence tomography, reveals that angiographic assessment of the coronary lumen grossly underestimates the presence, nature and extent of coronary artery plaque.CCT imaging for CAD initially quantified coronary artery calcification, as it was readily detected on CT images, and quantified to generate a coronary artery calcium score (CACS) that represented a surrogate marker of the presence and extent of CAD. Large studies with long-term follow-up confirmed the utility of CACS as a predictor of cardiovascular risk in populations. However, the predictive power of CACS in individual patients is limited. Very low or zero CACS is reassuring and clinically valuable, but age and other prevalent risk factors are major drivers of CACS,Coronary CT angiography (CCTA) has transformed the non-invasive assessment of CAD, enabling visualisation of the coronary lumen, stenoses and plaque features, in three dimensions (3D). These data are now available at low X-ray exposure (often comparable with CACS), and in short acquisition times that reduce the need for breath-holding or beta-blocker treatment to slow the heart rate. Protocol optimisation however does remain heterogeneous between individual centres internationally.The clinical utility of CCTA is supported by many large multicentre studies. In the PROMISE trial, over 10 000 patients presenting with chest pain were randomised to CCTA or an ischaemia test.Current non-invasive imaging strategies to quantify cardiovascular risk using ischaemia testing also have limited value, as shown in the recent ISCHEMIA trial.The shift away from ischaemia testing is also supported by the SCOT-HEART trial that tested the clinical impact of early CCTA in patients with chest pain, compared with routine clinical care.As a result of these seminal trials, CCTA is used increasingly as a first-line test for patients presenting with chest pain, for diagnosis and to guide management strategy.In 2010, the UK’s National Institute for Health and Clinical Excellence (NICE) recommended that CCTA should be the first-line test for people with recent onset chest pain (NICE CG95). The European Society of Cardiology guidelines, published in August 2019, upgraded CCTA to a first-line investigation with the highest level of evidence (class 1), as the initial test for patients with a low to moderate clinical likelihood of CAD, representing the majority of patients presenting with chest pain. The 2021 US guidelines also reflect the increased utility of CCTA, particularly in younger people.CT, with some studies showing a modest reduction in the need for ICA and intracoronary pressure wire studies.CT or reduction in subsequent ICA, and incurred 20% higher healthcare costs.CCTA generates important additional information, beyond the presence and extent of CAD  that has actionable clinical importance for patients. The functional significance of stenoses can be calculated using computational flow dynamic or machine learning techniques to derive FFRCCTA can quantify the extent, distribution and characteristics of coronary plaques, but even this is not sufficient for optimal risk prediction in individuals. It is well known that most acute MIs occur secondary to occlusion in vessels with minor coronary plaque disease that erodes or ruptures. This relates to the biology of the underlying coronary plaque, particularly inflammation. In the PROMISE trial, 54% of adverse events occurred in patients without significant stenoses, whereas patients with significant stenoses accounted for only 12% of the population undergoing CCTA.CCTA can identify patients with plaque characteristics associated with high risk, such as low-attenuation plaque, napkin ring sign, positive remodelling and spotty plaque calcification ; howeverThis observation is consistent with other CCTA and IVUS studies. In the SCOT-HEART trial, 1376 HRP features on CCTA were detected in 608 of 1769 participants.The PROSPECT Study used virtual histology-IVUS (VH-IVUS) to image coronary plaque in all three major coronary arteries of patients undergoing ICA following an acute coronary syndrome (ACS).CT. To improve prediction of future adverse cardiovascular events needs, CCTA data sets need to identify local biological processes that drive disease and events, such as inflammation. Coronary artery inflammation is a major factor in CAD progression, and a key determinant of high-risk plaques that drive adverse clinical events, in addition to the contributions of stenosis, flow limitation or adverse plaque features.CCTA shows great promise for early risk assessment in otherwise healthy individualsImaging perivascular adipose tissue (PVAT) around the coronary arteries has emerged as a promising technique to image inflammation in the coronary artery wall. A key recent discovery is that PVAT ‘senses’ the presence of inflammation in the wall of the coronary artery. These signals transduce changes in PVAT differentiation, leading to smaller, less lipid-rich adipocytes, corresponding to transcriptomic changes in adipocyte gene expression, greater inflammatory cell infiltration and higher tissue water content.18F sodium fluoride uptake on positron emission tomography imaging, a marker of plaque inflammation.The CRISP-CT Study demonstrated the clinical value of PVAT imaging using a derivation cohort of 1872 patients , and a validation cohort of 2040 patients  who had undergone CCTA