Screening for Lipid Disorders in Children and Adolescents: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Lipid screening in childhood and adolescence can lead to early dyslipidemia diagnosis. The long-term benefits of lipid screening and subsequent treatment in this population are uncertain. Objective: To review benefits and harms of screening and treatment of pediatric dyslipidemia due to familial hypercholesterolemia (FH) and multifactorial dyslipidemia. Data Sources: MEDLINE and the Cochrane Central Register of Controlled Trials through May 16, 2022; literature surveillance through March 24, 2023. Study Selection: English-language randomized clinical trials (RCTs) of lipid screening; recent, large US cohort studies reporting diagnostic yield or screen positivity; and RCTs of lipid-lowering interventions. Data Extraction and Synthesis: Single extraction, verified by a second reviewer. Quantitative synthesis using random-effects meta-analysis. Main Outcomes and Measures: Health outcomes, diagnostic yield, intermediate outcomes, behavioral outcomes, and harms. Results: Forty-three studies were included (n = 491 516). No RCTs directly addressed screening effectiveness and harms. Three US studies (n = 395 465) reported prevalence of phenotypically defined FH of 0.2% to 0.4% (1:250 to 1:500). Five studies (n = 142 257) reported multifactorial dyslipidemia prevalence; the prevalence of elevated total cholesterol level (≥200 mg/dL) was 7.1% to 9.4% and of any lipid abnormality was 19.2%. Ten RCTs in children and adolescents with FH (n = 1230) demonstrated that statins were associated with an 81- to 82-mg/dL greater mean reduction in levels of total cholesterol and LDL-C compared with placebo at up to 2 years. Nonstatin-drug trials showed statistically significant lowering of lipid levels in FH populations, but few studies were available for any single drug. Observational studies suggest that statin treatment for FH starting in childhood or adolescence reduces long-term cardiovascular disease risk. Two multifactorial dyslipidemia behavioral counseling trials (n = 934) demonstrated 3- to 6-mg/dL greater reductions in total cholesterol levels compared with the control group, but findings did not persist at longest follow-up. Harms reported in the short-term drug trials were similar in the intervention and control groups. Conclusions and Relevance: No direct evidence on the benefits or harms of pediatric lipid screening was identified. While multifactorial dyslipidemia is common, no evidence was found that treatment is effective for this condition. In contrast, FH is relatively rare; evidence shows that statins reduce lipid levels in children with FH, and observational studies suggest that such treatment has long-term benefit for this condition.

Anxiety Screening: Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Anxiety is commonly seen in primary care and associated with substantial burden. Objective: To review the benefits and harms of screening and treatment for anxiety and the accuracy of instruments to detect anxiety among primary care patients. Data Sources: MEDLINE, PsychINFO, Cochrane library through September 7, 2022; references of existing reviews; ongoing surveillance for relevant literature through November 25, 2022. Study Selection: English-language original studies and systematic reviews of screening or treatment compared with control conditions and test accuracy studies of a priori-selected screening instruments were included. Two investigators independently reviewed abstracts and full-text articles for inclusion. Two investigators independently rated study quality. Data Extraction and Synthesis: One investigator abstracted data; a second checked accuracy. Meta-analysis results were included from existing systematic reviews where available; meta-analyses were conducted on original research when evidence was sufficient. Main Outcomes and Measures: Anxiety and depression outcomes; global quality of life and functioning; sensitivity and specificity of screening tools. Results: Of the 59 publications included, 40 were original studies (N = 275 489) and 19 were systematic reviews (including ≈483 studies [N≈81 507]). Two screening studies found no benefit for screening for anxiety. Among test accuracy studies, only the Generalized Anxiety Disorder (GAD) GAD-2 and GAD-7 screening instruments were evaluated by more than 1 study. Both screening instruments had adequate accuracy for detecting generalized anxiety disorder (eg, across 3 studies the GAD-7 at a cutoff of 10 had a pooled sensitivity of 0.79 [95% CI, 0.69 to 0.94] and specificity of 0.89 [95% CI, 0.83 to 0.94]). Evidence was limited for other instruments and other anxiety disorders. A large body of evidence supported the benefit of treatment for anxiety. For example, psychological interventions were associated with a small pooled standardized mean difference of -0.41 in anxiety symptom severity in primary care patients with anxiety (95% CI, -0.58 to -0.23]; 10 RCTs [n = 2075]; I2 = 40.2%); larger effects were found in general adult populations. Conclusions and Relevance: Evidence was insufficient to draw conclusions about the benefits or harms of anxiety screening programs. However, clear evidence exists that treatment for anxiety is beneficial, and more limited evidence indicates that some anxiety screening instruments have acceptable accuracy to detect generalized anxiety disorder.

