Emerging therapeutic drug monitoring technologies: considerations and opportunities in precision medicine.

In recent years, the development of sensor and wearable technologies have led to their increased adoption in clinical and health monitoring settings. One area that is in early, but promising, stages of development is the use of biosensors for therapeutic drug monitoring (TDM). Traditionally, TDM could only be performed in certified laboratories and was used in specific scenarios to optimize drug dosage based on measurement of plasma/blood drug concentrations. Although TDM has been typically pursued in settings involving medications that are challenging to manage, the basic approach is useful for characterizing drug activity. TDM is based on the idea that there is likely a clear relationship between plasma/blood drug concentration (or concentration in other matrices) and clinical efficacy. However, these relationships may vary across individuals and may be affected by genetic factors, comorbidities, lifestyle, and diet. TDM technologies will be valuable for enabling precision medicine strategies to determine the clinical efficacy of drugs in individuals, as well as optimizing personalized dosing, especially since therapeutic windows may vary inter-individually. In this mini-review, we discuss emerging TDM technologies and their applications, and factors that influence TDM including drug interactions, polypharmacy, and supplement use. We also discuss how using TDM within single subject (N-of-1) and aggregated N-of-1 clinical trial designs provides opportunities to better capture drug response and activity at the individual level. Individualized TDM solutions have the potential to help optimize treatment selection and dosing regimens so that the right drug and right dose may be matched to the right person and in the right context.

The relationship between 11 different polygenic longevity scores, parental lifespan, and disease diagnosis in the UK Biobank.

Large-scale genome-wide association studies (GWAS) strongly suggest that most traits and diseases have a polygenic component. This observation has motivated the development of disease-specific "polygenic scores (PGS)" that are weighted sums of the effects of disease-associated variants identified from GWAS that correlate with an individual's likelihood of expressing a specific phenotype. Although most GWAS have been pursued on disease traits, leading to the creation of refined "Polygenic Risk Scores" (PRS) that quantify risk to diseases, many GWAS have also been pursued on extreme human longevity, general fitness, health span, and other health-positive traits. These GWAS have discovered many genetic variants seemingly protective from disease and are often different from disease-associated variants (i.e., they are not just alternative alleles at disease-associated loci) and suggest that many health-positive traits also have a polygenic basis. This observation has led to an interest in "polygenic longevity scores (PLS)" that quantify the "risk" or genetic predisposition of an individual towards health. We derived 11 different PLS from 4 different available GWAS on lifespan and then investigated the properties of these PLS using data from the UK Biobank (UKB). Tests of association between the PLS and population structure, parental lifespan, and several cancerous and non-cancerous diseases, including death from COVID-19, were performed. Based on the results of our analyses, we argue that PLS are made up of variants not only robustly associated with parental lifespan, but that also contribute to the genetic architecture of disease susceptibility, morbidity, and mortality.

Assessing brain and biological aging trajectories associated with Alzheimer's disease.

The development of effective treatments to prevent and slow Alzheimer's disease (AD) pathogenesis is needed in order to tackle the steady increase in the global prevalence of AD. This challenge is complicated by the need to identify key health shifts that precede the onset of AD and cognitive decline as these represent windows of opportunity for intervening and preventing disease. Such shifts may be captured through the measurement of biomarkers that reflect the health of the individual, in particular those that reflect brain age and biological age. Brain age biomarkers provide a composite view of the health of the brain based on neuroanatomical analyses, while biological age biomarkers, which encompass the epigenetic clock, provide a measurement of the overall health state of an individual based on DNA methylation analysis. Acceleration of brain and biological ages is associated with changes in cognitive function, as well as neuropathological markers of AD. In this mini-review, we discuss brain age and biological age research in the context of cognitive decline and AD. While more research is needed, studies show that brain and biological aging trajectories are variable across individuals and that such trajectories are non-linear at older ages. Longitudinal monitoring of these biomarkers may be valuable for enabling earlier identification of divergent pathological trajectories toward AD and providing insight into points for intervention.

Does Modulation of an Epigenetic Clock Define a Geroprotector?

