Colorectal cancer (CRC) remains a significant cause of morbidity and mortality in the United States.
To systematically review the effectiveness, diagnostic accuracy, and harms of screening for CRC.
...Searches of MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials for relevant studies published from January 1, 2008, through December 31, 2014, with surveillance through February 23, 2016.
English-language studies conducted in asymptomatic populations at general risk of CRC.
Two reviewers independently appraised the articles and extracted relevant study data from fair- or good-quality studies. Random-effects meta-analyses were conducted.
Colorectal cancer incidence and mortality, test accuracy in detecting CRC or adenomas, and serious adverse events.
Four pragmatic randomized clinical trials (RCTs) evaluating 1-time or 2-time flexible sigmoidoscopy (n = 458,002) were associated with decreased CRC-specific mortality compared with no screening (incidence rate ratio, 0.73; 95% CI, 0.66-0.82). Five RCTs with multiple rounds of biennial screening with guaiac-based fecal occult blood testing (n = 419,966) showed reduced CRC-specific mortality (relative risk RR, 0.91; 95% CI, 0.84-0.98, at 19.5 years to RR, 0.78; 95% CI, 0.65-0.93, at 30 years). Seven studies of computed tomographic colonography (CTC) with bowel preparation demonstrated per-person sensitivity and specificity to detect adenomas 6 mm and larger comparable with colonoscopy (sensitivity from 73% 95% CI, 58%-84% to 98% 95% CI, 91%-100%; specificity from 89% 95% CI, 84%-93% to 91% 95% CI, 88%-93%); variability and imprecision may be due to differences in study designs or CTC protocols. Sensitivity of colonoscopy to detect adenomas 6 mm or larger ranged from 75% (95% CI, 63%-84%) to 93% (95% CI, 88%-96%). On the basis of a single stool specimen, the most commonly evaluated families of fecal immunochemical tests (FITs) demonstrated good sensitivity (range, 73%-88%) and specificity (range, 90%-96%). One study (n = 9989) found that FIT plus stool DNA test had better sensitivity in detecting CRC than FIT alone (92%) but lower specificity (84%). Serious adverse events from colonoscopy in asymptomatic persons included perforations (4/10,000 procedures, 95% CI, 2-5 in 10,000) and major bleeds (8/10,000 procedures, 95% CI, 5-14 in 10,000). Computed tomographic colonography may have harms resulting from low-dose ionizing radiation exposure or identification of extracolonic findings.
Colonoscopy, flexible sigmoidoscopy, CTC, and stool tests have differing levels of evidence to support their use, ability to detect cancer and precursor lesions, and risk of serious adverse events in average-risk adults. Although CRC screening has a large body of supporting evidence, additional research is still needed.
Elevated blood pressure (BP) is the largest contributing risk factor to all-cause and cardiovascular mortality.
To update a systematic review on the benefits and harms of screening for high BP in ...adults and to summarize evidence on rescreening intervals and diagnostic and predictive accuracy of different BP methods for cardiovascular events.
Selected databases searched through 24 February 2014.
Fair- and good-quality trials and diagnostic accuracy and cohort studies conducted in adults and published in English.
One investigator abstracted data, and a second checked for accuracy. Study quality was dual-reviewed.
Ambulatory BP monitoring (ABPM) predicted long-term cardiovascular outcomes independently of office BP (hazard ratio range, 1.28 to 1.40, in 11 studies). Across 27 studies, 35% to 95% of persons with an elevated BP at screening remained hypertensive after nonoffice confirmatory testing. Cardiovascular outcomes in persons who were normotensive after confirmatory testing (isolated clinic hypertension) were similar to outcomes in those who were normotensive at screening. In 40 studies, hypertension incidence after rescreening varied considerably at each yearly interval up to 6 years. Intrastudy comparisons showed at least 2-fold higher incidence in older adults, those with high-normal BP, overweight and obese persons, and African Americans.
Few diagnostic accuracy studies of office BP methods and protocols in untreated adults.
Evidence supports ABPM as the reference standard for confirming elevated office BP screening results to avoid misdiagnosis and overtreatment of persons with isolated clinic hypertension. Persons with BP in the high-normal range, older persons, those with an above-normal body mass index, and African Americans are at higher risk for hypertension on rescreening within 6 years than are persons without these risk factors.