Depression and Suicide Risk Screening: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Depression is common and associated with substantial burden. Suicide rates have increased over the past decade, and both suicide attempts and deaths have devastating effects on individuals and families. Objective: To review the benefits and harms of screening and treatment for depression and suicide risk and the accuracy of instruments to detect these conditions among primary care patients. Data Sources: MEDLINE, PsychINFO, Cochrane library through September 7, 2022; references of existing reviews; ongoing surveillance for relevant literature through November 25, 2022. Study Selection: English-language studies of screening or treatment compared with control conditions, or test accuracy of screening instruments (for depression, instruments were selected a priori; for suicide risk, all were included). Existing systematic reviews were used for treatment and test accuracy for depression. Data Extraction and Synthesis: One investigator abstracted data; a second checked accuracy. Two investigators independently rated study quality. Findings were synthesized qualitatively, including reporting of meta-analysis results from existing systematic reviews; meta-analyses were conducted on original research when evidence was sufficient. Main Outcomes and Measures: Depression outcomes; suicidal ideation, attempts, and deaths; sensitivity and specificity of screening tools. Results: For depression, 105 studies were included: 32 original studies (N=385 607) and 73 systematic reviews (including ≈2138 studies [N ≈ 9.8 million]). Depression screening interventions, many of which included additional components beyond screening, were associated with a lower prevalence of depression or clinically important depressive symptomatology after 6 to 12 months (pooled odds ratio, 0.60 [95% CI, 0.50-0.73]; reported in 8 randomized clinical trials [n=10 244]; I2 = 0%). Several instruments demonstrated adequate test accuracy (eg, for the 9-item Patient Health Questionnaire at a cutoff of 10 or greater, the pooled sensitivity was 0.85 [95% CI, 0.79-0.89] and specificity was 0.85 [95% CI, 0.82-0.88]; reported in 47 studies [n = 11 234]). A large body of evidence supported benefits of psychological and pharmacologic treatment of depression. A pooled estimate from trials used for US Food and Drug Administration approval suggested a very small increase in the absolute risk of a suicide attempt with second-generation antidepressants (odds ratio, 1.53 [95% CI, 1.09-2.15]; n = 40 857; 0.7% of antidepressant users had a suicide attempt vs 0.3% of placebo users; median follow-up, 8 weeks). Twenty-seven studies (n = 24 826) addressed suicide risk. One randomized clinical trial (n=443) of a suicide risk screening intervention found no difference in suicidal ideation after 2 weeks between primary care patients who were and were not screened for suicide risk. Three studies of suicide risk test accuracy were included; none included replication of any instrument. The included suicide prevention studies generally did not demonstrate an improvement over usual care, which typically included specialty mental health treatment. Conclusions and Relevance: Evidence supported depression screening in primary care settings, including during pregnancy and postpartum. There are numerous important gaps in the evidence for suicide risk screening in primary care settings.