and were followed up for up to a median of 9 years.Combining coronary PVAT inflammation from CCTA with HRP features may provide additional insights into the relative importance of ‘biological’ versus ‘structural’ readouts for cardiovascular risk prediction and for understanding CAD pathogenesis . A recenCOL1A1 expression) and vascularity (CD31 expression). These features significantly improved prediction of adverse cardiovascular events in 1575 participants in the SCOT-HEART trial, beyond traditional risk stratification .The evaluation of FAI from the pericoronary adipose tissue imaged by CCTA offers the potential to derive other biomarkers from CCTA that reflect molecular changes related to cardiovascular risk. The ‘radiotranscriptomic’ approach, used to derive FAI from CT images of adipose tissue biopsies that underwent transcriptomic analysis of adipose tissue gene expression,FAI provides a powerful, convenient and clinically applicable tool to stratify cardiovascular risk based on CCT scans performed routinely in clinical practice. It has the potential to reclassify CVD risk and treatment allocation, leading to earlier and improved CVD diagnosis and treatment, which may reduce CVD mortality and morbidity, improve cost-effectiveness and reduce the economic burden of CVD.A recent algorithm demonstrates how incorporation of FAI analysis in patients undergoing CCTA could improve risk stratification and clinical management pathways.The ability to detect coronary artery inflammation, non-invasively, opens up the potential to understand the drivers of early CAD to prevent atherosclerotic plaque progression, before it confers significant cardiovascular risk. CAD begins very early in life, with inflammation driven by exposure to potentially modifiable risk factors. While the absolute risk of major cardiovascular events in younger people is low, CAD progresses silently over the life course, for many years before cardiovascular events occur. Many individuals in the population have an accelerated trajectory for the development of CAD, and could benefit from early-life identification and more proactive implementation of prevention measures. These are currently limited to generic health advice on smoking, cholesterol, blood pressure and lifestyle. Coronary artery inflammation is now recognised as a major factor in early disease pathogenesis, and is driven by classic cardiovascular risk factors and influences such as obesity, systemic inflammation and genetic susceptibility. Non-invasive detection of coronary artery inflammation is feasible by pericoronary adipose tissue imaging, even in young patients, and the significance of this will be an important focus for future studies. These will improve understanding of the pathophysiology of early atherosclerosis and guide timing and choice of early risk factor therapy as part of a personalised prevention approach. A focus on prevention is central to the current National Health Service Long Term Plan.CCTA has emerged as the preferred non-invasive modality for the study of chest pain due to possible underlying CAD, and for the assessment of cardiovascular risk. Technical advances and realignment of patient pathways make CCTA a first-line investigation for assessment of CAD . CCTA ca


Hypertrophic cardiomyopathy (HCM) follows highly variable paradigms and disease-specific patterns of progression towards heart failure, arrhythmias and sudden cardiac death. Therefore, a generalized standard approach, shared with other cardiomyopathies, can be misleading in this setting. A multimodality imaging approach facilitates differential diagnosis of phenocopies and improves clinical and therapeutic management of the disease. However, only a profound knowledge of the progression patterns, including clinical features and imaging data, enables an appropriate use of all these resources in clinical practice. Combinations of various imaging tools and novel techniques of artificial intelligence have a potentially relevant role in diagnosis, clinical management and definition of prognosis. Nonetheless, several barriers persist such as unclear appropriate timing of imaging or universal standardization of measures and normal reference limits. This review provides an overview of the current knowledge on multimodality imaging and potentialities of novel tools, including artificial intelligence, in the management of patients with sarcomeric HCM, highlighting the importance of specific “red alerts” to understand the phenotype–genotype linkage. Hypertrophic cardiomyopathy (HCM) is the most common inheritable cardiomyopathy with autosomal dominant transmission, and it is characterized by heterogeneous presentation and outcome . The assIn addition, cardiac hypertrophy can be the manifestation of inherited and acquired systemic disorders with different genetic background, prognosis, and treatment. Multimodality imaging can be useful in differentiating phenocopies and identifying specific red flags.Although multiple imaging modalities are available, an integrated approach is yet to be defined.The aim of this review is to provide a wide overview of the current knowledge and future frontiers in multimodality imaging for HCM, highlighting the potentialities of different techniques in the management of this cardiomyopathy. The literature research methods adopted are described in Transthoracic echocardiography (TTE) is the initial and preferred imaging modality to confirm diagnosis, stratify prognosis and family screening . TTE enaHCM is defined by the presence of an end diastolic wall thickness ≥15 mm in any LV segment, in the absence of abnormal loading conditions; however, a wall thickness ≥13 mm is diagnostic in case of family history of HCM or in disease-causing gene carriers ,6. HCM cMyocardial hypertrophy and fibrosis are the main determinants of global and regional abnormalities in LV myocardial mechanics and contribute to systolic dysfunction and LV remodeling. Due to increased wall thickness with a smaller LV cavity, HCM patients show a reduced stroke volume index, longer LV isovolumetric contractions and ejection times, with a delayed peak systolic velocity . The LV Previous observations have suggested that the reduction in the GLS is counterbalanced by an increase in the global circumferential strain (GCS), resulting in a biplanar strain vector more circumferentially orientated and in a normal LVEF . AnalyseMoreover, an increased base-to-apex gradient rotation with a higher degree of twist displaced to the apex has been observed . AccordiOverall, analyses of strain-derived longitudinal and circumferential mechanics, LV torsion and twist give valuable information to better understand the underlying pathophysiology of HCM. In addition, these parameters may help in early identification of structural changes in genotype-positive, phenotype-negative patients.Data on myocardial mechanics may also help in risk stratification and therapeutic management during follow-up: on top of the conventional sudden cardiac death (SCD) risk factors, a reduction in the GLS, a marker of myocardial fibrosis, was shown to be an independent predictor of appropriate ICD therapy . Althoug2, average E/e’ ratio > 14 and a peak TR velocity > 2.8 m/s) is indicative of elevated LA pressures. In the presence of significant MR (≥moderate), peak TR velocity and pulmonary vein atrial reversal velocity are the most reliable indexes of LV filling pressures [Diastolic dysfunction is the hallmark of the disease. It is a common finding in symptomatic HCM patients and is due to impaired LV relaxation, as a consequence of increased myocardial stiffness, and impaired left atrial (LA) function . Althougressures ,18. A reressures ,18,19.While these metrics are not accurate in all clinical scenarios , recent LA remodeling results from left ventricular stiffness, LVOTO, and MR, but also from primary atrial involvement in the myopathic process . Impairment of LA function is an important contributor to diastolic dysfunction in HCM and can be assessed by the LA strain ,22: a reAdditionally, this technique was further used in family members of HCM patients for early detection of myocardial changes, especially in pathogenic mutation carriers : The LA LVOTO occurs in up to two-thirds of HCM patients ,3,5. ResTraditionally, the M-mode has been used to assess the anterior mitral leaflet–septal contact, with severe LVOTO defined as contact for ≥30% of systole, and to depict mid-systolic closure (“notching”) of the aortic valve, caused by a drop in subaortic pressure . Color DResting or provoked gradients of ≥50 mmHg are considered a threshold for invasive therapy in patients who have refractory symptoms, despite maximally tolerated dose of medical therapy ,3. TTE aLess frequently, echocardiography may identify mid-cavity obstruction, which can coexist with LVOTO or represent the main obstruction pattern, promoting the formation and growth of apical aneurysms . In mid-2) and/or a posterior leaflet >1.5 cm [Many patients with obstructive HCM have abnormalities of the mitral valve and the subvalvular apparatus, which contribute to SAM. In fact, SAM is a result of the Venturi effect on elongated mitral valve leaflets, defined as an anterior mitral leaflet >2.5 cm  . Other sStress echocardiography may improve SCD risk prediction also in case of hypotensive response to exercise or a reduced increase in blood pressure (<20 mmHg) compared to basal values . MoreoveFinally, a classical application of exercise echocardiography, as the detection of myocardial ischemia, can be useful in hypertrophic cardiomyopathy. Chest pain and myocardial ischemia are common in HCM patients and have multiple underlying mechanisms . Although LV wall motion abnormalities are frequent in this setting , the preCardiovascular Magnetic Resonance (CMR) represents the most accurate imaging modality to define and differentiate the spectrum of myocardial disease, with higher diagnostic sensitivity than echocardiography. Despite being the first imaging diagnostic approach for patients with suspected HCM, echocardiography has several limitations caused by poor acoustic windows, particularly for segments not well visualized by ultrasound . SeveralWhat makes CMR a unique imaging modality is the opportunity of tissue characterization. Late gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) represents the gold standard imaging method to assess myocardial fibrosis. Fibrosis detection in HCM plays a crucial role in risk stratification, being a strong and independent predictor of several complications of HCM and correlating with HF symptoms and advanced stages . A reducHowever, the myocardium in HCM is typically characterized by many forms of tissue remodeling . InterstParticularly in this