Agency for Healthcare Research and Quality.
ObjectivesOpioid use disorder (OUD) is a major public health concern in the USA, resulting in high rates of overdose and other negative outcomes. Methadone, an OUD treatment, has been shown to be ...effective in reducing the risk of overdose and improving overall health and quality of life. This study analysed the distribution of methadone for the treatment of OUD across the USA over the past decade and through the COVID-19 pandemic.DesignRetrospective observational study using secondary data analysis of the Drug Enforcement Administration and Medicaid Databases.SettingUSA.ParticipantsPatients who were dispensed methadone at US opioid treatment programmes (OTPs).Primary and secondary outcome measuresThe primary outcomes were the overall pattern in methadone distribution and the number of OTPs in the USA per year. The secondary outcome was Medicaid prescriptions for methadone.ResultsMethadone distribution for OUD has expanded significantly over the past decade, with an average state increase of +96.96% from 2010 to 2020. There was a significant increase in overall distribution of methadone to OTP from 2010 to 2020 (+61.00%, p<0.001) and from 2015 to 2020 (+26.22%, p<0.001). However, the distribution to OTPs did not significantly change from 2019 to 2021 (−5.15%, p=0.491). There was considerable state-level variation in methadone prescribing to Medicaid patients with four states having no prescriptions.ConclusionsThere have been dynamic changes in methadone distribution for OUD. Furthermore, pronounced variation in methadone distribution among states was observed, with some states having no OTPs or Medicaid coverage. New policies are urgently needed to increase access to methadone treatment, address the opioid epidemic in the USA and reduce overdose deaths.
Genome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder enables clinical ...interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource of information regarding the clinical relevance of genomic variation for use in precision medicine and research.
We developed a practical, standardized protocol to identify available evidence and generate qualitative summary reports of actionability for disorders and associated genes. We applied a semiquantitative metric to score actionability.
We generated summary reports and actionability scores for the 56 genes and associated disorders recommended by the American College of Medical Genetics and Genomics for return as secondary findings from clinical genome-scale sequencing. We also describe the challenges that arose during the development of the protocol that highlight important issues in characterizing actionability across a range of disorders.
The ClinGen framework for actionability assessment will assist research and clinical communities in making clear, efficient, and consistent determinations of actionability based on transparent criteria to guide analysis and reporting of findings from clinical genome-scale sequencing.
Genet Med18 12, 1258–1268.
This article defines and describes best practices for the academic and business community to generate evidence of clinical utility for cancer molecular diagnostic assays. Beyond analytical and ...clinical validation, successful demonstration of clinical utility involves developing sufficient evidence to demonstrate that a diagnostic test results in an improvement in patient outcomes. This discussion is complementary to theoretical frameworks described in previously published guidance and literature reports by the U.S. Food and Drug Administration, Centers for Disease Control and Prevention, Institute of Medicine, and Center for Medical Technology Policy, among others. These reports are comprehensive and specifically clarify appropriate clinical use, adoption, and payer reimbursement for assay manufacturers, as well as Clinical Laboratory Improvement Amendments-certified laboratories, including those that develop assays (laboratory developed tests). Practical criteria and steps for establishing clinical utility are crucial to subsequent decisions for reimbursement without which high-performing molecular diagnostics will have limited availability to patients with cancer and fail to translate scientific advances into high-quality and cost-effective cancer care. See all articles in this CCR Focus section, "The Precision Medicine Conundrum: Approaches to Companion Diagnostic Co-development."
Regulation of energy balance depends on pro-opiomelanocortin (POMC)-derived peptides and melanocortin-4 receptor (MC4R). Alpha-melanocyte stimulating hormone (α-MSH) is the predicted natural ...POMC-derived peptide that regulates energy balance. Desacetyl-α-MSH, the precursor for α-MSH, is present in brain and blood. Desacetyl-α-MSH is considered to be unimportant for regulating energy balance despite being more potent (compared with α-MSH) at activating the appetite-regulating MC4R in vitro. Thus, the physiological role for desacetyl-α-MSH is still unclear.
We created a novel mouse model to determine whether desacetyl-α-MSH plays a role in regulating energy balance. We engineered a knock in targeted QKQR mutation in the POMC protein cleavage site that blocks the production of both desacetyl-α-MSH and α-MSH from adrenocorticotropin (ACTH1-39).