Screening for Hypertension in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Hypertension is a major risk factor for cardiovascular disease and can be modified through lifestyle and pharmacological interventions to reduce cardiovascular events and mortality. Objective: To systematically review the benefits and harms of screening and confirmatory blood pressure measurements in adults, to inform the US Preventive Services Task Force. Data Sources: MEDLINE, PubMed, Cochrane Collaboration Central Registry of Controlled Trials, and CINAHL; surveillance through March 26, 2021. Study Selection: Randomized clinical trials (RCTs) and nonrandomized controlled intervention studies for effectiveness of screening; accuracy studies for screening and confirmatory measurements (ambulatory blood pressure monitoring as the reference standard); RCTs and nonrandomized controlled intervention studies and observational studies for harms of screening and confirmation. Data Extraction and Synthesis: Independent critical appraisal and data abstraction; meta-analyses and qualitative syntheses. Main Outcomes and Measures: Mortality; cardiovascular events; quality of life; sensitivity, specificity, positive and negative predictive values; harms of screening. Results: A total of 52 studies (N = 215 534) were identified in this systematic review. One cluster RCT (n = 140 642) of a multicomponent intervention including hypertension screening reported fewer annual cardiovascular-related hospital admissions for cardiovascular disease in the intervention group compared with the control group (difference, 3.02 per 1000 people; rate ratio, 0.91 [95% CI, 0.86-0.97]). Meta-analysis of 15 studies (n = 11 309) of initial office-based blood pressure screening showed a pooled sensitivity of 0.54 (95% CI, 0.37-0.70) and specificity of 0.90 (95% CI, 0.84-0.95), with considerable clinical and statistical heterogeneity. Eighteen studies (n = 57 128) of various confirmatory blood pressure measurement modalities were heterogeneous. Meta-analysis of 8 office-based confirmation studies (n = 53 183) showed a pooled sensitivity of 0.80 (95% CI, 0.68-0.88) and specificity of 0.55 (95% CI, 0.42-0.66). Meta-analysis of 4 home-based confirmation studies (n = 1001) showed a pooled sensitivity of 0.84 (95% CI, 0.76-0.90) and a specificity of 0.60 (95% CI, 0.48-0.71). Thirteen studies (n = 5150) suggested that screening was associated with no decrement in quality of life or psychological distress; evidence on absenteeism was mixed. Ambulatory blood pressure measurement was associated with temporary sleep disturbance and bruising. Conclusions and Relevance: Screening using office-based blood pressure measurement had major accuracy limitations, including misdiagnosis; however, direct harms of measurement were minimal. Research is needed to determine optimal screening and confirmatory algorithms for clinical practice.

Interventions for Tobacco Cessation in Adults, Including Pregnant Persons: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: It has been estimated that in 2018 nearly 20% of adults in the US were currently using a tobacco product. Objective: To systematically review the effectiveness and safety of pharmacotherapy, behavioral interventions, and electronic cigarettes for tobacco cessation among adults, including pregnant persons, to inform the US Preventive Services Task Force. Data Sources: PubMed, PsycInfo, Database of Abstracts of Reviews of Effects, Cochrane Database of Systematic Reviews, Centre for Reviews and Dissemination of Health Technology Assessment; surveillance through September 25, 2020. Study Selection: Systematic reviews of tobacco cessation interventions and randomized clinical trials that evaluated the effects of electronic cigarettes (e-cigarettes) or pharmacotherapy among pregnant persons. Data Extraction and Synthesis: Independent critical appraisal and data abstraction; qualitative synthesis and random-effects meta-analyses. Main Outcomes and Measures: Health outcomes, tobacco cessation at 6 months or more, and adverse events. Results: Sixty-seven reviews addressing pharmacotherapy and behavioral interventions were included as well as 9 trials (N = 3942) addressing e-cigarettes for smoking cessation and 7 trials (N = 2285) of nicotine replacement therapy (NRT) use in pregnancy. Combined pharmacotherapy and behavioral interventions (pooled risk ratio [RR], 1.83 [95% CI, 1.68-1.98]), NRT (RR, 1.55 [95% CI, 1.49-1.61]), bupropion (RR, 1.64 [95% CI, 1.52-1.77]), varenicline (RR, 2.24 [95% CI, 2.06-2.43]), and behavioral interventions such as advice from clinicians (RR, 1.76 [95% CI, 1.58-1.96]) were all associated with increased quit rates compared with minimal support or placebo at 6 months or longer. None of the drugs were associated with serious adverse events. Five trials (n = 3117) reported inconsistent findings on the effectiveness of electronic cigarettes on smoking cessation at 6 to 12 months among smokers when compared with placebo or NRT, and none suggested higher rates of serious adverse events. Among pregnant persons, behavioral interventions were associated with greater smoking cessation during late pregnancy (RR, 1.35 [95% CI, 1.23-1.48]), compared with no intervention. Rates of validated cessation among pregnant women allocated to NRT compared with placebo were not significantly different (pooled RR, 1.11 [95% CI, 0.79-1.56], n = 2033). Conclusions and Relevance: There is strong evidence that a range of pharmacologic and behavioral interventions, both individually and in combination, are effective in increasing smoking cessation in nonpregnant adults. In pregnancy, behavioral interventions are effective for smoking cessation, but data are limited on the use of pharmacotherapy for smoking cessation. Data on the effectiveness and safety of electronic cigarettes for smoking cessation among adults are also limited and results are inconsistent.