There is growing interest in the development of interventions (e.g., drugs, diets, dietary supplements, behavioral therapies, etc.) that can enhance health during the aging process, prevent or delay multiple age-related diseases, and ultimately extend lifespan. However, proving that such 'geroprotectors' do what they are hypothesized to do in relevant clinical trials is not trivial. We briefly discuss some of the more salient issues surrounding the design and interpretation of clinical trials of geroprotectors, including, importantly, how one defines a geroprotector. We also discuss whether emerging surrogate endpoints, such as epigenetic clocks, should be treated as primary or secondary endpoints in such trials. Simply put, geroprotectors should provide overt health and disease prevention benefits but the time-dependent relationships between epigenetic clocks and health-related phenomena are complex and in need of further scrutiny. Therefore, studies that enable understanding of the relationships between epigenetic clocks and disease processes while simultaneously testing the efficacy of a candidate geroprotector are crucial to move the field forward.

Strategies for Testing Intervention Matching Schemes in Cancer.

Personalized medicine, or the tailoring of health interventions to an individual's nuanced and often unique genetic, biochemical, physiological, behavioral, and/or exposure profile, is seen by many as a biological necessity given the great heterogeneity of pathogenic processes underlying most diseases. However, testing and ultimately proving the benefit of strategies or algorithms connecting the mechanisms of action of specific interventions to patient pathophysiological profiles (referred to here as "intervention matching schemes" (IMS)) is complex for many reasons. We argue that IMS are likely to be pervasive, if not ubiquitous, in future health care, but raise important questions about their broad deployment and the contexts within which their utility can be proven. For example, one could question the need to, the efficiency associated with, and the reliability of, strategies for comparing competing or perhaps complementary IMS. We briefly summarize some of the more salient issues surrounding the vetting of IMS in cancer contexts and argue that IMS are at the foundation of many modern clinical trials and intervention strategies, such as basket, umbrella, and adaptive trials. In addition, IMS are at the heart of proposed "rapid learning systems" in hospitals, and implicit in cell replacement strategies, such as cytotoxic T-cell therapies targeting patient-specific neo-antigen profiles. We also consider the need for sensitivity to issues surrounding the deployment of IMS and comment on directions for future research.

Genetic Support for Longevity-Enhancing Drug Targets: Issues, Preliminary Data, and Future Directions.

Interventions meant to promote longevity and healthy aging have often been designed or observed to modulate very specific gene or protein targets. If there are naturally occurring genetic variants in such a target that affect longevity as well as the molecular function of that target (eg, the variants influence the expression of the target, acting as "expression quantitative trait loci" or "eQTLs"), this could support a causal relationship between the pharmacologic modulation of the target and longevity and thereby validate the target at some level. We considered the gene targets of many pharmacologic interventions hypothesized to enhance human longevity and explored how many variants there are in those targets that affect gene function (eg, as expression quantitative trait loci). We also determined whether variants in genes associated with longevity-related phenotypes affect gene function or are in linkage disequilibrium with variants that do, and whether pharmacologic studies point to compounds exhibiting activity against those genes. Our results are somewhat ambiguous, suggesting that integrating genetic association study results with functional genomic and pharmacologic studies is necessary to shed light on genetically mediated targets for longevity-enhancing drugs. Such integration will require more sophisticated data sets, phenotypic definitions, and bioinformatics approaches to be useful.

Personalized medicine: motivation, challenges, and progress.

There is a great deal of hype surrounding the concept of personalized medicine. Personalized medicine is rooted in the belief that since individuals possess nuanced and unique characteristics at the molecular, physiological, environmental exposure, and behavioral levels, they may need to have interventions provided to them for diseases they possess that are tailored to these nuanced and unique characteristics. This belief has been verified to some degree through the application of emerging technologies such as DNA sequencing, proteomics, imaging protocols, and wireless health monitoring devices, which have revealed great inter-individual variation in disease processes. In this review, we consider the motivation for personalized medicine, its historical precedents, the emerging technologies that are enabling it, some recent experiences including successes and setbacks, ways of vetting and deploying personalized medicines, and future directions, including potential ways of treating individuals with fertility and sterility issues. We also consider current limitations of personalized medicine. We ultimately argue that since aspects of personalized medicine are rooted in biological realities, personalized medicine practices in certain contexts are likely to be inevitable, especially as relevant assays and deployment strategies become more efficient and cost-effective.

Single-Subject Studies in Translational Nutrition Research.