The mutant ACTH1-39 (ACTHQKQR) functions similar to native ACTH1-39 (ACTHKKRR) at the melanocortin 2 receptor (MC2R) in vivo and MC4R in vitro. Male and female homozygous mutant ACTH1-39 (Pomctm1/tm1) mice develop the characteristic melanocortin obesity phenotype. Replacement of either desacetyl-α-MSH or α-MSH over 14 days into Pomctm1/tm1 mouse brain significantly reverses excess body weight and fat mass gained compared to wild type (WT) (Pomcwt/wt) mice. Here, we identify both desacetyl-α-MSH and α-MSH peptides as regulators of energy balance and highlight a previously unappreciated physiological role for desacetyl-α-MSH.
Based on these data we propose that there is potential to exploit the naturally occurring POMC-derived peptides to treat obesity but this relies on first understanding the specific function(s) for desacetyl-α-MSH and α-MSH.
•KKRR → QKQR mutation in the cleavage site of POMC prevents the production of desacetyl-α-MSH and α-MSH in mice.•Male and female mutant mice develop characteristic melanocortin obesity.•Central administration of α-MSH is more potent at reducing body weight in female mutant mice.•Central administration of desacetyl-α-MSH and α-MSH are similarly potent at reducing body weight in male mutant mice.
The development of genomic tests is one of the most significant technological advances in medical testing in recent decades. As these tests become increasingly available, so does the need for a ...pragmatic framework to evaluate the evidence base and evidence gaps in order to facilitate informed decision-making. In this article we describe such a framework that can provide a common language and benchmarks for different stakeholders of genomic testing. Each stakeholder can use this framework to specify their respective thresholds for decision-making, depending on their perspective and particular needs. This framework is applicable across a broad range of test applications and can be helpful in the application and communication of a regulatory science for genomic testing. Our framework builds upon existing work and incorporates principles familiar to researchers involved in medical testing (both diagnostic and prognostic) generally, as well as those involved in genomic testing. This framework is organized around six phases in the development of genomic tests beginning with marker identification and ending with population impact, and highlights the important knowledge gaps that need to be filled in establishing the clinical relevance of a test. Our framework focuses on the clinical appropriateness of the four main dimensions of test research questions (population/setting, intervention/index test, comparators/reference test, and outcomes) rather than prescribing a hierarchy of study designs that should be used to address each phase.
At least 2 RCTs are already underway, as noted in the accompanying editorial by Ginsburg and Voora (4). ...this study could have been conducted as an RCT simply by sending the test results randomly ...to one-half of the physicians caring for patients tested. Because of these limitations, the results of this study need to be validated in an RCT before we can conclude that genetic testing for warfarin dosing confers clinical benefits.
Objectives: The onset and severity of the clinical expression of most diseases that are of public health importance are influenced by genetic predisposition. The ability to assess human genetic ...predisposition for many diseases is increasing rapidly. Therefore, state public health agencies should be incorporating new developments in genetics and disease prevention into their core functions of assessment, policy development, and assurance. The authors assessed the status of this process. Methods: The Council of State and Territorial Epidemiologists (CSTE) surveyed states about projects and concerns related to genetics and public health activities. Respondents were the Health Officer, the Maternal and Child Health/Genetics Program Director, the Chronic Disease Program Director, and the Laboratory Director. Where applicable, responses were categorized into assessment, policy development, and assurance functions. Results: Thirty-eight (76%) state health departments responded. Ongoing genetics activities were assurance (82%), assessment (17%), and policy development (2%). In contrast, Health Officers responded that future genetics activities would be distributed differently: assurance, 41%; assessment, 36%; and policy development, 23%. Future assurance activities would be largely educational. Topics of interest and recently initiated activities in genetics were primarily assessment functions. Funding was the greatest concern, followed by lack of proven disease prevention measures and outcomes data. Conclusions: State health departments recognize a need to realign their activities to meet future developments in genetics. Lack of adequate resources, proven disease prevention measures, and outcomes data are potential barriers. Public health agencies need to develop a strategic plan to meet the opportunities associated with the development and implementation of genetic tests and procedures.
PDF