Primary Care Screening for Abdominal Aortic Aneurysm: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Ruptured abdominal aortic aneurysms (AAAs) have mortality estimated at 81%. Objective: To systematically review the evidence on benefits and harms of AAA screening and small aneurysm treatment to inform the US Preventive Services Task Force. Data Sources: MEDLINE, PubMed (publisher supplied only), Database of Abstracts of Reviews of Effects, and Cochrane Central Register of Controlled Trials for relevant English-language studies published through September 2018. Surveillance continued through July 2019. Study Selection: Trials of AAA screening benefits and harms; trials and cohort studies of small (3.0-5.4 cm) AAA treatment benefits and harms. Data Extraction and Synthesis: Two investigators independently reviewed abstracts and full-text articles and extracted data. The Peto method was used to pool odds ratios (ORs) for AAA-related mortality, rupture, and operations; the DerSimonian and Laird random-effects model was used to pool calculated risk ratios for all-cause mortality. Main Outcomes and Measures: AAA and all-cause mortality; AAA rupture; treatment complications. Results: Fifty studies (N = 323 279) met inclusion criteria. Meta-analysis of population-based randomized clinical trials (RCTs) estimated that a screening invitation to men 65 years or older was associated with a reduction in AAA-related mortality over 12 to 15 years (OR, 0.65 [95% CI, 0.57-0.74]; 4 RCTs [n = 124 926]), AAA-related ruptures over 12 to 15 years (OR, 0.62 [95% CI, 0.55-0.70]; 4 RCTs [n = 124 929]), and emergency surgical procedures over 4 to 15 years (OR, 0.57 [95% CI, 0.48-0.68]; 5 RCTS [n = 175 085]). In contrast, no significant association with all-cause mortality benefit was seen at 12- to 15-year follow-up (relative risk, 0.99 [95% CI 0.98-1.00]; 4 RCTs [n = 124 929]). One-time screening was associated with significantly more procedures over 4 to 15 years in the invited group compared with the control group (OR, 1.44 [95% CI, 1.34-1.55]; 5 RCTs [n = 175 085]). Four trials (n = 3314) of small aneurysm surgical treatment demonstrated no significant difference in AAA-related mortality or all-cause mortality compared with surveillance over 1.7 to 12 years. These 4 early surgery trials showed a substantial increase in procedures in the early surgery group. For small aneurysm treatment, registry data (3 studies [n = 14 424]) showed that women had higher surgical complications and postoperative mortality compared with men. Conclusions and Relevance: One-time AAA screening in men 65 years or older was associated with decreased AAA-related mortality and rupture rates but was not associated with all-cause mortality benefit. Higher rates of elective surgery but no long-term differences in quality of life resulted from screening.

Interventions to Prevent Perinatal Depression: Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Depression during pregnancy and the postpartum period is relatively common and can have adverse effects on both mother and child. Objective: To systematically review benefits and harms of primary care-relevant interventions to prevent perinatal depression, a major or minor depressive episode during pregnancy or up to 1 year after childbirth, to inform the US Preventive Services Task Force. Data Sources: MEDLINE, PubMED (for publisher-supplied records only), PsycINFO, and the Cochrane Central Register of Controlled Trials; surveillance through December 5, 2018. Study Selection: Randomized clinical trials (RCTs) and nonrandomized controlled intervention studies of interventions (eg, behavior-based, antidepressants, dietary supplements) to prevent perinatal depression in general populations of pregnant and postpartum individuals or in those at increased risk of perinatal depression. Large cohort studies were considered for harms of antidepressant use only. Data Extraction and Synthesis: Two investigators independently reviewed abstracts and full-text articles and quality rated included studies. Random-effects meta-analysis was used to estimate the benefits of the interventions. Main Outcomes and Measures: Depression status; depression symptoms; maternal, infant, and child health outcomes. Results: Fifty studies (N = 22 385) that met inclusion criteria were identified. Counseling interventions were the most widely studied interventions. Compared with controls, counseling interventions were associated with a lower likelihood of onset of perinatal depression (pooled risk ratio [RR], 0.61 [95% CI, 0.47-0.78]; 17 RCTs [n = 3094]; I2 = 39.0%). The absolute difference in the risk of perinatal depression ranged from 1.3% greater reduction in the control group to 31.8% greater reduction in the intervention group. Health system interventions showed a benefit in 3 studies (n = 5321) and had a pooled effect size similar to that of the counseling interventions, but the pooled effect was not statistically significant using a method appropriate for pooling a small number of studies (restricted maximum likelihood RR, 0.58 [95% CI, 0.22-1.53]; n = 4738; I2 = 66.3%; absolute risk reduction range, -3.1% to -13.1%). None of the behavior-based interventions reported on harms directly. A smaller percentage of participants prescribed sertraline had a depression recurrence compared with those prescribed placebo (7% vs 50%, P = .04) at 20 weeks postpartum in 1 very small RCT (n = 22 analyzed) but with an increased risk of adverse effects to the mother. Conclusions and Relevance: Counseling interventions can be effective in preventing perinatal depression, although most evidence was limited to women at increased risk for perinatal depression. A variety of other intervention approaches provided some evidence of effectiveness but lacked a robust evidence base and need further research.