setting, T1 mapping represents a valuable tool in HCM. T1 mapping is a CMR technique that enables the identification of tissue abnormalities, including interstitial fibrosis, oedema and amyloid, through quantification of longitudinal relaxation time. T1 time varies in correlation with the state of the molecular environment, and is susceptible to pathological processes that modify tissue water composition . It reprChallenges in CMR for HCM include the variability in quantification techniques, lack of standardized approaches and cut-offs, as well as limited knowledge of LGE progression patterns.Although LV hypertrophy (LVH) is a key feature in sarcomeric HCM, several other cardiac, systemic or metabolic diseases mimic the hypertrophic phenotype. Given that the management and prognosis of different aetiologias of LVH may significantly differ, an accurate diagnosis is crucial .The distinction between hypertrophic cardiomyopathy and the athlete’s heart is a common clinical dilemma, since LVH is a key feature of both phenotypes. The athlete’s heart is defined by structural, electrical and functional adaptation to repetitive, high-intensive or extensive exercise . In partUp to 2% of athletes may develop a borderline LVWT between 13 and 15 mm ,66. As sCMR further helps in distinguishing between physiological remodeling of the athlete’s heart from HCM: in the latter, LGE is often present in contrast to the athlete’s heart and is a well-validated sign of focal myocardial lesions and fibrosis due to pathogenic HCM-related sarcomeric alterations ,70.Amyloidosis is a restrictive infiltrative cardiomyopathy characterized by deposition of amyloidogenic, misfolded insoluble proteins—mostly wild-type or inherited mutated transthyretin (ATTR) and light chains (AL)—in the extracellular matrix between myocytes . This acGiven the high affinity of transtiretin for bone tracers, single-photon emission computerized tomography (SPECT) with bisphosphonates has emerged as a crucial tool for diagnosing transtiretin amyloidosis: specific diagnostic algorithms, that integrate bone SPECT, hematologic tests and imaging with ETT and CMR, have been proposed .Systemic arterial hypertension is highly prevalent and is a leading cause of cardiovascular morbidity and mortality. Since both HCM and hypertensive heart disease are characterized by an increase in LV mass, differentiation of these two phenotypes can be challenging, also due to their considerable morphological overlap. Increased LV mass, determined by echocardiography, is present in 23% to 48% of hypertensive patients . The degResting or exercise-induced LVOTO can be observed also in hypertension  and does not constitute a diagnostic criteria .Although LGE may be present in the mid-myocardium and epicardium also in hypertensive patients, in HCM, it is typically located in the areas of maximal hypertrophy and at the insertion of RV into ventricular septum . An incrFabry disease is an X-linked recessive lysosomal storage disorder that causes progressive myocardial accumulation of glycoshpingolipids, leading to LV hypertrophy, myocardial fibrosis and HF .Morphological imaging assessment in Fabry cardiomyopathy may display concentric LV hypertrophy, disproportionate hypertrophy of papillary muscles, loss of base-to-apex circumferential strain gradient, and RV hypertrophy with normal systolic function, although none of them is a pathognomonic feature . AsymmetNovel echocardiography techniques may increase the diagnostic capacity in this setting. In fact, a recent study showed an independent and incremental value of RV speckle-tracking analysis in discriminating Fabry cardiomyopathy from HCM, above conventional echocardiographic ‘red flags’ .In summary, echocardiography and CMR represent the main imaging tools for the differential diagnosis of HCM from its phenocopies. In particular, LV and RV speckle-tracking analysis and the GLS represent novel promising techniques ,56,67,77Among new imaging techniques, cardiac positron emission tomography (PET) has been proposed to quantify the myocardial blood flow in HCM. Impaired myocardial flow reserve is directly related with myocardial fiber disarray and hypertrophy in HCM and may lead to myocardial ischemia and ventricular arrhythmias . AlthougIn the “non-hypertrophic” phase, regular follow-up with imaging is used for screening of early phenotypical expression. However, due to incomplete penetrance and age-related onset, genotype-positive individuals may not phenotypically express the disease until the 7th decade. Even if the main diagnostic criterion for HCM is myocardial hypertrophy, several other functional and morphological abnormalities may be detected, as previously described in this review. None of them is essential for the diagnosis or adds information on prognosis, but their presence may lead to a closer follow-up. Current European recommendations suggest TTE in first-degree relatives as part of the initial family screening ,4. AfterStable phases in HCM are defined as “classic phenotype” stages . These rPatients with HCM and LVOTO or AF are more symptomatic for heart failure; therefore, yearly TTE should be performed.Exercise echocardiography is a routine test in patients with HCM and should be repeated every 6 months in the obstructive phenotype and every two years in all the other HCM patients, to screen for indication for myectomy or