There is a great deal of interest in personalized, individualized, or precision interventions for disease and health-risk mitigation. This is as true of nutrition-based intervention and prevention strategies as it is for pharmacotherapies and pharmaceutical-oriented prevention strategies. Essentially, technological breakthroughs have enabled researchers to probe an individual's unique genetic, biochemical, physiological, behavioral, and exposure profile, allowing them to identify very specific and often nuanced factors that an individual might possess, which may make it more or less likely that he or she responds favorably to a particular intervention (e.g., nutrient supplementation) or disease prevention strategy (e.g., specific diet). However, as compelling and intuitive as personalized nutrition might be in the current era in which data-intensive biomedical characterization of individuals is possible, appropriately and objectively vetting personalized nutrition strategies is not trivial and requires novel study designs and data analytical methods. These designs and methods must consider a very integrated use of the multiple contemporary biomedical assays and technologies that motivate them, which adds to their complexity. Single-subject or N-of-1 trials can be used to assess the utility of personalized interventions and, in addition, can be crafted in such a way as to accommodate the necessarily integrated use of many emerging biomedical technologies and assays. In this review, we consider the motivation, design, and implementation of N-of-1 trials in translational nutrition research that are meant to assess the utility of personalized nutritional strategies. We provide a number of example studies, discuss appropriate analytical methods given the complex data they generate and require, and consider how such studies could leverage integration of various biomarker assays and clinical end points. Importantly, we also consider the development of strategies and algorithms for matching nutritional needs to individual biomedical profiles and the issues surrounding them. Finally, we discuss the limitations of personalized nutrition studies, possible extensions of N-of-1 nutritional intervention studies, and areas of future research.

Admixture and clinical phenotypic variation.

All human populations exhibit some level of genetic differentiation. This differentiation, or population stratification, has many interacting sources, including historical migrations, population isolation over time, genetic drift, and selection and adaptation. If differentiated populations remained isolated from each other over a long period of time such that there is no mating of individuals between those populations, then some level of global consanguinity within those populations will lead to the formation of gene pools that will become more and more distinct over time. Global genetic differentiation of this sort can lead to overt phenotypic differences between populations if phenotypically relevant variants either arise uniquely within those populations or begin to exhibit frequency differences across the populations. This can occur at the single variant level for monogenic phenotypes or at the level of aggregate variant frequency differences across the many loci that contribute to a phenotype with a multifactorial or polygenic basis. However, if individuals begin to interbreed (or 'admix') from populations with different frequencies of phenotypically relevant genetic variants, then these admixed individuals will exhibit the phenotype to varying degrees. The level of phenotypic expression will depend on the degree to which the admixed individuals have inherited causative variants that have descended from the ancestral population in which those variants were present (or, more likely, simply more frequent). We review studies that consider the association between the degree of admixture (or ancestry) and phenotypes of clinical relevance. We find a great deal of literature-based evidence for associations between the degree of admixture and phenotypic variation for a number of admixed populations and phenotypes, although not all this evidence is confirmatory. We also consider the implications of such associations for gene-mapping initiatives as well as general clinical epidemiology studies and medical practice. We end with some thoughts on the future of studies exploring phenotypic differences among admixed individuals as well as individuals with different ancestral backgrounds.

Global health in general surgery residency: a national survey.

BACKGROUND: Interest in global health during postgraduate training is increasing across disciplines. There are limited data from surgery residency programs on their attitudes and scope of activities in this area. This study aims to understand how global health education fits into postgraduate surgical training in the US. STUDY DESIGN: In 2007 to 2008, we conducted a nationwide survey of program directors at all 253 US general surgery residencies using a Web-based questionnaire modified from a previously published survey. The goals of global health activities, type of activity (ie, clinical versus research), and challenges to establishing these programs were analyzed. RESULTS: Seventy-three programs responded to the survey (29%). Of the respondents, 23 (33%) offered educational activities in global health and 86% (n = 18) of these offered clinical rotations abroad. The primary goals of these activities were to prepare residents for a career in global health and to improve resident recruitment. The greatest barriers to establishing these activities were time constraints for faculty and residents, lack of approval from the Accreditation Council for Graduate Medical Education and Residency Review Committee, and funding concerns. Lack of interest at the institution level was listed by only 5% of program directors. Of the 47 programs not offering such activities, 57% (n = 27) were interested in establishing them. CONCLUSIONS: Few general surgery residency programs currently offer clinical or other educational opportunities in global health. Most residencies that responded to our survey are interested in such activities but face many barriers, including time constraints, Residency Review Committee restrictions, and funding.

Management of recurrent rectal prolapse: surgical approach influences outcome.