Nontraditional Risk Factors in Cardiovascular Disease Risk Assessment: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Incorporating nontraditional risk factors may improve the performance of traditional multivariable risk assessment for cardiovascular disease (CVD). Objective: To systematically review evidence for the US Preventive Services Task Force on the benefits and harms of 3 nontraditional risk factors in cardiovascular risk assessment: the ankle-brachial index (ABI), high-sensitivity C-reactive protein (hsCRP) level, and coronary artery calcium (CAC) score. Data Sources: MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials for studies published through May 22, 2017. Surveillance continued through February 7, 2018. Study Selection: Studies of asymptomatic adults with no known cardiovascular disease. Data Extraction and Synthesis: Independent critical appraisal and data abstraction by 2 reviewers. Main Outcomes and Measures: Cardiovascular events, mortality, risk assessment performance measures (calibration, discrimination, or risk reclassification), and serious adverse events. Results: Forty-three studies (N = 267 244) were included. No adequately powered trials have evaluated the clinical effect of risk assessment with nontraditional risk factors on patient health outcomes. The addition of the ABI (10 studies), hsCRP level (25 studies), or CAC score (19 studies) can improve both discrimination and reclassification; the magnitude and consistency of improvement varies by nontraditional risk factor. For the ABI, improvements in performance were the greatest for women, in whom traditional risk assessment has poor discrimination (C statistic change of 0.112 and net reclassification index [NRI] of 0.096). Results were inconsistent for hsCRP level, with the largest analysis (n = 166 596) showing a minimal effect on risk prediction (C statistic change of 0.0039, NRI of 0.0152). The largest improvements in discrimination (C statistic change ranging from 0.018 to 0.144) and reclassification (NRI ranging from 0.084 to 0.35) were seen for CAC score, although CAC score may inappropriately reclassify individuals not having cardiovascular events into higher-risk categories, as determined by negative nonevent NRI. Evidence for the harms of nontraditional risk factor assessment was limited to computed tomography imaging for CAC scoring (8 studies) and showed that radiation exposure is low but may result in additional testing. Conclusions and Relevance: There are insufficient adequately powered clinical trials evaluating the incremental effect of the ABI, hsCRP level, or CAC score in risk assessment and initiation of preventive therapy. Furthermore, the clinical meaning of improvements in measures of calibration, discrimination, and reclassification risk prediction studies is uncertain.