pharmacological therapy such as mavacamten.CMR is recommended by the ESC guidelines during the initial diagnostic work-up in all patients with HCM and repeated every 5 years afterwards. The LGE extent and distribution identify the typical sarcomeric form and strongly correlates with prognosis. In fact, a repeated scan between 3 and 5 years is recommended by the American Heart Association to better predict SCD. Although not included in the HCM Risk-SCD score, the greater importance of the LGE extent and apical aneurisms is acknowledged in the latest ESC guidelines on ventricular arrhythmias and SCD ,96,97. IFifteen to twenty percent of patients with HCM present an unfavorable clinical profile, with slow and progressive adverse ventricular remodeling. Overt LV dysfunction occurs in 5–10% of cases with two different morphofunctional patterns: the “hypokinetic-dilated” variant, characterized by volume increase and LVEF impairment (<50%); and the “hypokinetic-restrictive” variant, characterized by a small and stiff LV, with severe diastolic dysfunction, regardless of any systolic function deterioration. In patients with “adverse remodeling” and “overt dysfunction” phase, the outpatient clinical and echocardiographic follow-up needs to be scheduled every 3–6 months . The useA summary of multimodality imaging findings at each HCM stage is shown in There are not specific criteria to define advanced heart failure (AdvHF) in HCM. However, referral to a transplant center ought to be considered in a timely manner when high-risk features occur, due to possible rapid deterioration. Progression to AdvHF occurs in 3.5 to 17% of patients with HCM, and patients with sarcomere protein disease have higher probability to develop end-stage disease with LV systolic dysfunction compared to patients without mutations ,100. TimAdvHF in HCM is characterized by an increase in arrhythmic burden and/or decline in functional capacity. According to the 2020 AHA Guidelines, in patients with recurrent poorly tolerated life-threatening ventricular tachycardia, refractory to maximal anti-arrhythmic therapy and ablation, heart transplantation assessment is indicated with class I recommendation . In addiReduced exercise capacity and progression to NYHA class III/IV is multifactorial and reflects different mechanisms. It is mainly due to the inability to increase the stroke volume secondary to diastolic dysfunction, chronotropic incompetence and severe LV obstruction. Interestingly, Maron et al. described a correlation between obstruction and rate of HF symptoms progression . HoweverHowever, it is important to note that the populations considered were heterogeneous, including patients with obstructive and non-obstructive patterns, and the authors mainly investigated composite endpoints. Therefore, it is difficult to extrapolate binary prognostic markers to apply during routine clinical practice. Peak oxygen consumption alone does not fully reflect the complex physiopathology of advanced stages in HCM. Although useful to refer patients to specialized centers, decision to pursue heart transplantation should be based on the broad clinical assessment beyond CPET results.On a different note, a combined approach of CPET and echocardiography enables evaluating the presence of exercise induced pulmonary arterial hypertension (EiPAH), that represents an important determinant of functional limitation in HCM patients. EiPAH was present in about one fifth of HCM patients without evidence of elevated pulmonary pressures at rest and was associated with adverse clinical outcome. Diagnosing EiPAH by exercise echo/CPET may help physicians to detect early stage of PAH requiring a closer clinical monitoring and individualized treatment strategies. Moreover, close vigilance for pulmonary hypertension (PH) is recommended in those patients who may become transplant candidates. PH is a potentially reversible contraindication for heart transplant usually treated with vasodilators, inotropes and/or durable left ventricle assist device (LVAD). Although LVAD implant as bridge to candidacy has been described in non-obstructive HCM, the majority of these patients is not suitable due to small LV cavity dimensions and severely impaired filling ,113. TheArtificial intelligence (AI) is described as “the theory and development of computer systems that can do activities that would ordinarily require human intellect, such as visual perception, speech recognition, decision-making, and language translation”. AI has been playing an increasingly important role in cardiology as a result of considerable advancements in information and communication technology, such as the straightforward storage, acquisition, and retrieval of vast amounts of data and knowledge .AI has been increasingly used in HCM diagnosis, SCD prediction and treatment. Indeed, the multifactorial etiology of HCM, which includes structural and functional abnormalities, the burden of SCD in young adults with HCM and the severe morbidity in all age groups complicate diagnosis and treatment ,117.Since electrocardiographic abnormalities occur in more than 90% of HCM patients, 12-lead ECG may be a promising non-invasive, affordable, and quick method of screening . HoweverThe use of an AI-based deep learning network has the potential to overcome these obstacles because it is trained to detect even the most subtle ECG patterns