INTRODUCTION: Recurrent rectal prolapse is an unresolved problem and the optimal treatment is debated. This study was designed to review patterns of care and outcomes in a large cohort of patients after surgery for recurrent prolapse. METHODS: From 685 patients who underwent operative repair for full-thickness external rectal prolapse, we identified 78 patients (70 females; mean age, 66.9 years) who underwent surgery for recurrence. We reviewed the subsequent management and outcomes for these 78 patients. RESULTS: Mean interval to their first recurrence was 33 (range, 1-168) months. There were significantly more re-recurrences after reoperation using a perineal procedure (19/51) compared with an abdominal procedure (4/27) for their recurrent rectal prolapse (P = 0.03) at a mean follow-up of nine (range, 1-82) months. Patients undergoing abdominal repair of recurrence were significantly younger than those who underwent perineal repair (mean age, 58.5 vs. 71.5 years; P < 0.01); however, there was nosignificant difference between the two groups with regard to the American Society of Anesthesiologists classification (P = 0.89). Eighteen patients had surgery for a second recurrence, with perineal repairs associated with higher failure rates (50 vs. 8 percent; P = 0.07). Finally, when combining all repairs, the abdominal approach continued to have significantly lower recurrence rates (39 vs. 13 percent; P < 0.01). CONCLUSIONS: The re-recurrence rate after surgery for recurrent rectal prolapse is high, even at a relatively short follow-up interval. Our data suggest that abdominal repair of recurrent rectal prolapse should be undertaken if the patient's risk profile permits this approach.

Overlapping sphincteroplasty: is it the standard of care?

Anal sphincter injury secondary to obstetric trauma during vaginal delivery occurs in nearly one of every five women. Episiotomy, forceps delivery, and prolonged second stage of labor have all been shown to increase the risk of sphincter disruption. One third of these women will go on to have alterations in anal continence ranging from occasional incontinence to gas to severely debilitating incontinence to solid stool. Symptoms often arise many years after delivery, suggesting that factors such as nerve damage and progressive degeneration of muscle fibers contribute to incontinence. Surgical treatment of fecal incontinence secondary to sphincter injury has been varied and creative attempts have been made to find the repair with the greatest durability and fewest complications. Over the past few decades, overlapping sphincteroplasty emerged as such a repair with many reports of excellent short-term outcomes. Recently, however, published reports of long-term data reveal decreased function over time, causing many to question whether this repair truly is the best possible treatment. Several controversies have arisen. These include (1) optimum timing from injury to repair; (2) how best to perform the repair; (3) whether or not fecal diversion, either medical or surgical, is beneficial; (4) whether or not pudendal neuropathy predicts outcome; and finally, (5) if patient's age at the time of repair affects outcome. Randomized controlled trials are lacking, so any conclusions drawn from reviewing current literature must be evaluated with this in mind. Nonetheless, important information can be gleaned from the available literature and future studies designed with the hope of improving treatment for this life-altering condition.

Primary cancers of the small bowel: analysis of prognostic factors and results of surgical management.

HYPOTHESIS: This study was done to review the clinical presentation, surgical management, pathologic features, and prognostic factors for primary small-bowel cancers. DESIGN: Retrospective case series. SETTING: Tertiary care, university hospital. PATIENTS: One hundred twenty-nine patients were surgically treated between January 1, 1977, and December 31, 2000. There were 73 men and 56 women, with a median age of 55 years (age range, 19-82 years). Median follow-up was 36 months. MAIN OUTCOME MEASURES: Presenting symptoms and signs, operations performed, and surgical pathologic features were analyzed and survival curves were generated. RESULTS: Clinical findings included abdominal pain (63%), vomiting (48%), weight loss (44%), and gastrointestinal tract bleeding (23%). The distribution of tumors by histological features was as follows: adenocarcinoma (33%), carcinoid tumor (29%), lymphoma (19%), and sarcoma (19%). Cumulative 5-year survival rate was 37% in the adenocarcinoma group, 64% in the carcinoid tumor group, 29% in the lymphoma group, and 22% in the sarcoma group. Significant prognostic predictors of overall survival for the entire cohort and for each tumor subtype included complete resection and American Joint Committee on Cancer tumor stage (P<.05). Patient age, tumor location, histological grade, and use of chemotherapy and radiation therapy did not significantly influence survival. Curative resections were accomplished in 83 patients (64%) with a median survival of 37 months compared with 46 patients undergoing incomplete or palliative resections with a median survival of 10 months (P<.05). Adjacent organ resection was required in 18 (22%) of the 83 patients undergoing potentially curative resections. The median time to recurrence was 16 months. Twenty-one patients (16%) developed associated primary cancers. CONCLUSIONS: Aggressive surgical resection in an attempt to achieve complete tumor removal seems warranted. Despite complete resections, patients with high-stage tumors remain at risk for recurrence.