Interventions to Prevent Falls in Older Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Falls are the most common cause of injury-related morbidity and mortality among older adults. Objective: To systematically review literature on the effectiveness and harms of fall prevention interventions in community-dwelling older adults to inform the US Preventive Services Task Force. Data Sources: MEDLINE, PubMed, Cumulative Index for Nursing and Allied Health Literature, and Cochrane Central Register of Controlled Trials for relevant English-language literature published through August 2016, with ongoing surveillance through February 7, 2018. Study Selection: Randomized clinical trials of interventions to prevent falls in community-dwelling adults 65 years and older. Data Extraction and Synthesis: Independent critical appraisal and data abstraction by 2 reviewers. Random-effects meta-analyses using the method of DerSimonian and Laird. Main Outcomes and Measures: Number of falls (number of unexpected events in which a person comes to rest on the ground, floor, or lower level), people experiencing 1 or more falls, injurious falls, people experiencing injurious falls, fractures, people experiencing fractures, mortality, hospitalizations, institutionalizations, changes in disability, and treatment harms. Results: Sixty-two randomized clinical trials (N = 35 058) examining 7 fall prevention intervention types were identified. This article focused on the 3 most commonly studied intervention types: multifactorial (customized interventions based on initial comprehensive individualized falls risk assessment) (26 trials [n = 15 506]), exercise (21 trials [n = 7297]), and vitamin D supplementation (7 trials [n = 7531]). Multifactorial intervention trials were associated with a reduction in falls (incidence rate ratio [IRR], 0.79 [95% CI, 0.68-0.91]) but were not associated with a reduction in other fall-related morbidity and mortality outcomes. Exercise trials were associated with statistically significant reductions in people experiencing a fall (relative risk, 0.89 [95% 13 CI, 0.81-0.97]) and injurious falls (IRR, 0.81 [95% CI, 0.73-0.90]) and with a statistically nonsignificant reduction in falls (IRR, 0.87 [95% CI, 0.75-1.00]) but showed no association with mortality. Few exercise trials reported fall-related fractures. Seven heterogeneous trials of vitamin D formulations (with or without calcium) showed mixed results. One trial of annual high-dose cholecalciferol (500 000 IU), which has not been replicated, showed an increase in falls, people experiencing a fall, and injuries, while 1 trial of calcitriol showed a reduction in falls and people experiencing a fall; the remaining 5 trials showed no significant difference in falls, people experiencing a fall, or injuries. Harms of multifactorial and exercise trials were rarely reported but generally included minor musculoskeletal injuries. Conclusions and Relevance: Multifactorial and exercise interventions were associated with fall-related benefit, but evidence was most consistent across multiple fall-related outcomes for exercise. Vitamin D supplementation interventions had mixed results, with a high dose being associated with higher rates of fall-related outcomes.

DROIDS 1.20: A GUI-Based Pipeline for GPU-Accelerated Comparative Protein Dynamics.

Traditional informatics in comparative genomics work only with static representations of biomolecules (i.e., sequence and structure), thereby ignoring the molecular dynamics (MD) of proteins that define function in the cell. A comparative approach applied to MD would connect this very short timescale process, defined in femtoseconds, to one of the longest in the universe: molecular evolution measured in millions of years. Here, we leverage advances in graphics-processing-unit-accelerated MD simulation software to develop a comparative method of MD analysis and visualization that can be applied to any two homologous Protein Data Bank structures. Our open-source pipeline, DROIDS (Detecting Relative Outlier Impacts in Dynamic Simulations), works in conjunction with existing molecular modeling software to convert any Linux gaming personal computer into a "comparative computational microscope" for observing the biophysical effects of mutations and other chemical changes in proteins. DROIDS implements structural alignment and Benjamini-Hochberg-corrected Kolmogorov-Smirnov statistics to compare nanosecond-scale atom bond fluctuations on the protein backbone, color mapping the significant differences identified in protein MD with single-amino-acid resolution. DROIDS is simple to use, incorporating graphical user interface control for Amber16 MD simulations, cpptraj analysis, and the final statistical and visual representations in R graphics and UCSF Chimera. We demonstrate that DROIDS can be utilized to visually investigate molecular evolution and disease-related functional changes in MD due to genetic mutation and epigenetic modification. DROIDS can also be used to potentially investigate binding interactions of pharmaceuticals, toxins, or other biomolecules in a functional evolutionary context as well.

Triplet-Based Codon Organization Optimizes the Impact of Synonymous Mutation on Nucleic Acid Molecular Dynamics.