associated with structural changes, that may be undetectable by the human eye or traditional automated algorithms. Ko and co-workers developed an artificial intelligence approach for the detection of HCM based on ECG using a convolutional neural network (CNN) trained and validated on 2448 HCM patients and 51,153 non-HCM age- and sex-matched control subjects . OverallConcerning SCD prediction, the guidelines-recommended HCM Risk-SCD prediction model for guiding ICD implantation has a C-index of approximately 0.69, illustrating how fragile these methods are in the face of new data and how inadequately they perform . The useAdditionally, scar quantification by LGE-CMR, that may help in SCD risk stratification as previously reported, frequently relies on subjective, difficult, and time-consuming human demarcation of the myocardial borders and the hyperenhanced regions on LGE images . The appIn recent years, even if the great development of imaging technique and genetics have made significant contributions to our understanding of HCM, a more comprehensive approach incorporating broad-based testing across multiple ‘omics’  may allow for improved precision in monitoring health and disease . To dateAmong the obstacles to the development of machine learning is the need for a large dataset as a reference point for interpretation. This raises ethical concerns around the usage of patient data and the machines’ ability to maintain data security and confidentiality.While the continuous advances in imaging techniques offer superb opportunities for a comprehensive evaluation of patients with HCM, only a profound knowledge of the specific mechanisms and patterns of disease will allow the appropriate use of these resources in each clinical setting of HCM. The comprehensive analysis of imaging data coupled with the potential of artificial intelligence is crucial to assessing the differential diagnosis with phenocopies, maximizing clinical management and achieving therapeutic benefits for specific needs at each stage of HCM. Promptly identifying patients at risk of developing advanced LV dysfunction and HF may drive preventive strategies over a period of several years. Disease progression towards HF, LVOT obstruction and risk of SCD may change over time: close clinical and well-scheduled imaging surveillance may potentially allow preventive treatment.


Utilization of human material in surgical simulation training has been well-established as an effective teaching method. Despite the value of donor-based surgical simulation training, its application may be hampered by difficulties regarding access to donated bodies. Therefore, the aim of this review is to assess body donation and body acquisition practices with regard to surgical simulation training programs around the world. The results of this review highlight discrepancies regarding body donation practices and surgical simulation programs among continents and countries. The utilization of donor bodies in surgical simulation appears to mirror body donation practices. In countries that rely mostly or exclusively upon unclaimed bodies or executed criminals, there are scant reports of donor-based surgical simulation programs. In countries where willed-body donation is the principal source of human material, there tend to be many surgical simulation programs that incorporate human material as part of surgical training. This review suggests that, in anatomical and surgical education, the utilization of active willed-body donation programs, as opposed to the utilization of unclaimed human bodies, positively corresponds with the development of beneficial donor-based surgical simulation programs. Likewise, donor-based surgical simulation training programs may have an influence on the perpetualization of willed-body donations. Otherwise, terms such as deceased human bodies, deceased person, or decedents will be used whenever possible. This nomenclature comes in an effort to limit or eliminate the commonly used term “cadaver” which objectifies the human body.With regard to nomenclature throughout this review, the term Deceased human bodies are utilized in many different ways as part of anatomical education and clinical training  organized a panel titled “Ethical and Proper Use of Cadavers in Surgical Education” during the First National Anatomy and Cadaveric Dissection Symposium of SATA, held in the year 2018   gave its summary of body donation throughout Europe  were introduced to a donor-based surgery program  utilized donor-based surgical training via filming procedures performed on body donors and subsequently distributing footage as a master class video presentation   has demonstrated that, by implementing a body donation program, a curriculum reliant upon of mostly unclaimed bodies  can transition to a curriculum, where most of the bodies are sourced from willing donors  might be reflective of difficulties in developing a vibrant and active willed-body donation program. Thus, medical schools might strive to develop active willed-body donation programs to subsequently incorporate beneficial donor-based surgical simulation programs. Such surgical simulation programs may, in effect, aid in the perpetualization of willed-donor programs. This report also highlights the important contribution and impact that that body donors have upon surgical trainees and, as an extension, patient care.