Since the elucidation of the genetic code almost 50 years ago, many nonrandom aspects of its codon organization remain only partly resolved. Here, we investigate the recent hypothesis of 'dual-use' codons which proposes that in addition to allowing adjustment of codon optimization to tRNA abundance, the degeneracy in the triplet-based genetic code also multiplexes information regarding DNA's helical shape and protein-binding dynamics while avoiding interference with other protein-level characteristics determined by amino acid properties. How such structural optimization of the code within eukaryotic chromatin could have arisen from an RNA world is a mystery, but would imply some preadaptation in an RNA context. We analyzed synonymous (protein-silent) and nonsynonymous (protein-altering) mutational impacts on molecular dynamics in 13823 identically degenerate alternative codon reorganizations, defined by codon transitions in 7680 GPU-accelerated molecular dynamic simulations of implicitly and explicitly solvated double-stranded aRNA and bDNA structures. When compared to all possible alternative codon assignments, the standard genetic code minimized the impact of synonymous mutations on the random atomic fluctuations and correlations of carbon backbone vector trajectories while facilitating the specific movements that contribute to DNA polymer flexibility. This trend was notably stronger in the context of RNA supporting the idea that dual-use codon optimization and informational multiplexing in DNA resulted from the preadaptation of the RNA duplex to resist changes to thermostability. The nonrandom and divergent molecular dynamics of synonymous mutations also imply that the triplet-based code may have resulted from adaptive functional expansion enabling a primordial doublet code to multiplex gene regulatory information via the shape and charge of the minor groove.

A Peculiar Primary Paraganglioma of the Distal Thumb.

A paraganglioma is a highly vascularized neuroendocrine tumor most commonly found within the adrenal gland as a pheochromocytoma. Extra-adrenal paragangliomas are frequently located in the head, neck, thorax, and abdomen. We report the first documented case of a primary paraganglioma found within the appendicular skeleton. Only 2 additional cases of paragangliomas in the extremities have been documented, one in the soft tissue of the forearm and other within the median nerve. Our patient underwent amputation of the distal phalanx, with no sign of recurrence at greater than 1 year of follow-up. Because of the geographic and clinical similarity to a benign enchondroma, radiographic imaging alone may not be sufficient to rule out malignancies inside bones. Thus paraganglioma should remain in the differential and immunohistochemistry is both vital and necessary to confirm the diagnosis. Vigilant and appropriate follow-up is necessary to detect metastases early in these patients.

Can all heritable biology really be reduced to a single dimension?

A long-held presupposition in the field of bioinformatics holds that genetic, and now even epigenetic 'information' can be abstracted from the physicochemical details of the macromolecular polymers in which it resides. It is perhaps rather ironic that this basic conjecture originated upon the first observations of DNA structure itself. This static model of DNA led very quickly to the conclusion that only the nucleobase sequence itself is rich enough in molecular complexity to replicate a complex biology. This idea has been pervasive throughout genomic science, higher education and popular culture ever since; to the point that most of us would accept it unquestioningly as fact. What is more alarming is that this conjecture is driving a significant portion of the technological development in modern genomics towards methods strongly rooted in DNA sequencing, thereby reducing a dynamic multi-dimensional biology into single-dimensional forms of data. Evidence countering this central tenet of bioinformatics has been quietly mounting over many decades, prompting some to propose that the genome must be studied from the perspective of its molecular reality, rather than as a body of information to be represented symbolically. Here, we explore the epistemological boundary between bioinformatics and molecular biology, and warn against an 'overtly' bioinformatic perspective. We review a selection of new bioinformatic methods that move beyond sequence-based approaches to include consideration of databased three dimensional structures. However, we also note that these hybrid methods still ignore the most important element of gene function when attempting to improve outcomes; the fourth dimension of molecular dynamics over time.

Perforator-based radial forearm fascial flap for management of recurrent carpal tunnel syndrome.

PURPOSE: To study the benefit of using the perforator-based radial forearm fascial flap for patients with recurrent carpal tunnel syndrome. METHODS: We used a perforator-based radial forearm fascial flap in 8 patients to cover the median nerve. All of the patients had undergone an index carpal tunnel release, and 3 of them had undergone at least 1 revision surgery to further decompress the median nerve. RESULTS: At average of 20 months (range, 6-30 mo) after the forearm fascial flap, all patients reported symptomatic improvement with complete resolution of nighttime symptoms. No patient reported worsening of symptoms; however, some subjective parasthesias persisted in 3 of the 8 patients. Objective assessment revealed complete resolution of a Tinel sign in 5 of 8 patients and noteworthy improvement in the remaining 3 patients. Average 2-point discrimination was 10.0 mm before surgery and 5.4 mm after surgery, average grip strength improved from 13.5 kg to 21.0 kg, and average tip pinch strength improved from 4.1 kg to 7.0 kg. CONCLUSIONS: The perforator-based radial forearm fascial flap may prove useful in the setting of recurrent carpal tunnel syndrome after surgical decompression. LEVEL OF EVIDENCE: Therapeutic IV.